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{ "doc_id": "210697221", "title": "Adaptive Compiler Strategies for Mitigating Timing Side Channel Attacks", "abstract": "Existing compiler techniques can transform code to make its timing behavior independent of sensitive values to prevent information leakage through time side channels. Those techniques are hampered, however, by their static nature and dependence on details of the processor targeted during the compilation. This paper presents a dynamic compiler approach based on offline profiles and JIT compiler strategies. This approach reduces overhead significantly and enables a trade-off between provided protection and overhead. Furthermore, it supports adaptive policies in which the protection adapts to run-time changes in the requirements. A prototype implementation in the Jikes Research VM is evaluated on RSA encryption, HMAC key verification, and IDEA encryption.", "corpus_id": 210697221 }

[ { "doc_id": "11171791", "title": "Yet another MicroArchitectural Attack:: exploiting I-Cache", "abstract": "MicroArchitectural Attacks (MA), which can be considered as a special form of Side-Channel Analysis, exploit microarchitectural functionalities of processor implementations and can compromise the security of computational environments even in the presence of sophisticated protection mechanisms like virtualization and sandboxing. This newly evolving research area has attracted significant interest due to the broad application range and the potentials of these attacks. Cache Analysis and Branch Prediction Analysis were the only types of MA that had been known publicly. In this paper, we introduce Instruction Cache (I-Cache) as yet another source of MA and present our experimental results which clearly prove the practicality and danger of I-Cache Attacks.", "corpus_id": 11171791, "score": 0 }, { "doc_id": "1429428", "title": "Trace-Driven Cache Attacks on AES", "abstract": "Cache based side-channel attacks have recently been attracted significant attention due to the new developments in the field. In this paper, we present efficient trace-driven cache attacks on a widely used implementation of the AES cryptosystem. We also evaluate the cost of the proposed attacks in detail under the assumption of a noiseless environment. We develop an accurate mathematical model that we use in the cost analysis of our attacks. We use two different metrics, specifically, the expected number of necessary traces and the cost of the analysis phase, for the cost evaluation purposes. Each of these metrics represents the cost of a different phase of the attack.", "corpus_id": 1429428, "score": 0 }, { "doc_id": "8058399", "title": "On the power of simple branch prediction analysis", "abstract": "Very recently, a new software side-channel attack, called Branch Prediction Analysis (BPA) attack, has been discovered and also demonstrated to be practically feasible on popular commodity PC platforms. While the above recent attack still had the flavor of a classical timing attack against RSA, where one uses many execution-time measurements under the same key in order to statistically amplify some small but key-dependent timing differences, we dramatically improve upon the former result. We prove that a carefully written spy-process running simultaneously with an RSA-process, is able to collect during one single RSA signing execution almost all of the secret key bits. We call such an attack, analyzing the CPU's Branch Predictor states through spying on a single quasi-parallel computation process, a Simple Branch Prediction Analysis (SBPA) attack --- sharply differentiating it from those one relying on statistical methods and requiring many computation measurements under the same key. The successful extraction of almost all secret key bits by our SBPA attack against an openSSL RSA implementation proves that the often recommended blinding or so called randomization techniques to protect RSA against side-channel attacks are, in the context of SBPA attacks, totally useless. Additional to that very crucial security implication, targeted at such implementations which are assumed to be at least statistically secure, our successful SBPA attack also bears another equally critical security implication. Namely, in the context of simple side-channel attacks, it is widely believed that equally balancing the operations after branches is a secure countermeasure against such simple attacks. Unfortunately, this is not true, as even such \"balanced branch\" implementations can be completely broken by our SBPA attacks. Moreover, despite sophisticated hardware-assisted partitioning methods such as memory protection, sandboxing or even virtualization, SBPA attacks empower an unprivileged process to successfully attack other processes running in parallel on the same processor. Thus, we conclude that SBPA attacks are much more dangerous than previously anticipated, as they obviously do not belong to the same category as pure timing attacks.", "corpus_id": 8058399, "score": 0 }, { "doc_id": "1279576", "title": "Predicting Secret Keys Via Branch Prediction", "abstract": "This paper announces a new software side-channel attack — enabled by the branch prediction capability common to all modern high-performance CPUs. The penalty paid (extra clock cycles) for a mispredicted branch can be used for cryptanalysis of cryptographic primitives that employ a data-dependent program flow. Analogous to the recently described cache-based side-channel attacks our attacks also allow an unprivileged process to attack other processes running in parallel on the same processor, despite sophisticated partitioning methods such as memory protection, sandboxing or even virtualization. In this paper, we will discuss several such attacks for the example of RSA, and experimentally show their applicability to real systems, such as OpenSSL and Linux. Moreover, we will also demonstrate the strength of the branch prediction side-channel attack by rendering the obvious countermeasure in this context (Montgomery Multiplication with dummy-reduction) as useless. Although the deeper consequences of the latter result make the task of writing an efficient and secure modular exponentiation (or scalar multiplication on an elliptic curve) a challenging task, we will eventually suggest some countermeasures to mitigate branch prediction side-channel attacks.", "corpus_id": 1279576, "score": 0 }, { "doc_id": "28944089", "title": "Differential Power Analysis", "abstract": "Cryptosystem designers frequently assume that secrets will be manipulated in closed, reliable computing environments. Unfortunately, actual computers and microchips leak information about the operations they process. This paper examines specific methods for analyzing power consumption measurements to find secret keys from tamper resistant devices. We also discuss approaches for building cryptosystems that can operate securely in existing hardware that leaks information.", "corpus_id": 28944089, "score": 0 }, { "doc_id": "11665450", "title": "Collision attacks on processors with cache and countermeasures", "abstract": "Implementing cryptographic algorithms is a difficult problem since additional secret information can be recovered from some physical characteristics of a cryptographic device. Among all side-channel attacks, collision attacks and cache attacks are the most recent ones. The first technique uses side-channel information to detect internal collisions related to the algorithm. The second one exploits timing or power consumptions related to the memory accesses. This paper presents a new attack on the first round of AES based on power analysis, which combines both collision attacks and cache attacks. It provides many linear relations between the secret key bits from the encryption of a few chosen plaintexts. For instance, for a classical implementation using 4 lookup tables on a processor with 64-byte cache blocks, 48 linear relations involving half of the key bits are derived. Some countermeasures which defeat such attacks are also presented. C. Wolf, S. Lucks, P.-W. Yau (Eds.): WEWoRC 2005, LNI P-74, pp. 76–85, 2005. c Gesellschaft fur Informatik e.V.", "corpus_id": 11665450, "score": 0 }, { "doc_id": "17988199", "title": "New Results on Instruction Cache Attacks", "abstract": "We improve instruction cache data analysis techniques with a framework based on vector quantization and hidden Markov models. As a result, we are capable of carrying out efficient automated attacks using live I-cache timing data. Using this analysis technique, we run an I-cache attack on OpenSSL's DSA implementation and recover keys using lattice methods. Previous I-cache attacks were proof-of-concept: we present results of an actual attack in a real-world setting, proving these attacks to be realistic. We also present general software countermeasures, along with their performance impact, that are not algorithm specific and can be employed at the kernel and/or compiler level.", "corpus_id": 17988199, "score": 0 }, { "doc_id": "18861780", "title": "Cache-Timing Template Attacks", "abstract": "Cache-timing attacks are a serious threat to security-critical software. We show that the combination of vector quantization and hidden Markov model cryptanalysis is a powerful tool for automated analysis of cache-timing data; it can be used to recover critical algorithm state such as key material. We demonstrate its effectiveness by running an attack on the elliptic curve portion of OpenSSL (0.9.8k and under). This involves automated lattice attacks leading to key recovery within hours. We carry out the attack on live cache-timing data without simulating the side channel, showing these attacks are practical and realistic.", "corpus_id": 18861780, "score": 0 }, { "doc_id": "1060331", "title": "Cache Games -- Bringing Access-Based Cache Attacks on AES to Practice", "abstract": "Side channel attacks on cryptographic systems exploit information gained from physical implementations rather than theoretical weaknesses of a scheme. In recent years, major achievements were made for the class of so called access-driven cache attacks. Such attacks exploit the leakage of the memory locations accessed by a victim process. In this paper we consider the AES block cipher and present an attack which is capable of recovering the full secret key in almost real time for AES-128, requiring only a very limited number of observed encryptions. Unlike previous attacks, we do not require any information about the plaintext (such as its distribution, etc.). Moreover, for the first time, we also show how the plaintext can be recovered without having access to the cipher text at all. It is the first working attack on AES implementations using compressed tables. There, no efficient techniques to identify the beginning of AES rounds is known, which is the fundamental assumption underlying previous attacks. We have a fully working implementation of our attack which is able to recover AES keys after observing as little as 100 encryptions. It works against the OpenS SL 0.9.8n implementation of AES on Linux systems. Our spy process does not require any special privileges beyond those of a standard Linux user. A contribution of probably independent interest is a denial of service attack on the task scheduler of current Linux systems (CFS), which allows one to observe (on average) every single memory access of a victim process.", "corpus_id": 1060331, "score": 0 }, { "doc_id": "33554560", "title": "Advances on Access-Driven Cache Attacks on AES", "abstract": "An access-driven attack is a class of cache-based side channel analysis. Like the time-driven attack, the cache's timings are under inspection as a source of information leakage. Access-driven attacks scrutinize the cache behavior with a finer granularity, rather than evaluating the overall execution time. Access-driven attacks leverage the ability to detect whether a cache line has been evicted, or not, as the primary mechanism for mounting an attack. In this paper we focus on the case of AES and we show that the vast majority of processors suffer from this cache-based vulnerability. Our best results are indeed performed on a processor without the multi-threading capabilities -- in contrast to previous works in this area that had suggested that multi-threading actually improved, or even made possible, this class of attack. \n \nDespite some technical difficulties required to mount such attacks, our work shows that access-driven cache-based attacks are becoming easier to understand and analyze. Also, when such attacks are mounted against systems performing AES, only a very limited number of encryptions are required to recover the whole key with a high probability of success, due to our last round analysis from the ciphertext.", "corpus_id": 33554560, "score": 0 }, { "doc_id": "8034563", "title": "Cache Attacks and Countermeasures: The Case of AES", "abstract": "We describe several software side-channel attacks based on inter-process leakage through the state of the CPU’s memory cache. This leakage reveals memory access patterns, which can be used for cryptanalysis of cryptographic primitives that employ data-dependent table lookups. The attacks allow an unprivileged process to attack other processes running in parallel on the same processor, despite partitioning methods such as memory protection, sandboxing and virtualization. Some of our methods require only the ability to trigger services that perform encryption or MAC using the unknown key, such as encrypted disk partitions or secure network links. Moreover, we demonstrate an extremely strong type of attack, which requires knowledge of neither the specific plaintexts nor ciphertexts, and works by merely monitoring the effect of the cryptographic process on the cache. We discuss in detail several such attacks on AES, and experimentally demonstrate their applicability to real systems, such as OpenSSL and Linux’s dm-crypt encrypted partitions (in the latter case, the full key can be recovered after just 800 writes to the partition, taking 65 milliseconds). Finally, we describe several countermeasures for mitigating such attacks.", "corpus_id": 8034563, "score": 0 }, { "doc_id": "1276493", "title": "Hey, you, get off of my cloud: exploring information leakage in third-party compute clouds", "abstract": "Third-party cloud computing represents the promise of outsourcing as applied to computation. Services, such as Microsoft's Azure and Amazon's EC2, allow users to instantiate virtual machines (VMs) on demand and thus purchase precisely the capacity they require when they require it. In turn, the use of virtualization allows third-party cloud providers to maximize the utilization of their sunk capital costs by multiplexing many customer VMs across a shared physical infrastructure. However, in this paper, we show that this approach can also introduce new vulnerabilities. Using the Amazon EC2 service as a case study, we show that it is possible to map the internal cloud infrastructure, identify where a particular target VM is likely to reside, and then instantiate new VMs until one is placed co-resident with the target. We explore how such placement can then be used to mount cross-VM side-channel attacks to extract information from a target VM on the same machine.", "corpus_id": 1276493, "score": 0 }, { "doc_id": "1897883", "title": "Exploiting Hardware Performance Counters", "abstract": "We introduce the usage of hardware performance counters (HPCs) as a new method that allows very precise access to known side channels and also allows access to many new side channels. Many current architectures provide hardware performance counters, which allow the profiling of software during runtime. Though they allow detailed profiling they are noisy by their very nature; HPC hardware is not validated along with the rest of the microprocessor. They are meant to serve as a relative measure and are most commonly used for profiling software projects or operating systems. Furthermore they are only accessible in restricted mode and can only be accessed by the operating system. We discuss this security model and we show first implementation results, which confirm that HPCs can be used to profile relatively short sequences of instructions with high precision. We focus on cache profiling and confirm our results by rerunning a recently published time based cache attack in which we replaced the time profiling function by HPCs.", "corpus_id": 1897883, "score": 0 }, { "doc_id": "15297038", "title": "Covert and Side Channels Due to Processor Architecture", "abstract": "Information leakage through covert channels and side channels is becoming a serious problem, especially when these are enhanced by modern processor architecture features. We show how processor architecture features such as simultaneous multithreading, control speculation and shared caches can inadvertently accelerate such covert channels or enable new covert channels and side channels. We first illustrate the reality and severity of this problem by describing concrete attacks. We identify two new covert channels. We show orders of magnitude increases in covert channel capacities. We then present two solutions, Selective Partitioning and the novel random permutation cache (RPCache). The RPCache can thwart most cache-based software side channel attacks, with minimal hardware costs and negligible performance impact", "corpus_id": 15297038, "score": 0 }, { "doc_id": "15490163", "title": "Cache Based Remote Timing Attack on the AES", "abstract": "We introduce a new robust cache-based timing attack on AES. We present experiments and concrete evidence that our attack can be used to obtain secret keys of remote cryptosystems if the server under attack runs on a multitasking or simultaneous multithreading system with a large enough workload. This is an important difference to recent cache-based timing attacks as these attacks either did not provide any supporting experimental results indicating if they can be applied remotely, or they are not realistically remote attacks.", "corpus_id": 15490163, "score": 0 }, { "doc_id": "2217245", "title": "Cache-timing attacks on AES", "abstract": "This paper demonstrates complete AES key recovery from known-plaintext timings of a network server on another computer. This attack should be blamed on the AES design, not on the particular AES library used by the server; it is extremely difficult to write constant-time high-speed AES software for common general-purpose computers. This paper discusses several of the obstacles in detail.", "corpus_id": 2217245, "score": 1 }, { "doc_id": "2383416", "title": "Cache-Collision Timing Attacks Against AES", "abstract": "This paper describes several novel timing attacks against the common table-driven software implementation of the AES cipher. We define a general attack strategy using a simplified model of the cache to predict timing variation due to cache-collisions in the sequence of lookups performed by the encryption. The attacks presented should be applicable to most high-speed software AES implementations and computing platforms, we have implemented them against OpenSSL v. 0.9.8.(a) running on Pentium III, Pentium IV Xeon, and UltraSPARC III+ machines. The most powerful attack has been shown under optimal conditions to reliably recover a full 128-bit AES key with 213 timing samples, an improvement of almost four orders of magnitude over the best previously published attacks of this type [Ber05]. While the task of defending AES against all timing attacks is challenging, a small patch can significantly reduce the vulnerability to these specific attacks with no performance penalty.", "corpus_id": 2383416, "score": 0 }, { "doc_id": "9384357", "title": "Remote timing attacks are practical", "abstract": "Timing attacks are usually used to attack weak computing devices such as smartcards. We show that timing attacks apply to general software systems. Specifically, we devise a timing attack against OpenSSL. Our experiments show that we can extract private keys from an OpenSSL-based web server running on a machine in the local network. Our results demonstrate that timing attacks against network servers are practical and therefore security systems should defend against them.", "corpus_id": 9384357, "score": 0 }, { "doc_id": "6091977", "title": "Remote Timing Attacks Are Still Practical", "abstract": "For over two decades, timing attacks have been an active area of research within applied cryptography. These attacks exploit cryptosystem or protocol implementations that do not run in constant time. When implementing an elliptic curve cryptosystem with a goal to provide side-channel resistance, the scalar multiplication routine is a critical component. In such instances, one attractive method often suggested in the literature is Montgomery's ladder that performs a fixed sequence of curve and field operations. This paper describes a timing attack vulnerability in OpenSSL's ladder implementation for curves over binary fields. We use this vulnerability to steal the private key of a TLS server where the server authenticates with ECDSA signatures. Using the timing of the exchanged messages, the messages themselves, and the signatures, we mount a lattice attack that recovers the private key. Finally, we describe and implement an effective countermeasure.", "corpus_id": 6091977, "score": 0 }, { "doc_id": "9279233", "title": "Ucl Crypto Group Technical Report Series a Practical Implementation of the Timing Attack a Practical Implementation of the Timing Attack a Practical Implementation of the Timing Attack 2", "abstract": "When the running time of a cryptographic algorithm is nonconstant, timing measurements can leak informations about the secret key. This idea, rst publicly introduced by Kocher, is developed here to attack an earlier version of the CASCADE smart cardy. We propose several improvements on Kocher's ideas, leading to a practical implementation that is able to break a 512-bit key in a few minutes, provided we are able to collect 300 000 timing measurements (128-bit keys can be recovered in a few seconds using a personal computer and less than 10 000 samples). We therefore show that the timing attack represents an important threat against cryptosystems, which must be very seriously taken into account.", "corpus_id": 9279233, "score": 0 }, { "doc_id": "15475583", "title": "Timing Attacks on Implementations of Diffie-Hellman, RSA, DSS, and Other Systems", "abstract": "By carefully measuring the amount of time required tm perform private key operalions, attackers may be able to find fixed Diffie-Hellman exponents, factor RSA keys, and break other cryptosystems. Against, a valnerable system, the attack is computationally inexpensive and often requires only known ciphertext. Actual systems are potentially at risk, including cryptographic tokens, network-based cryptosystems, and other applications where attackers can make reasonably accurate timing measurements. Techniques for preventing the attack for RSA and Diffie-Hellman are presented. Some cryptosystems will need to be revised to protect against the attack, and new protocols and algorithms may need to incorporate measures to prevenl timing attacks.", "corpus_id": 15475583, "score": 0 }, { "doc_id": "15623531", "title": "Mutual Information Analysis", "abstract": "We propose a generic information-theoretic distinguisher for differential side-channel analysis. Our model of side-channel leakage is a refinement of the one given by Standaert et al.An embedded device containing a secret key is modeled as a black box with a leakage function whose output is captured by an adversary through the noisy measurement of a physical observable. Although quite general, the model and the distinguisher are practical and allow us to develop a new differential side-channel attack. More precisely, we build a distinguisher that uses the value of the Mutual Information between the observed measurements and a hypothetical leakage to rank key guesses. The attack is effective without any knowledge about the particular dependencies between measurements and leakage as well as between leakage and processed data, which makes it a universal tool. Our approach is confirmed by results of power analysis experiments. We demonstrate that the model and the attack work effectively in an attack scenario against DPA-resistant logic.", "corpus_id": 15623531, "score": 0 }, { "doc_id": "2882026", "title": "New cache designs for thwarting software cache-based side channel attacks", "abstract": "Software cache-based side channel attacks are a serious new class of threats for computers. Unlike physical side channel attacks that mostly target embedded cryptographic devices, cache-based side channel attacks can also undermine general purpose systems. The attacks are easy to perform, effective on most platforms, and do not require special instruments or excessive computation power. In recently demonstrated attacks on software implementations of ciphers like AES and RSA, the full key can be recovered by an unprivileged user program performing simple timing measurements based on cache misses.\n We first analyze these attacks, identifying cache interference as the root cause of these attacks. We identify two basic mitigation approaches: the partition-based approach eliminates cache interference whereas the randomization-based approach randomizes cache interference so that zero information can be inferred. We present new security-aware cache designs, the Partition-Locked cache (PLcache) and Random Permutation cache (RPcache), analyze and prove their security, and evaluate their performance. Our results show that our new cache designs with built-in security can defend against cache-based side channel attacks in general-rather than only specific attacks on a given cryptographic algorithm-with very little performance degradation and hardware cost.", "corpus_id": 2882026, "score": 0 }, { "doc_id": "976416", "title": "Software mitigations to hedge AES against cache-based software side channel vulnerabilities", "abstract": "Hardware side channel vulnerabilities have been studied for many years in embedded silicon-security arena including SmartCards, SetTop-boxes, etc. However, because various recent security activities have goals of improving the software isolation properties of PC platforms, software side channels have become a subject of interest. Recent publications discussed cache-based software side channel vulnerabilities of AES and RSA. Thus, following the classical approach — a new side channel vulnerability opens a new mitigation research path — this paper starts to investigate efficient mitigations to protect AES-software against side channel vulnerabilities. First, we will present several mitigation strategies to harden existing AES software against cache-based software side channel attacks and analyze their theoretical protection. Then, we will present a performance and security evaluation of our mitigation strategies. For ease of evaluation we measured the performance of our code against the performance of the openSSL AES implementation. In addition, we also analyzed our code under various existing attacks. Depending on the level of the required side channel protection, the measured performance loss of our mitigations strategies versus openSSL (respectively best assembler) varies between factors of 1.35 (2.66) and 2.85 (5.83).", "corpus_id": 976416, "score": 0 }, { "doc_id": "2012026", "title": "Practical Mitigations for Timing-Based Side-Channel Attacks on Modern x86 Processors", "abstract": "This paper studies and evaluates the extent to which automated compiler techniques can defend against timing-based side-channel attacks on modern x86 processors. We study how modern x86 processors can leak timing information through side-channels that relate to control flow and data flow. To eliminate key-dependent control flow and key-dependent timing behavior related to control flow, we propose the use of if-conversion in a compiler backend, and evaluate a proof-of-concept prototype implementation. Furthermore, we demonstrate two ways in which programs that lack key-dependent control flow and key- dependent cache behavior can still leak timing information on modern x86 implementations such as the Intel Core 2 Duo, and propose defense mechanisms against them.", "corpus_id": 2012026, "score": 1 }, { "doc_id": "8633065", "title": "Timing Aware Information Flow Security for a JavaCard-like Bytecode", "abstract": "Common protection mechanisms fail to provide end-to-end security; programs with legitimate access to secret information are not prevented from leaking this to the world. Information-flow aware analyses track the flow of information through the program to prevent such leakages, but often ignore information flows through covert channels even though they pose a serious threat. A typical covert channel is to use the timing of certain events to carry information. We present a timing-aware information-flow type system for a low-level language similar to a non-trivial subset of a sequential Java bytecode. The type system is parameterized over the time model of the instructions of the language and over the algorithm enforcing low-observational equivalence, used in the prevention of implicit and timing flows.", "corpus_id": 8633065, "score": 0 }, { "doc_id": "16422919", "title": "A Provably Secure and Efficient Countermeasure against Timing Attacks", "abstract": "We show that the amount of information about the key that an unknown-message attacker can extract from a deterministic side-channel is bounded from above by |O| log (n+1) bits, where n is the number of side-channel measurements and O is the set of possible observations. We use this bound to derive a novel countermeasure against timing attacks, where the strength of the security guarantee can be freely traded for the resulting performance penalty. We give algorithms that efficiently and optimally adjust this trade-off for given constraints on the side-channel leakage or on the efficiency of the cryptosystem. Finally, we perform a case-study that shows that applying our countermeasure leads to implementations with minor performance overhead and formal security guarantees.", "corpus_id": 16422919, "score": 0 }, { "doc_id": "5976894", "title": "The Program Counter Security Model: Automatic Detection and Removal of Control-Flow Side Channel Attacks", "abstract": "We introduce new methods for detecting control-flow side channel attacks, transforming C source code to eliminate such attacks, and checking that the transformed code is free of control-flow side channels. We model control-flow side channels with a program counter transcript, in which the value of the program counter at each step is leaked to an adversary. The program counter transcript model captures a class of side channel attacks that includes timing attacks and error disclosure attacks. \n \nFurther, we propose a generic source-to-source transformation that produces programs provably secure against control-flow side channel attacks. We implemented this transform for C together with a static checker that conservatively checks x86 assembly for violations of program counter security; our checker allows us to compile with optimizations while retaining assurance the resulting code is secure. We then measured our technique's effect on the performance of binary modular exponentiation and real-world implementations in C of RC5 and IDEA: we found it has a performance overhead of at most 5× and a stack space overhead of at most 2×. Our approach to side channel security is practical, generally applicable, and provably secure against an interesting class of side channel attacks.", "corpus_id": 5976894, "score": 1 }, { "doc_id": "1644086", "title": "Düppel: retrofitting commodity operating systems to mitigate cache side channels in the cloud", "abstract": "This paper presents the design, implementation and evaluation of a system called Düppel that enables a tenant virtual machine to defend itself from cache-based side-channel attacks in public clouds. Düppel includes defenses for time-shared caches such as per-core L1 and L2 caches. Experiments in the lab and on public clouds show that Düppel effectively obfuscates timing signals available to an attacker VM via these caches and incurs modest performance overheads (at most 7% and usually much less) in the common case of no side-channel attacks. Moreover, Düppel requires no changes to hypervisors or support from cloud operators.", "corpus_id": 1644086, "score": 0 }, { "doc_id": "1272330", "title": "Predictive mitigation of timing channels in interactive systems", "abstract": "Timing channels remain a difficult and important problem for information security. Recent work introduced predictive mitigation, a new way to mitigating leakage through timing channels; this mechanism works by predicting timing from past behavior, and then enforcing the predictions. This paper generalizes predictive mitigation to a larger and important class of systems: systems that receive input requests from multiple clients and deliver responses. The new insight is that timing predictions may be a function of any public information, rather than being a function simply of output events. Based on this insight, a more general mechanism and theory of predictive mitigation becomes possible. The result is that bounds on timing leakage can be tightened, achieving asymptotically logarithmic leakage under reasonable assumptions. By applying it to web applications, the generalized predictive mitigation mechanism is shown to be effective in practice.", "corpus_id": 1272330, "score": 0 }, { "doc_id": "14310180", "title": "Transforming out timing leaks", "abstract": "One aspect of security in mobile code is privacy: private (or secret) data should not be leaked to unauthorised agents. Most of the work on secure information flow has until recently only been concerned with detecting direct and indirect flows. Secret information can however be leaked to the attacker also through covert channels. It is very reasonable to assume that the attacker, even as an external observer, can monitor the timing (including termination) behaviour of the program. Thus to claim a program secure, the security analysis must take also these into account.\nIn this work we present a surprisingly simple solution to the problem of detecting timing leakages to external observers. Our system consists of a type system in which well-typed programs do not leak secret information directly, indirectly or through timing, and a transformation for removing timing leakages. For any program that is well typed according to Volpano and Smith [VS97a], our transformation generates a program that is also free of timing leaks.", "corpus_id": 14310180, "score": 0 }, { "doc_id": "12191009", "title": "Towards Side-Channel Resistant Block Cipher Usage or Can We Encrypt Without Side-Channel Countermeasures?", "abstract": "Based on re-keying techniques by Abdalla, Bellare, and Borst [1, 2], we consider two black-box secure block cipher based symmetric encryption schemes, which we prove secure in the physically observable cryptography model. They are proven side-channel secure against a strong type of adversary that can adaptively choose the leakage function as long as the leaked information is bounded. It turns out that our simple construction is side-channel secure against all types of attacks that satisfy some reasonable assumptions. In particular, the security turns out to be negligible in the block cipher’s block size n, for all attacks. We also show that our ideas result in an interesting alternative to the implementation of block ciphers using different logic styles or masking countermeasures.", "corpus_id": 12191009, "score": 0 }, { "doc_id": "15533469", "title": "The Montgomery Powering Ladder", "abstract": "This paper gives a comprehensive analysis of Montgomery powering ladder. Initially developed for fast scalar multiplication on elliptic curves, we extend the scope of Montgomery ladder to any exponentiation in an abelian group. Computationally, the Montgomery ladder has the triple advantage of presenting a Lucas chain structure, of being parallelized, and of sharing a common operand. Furthermore, contrary to the classical binary algorithms, it behaves very regularly, which makes it naturally protected against a large variety of implementation attacks.", "corpus_id": 15533469, "score": 0 }, { "doc_id": "1903469", "title": "On Subnormal Floating Point and Abnormal Timing", "abstract": "We identify a timing channel in the floating point instructions of modern x86 processors: the running time of floating point addition and multiplication instructions can vary by two orders of magnitude depending on their operands. We develop a benchmark measuring the timing variability of floating point operations and report on its results. We use floating point data timing variability to demonstrate practical attacks on the security of the Fire fox browser (versions 23 through 27) and the Fuzz differentially private database. Finally, we initiate the study of mitigations to floating point data timing channels with libfixedtimefixedpoint, a new fixed-point, constant-time math library. Modern floating point standards and implementations are sophisticated, complex, and subtle, a fact that has not been sufficiently recognized by the security community. More work is needed to assess the implications of the use of floating point instructions in security-relevant software.", "corpus_id": 1903469, "score": 1 }, { "doc_id": "807791", "title": "A first step towards automatic application of power analysis countermeasures", "abstract": "In cryptography, side channel attacks, such as power analysis, attempt to uncover secret information from the physical implementation of cryptosystems rather than exploiting weaknesses in the cryptographic algorithms themselves. The design and implementation of physically secure cryptosystems is a challenge for both hardware and software designers. Measuring and evaluating the security of a system is manual and empirical, which is costly and time consuming; this work demonstrates that it is possible to automate these processes. We introduce a systematic methodology for automatic application of software countermeasures and demonstrate its effectiveness on an AES software implementation running on an 8-bit AVR microcontroller. The framework identifies the most vulnerable instructions of the implementation to power analysis attacks, and then transforms the software using a chosen countermeasure to protect the vulnerable instructions. Lastly, it evaluates the security of the system using an information-theoretic metric and a direct attack.", "corpus_id": 807791, "score": 0 }, { "doc_id": "2001374", "title": "Compiler mitigations for time attacks on modern x86 processors", "abstract": "This paper studies and evaluates the extent to which automated compiler techniques can defend against timing-based side channel attacks on modern x86 processors. We study how modern x86 processors can leak timing information through side channels that relate to data flow. We study the efficiency, effectiveness, portability, predictability and sensitivity of several mitigating code transformations that eliminate or minimize key-dependent execution time variations. Furthermore, we discuss the extent to which compiler backends are a suitable tool to provide automated support for the proposed mitigations.", "corpus_id": 2001374, "score": 1 }, { "doc_id": "16282151", "title": "Utilization-aware load balancing for the energy efficient operation of the big.LITTLE processor", "abstract": "ARM's big.LITTLE architecture introduces the opportunity to optimize power consumption by selecting the core type most suitable for a level of processing demand. To take advantage of this new axis of optimization, we introduce processor utilization into the Linux kernel's load balancing algorithm. Our method improves the Linux kernel's ability to schedule tasks in an energy efficient manner without making it directly aware of the available core types. Experimental results show an energy consumption improvement over the standard Linux scheduler up to 11.35% with almost no reduction in performance.", "corpus_id": 16282151, "score": 0 }, { "doc_id": "4088732", "title": "Opportunities and Limits of Remote Timing Attacks", "abstract": "Many algorithms can take a variable amount of time to complete depending on the data being processed. These timing differences can sometimes disclose confidential information. Indeed, researchers have been able to reconstruct an RSA private key purely by querying an SSL Web server and timing the results. Our work analyzes the limits of attacks based on accurately measuring network response times and jitter over a local network and across the Internet. We present the design of filters to significantly reduce the effects of jitter, allowing an attacker to measure events with 15-100μs accuracy across the Internet, and as good as 100ns over a local network. Notably, security-related algorithms on Web servers and other network servers need to be carefully engineered to avoid timing channel leaks at the accuracy demonstrated in this article.", "corpus_id": 4088732, "score": 0 }, { "doc_id": "946530", "title": "Side-Channel Analysis of Cryptographic Software via Early-Terminating Multiplications", "abstract": "The design of embedded processors demands a careful trade-off between many conflicting objectives such as performance, silicon area and power consumption. Finding such a trade-off often ignores the issue of security, which can cause, otherwise secure, cryptographic software to leak information through so-called micro-architectural side channels. In this paper we show that early-terminating integer multipliers found in various embedded processors (e.g., ARM7TDMI) represent an instance of this problem. The early-termination mechanism causes differences in the time taken to execute a multiply instruction depending on the magnitude of the operands (e.g., up to three clock cycles on an ARM7TDMI processor), which are observable via variations in execution time and power consumption. Exploiting the early-termination mechanism makes Simple Power Analysis (SPA) attacks relatively straightforward to conduct, and may even allow one to attack implementations with integrated countermeasures that would not leak any information when executed on a processor with a constant-latency multiplier. We describe several case studies, including both secret-key (RC6, AES) and public-key algorithms (RSA, ECIES) to demonstrate the threat posed by embedded processors with early-terminating multipliers.", "corpus_id": 946530, "score": 0 }, { "doc_id": "39279813", "title": "Conversion of control dependence to data dependence", "abstract": "Program analysis methods, especially those which support automatic vectorization, are based on the concept of interstatement dependence where a dependence holds between two statements when one of the statements computes values needed by the other. Powerful program transformation systems that convert sequential programs to a form more suitable for vector or parallel machines have been developed using this concept [AllK 82, KKLW 80].The dependence analysis in these systems is based on data dependence. In the presence of complex control flow, data dependence is not sufficient to transform programs because of the introduction of control dependences. A control dependence exists between two statements when the execution of one statement can prevent the execution of the other. Control dependences do not fit conveniently into dependence-based program translators.One solution is to convert all control dependences to data dependences by eliminating goto statements and introducing logical variables to control the execution of statements in the program. In this scheme, action statements are converted to IF statements. The variables in the conditional expression of an IF statement can be viewed as inputs to the statement being controlled. The result is that control dependences between statements become explicit data dependences expressed through the definitions and uses of the controlling logical variables.This paper presents a method for systematically converting control dependences to data dependences in this fashion. The algorithms presented here have been implemented in PFC, an experimental vectorizer written at Rice University.", "corpus_id": 39279813, "score": 0 }, { "doc_id": "53766395", "title": "Modern Processor Design: Fundamentals of Superscalar Processors", "abstract": "Modern Processor Design: Fundamentals of Superscalar Processors is an exciting new first edition from John Shen of Carnegie Mellon University & Intel and Mikko Lipasti of the University of Wisconsin-Madison. This book brings together the numerous microarchitectural techniques for harvesting more instruction-level parallelism (ILP) to achieve better processor performance that have been proposed and implemented in real machines. These techniques, as well as the foundational principles behind them, are organized and presented within a clear framework that allows for ease of comprehension. This text is intended for an advanced computer architecture course or a course in superscalar processor design. It is written at a level appropriate for senior or first year graduate level students.", "corpus_id": 53766395, "score": 0 }, { "doc_id": "207605595", "title": "The Jalapeño virtual machine", "abstract": "Jalapeno is a virtual machine for JavaTM servers written in the Java language. To be able to address the requirements of servers (performance and scalability in particular), Jalapeno was designed \"from scratch\" to be as self-sufficient as possible. Jalapeno's unique object model and memory layout allows a hardware null-pointer check as well as fast access to array elements, fields, and methods. Run-time services conventionally provided in native code are implemented primarily in Java. Java threads are multiplexed by virtual processors (implemented as operating system threads). A family of concurrent object allocators and parallel type-accurate garbage collectors is supported. Jalapeno's interoperable compilers enable quasi-preemptive thread switching and precise location of object references. Jalapeno's dynamic optimizing compiler is designed to obtain high quality code for methods that are observed to be frequently executed or computationally intensive.", "corpus_id": 207605595, "score": 0 }, { "doc_id": "2392313", "title": "Formally Bounding the Side-Channel Leakage in Unknown-Message Attacks", "abstract": "We propose a novel approach for quantifying a system's resistance to unknown-message side-channel attacks. The approach is based on a measure of the secret information that an attacker can extract from a system from a given number of side-channel measurements. We provide an algorithm to compute this measure, and we use it to analyze the resistance of hardware implementations of cryptographic algorithms with respect to timing attacks. In particular, we show that message-blinding --- the common countermeasure against timing attacks --- reduces the rate at which information about the secret is leaked, but that the complete information is still eventually revealed. Finally, we compare information measures corresponding to unknown-message, known-message, and chosen-message attackers and show that they form a strict hierarchy.", "corpus_id": 2392313, "score": 0 }, { "doc_id": "122607594", "title": "EDF Statistics for Goodness of Fit and Some Comparisons", "abstract": "Abstract This article offers a practical guide to goodness-of-fit tests using statistics based on the empirical distribution function (EDF). Five of the leading statistics are examined—those often labelled D, W 2, V, U 2, A 2—and three important situations: where the hypothesized distribution F(x) is completely specified and where F(x) represents the normal or exponential distribution with one or more parameters to be estimated from the data. EDF statistics are easily calculated, and the tests require only one line of significance points for each situation. They are also shown to be competitive in terms of power.", "corpus_id": 122607594, "score": 0 }, { "doc_id": "17199285", "title": "Computer systems are dynamical systems.", "abstract": "In this paper, we propose a nonlinear dynamics-based framework for modeling and analyzing computer systems. Working with this framework, we use a custom measurement infrastructure and delay-coordinate embedding to study the dynamics of these complex nonlinear systems. We find strong indications, from multiple corroborating methods, of low-dimensional dynamics in the performance of a simple program running on a popular Intel computer-including the first experimental evidence of chaotic dynamics in real computer hardware. We also find that the dynamics change completely when we run the same program on a different type of Intel computer, or when that program is changed slightly. This not only validates our framework; it also raises important issues about computer analysis and design. These engineered systems have grown so complex as to defy the analysis tools that are typically used by their designers: tools that assume linearity and stochasticity and essentially ignore dynamics. The ideas and methods developed by the nonlinear dynamics community, applied and interpreted in the context of the framework proposed here, are a much better way to study, understand, and design modern computer systems.", "corpus_id": 17199285, "score": 0 }, { "doc_id": "1184319", "title": "Producing wrong data without doing anything obviously wrong!", "abstract": "This paper presents a surprising result: changing a seemingly innocuous aspect of an experimental setup can cause a systems researcher to draw wrong conclusions from an experiment. What appears to be an innocuous aspect in the experimental setup may in fact introduce a significant bias in an evaluation. This phenomenon is called measurement bias in the natural and social sciences.\n Our results demonstrate that measurement bias is significant and commonplace in computer system evaluation. By significant we mean that measurement bias can lead to a performance analysis that either over-states an effect or even yields an incorrect conclusion. By commonplace we mean that measurement bias occurs in all architectures that we tried (Pentium 4, Core 2, and m5 O3CPU), both compilers that we tried (gcc and Intel's C compiler), and most of the SPEC CPU2006 C programs. Thus, we cannot ignore measurement bias. Nevertheless, in a literature survey of 133 recent papers from ASPLOS, PACT, PLDI, and CGO, we determined that none of the papers with experimental results adequately consider measurement bias.\n Inspired by similar problems and their solutions in other sciences, we describe and demonstrate two methods, one for detecting (causal analysis) and one for avoiding (setup randomization) measurement bias.", "corpus_id": 1184319, "score": 0 }, { "doc_id": "770578", "title": "A tool for static detection of timing channels in Java", "abstract": "A timing attack exploits the variance in the running time of a crypto-algorithm’s implementation in order to infer confidential information. Such a dependence between confidential information and the running time, called a timing channel, is often caused by branching of the control flow in the implementation’s source code with branching conditions depending on the attacked secrets. We present the Side Channel Finder, a static analysis tool for detection of such timing channels in Java implementations of cryptographic algorithms.", "corpus_id": 770578, "score": 0 }, { "doc_id": "556070", "title": "Robust and Efficient Elimination of Cache and Timing Side Channels", "abstract": "Timing and cache side channels provide powerful attacks against many sensitive operations including cryptographic implementations. Existing defenses cannot protect against all classes of such attacks without incurring prohibitive performance overhead. A popular strategy for defending against all classes of these attacks is to modify the implementation so that the timing and cache access patterns of every hardware instruction is independent of the secret inputs. However, this solution is architecture-specific, brittle, and difficult to get right. In this paper, we propose and evaluate a robust low-overhead technique for mitigating timing and cache channels. Our solution requires only minimal source code changes and works across multiple languages/platforms. We report the experimental results of applying our solution to protect several C, C++, and Java programs. Our results demonstrate that our solution successfully eliminates the timing and cache side-channel leaks while incurring significantly lower performance overhead than existing approaches.", "corpus_id": 556070, "score": 0 }, { "doc_id": "14661450", "title": "Thwarting Cache Side-Channel Attacks Through Dynamic Software Diversity", "abstract": "We explore software diversity as a defense against side-channel attacks by dynamically and systematically random- izing the control flow of programs. Existing software diversity techniques transform each program trace identically. Our di- versity based technique instead transforms programs to make each program trace unique. This approach offers probabilistic protection against both online and off-line side-channel attacks. In particular, we create a large number of unique program execution paths by automatically generating diversified replicas for parts of an input program. Replicas derived from the same original program fragment have different implementations, but perform semantically equivalent computations. At runtime we then randomly and frequently switch between these replicas. We evaluate how well our approach thwarts cache-based side- channel attacks, in which an attacker strives to recover cryp- tographic keys by analyzing side-effects of program execution. Our method requires no manual effort or hardware changes, has a reasonable performance impact, and reduces side-channel information leakage significantly.", "corpus_id": 14661450, "score": 0 }, { "doc_id": "18553859", "title": "Diversified Remote Code Execution Using Dynamic Obfuscation of Conditional Branches", "abstract": "Information leakage via timing side-channel attacksis one of the main threats that target code executing on remoteplatforms such as the cloud computing environment. Theseattacks can be further leveraged to reverse-engineer or eventamper with the running code. In this paper, we propose asecurity obfuscation technique, which helps making the generatedcode more resistant to these attacks, by means of increasinglogical complexity to hinder the formulation of a solid hypothesisabout code behavior. More importantly, this software solutionis portable, generic and does not require special setup orhardware or software modifications. In particular, we considermangling the control-flow inside a program via converting arandom set of conditional branches into linear code, using ifconversiontransformation. Moreover, our method exploits thedynamic compilation technology to continually and randomlyalter the branches. All of this mangling should diversify codeexecution, hence it becomes difficult for an attacker to infertiming correlations through statistical analysis. We extend theLLVM JIT compiler to provide for an initial investigation of thisapproach. This makes our system applicable to a wide varietyof programming languages and hardware platforms. We havestudied the system using a simple test program and selectedbenchmarks from the standard SPEC CPU 2006 suite withdifferent input loads and experimental setups. Initial results showsignificant changes in program's control-flow and hence datadependences, resulting in noticeable different execution timeseven for the same input data, thereby complicating such attacks.More notably, the performance penalty is within reasonablemargins.", "corpus_id": 18553859, "score": 0 } ]

{ "doc_id": "23979974", "title": "Spinal extradural angiolipoma: report of two cases and review of the literature", "abstract": "Spinal angiolipomas are benign uncommon neoplasm composed of mature lipocytes admixed with abnormal blood vessels. They account for only 0.04–1.2% of all spinal tumors. We report two cases of lumbar extradural angiolipoma and review previously reported cases. We found 118 cases of spinal epidural angiolipoma (70 females and 48 males; age range 1.5–85 years, mean 44.03) spanning from 1890 to 2006. Prior to diagnosis 40.6% of the patients had weakness of the lower limbs. The interval between the initial symptoms and tumor diagnosis ranged from 1 day to 17 years (mean 20.2 months). Except for four cases diagnosed at autopsy, 109 patients underwent surgery and gross-total resection was performed in 79 cases (72.4%). Spinal angiolipomas are tumors containing angiomatous and lipomatous tissue, predominantly located in the mid-thoracic region. All angiolipomas show iso- or hyperintensity on T1-weighted images and hyperintensity on T2-weighted images and most lesions enhance with gadolinium administration. The treatment for spinal extradural angiolipomas is total surgical resection and no adjuvant therapy should be administered.", "corpus_id": 23979974 }

[ { "doc_id": "25265668", "title": "Spinal angiolipomas. Report of three cases.", "abstract": "Spinal angiolipomas are distinct, benign lesions composed of mature lipocytes admixed with abnormal blood vessels. Three new cases of spinal angiolipoma are presented and 34 previously reported cases are analyzed. The 37 total cases (23 females and 14 males) ranged in age from 17 to 73 years (mean 43 years; median 45 years). The mean age of the female patients was older than that for the males (45.0 vs. 41.6 years; p < 0.001, Student's t-test) and most were peri- or postmenopausal. Prior to diagnosis, 97% of the patients had weakness of the lower extremities, 94% had sensory dysfunction, 84% had hyperreflexia and spasticity, 51% had sphincter dysfunction, and 41% had back pain lasting from 1 to 180 months (mean 28 months). Five (22%) of the 23 female patients were pregnant and two had exhibited significant weight gain coincident with the onset of symptoms. The angiolipomas were extradural in 35 patients and intramedullary in two; seven of the extradural lesions infiltrated the surrounding bone. The tumors extended from C-6 to L-4 and had a predilection for the midthoracic region (53% of cases). Plain radiographs were abnormal in 11 (39%) of 28 patients and in all patients with bone infiltration. Myelograms were abnormal in 97% of 32 patients and showed a complete block in 63% of patients. Computerized tomography (CT) and magnetic resonance (MR) imaging revealed the fat-density lesions in all cases studied. There was vascular enhancement in three of five cases with contrast-infused CT and in the one case with gadolinium-infused MR imaging. All patients improved following resection of the epidural lesions and internal decompression of the intramedullary lesions. It is concluded that spinal angiolipomas predominantly affect women. They involve the thoracic (especially the midthoracic) region, and produce symptoms and signs of spinal compression and, in some cases, bone erosion and pathological fractures. Their symptomatology can be exacerbated by pregnancy and weight gain, suggesting that vascular engorgement and the presence of obesity influence their evolution. Their preponderance in older, peri-, or postmenopausal women, and their clinical exacerbation in pregnant women support a role for hormonal influence. Magnetic resonance imaging is the investigation of choice for the diagnosis of these lesions. Surgery is universally successful in relieving symptoms.", "corpus_id": 25265668, "score": 0 }, { "doc_id": "22627622", "title": "[Spinal extradural angiolipoma: a case report].", "abstract": "This 60-year-old man had been well until four years prior to admission, when he developed slowly progressive weakness of the lower extremities. On admission he was found to have a spastic paraparesis, sensory disturbance below the level of T10 and mild sphincter dysfunction. Conventional myelography and CT myelography demonstrated an epidural mass located from T5 to T8 vertebral level. MRI revealed that the epidural mass was fusiform and markedly enhanced by the contrast medium. Laminectomy was performed and a fibrous tumor red in color was subtotally removed. Histological findings were consistent with those of angiolipoma. Angiolipoma is a rare tumor in the central nervous system and is regarded as a clinical entity different from a spinal lipoma. Occurrence of angiolipoma in the central nervous system has been reported in 40 cases in the world literature. Thirty nine cases of them occurred in the spinal canal, especially in the dorsal epidural space of the thoracic region. The fusiform shape demonstrated in this case might also be characteristic of angiolipoma in this region.", "corpus_id": 22627622, "score": 0 }, { "doc_id": "34150329", "title": "Spinal extradural angiolipoma: a report of two cases and review of the literature.", "abstract": "Extradural angiolipomas are rare tumors that can produce spinal cord compression. Two patients with thoracic spinal angiolipoma are presented that were treated with surgical resection and radiation. The histological and clinical features of the 18 previously reported cases of these tumors are discussed.", "corpus_id": 34150329, "score": 1 }, { "doc_id": "74735082", "title": "Report of two cases and review of the literature", "abstract": "U Chondroblastoma is a benign cartilaginous neoplasm that generally affects the appendicular skeleton. Twenty-six cases of spinal chondroblastoma have been reported in the past 50 years, only six of which were located in the lumbar region. The authors report two cases involving this exceptional location. In both patients, low-back pain, in the absence of radicular pain, was the presenting symptom. In both cases, plain radiography and computerized tomography scanning revealed an osteolytic lesion surrounded by marginal sclerosis. Magnetic resonance imaging allowed the authors to study the tumor’s local extension. Examination of a percutaneous fluoroscopy-guided biopsy sample revealed the following typical histological features of chondroblastoma: chondroid tissue, focally alternating with cellular areas, and no nuclear atypia or pleomorphism. To reduce the risk of local recurrence, vertebrectomy and anterior‐posterior fusion were performed in both cases. In one case, a structural lumbar scoliosis was corrected during the posterior procedure. There was no postoperative complication. No recurrence was observed during the 3- to 6-year follow-up period. The surgery-related results were deemed successful. Although exceptional, the diagnosis of chondroblastoma is possible in lesions involving the lumbar spine. Other spinal locations are described in the literature, and frequency of recurrence is stressed. A vertebrectomy is advised to reduce the risk of local recurrence.", "corpus_id": 74735082, "score": 0 }, { "doc_id": "37192803", "title": "Dorsal thoracic cord compression from a spinal angiolipoma: case report and brief comment.", "abstract": "Angiolipomas are benign tumors usually found in the forearms of young adults. To the best of our knowledge only 63 cases of spinal angiolipomas have been reported in the literature up until 1999 (MEDLINE 1966-1999). We report a case of a spinal angiolipoma causing dorsal cord compression in a 44-year-old woman presenting with subacute lower limb paresthesias, in the absence of sensory or motor findings, which mimicked multiple sclerosis by history. Operative intervention was curative.", "corpus_id": 37192803, "score": 0 }, { "doc_id": "1627537", "title": "Epidural angiolipoma producing compression of the cauda equina.", "abstract": "Epidural angiolipomas are rare tumours and are histologically benign, but their myelographic and macroscopic appearance is malignant. Surgical results are satisfactory. A case is reported in a 48-year-old woman with a slowly progressive cauda equina compression syndrome in whom an epidural angiolipoma was successfully removed. The special feature of this case was a generalized severe spinal osteoporosis with a pathological fracture of a vertebral body at the level of the tumour.", "corpus_id": 1627537, "score": 0 }, { "doc_id": "36687584", "title": "Infiltrating Spinal Angiolipoma: A Case Report and Review of the Literature", "abstract": "Abstract Angiolipomas are rarely encountered in the spine. We report the case of a 47-year-old man with a thoracic angiolipoma involving the T9 vertebral body. A preoperative spinal angiogram confirmed a highly vascular neoplasm. The lesion was treated with endovascular embolization prior to a T9 corpectomy and resection of the epidural component of the tumor. At time of surgery, minimal blood loss occurred during resection of the vertebral body and the epidural mass. Pathologic examination demonstrated features consistent with spinal angiolipoma. This report emphasizes the clinical, radiographic, and pathologic features of infiltrating spinal angiolipoma and discusses therapeutic management options.", "corpus_id": 36687584, "score": 0 }, { "doc_id": "24537956", "title": "Spinal angiolipomas: MR features.", "abstract": "PURPOSE\nTo determine the MR features of spinal angiolipomas and to compare these findings with their histologic appearance.\n\n\nMETHODS\nThe MR examinations of three patients with surgically proved angiolipomas were reviewed for tumor location and extent, signal characteristics, and pattern of contrast enhancement, and were then compared with the histologic findings.\n\n\nRESULTS\nFour tumors were found in the three patients, all located in the posterior epidural compartment, averaging about 2.5 vertebral bodies in length. On noncontrast T1-weighted images, all lesions were inhomogeneous and hypointense relative to epidural fat. Inhomogeneous enhancement was seen in three lesions on postcontrast T1-weighted images obtained with fat-saturation techniques. Angiolipomas were least conspicuous on T2-weighted images. A high vascular content correlated with the presence of large hypointense regions on T1-weighted images.\n\n\nCONCLUSION\nSpinal angiolipomas are typically hyperintense on noncontrast T-1-weighted images relative to other tumors. Angiolipomas that contain large hypointense foci on noncontrast T1-weighted images can be expected to have a high degree of vascularity.", "corpus_id": 24537956, "score": 1 }, { "doc_id": "29919188", "title": "Spinal angiolipomas: report of a case and review of the cases published since the discovery of the tumour in 1890.", "abstract": "Angiolipomas of the spinal canal are extremely uncommon benign neoplasms composed of mature lipomatous and angiomatous elements. A case of thoracic spinal extradural angiolipoma producing progressive spinal cord compression in a 54-year old housewife is presented and 74 previously reported cases in the world literature over a period spanning nearly one century from 1890 to the present are analysed. The 75 total cases (46 females and 29 males) ranged in age from 6 to 73 years (mean 42.7, SD 15.9; median 43). The angiolipomas were located in the extradural compartment in 72 patients and intradural compartment in 3; 14 of the extradural lesions infiltrated the surrounding bone (infiltrating subgroup). Computed tomography (CT) and magnetic resonance imaging (MRI) revealed the fat-density lesions in all the cases that we studied. The findings indicate that spinal angiolipomas predominantly affect women. Their preponderance in peri- or postmenopausal women, and their fluctuating clinical course during the pregnancy support a role of hormonal influence on the development of the lesion. They often involve the thoracic region, and produce symptoms and signs of spinal compression and, in some cases, bone involvement. MRI is the investigation of choice for the diagnosis of these lesions. Non-infiltrating angiolipomas can usually be removed easily through a laminectomy, but infiltrating angiolipoma can be only partially resected. However, outcome is not worse in the infiltrating than in the non-infiltrating lesions and appears to be relatively independent of the completeness of the surgical removal. Subtotal resection usually provides substantial symptomatic relief, because these lesions are slow growing and do not undergo malignant transformation. The results of this review show that angiolipomas of the spinal canal have a good prognosis after surgical removal, even if infiltrating.", "corpus_id": 29919188, "score": 1 }, { "doc_id": "30306284", "title": "Spinal extradural angiolipoma: case report and literature review.", "abstract": "A case report of a 12-year-old child with a spinal extradural angiolipoma is presented. The tumor was totally removed and a good recovery was obtained. In a review of 43 previous cases, the clinical, radiological, and histological features of the tumor are discussed. It is stressed that spinal angiolipomas and spinal lipomas have to be considered as two different clinicopathological entities in order to ensure adequate treatment and prognosis.", "corpus_id": 30306284, "score": 1 }, { "doc_id": "29530660", "title": "Lumbar spinal angiolipomas: report of two cases and review of the literature", "abstract": "Study design: Case report and review of the literature.Objectives: To describe two patients with angiolipoma in the ventral aspect of the lumbar epidural space, to discuss the clinical, radiologic, and surgical features of these lesions, and to review previously reported cases.Setting: Rome, Italy.Methods: Two cases, a 60-year-old man and a 54-year-old woman presented with lumbar–sciatic pain but with no abnormal neurological signs. Investigation (CT and MRI) demonstrated lumbar tumours.Results: Laminectomy and excision of the tumors were performed, and symptoms improved immediately.Conclusions: Magnetic resonance imaging with suppression fat sequences allows the recognition of these lesions. The prognosis after surgical removal of spinal angiolipoma is favorable.", "corpus_id": 29530660, "score": 0 }, { "doc_id": "2634374", "title": "Spinal angiolipoma: case report and review of the literature", "abstract": "SummarySpinal angiolipomas are rare lesions usually found in the epidural space of the thoracic spine. This report presents a case of and reviews the literature on this rare entity. The etiology, clinical presentation, imaging, and treatment are discussed. In 92 reported cases of spinal angiolipoma 56 occurred in women (61%), and 36 in men (39%). Mean age of occurrence is 42.9 years (range 10 days–85 years) with most patients presenting with slowly progressive symptoms of spinal cord compression. Most cases occur in the extradural compartment, and are of the non-invasive subtype. This rare clinical entity must be considered in the differential diagnosis of spinal epidural lesions. In most cases complete removal is possible, however, prognosis is good even for infiltrating lesions. Thus, one must not risk neurological damage to attain complete resection.", "corpus_id": 2634374, "score": 0 }, { "doc_id": "42487496", "title": "Angiolipomas of the Central Nervous System", "abstract": "Angiolipomas are neoplasms composed of mature adipocytes admixed with abnormal vascular elements. They are most commonly found in the subcutaneous tissue of the trunk and extremities, but other sites have been reported. The craniospinal axis is an uncommon but significant site. An extensive review of the literature is conducted. We summarize 94 cases of angiolipomas in the central nervous system (CNS) in 92 patients, including five in our own series, to highlight the most prominent features of these tumors. The increasing number of cases of CNS angiolipoma in the era of magnetic resonance imaging raises the question of the rarity of these lesions.", "corpus_id": 42487496, "score": 1 }, { "doc_id": "44484489", "title": "Infiltrating extradural spinal angiolipoma.", "abstract": "BACKGROUND\nAngiolipomas are considered to be rare. They are benign mesenchymal tumors generally located in the subcutaneous tissue of trunk and limbs.\n\n\nMETHODS\nThe authors report a thoracic epidural angiolipoma mimicking a vertebro-epidural metastasis. The patient suffered from medullary compression related to an extradural mass in T6.\n\n\nRESULTS\nPathological ex-, amination was obtained from tumoral samples. They consisted of mature adipose tissue with numerous sections of abnormal vascular channels.\n\n\nCONCLUSIONS\nReviewing literature particular attention is paid to some questions raised in connection with different kinds of vertebro-epidural tumors. The authors give importance to relationships between angiolipomas and angiomyolipomas using MRI as a tool in differential diagnosis. Pathogenesis is evokated especially regarding the role of corticotherapy, the case herein reported lying within this therapeutical context.", "corpus_id": 44484489, "score": 0 }, { "doc_id": "25876392", "title": "Thoracic Spinal Angiomyolipoma With Extracanal Extension to the Thoracic Cavity: A Case Report", "abstract": "Study Design. Case report and review of the literature. Objective. To describe a 72‐year‐old man with thoracic spinal angiomyolipoma in the ventral aspect of the epidural space and extracanal extension to the posterior mediastinum, to discuss the clinical and radiologic features and unique biologic behavior of this entity, and to review of the literature on angiolipoma and angiomyolipoma. Summary of Background Data. Spinal angiolipoma and angiomyolipoma are rare tumors, which are localized almost exclusively in the dorsal epidural space of the thoracic spine. Most reported cases have no tendency to involve the surrounding tissue. Methods. The authors describe the radiologic, surgical, and pathologic findings of this patient and review the findings from other reported cases. Results. Anterior decompression was performed using a right transthoracic incision, and the neurologic symptoms improved immediately. There were no signs of recurrence of the tumor or neurologic deficit within a 2‐year follow‐up period. Conclusion. Results of a literature survey of these tumors support management by prompt and radical surgical intervention for long‐term cure, even in cases in which the infiltrating nature is recognized.", "corpus_id": 25876392, "score": 0 }, { "doc_id": "20743385", "title": "Spinal angiolipoma.", "abstract": "BACKGROUND\nSpinal epidural angiolipoma is a rare cause of spinal cord compression. We present a case and review the clinical presentation, radiological appearance, pathological aspects and treatment of this distinct clinico-pathological entity.\n\n\nMETHODS\nA case of a 46-year-old woman with a five-month history of progressive myelopathy affecting her lower extremities is presented. CT and MRI revealed a large epidural fat-containing mass compressing the spinal cord dorsally at the T7-T8 level. A laminectomy was performed with gross total resection of the lesion.\n\n\nRESULTS\nThe patient's neurologic symptoms improved postoperatively. A two-year follow-up period has revealed no signs of tumor recurrence and no neurological deficit.\n\n\nCONCLUSION\nThe diagnosis of spinal angiolipoma should be considered in the differential diagnosis of spinal cord compression. Magnetic resonance imaging is the investigation of choice. The surgical objective is complete excision but, for anterior lesions involving bone, an overly aggressive approach should be tempered by an awareness of the overall indolent natural history of so-called \"infiltrating\" spinal angiolipomas that are only partially excised.", "corpus_id": 20743385, "score": 0 }, { "doc_id": "9709993", "title": "Concurrent occurrence of solitary spinal epidural osteochondroma and angiolipoma.", "abstract": "A unique concurrent occurrence of spinal epidural osteochondroma and angiolipoma was found in the first thoracic level of a 21-year-old man. The combined lesions produced longstanding motor and sensory disturbances because of compression of the corresponding segment of the spinal cord, and abrupt paraparesis presumably due to spontaneous hemorrhage from the angiomatous component of the angiolipoma. The neurological deficits were satisfactorily improved after surgical removal of the hematoma as well as of both lesions which were regarded as mesenchymal hamartomas.", "corpus_id": 9709993, "score": 0 }, { "doc_id": "41809429", "title": "Spinal angiolipoma: case report and review of literature.", "abstract": "Spinal extradural angiolipomas are distinct, benign, and rare lesions composed of mature lipocytes admixed with abnormal blood vessels. They account for 0.14% of all spinal axis tumors. The case described here was a 72-year-old patient presenting with a history of paraparesis, hypoesthesia under the T2 level, hyperreflexia, and urinary overflow incontinence that appeared within 7 days after the administration of a coronary vasodilator drug regimen. The spinal magnetic resonance scan showed a lipomatous mass with signal void lesions, suggesting a vascular component of the tumor. The patient improved rapidly after surgical resection of the epidural tumor and decompression of the cord. According to the present literature, the duration of neurological symptoms ranges from 1 to 180 months (mean 28 months). But this patient's neurological deterioration took place 4 days before hospitalization. We believe that this can be explained by the increased tumor blood volume caused by vasodilator drugs, which in turn exerted a pulsatile compressive effect on the cord.", "corpus_id": 41809429, "score": 0 }, { "doc_id": "22627622", "title": "[Spinal extradural angiolipoma: a case report].", "abstract": "This 60-year-old man had been well until four years prior to admission, when he developed slowly progressive weakness of the lower extremities. On admission he was found to have a spastic paraparesis, sensory disturbance below the level of T10 and mild sphincter dysfunction. Conventional myelography and CT myelography demonstrated an epidural mass located from T5 to T8 vertebral level. MRI revealed that the epidural mass was fusiform and markedly enhanced by the contrast medium. Laminectomy was performed and a fibrous tumor red in color was subtotally removed. Histological findings were consistent with those of angiolipoma. Angiolipoma is a rare tumor in the central nervous system and is regarded as a clinical entity different from a spinal lipoma. Occurrence of angiolipoma in the central nervous system has been reported in 40 cases in the world literature. Thirty nine cases of them occurred in the spinal canal, especially in the dorsal epidural space of the thoracic region. The fusiform shape demonstrated in this case might also be characteristic of angiolipoma in this region.", "corpus_id": 22627622, "score": 0 }, { "doc_id": "33051912", "title": "Spinal epidural angiolipoma complicated by an intratumoral abscess. Case report.", "abstract": "Spinal angiolipomas are rare, benign lesions representing 0.14 to 1.2% of all spinal axis tumors. They most commonly involve the midthoracic spine and are located in the posterior epidural space. Up to now, six pediatric cases have been reported in the literature; two of them involved an acute clinical onset that was related to a venous infarction of a tumor. The authors report the case of a 16-year-old boy with a midthoracic epidural angiolipoma who was admitted with a clinical history of an acute paraparesis. In contrast to previous descriptions, the acute onset in this case was related to a spontaneous intratumoral abscess within the tumor.", "corpus_id": 33051912, "score": 0 }, { "doc_id": "20764235", "title": "Spinal intramedullary angiolipoma", "abstract": "We report the case of a young patient with a thoracolumbar (T11-L3) intramedullary angiolipoma. Total removal of the tumor was possible and after operation the patient's neurological condition greatly improved. Only two previous cases of intramedullary angiolipomas have been reported, and in neither could the lesion be wholly removed. The histopathological and radiological features of these tumors are discussed and the extreme rareness of this case is emphasized.", "corpus_id": 20764235, "score": 0 }, { "doc_id": "28268920", "title": "Radiological and histological findings in spinal intramedullary angiolipoma", "abstract": "Abstract We report an intramedullary angiolipoma with spinal cord compression studied by MRI, angiography and CT. Angiolipomas of the spine are rare benign tumours containing vascular and mature adipose elements. They are epidural in more than 90 % of the cases; only three cases of intramedullary angiolipoma are described. The clinical picture is nonspecific, but MRI and CT suggest the diagnosis.", "corpus_id": 28268920, "score": 0 }, { "doc_id": "40844699", "title": "Spinal angiolipomas: CT and MR aspects.", "abstract": "Spinal angiolipomas are rare benign tumors containing vascular and mature adipose elements. In greater than 90% of the cases they are located in the epidural space. The clinical symptomatology is nonspecific, but CT and particularly MR studies allow for a precise diagnosis. Computed tomography (four cases in the literature plus one explored in our department) showed a hypodense lesion in 80% of the cases. In one case the angiolipoma was isodense to the cord. Magnetic resonance (three cases in the literature plus two explored in our department) showed a more or less homogeneous mass with a signal in T1- and T2-weighted images close to that of the subcutaneous fat. The infusion of gadolinium (one case in the literature plus one of ours) is helpful as an indicator to the degree of vascularization of the angiolipoma.", "corpus_id": 40844699, "score": 0 }, { "doc_id": "10837453", "title": "Intracranial angiolipoma.", "abstract": "Fat containing tumours within the central nervous system are rare. The second reported case of intracranial angiolipoma is described.", "corpus_id": 10837453, "score": 0 }, { "doc_id": "73953041", "title": "INTRASPINAL LIPOMAS: REPORT OF CASES; REVIEW OF THE LITERATURE, AND CLINICAL AND PATHOLOGIC STUDY", "abstract": "Masses of adipose tissue within the cranium and within the spinal canal not associated with bifid spines are rare. Intracranial lipoma, reported cases of which numbered 74 up to 1936 (Sperling and Alpers1), rarely produces clinical symptoms because of its small size, and no reported tumor of this sort had been attacked surgically. Intraspinal lipoma is even less common, but it frequently grows to enormous size, produces compression of the spinal cord and is surgically exposed. When it is encountered, its true nature is unsuspected until the yellow mass is visualized or, when the tumor is reddish or white, until histologic examination is made. Elsberg's2series of data on 267 cases of extra-medullary tumors, compiled in 1941, included 6 instances of lipoma. It is probable, however, that the 2 tumors lying both intradurally and extradurally were associated with spina bifida, since Wolf,3in discussing what appears to", "corpus_id": 73953041, "score": 0 }, { "doc_id": "6843973", "title": "Revisited: spinal angiolipoma--three additional cases.", "abstract": "Angiolipomas are benign tumours which usually arise from subcutaneous tissue, particularly in the forearm, but they do occur rarely in the spinal canal. To the best of our knowledge 60 cases of histologically confirmed spinal angiolipoma have been reported in the medical literature. They show a female predominance (1.6:1), and the mean age at presentation is 43 years. They usually arise in the thoracic spine, most cases presenting with slowly progressive signs and symptoms of cord compression. Rarely, massive acute haemorrhage into the tumour may herald its presence. Surgical resection or decompression are the most satisfactory methods of treatment in most patients. We describe three further cases of spinal angiolipoma, and discuss their aetiology, pathogenesis, clinico-pathological features and surgical management.", "corpus_id": 6843973, "score": 0 }, { "doc_id": "3032271", "title": "Spinal extrathecal hemangiolipomas: report of two cases and review of the literature.", "abstract": "Two cases of a rare entity, spinal extrathecal hemangiolipoma, are presented. The clinical and histological features of the tumor are discussed, with particular attention to the uncommonly sudden onset of symptoms in one patient. Complete neurological recovery was exhibited by one patient after excision of the lesion, whereas only a partial recovery was achieved in the other case. The pathogenetic aspects of hemangiolipomas and the literature dealing with the previously reported 12 cases are reviewed.", "corpus_id": 3032271, "score": 0 }, { "doc_id": "41676523", "title": "Spinal angiolipoma mimicking extradural lipomatosis.", "abstract": "Spinal angiolipoma is a rare, benign tumour. More than 90% of cases arise extradurally. The authors report an extradural spinal angiolipoma in a 54-year-old man. Conventional T1-weighted and T2-weighted magnetic resonance imaging (MRI) demonstrated an excessive amount of extradural adipose tissue posteriorly, extending from the level of the third to the ninth thoracic vertebra. The signal intensity within the spinal cord was normal. These findings were initially misinterpreted as being of little clinical significance. When the patient's condition deteriorated, myelography was performed, and extradural compression of the thecal sac was demonstrated. At surgery spinal angiolipoma was confirmed. The ease with which the MRI features of this lesion can be overlooked, as well as imaging strategies to avoid this pitfall, are discussed.", "corpus_id": 41676523, "score": 0 }, { "doc_id": "29003677", "title": "Spinal cord compression by extradural fat after prolonged corticosteroid therapy.", "abstract": "This young man was operated on twice for thoracic spinal cord compression. He had been on corticosteroid therapy for the last 2 years subsequent to a renal transplant. The only anomaly discovered during the operation was a large quantity of extradural fat that did not present the characteristics of lipoma. The remarkable postoperative clinical improvement suggested that the fat deposit was responsible for the spinal cord compression.", "corpus_id": 29003677, "score": 0 }, { "doc_id": "13198760", "title": "Spinal stenosis caused by epidural lipomatosis in cushing's syndrome.", "abstract": "CENTRIPETAL fat deposition is a well known clinical feature of excessive endogenous or exogenous adrenal glucocorticoids. We describe an unusual case of central spinal stenosis caused by excessive epidural fat in a patient with Cushing's syndrome secondary to prolonged therapy with high doses of glucocorticoids. Only one other case report of this phenomenon could be located in the medical literature.1 Case Report A 53-year-old woman with Graves' disease, euthyroid after radioiodine therapy, had infiltrative ophthalmopathy with optic-nerve involvement. When she was treated with prednisone, 150 mg per day, cushingoid features developed rapidly. Two months after the initiation of therapy, with . . .", "corpus_id": 13198760, "score": 0 }, { "doc_id": "35161208", "title": "Two entities in angiolipoma(A study of 459 cases of lipoma with review of literature on infiltrating angiolipoma)", "abstract": "A study of lipomas collected over the past 20 years in a university hospital indicated that there are two types of angiolipoma, namely noninfiltrating and infiltrating. Noninfiltrating angiolipoma is seen in young individuals and presents as painful, soft, cutaneous nodules. Occasional compression of nerve fibers that accompany the vascular channels could be demonstrated. Treatment is merely enucleation. Infiltrating angiolipoma is rather rare. Only 23 cases have been reported in the English literature. Though histologically benign, the tumor can infiltrate bony, muscular, neural, and fibrocollagenous tissues to cause unusual symptoms and signs and can clinically simulate malignant neoplasms. Wide excision to include the normal tissue surrounding the tumor is mandatory. Radiotherapy should be rendered to cases with recurrence.", "corpus_id": 35161208, "score": 0 }, { "doc_id": "12670497", "title": "Cytogenetic analysis of subcutaneous angiolipoma: further evidence supporting its difference from ordinary pure lipomas: a report of the CHAMP Study Group.", "abstract": "Subcutaneous angiolipomas are benign soft-tissue lesions consisting of two mesenchymal elements (i.e., adipose tissue and blood vessels) and having distinct clinical features. They usually are multiple, with an obvious male predominance, and hereditary occurrence has been described. Twenty subcutaneous angiolipomas from 10 patients with typical clinical and morphologic features were reviewed. All lesions had a normal karyotype. This finding is in striking contrast with ordinary lipomas, spindle-cell and pleomorphic lipomas, lipoblastomas, and hibernomas, most of which have characteristic clonal chromosomal aberrations. The normal karyotype of subcutaneous angiolipoma as well as its distinct clinical and morphologic features suggest a different pathogenesis from pure lipomas.", "corpus_id": 12670497, "score": 0 }, { "doc_id": "11511879", "title": "Lumbar spinal angiolipoma: case report and review of the literature", "abstract": "Spinal angiolipomas are extremely rare benign tumors composed of mature lipomatous and angiomatous elements. Most are symptomatic due to progressive spinal cord or root compression. This article describes the case of a 60-year-old woman who presented with a 6-month history of low back pain radiating to her right leg. The pain was multisegmental. The condition had worsened with time. Lumbar magnetic resonance imaging revealed a dorsal epidural mass at L5 and erosion of the lamina of the L5 vertebra. Laminectomy was performed, and an extradural tumor was totally excised. Neuropathologic examination identified it as a lumbar spinal angiolipoma. There was no evidence of recurrence in follow-up 12 months later. This rare clinical entity must be considered in the differential diagnosis for any spinal epidural lesion.", "corpus_id": 11511879, "score": 0 } ]

{ "doc_id": "31354260", "title": "Risk and protective factors associated with substance use disorders in adolescents with first-episode mania.", "abstract": "OBJECTIVE\nAdolescents with bipolar disorder (BD) are more likely to develop substance use disorders (SUDs) than adolescents without psychiatric disorders; however, to our knowledge, specific risk factors underlying this relationship have not been prospectively examined. The purpose of this study was to identify predictors of developing SUDs after a first manic episode.\n\n\nMETHOD\nParticipants aged 12 to 20 years and hospitalized with their first manic episode associated with bipolar I disorder (BP-I) were recruited as part of the University of Cincinnati First-Episode Mania Study and prospectively evaluated for patterns of substance use. Follow-up ranged between 17 and 283 weeks (mean = 113 weeks, SD = 71.9 weeks). Demographic and clinical variables were compared between adolescents with and without SUDs.\n\n\nRESULTS\nOf the 103 adolescents with BD, 49 (48%) either had a SUD at baseline or developed one during follow-up. Of the 71 participants who did not have a SUD at study entry, 17 (24%) developed one during follow-up (median = 40 weeks). Later onset of BD, manic (versus mixed) mood episode, and comorbid disruptive behavior disorders were associated with an increased risk of developing a SUD in univariate analyses. Adolescents treated with psychostimulant treatment before their first manic episode were significantly less likely to develop a SUD independent of attention-deficit/hyperactivity disorder (ADHD) diagnosis. Comorbid posttraumatic stress disorder (PTSD) and psychotic symptoms were the strongest predictors of SUD development.\n\n\nCONCLUSION\nOur results confirm high rates of SUD in adolescents with BD. In addition, our findings identify potential risk factors associated with SUDs in adolescents with BD. These data are preliminary in nature and should be explored further in future studies.", "corpus_id": 31354260 }

[ { "doc_id": "18544498", "title": "Predictors of alcohol intake and heavy drinking in early adulthood: a 5-year follow-up of 15-19-year-old Finnish adolescents.", "abstract": "Relative contributions of earlier drinking and smoking vs mental health risk factors in predicting alcohol intake and heavy drinking in young adulthood were assessed. Higher average alcohol intake and heavy drinking (13 or more drinks on one occasion) in 1995 were significantly related to male gender and earlier high scores in 1990 of relief smoking, relief drinking, and their interaction. Parental alcohol problems, social group, perceived degree of social support, trait anxiety, number of negative life events, self-esteem, grade-point average, somatic symptoms score, or immature, neurotic, or mature defence style measured in 1990 did not predict alcohol intake or heavy drinking 5 years later. The findings suggest that alcohol intake and heavy drinking in young adulthood can be predicted by earlier self-reports on relief smoking and alcohol intake in adolescence.", "corpus_id": 18544498, "score": 0 }, { "doc_id": "25629930", "title": "Socioeconomic status and drinking patterns in young adults.", "abstract": "AIMS\nTo investigate the relationship between several indicators of socioeconomic status and drinking patterns in young adulthood.\n\n\nDESIGN\nData collected in a longitudinal study of young adults was analysed using repeated-measures models to examine the relationship between income, occupational activity and educational achievement and patterns of drinking.\n\n\nSETTING\nThese data were collected as part of a longitudinal study ofa birth cohort of New Zealanders. They were interviewed for the most part in a central location using a face-to-face method and a computer-assisted alcohol interview.\n\n\nPARTICIPANTS\nThe participants were members of the Dunedin Multidisciplinary Health and Development study aged 18, 21 and 26 years. Nine hundred and sixty-nine study members contributed to the analysis. Study members have been found to be broadly representative of the New Zealand population and cross national studies suggest findings are generalizable to other similar market economies.\n\n\nMEASUREMENTS\nThree indicators of socioeconomic status were used; educational achievement, occupational activity and income. The educational achievement indicator at age 18 had three levels that ranged from no school qualifications to higher school qualifications. For age 21 two additional categories of tertiary educational achievement were included to make five categories and for age 26 higher tertiary degrees were included in the measure to make six categories. Five categories of occupational activity were used. Income data was also used. Two measures of alcohol consumption were used. These were the frequency of drinking and the typical quantity of alcohol consumed per drinking occasion in the past year.\n\n\nFINDINGS\nFrequency of drinking increased over these early adult years and the quantities consumed peaked at age 21 and decreased thereafter for both males and females. Frequency of drinking was influenced by income with the higher income respondents drinking more often and this was persistent overtime. Quantity of drinking was most influenced by educational achievement. The less well-educated young adult drank significantly more during a drinking occasion and at all ages. There was also a relationship between educational achievement and frequency of drinking for males at age 18 and a relationship between women's occupational activity and the quantities they consumed.\n\n\nCONCLUSIONS\nThe finding that the dimensions of drinking operate differently explains the lack of consistency in previous research, which has investigated socioeconomic status and the volumes of alcohol consumed. The findings of higher quantities consumed among those of lower social status may explain some of the reduced life expectancy found among those with lower socioeconomic status.", "corpus_id": 25629930, "score": 0 }, { "doc_id": "21004451", "title": "Parent, family, and neighborhood effects on the development of child substance use and other psychopathology from preschool to the start of adulthood.", "abstract": "OBJECTIVE\nWe examined the long-term effects of childhood familial and neighborhood risk on adolescent substance use and psychiatric symptomatology.\n\n\nMETHOD\nThis study used data from an ongoing 2-decade long study that recruited alcoholic and neighborhood control families through fathers' drunk-driving records and door-to-door canvassing in a four county area. The sample included 220 male, initially 3- to 5-year-old children of the participant families, who received in-home assessments at baseline and thereafter at 3-year intervals. Parental lifetime psychopathology and offspring symptomatology at ages 18-20 were assessed by semistructured diagnostic interviews. Census tract variables were used to indicate neighborhood characteristics.\n\n\nRESULTS\nThe isomorphic parental symptomatology predicted offspring psychopathology. For marijuana-use disorder, major depressive disorder, and nicotine dependence, the other parental comorbidities were also significant predictors. Neighborhood residential instability in childhood contributed to the development of late adolescent alcohol-use disorder, marijuana-use disorder, major depressive disorder, antisocial personality disorder, and nicotine-dependence symptomatology. Although lower family socioeconomic status in childhood contributed to more adolescent marijuana-use disorder, major depressive disorder, and nicotine-dependence symptoms, neighborhood socioeconomic status did not predict adolescent psychopathology. Longitudinal changes in neighborhood environments from early childhood to adolescence had significant effects on alcohol-use disorder, marijuana-use disorder, and major depressive disorder symptoms in late adolescence. A higher frequency of family mobility from early childhood to adolescence predicted more nicotine-dependence symptoms in late adolescence.\n\n\nCONCLUSIONS\nFindings indicate that parental psychopathology, family socioeconomic status, and neighborhood residential instability are all important risk factors for the development of substance-use disorder and other comorbid psychopathology. Intervention programming might effectively use these early parental psychopathology indicators to identify risk and might target community activity to stabilize the social environment and provide youth services to counteract the effects of family transience.", "corpus_id": 21004451, "score": 0 }, { "doc_id": "20211712", "title": "The contextual role of alcohol outlet density in college drinking.", "abstract": "OBJECTIVE\nThe objective of the study is to examine the relationship between the physical availability of off-campus alcohol and drinking outcomes among college students.\n\n\nMETHOD\nA multilevel analysis of students (N = 17,051) nested within college campuses (N = 32) was conducted. Four problem-drinking-related outcomes (i.e., average number of drinks when partying, frequency of drunkenness in past 2 weeks, 30-day frequency of drinking, and greatest number of drinks in one sitting) along with individual level covariates of drinking were introduced at the student level. The physical availability of alcohol was assessed as the number of on-premise and off-premise alcohol outlets within 3 miles of campus per 1,000 students enrolled.\n\n\nRESULTS\nHigher densities of on-premise alcohol outlets were strongly related to drinking outcomes even after controlling for individual predictors of college drinking. The association indicated that the campus means for the average number of drinks when partying and the number of drinking occasions in the past 30 days were, respectively, 1.13 drinks and 1.32 occasions greater when the outlet density was 2 SDs higher.\n\n\nCONCLUSIONS\nOff-campus, on-premise outlet density is strongly associated with college-drinking outcomes. Given the limited number of modifiable factors that affect college drinking, on-premise outlet density represents a potential modifiable means of addressing the problem.", "corpus_id": 20211712, "score": 0 }, { "doc_id": "25901988", "title": "The role of mental disorders in the risk and speed of transition to alcohol use disorders among community youth", "abstract": "Background Among adolescents and young adults with DSM-IV alcohol use disorders (AUDs), there are inter-individual differences in the speed of transition from initial alcohol use (AU) to AUD. AUDs are highly co-morbid with other mental disorders. The factors associated with rapid transition from first AU to AUD remain unknown and the role of mental disorders in rapid transitions is unclear. Given this background we examined (1) whether prior anxiety, mood, externalizing and non-alcohol substance use disorders are related to the risk and speed of transition from first AU to DSM-IV alcohol abuse (AA) and alcohol dependence (AD) and (2) whether early age of onset of prior mental disorders (PMDs) is a promoter of rapid transition. Method A total of 3021 community subjects (97.7% lifetime AU) aged 14–24 years at baseline were followed up prospectively for up to 10 years. AU and mental disorders were assessed with the DSM-IV/M-CIDI. Results Among subjects with lifetime AU, several PMDs, such as specific phobia, bipolar disorder and nicotine dependence, were associated with an increased risk of AUD independent of externalizing disorders. Associations of PMDs with the speed of transition to AUDs were mostly weak and inconsistent. Only social phobia and externalizing disorders were associated with faster transitions to AD even after adjustment for other PMDs. Earlier age of onset of PMD was not associated with rapid transition. Conclusions Mental disorders are associated with the risk of AUD. With the possible exception of social phobia and externalizing disorders, they do not promote rapid transition, even if they occur particularly early. Future research needs to identify factors relevant to rapid transition to AUD.", "corpus_id": 25901988, "score": 0 }, { "doc_id": "25880231", "title": "Does conduct disorder mediate the development of substance use disorders in adolescents with bipolar disorder? A case-control family study.", "abstract": "BACKGROUND\nRecent work has highlighted important relationships among conduct disorder (CD), substance use disorders (SUD), and bipolar disorder in youth. However, because bipolar disorder and CD are frequently comorbid in the young, the impact of CD in mediating SUD in bipolar disorder youth remains unclear.\n\n\nMETHOD\n105 adolescents with DSM-IV bipolar disorder (mean +/- SD age = 13.6 +/- 2.50 years) and 98 controls (mean +/- SD age = 13.7 +/- 2.10 years) were comprehensively assessed with a structured psychiatric diagnostic interview for psychopathology and SUD. The study was conducted from January 2000 through December 2004.\n\n\nRESULTS\nAmong bipolar disorder youth, those with CD were more likely to report cigarette smoking and/or SUD than youth without CD. However, CD preceding SUD or cigarette smoking did not significantly increase the subsequent risk of SUD or cigarette smoking. Adolescents with bipolar disorder and CD were significantly more likely to manifest a combined alcohol plus drug use disorder compared to subjects with bipolar disorder without CD (chi(2) = 11.99, p < .001).\n\n\nCONCLUSIONS\nWhile bipolar disorder is a risk factor for SUD and cigarette smoking in a sample of adolescents, comorbidity with preexisting CD does not increase the risk for SUD. Further follow-up of this sample through the full risk of SUD into adulthood is necessary to confirm these findings.", "corpus_id": 25880231, "score": 0 }, { "doc_id": "23345147", "title": "Further evidence of an association between adolescent bipolar disorder with smoking and substance use disorders: a controlled study.", "abstract": "Although previous work suggests that juvenile onset bipolar disorder increases risk for substance use disorders and cigarette smoking, the literature on the subject is limited. We evaluated the association of risk for substance use disorders and cigarette smoking with bipolar disorder in adolescents in a case-control study of adolescents with bipolar disorder (n=105, age 13.6+/-2.5 years [mean]; 70% male) and without bipolar disorder (\"controls\"; n=98, age 13.7+/-2.1 years; 60% male). Rates of substance use and other disorders were assessed with structured interviews (KSADS-E for subjects younger than 18, SCID for 18-year-old subjects). Bipolar disorder was associated with a significant age-adjusted risk for any substance use disorder (hazard ratio[95% confidence interval]=8.68[3.02 25.0], chi(2)=16.06, p<0.001, df=1), alcohol abuse (7.66 [2.20 26.7], chi(2)=10.2, p=0.001, df=1), drug abuse (18.5 [2.46 139.10], chi(2)=8.03, p=0.005, df=1) and dependence (12.1 [1.54 95.50], chi(2)=5.61, p=0.02, df=1), and cigarette smoking (12.3 [2.83 53.69], chi(2)=11.2, p<0.001, df=1), independently of attention deficit/hyperactivity disorder, multiple anxiety, and conduct disorder (CD). The primary predictor of substance use disorders in bipolar youth was older age (BPD-SUD versus BPD+SUD, logistic regression: chi(2)=89.37, p<0.001). Adolescent bipolar disorder is a significant risk factor for substance use disorders and cigarette smoking, independent of psychiatric comorbidity. Clinicians should carefully screen adolescents with bipolar disorder for substance and cigarette use.", "corpus_id": 23345147, "score": 1 }, { "doc_id": "35767087", "title": "Clinical characteristics of psychiatrically referred adolescent outpatients with substance use disorder.", "abstract": "OBJECTIVE\nThere is increasing interest in the developmental relationship of psychopathology and substance use disorders (SUD) in youths. Because the bulk of literature is focused in inpatient or incarcerated youths, inferences and generalizations are limited in outpatient settings. The clinical characteristics of psychiatrically referred outpatients were studied to determine whether differences existed in the nature and severity of comorbid psychiatric disorders when substance abuse was involved.\n\n\nMETHOD\nAll diagnoses were derived from structured psychiatric interviews completed on all youths on intake assessment. Adolescents with an identified SUD (n = 38) were compared with those without SUD (n = 321) on a number of variables including past and current psychopathology, cognitive and school functioning, and overall impairment.\n\n\nRESULTS\nEleven percent of referred outpatients (mean age = 15.9 +/- 1.3 years) met full criteria for a SUD by parental report. Controlling for age, adolescents with SUD had higher risk for mood and disruptive behavioral disorders compared with psychiatric controls. In the majority of cases, the onset of psychopathology preceded the onset of SUD by at least 1 year. The group with SUD also had lower overall functioning and more school dysfunction and psychiatric hospitalizations than their non-SUD peers.\n\n\nCONCLUSIONS\nDespite the small number of adolescents with SUD in this sample, these data indicate that SUD is common in outpatient psychiatry referrals. Youths with SUD appear to be at increased risk for more psychopathology and dysfunction in a number of domains.", "corpus_id": 35767087, "score": 1 }, { "doc_id": "11626011", "title": "Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study.", "abstract": "The prevalence of comorbid alcohol, other drug, and mental disorders in the US total community and institutional population was determined from 20,291 persons interviewed in the National Institute of Mental Health Epidemiologic Catchment Area Program. Estimated US population lifetime prevalence rates were 22.5% for any non-substance abuse mental disorder, 13.5% for alcohol dependence-abuse, and 6.1% for other drug dependence-abuse. Among those with a mental disorder, the odds ratio of having some addictive disorder was 2.7, with a lifetime prevalence of about 29% (including an overlapping 22% with an alcohol and 15% with another drug disorder). For those with either an alcohol or other drug disorder, the odds of having the other addictive disorder were seven times greater than in the rest of the population. Among those with an alcohol disorder, 37% had a comorbid mental disorder. The highest mental-addictive disorder comorbidity rate was found for those with drug (other than alcohol) disorders, among whom more than half (53%) were found to have a mental disorder with an odds ratio of 4.5. Individuals treated in specialty mental health and addictive disorder clinical settings have significantly higher odds of having comorbid disorders. Among the institutional settings, comorbidity of addictive and severe mental disorders was highest in the prison population, most notably with antisocial personality, schizophrenia, and bipolar disorders.", "corpus_id": 11626011, "score": 0 }, { "doc_id": "38386131", "title": "Substance abuse in bipolar disorder.", "abstract": "BACKGROUND\nHigh rates of substance abuse have been reported in the general population, with males more often affected than females. Although high rates of substance abuse have also been reported in bipolar patients, the relationship between substance abuse and bipolar disorder has not been well characterized.\n\n\nMETHODS\nSubstance abuse histories were obtained in 392 patients hospitalized for manic or mixed episodes of bipolar disorder and rates of current and lifetime abuse calculated. Analyses comparing sex, subtype (manic vs. mixed) and clinical history variables were conducted.\n\n\nRESULTS\nRates of lifetime substance abuse were high for both alcohol (48.5%) and drugs (43.9%). Nearly 60% of the cohort had a history of some lifetime substance abuse. Males had higher rates of abuse than females, but no differences in substance abuse were observed between subjects in manic and mixed bipolar states. Rates of active substance abuse were lower in older age cohorts. Subjects with a comorbid diagnosis of lifetime substance abuse had more psychiatric hospitalizations.\n\n\nCONCLUSIONS\nSubstance abuse is a major comorbidity in bipolar patients. Although rates decrease in older age groups, substance abuse is still present at clinically important rates in the elderly. Bipolar patients with comorbid substance abuse may have a more severe course. These data underscore the significance of recognition and treatment of substance abuse in bipolar disorder patients.", "corpus_id": 38386131, "score": 0 }, { "doc_id": "38763279", "title": "Substance abuse in first-episode bipolar I disorder: indications for early intervention.", "abstract": "OBJECTIVE\nThis study clarified the early characteristics of substance use disorders in patients with first-episode bipolar I disorder.\n\n\nMETHOD\nThe authors evaluated substance use disorders, associated factors, and clinical course, prospectively, in the first 2 years of DSM-IV bipolar I disorder with standardized methods.\n\n\nRESULTS\nBaseline substance use disorder was found in 33% (37 of 112) of the patients at baseline and in 39% at 24 months. Anxiety disorders were more frequent in the patients with than without substance use disorder (30% and 13%, respectively). Associations of alcohol dependence with depressive symptoms and cannabis dependence with manic symptoms were suggested. Patients using two or more substances had worse outcomes.\n\n\nCONCLUSIONS\nSince substance use disorders were frequent from the beginning of bipolar I disorder and were associated with anxiety disorders and poor outcome, early interventions for substance use disorder and anxiety might improve later outcome.", "corpus_id": 38763279, "score": 0 }, { "doc_id": "29179727", "title": "Relation between childhood disruptive behavior disorders and substance use and dependence symptoms in young adulthood: individuals with symptoms of attention-deficit/hyperactivity disorder and conduct disorder are uniquely at risk.", "abstract": "Most prior literature examining the relations among attention-deficit/hyperactivity disorder (ADHD), conduct disorder (CD), and substance use and abuse suggests that CD fully account for the ADHD-substance abuse relation. This study sought to test an alternate theory that individuals with symptoms of both ADHD and CD are at a special risk for substance abuse. Relations between childhood ADHD and CD symptoms, and young adult tobacco, alcohol, marijuana, and hard drug use and dependence symptoms, were examined in a sample of 481 young adults. ADHD and CD symptoms interacted to predict marijuana dependence symptoms and hard drug use and dependence symptoms, such that individuals with high levels of both ADHD and CD had the highest levels of these outcomes.", "corpus_id": 29179727, "score": 0 }, { "doc_id": "144638334", "title": "Is ADHD a risk factor for psychoactive substance use disorders : Findings from a four-year prospective follow-up study", "abstract": "ABSTRACT Objective To evaluate whether attention-deficit hyperactivity disorder (ADHD) is a risk factor for psychoactive substance use disorders (PSUD), attending to issues of psychiatric comorbidity, family history, and adversity. Method Using assessments from multiple domains, the authors examined 140 ADHD and 120 normal control subjects at baseline and 4 years later. Drug and alcohol abuse and dependence were operationally defined. Results No differences were detected in the rates of alcohol or drug abuse or dependence or in the rates of abuse of individual substances between the groups; both ADHD and control probands had a 15% rate of PSUD. Conduct and bipolar disorders predicted PSUD, independently of ADHD status. Family history of substance dependence and antisocial disorders was associated with PSUD in controls but less clearly so in ADHD probands. Family history of ADHD was not associated with risk for PSUD. ADHD probands had a significantly shorter time period between the onsets of abuse and dependence compared with controls (1.2 years versus 3 years, p Conclusions Adolescents with and without ADHD had a similar risk for PSUD that was mediated by conduct and bipolar disorder. Since the risk for PSUD has been shown to be elevated in adults with ADHD when compared with controls, a sharp increase in PSUD is to be expected in grown-up ADHD children during the transition from adolescence to adulthood.", "corpus_id": 144638334, "score": 0 }, { "doc_id": "27333261", "title": "Substance Use Disorder and ADHD", "abstract": "Objective: To assess the pattern of substance use disorder (SUD) in adolescents with and without history of attention - deficit / hyperactivity disorder (ADHD) using an Iranian sample in the context of a cultural background and drug availability is differing from Western countries. Method: In this case- control study, the participants were interviewed by a child psychiatrist and the measures included: kiddie Schedule for Affective Disorder and Schizophrenia for school age children (K-SADS), Opium Treatment Index (OTI) and Global Assessment Functioning (GAF). Data were analyzed with chi square test and T test and fisher exact test by EPI.6 soft ware. Results: Adolescents with ADHD were younger at the time of starting cigarette smoking, substance use, abuse and dependency (p = 0.0001), a shorter period between their first-time substance use and substance dependence or abuse (p = 0.0001), more severe substance use (for cannabis, heroine, cigarette and drugs such as benzodiazepines p < 0.05) and more functional impairment (p = 0.0007). Average number of co morbid disorders were higher in ADHD group. (p = 0.03) Conclusion: Although the pattern and type of substance use may be different in Iranian culture, our findings about the relationship between ADHD and SUD are similar to other western and non western countries. The presence of ADHD may over-ride cultural barriers and lower availability of drugs to the development of SUD in Iranian adolescents. Early diagnosis and treatment of ADHD may propose with better prognosis of SUD and subsequent decrease in the prevalence of SUD and the costs of SUD-related pathology in this population.", "corpus_id": 27333261, "score": 0 }, { "doc_id": "8376407", "title": "Substance use in a population-based clinic sample of people with first-episode psychosis", "abstract": "Background Substance use is implicated in the cause and course of psychosis. Aims To characterise substance and alcohol use in an epidemiologically representative treatment sample of people experiencing a first psychotic episode in south Cambridgeshire. Method Current and lifetime substance use was recorded for 123 consecutive referrals to a specialist early intervention service. Substance use was compared with general population prevalence estimates from the British Crime Survey. Results Substance use among people with first-episode psychosis was twice that of the general population and was more common in men than women. Cannabis abuse was reported in 51% of patients (n=62) and alcohol abuse in 43% (n=53). More than half (n=68, 55%) had used Class A drugs, and 38% (n=43) reported polysubstance abuse. Age at first use of cannabis, cocaine, ecstasy and amphetamine was significantly associated with age at first psychotic symptom. Conclusions Substance misuse is present in the majority of people with first-episode psychosis and has major implications for management. The association between age at first substance use and first psychotic symptoms has public health implications.", "corpus_id": 8376407, "score": 0 }, { "doc_id": "25181787", "title": "Demographic and clinical correlates of comorbid substance use disorders in psychosis: multivariate analyses from an epidemiological sample", "abstract": "BACKGROUND\nWhile there has been substantial research examining the correlates of comorbid substance abuse in psychotic disorders, it has been difficult to tease apart the relative importance of individual variables. Multivariate analyses are required, in which the relative contributions of risk factors to specific forms of substance misuse are examined, while taking into account the effects of other important correlates.\n\n\nMETHODS\nThis study used multivariate correlates of several forms of comorbid substance misuse in a large epidemiological sample of 852 Australians with DSM-III-R-diagnosed psychoses.\n\n\nRESULTS\nMultiple substance use was common and equally prevalent in nonaffective and affective psychoses. The most consistent correlate across the substance use disorders was male sex. Younger age groups were more likely to report the use of illegal drugs, while alcohol misuse was not associated with age. Side effects secondary to medication were associated with the misuse of cannabis and multiple substances, but not alcohol. Lower educational attainment was associated with cannabis misuse but not other forms of substance abuse.\n\n\nCONCLUSION\nThe profile of substance misuse in psychosis shows clinical and demographic gradients that can inform treatment and preventive research.", "corpus_id": 25181787, "score": 0 }, { "doc_id": "37430028", "title": "The impact of substance use disorders on clinical outcome in 643 patients with first‐episode psychosis", "abstract": "Objective:  Studies investigating the impact of comorbid substance use disorders (SUD) in psychosis have tended to focus on cross‐sectional data, with few studies examining the effects of substance use course on clinical outcome. The main aim of the present study was to assess the impact of baseline SUD and course of SUD on remission of positive symptoms.", "corpus_id": 37430028, "score": 0 }, { "doc_id": "40797738", "title": "Substance abuse and the onset of schizophrenia", "abstract": "Up to 60% of chronic schizophrenic patients are reported to abuse alcohol or drugs. This comorbidity raises the question whether one disorder is a consequence of the other. With the structured interview \"IRAOS,\" the onset and course of schizophrenia and substance abuse were retrospectively assessed in a representative first-episode sample of 232 schizophrenic patients. Information by relatives validated the patients' reports. Alcohol abuse prior to first admission was found in 24%, drug abuse in 14%-twice the rates in the general population. Alcohol abuse more often followed than preceded the first symptom of schizophrenia. Drug abuse preceded the first symptom in 27.5%, followed it in 37.9%, and emerged within the same month in 34.6% of the cases. The study demonstrates a remarkable association between first-episode schizophrenia and substance abuse, but a unidirectional causality is not supported, nor is a specific psychotic disorder in comorbid cases.", "corpus_id": 40797738, "score": 0 }, { "doc_id": "39981576", "title": "Risk of substance use disorders in adolescents with bipolar disorder.", "abstract": "OBJECTIVE\nPrevious work in adults and youths has suggested that juvenile onset bipolar disorder (BPD) is associated with an elevated risk of substance use disorders (SUD). Considering the public health importance of this issue, the authors now report on a controlled study of adolescents with and without BPD to evaluate the risk of SUD.\n\n\nMETHOD\nProbands with DSM-IV BPD (n=57, mean age +/- SD=13.3 +/- 2.4 years) and without DSM-IV BPD (n=46, 13.6 +/- 2.2 years) were studied. Structured psychiatric interviews and multiple measures of SUD were collected.\n\n\nRESULTS\nBipolar disorder was associated with a highly significant risk factor for SUD (32% versus 7%, Z=2.9, p=.004) that was not accounted for by conduct disorder (adjusted odds ratio=5.4, p=.018). Adolescent-onset BPD (> or =13 years) was associated with a higher risk of SUD compared with those with child-onset BPD (chi1=9.3, p=.002).\n\n\nCONCLUSIONS\nThese findings strongly indicate that BPD, especially adolescent onset, is a significant risk factor for SUD independently of conduct disorder.", "corpus_id": 39981576, "score": 1 }, { "doc_id": "205427113", "title": "Substance use disorders among adolescents with bipolar spectrum disorders.", "abstract": "OBJECTIVE\nWe set out to examine the prevalence and correlates of substance use disorders (SUD) in a large sample of adolescents with bipolar disorder (BP).\n\n\nMETHODS\nSubjects were 249 adolescents ages 12 to 17 years old who fulfilled DSM-IV criteria for bipolar I disorder [(BPI), n = 154], or bipolar II disorder [(BPII), n = 25], or operationalized criteria for BP not otherwise specified [(BP NOS), n = 70], via the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS). As part of the multi-site Course and Outcome of Bipolar Youth study, demographic, clinical, and family history variables were measured via intake clinical interview with the subject and a parent/guardian.\n\n\nRESULTS\nThe lifetime prevalence of SUD among adolescents with BP was 16% (40/249). Results from univariate analyses indicated that subjects with, as compared to without, SUD were significantly less likely to be living with both biological parents, and that there was significantly greater lifetime prevalence of physical abuse, sexual abuse, suicide attempts, conduct disorder, and posttraumatic stress disorder among subjects with SUD. Subjects with SUD reported significantly greater 12-month prevalence of trouble with police, and females with SUD reported significantly greater 12-month prevalence of pregnancy and abortion. Significant predictors of SUD in a logistic regression model included living with both biological parents (lower prevalence), conduct disorder and suicide attempts (increased prevalence). In logistic regression analyses controlling for demographic differences and conduct disorder, SUD remained significantly associated with trouble with police, whereas the association of SUD with pregnancy and abortion was reduced to a statistical trend. The prevalence of SUD was not significantly different among child- versus adolescent-onset BP subjects.\n\n\nCONCLUSIONS\nSUD among adolescents with BP is associated with profound hazards including suicide attempts, trouble with police, and teenage pregnancy and abortion.", "corpus_id": 205427113, "score": 0 }, { "doc_id": "29070437", "title": "Comorbid substance use disorders among youth with bipolar disorder: opportunities for early identification and prevention.", "abstract": "OBJECTIVE\nThe burden of substance use disorders (SUDs) among adults with bipolar disorder is well documented. Comparatively less is known regarding comorbid SUD among youth with bipolar disorder. This article aims to integrate the extant literature on this topic and to suggest strategies for delaying or preventing SUD among youth with bipolar disorder.\n\n\nDATA SOURCES AND STUDY SELECTION\nRelevant studies in English were identified using PubMed and MEDLINE (1950-February 2009). Search terms were bipolar disorder cross-referenced with child, adolescent, or youth, and alcohol, drug, or substance, and abuse, dependence, or disorder. Articles were selected on the basis of containing data regarding both bipolar disorder and SUD. The search was supplemented by manually reviewing reference lists from the identified publications.\n\n\nDATA SYNTHESIS\nEpidemiologic and clinical studies demonstrate that youth-onset bipolar disorder confers even greater risk of SUD in comparison with adult-onset bipolar disorder. Recent studies of youth with bipolar disorder have not identified childhood SUD (0%); however, the prevalence of SUD escalates during adolescence (16%-39%). Substance use disorder among bipolar youth is associated with legal and academic difficulties, pregnancy, and suicidality. Few studies have addressed interventions for this population, although studies are underway. Because bipolar disorder onset most commonly precedes SUD among youth (55%-83%), there is a window of opportunity for prevention.\n\n\nCONCLUSIONS\nPending the results of ongoing treatment studies, several strategies are suggested for curtailing the burden of SUD in youth with bipolar disorder. These include screening for substance use among bipolar youth beginning at age 10 irrespective of other risk factors, education and intervention at the family level, and implementation of preventive interventions that have been successful in other populations.", "corpus_id": 29070437, "score": 0 }, { "doc_id": "13777173", "title": "Cannabis involvement in individuals with bipolar disorder", "abstract": "In a study of 471 bipolar disorder (BD) cases and 1761 controls, individuals with BD were 6.8 times more likely to report a lifetime history of cannabis use. Rates of DSM-IV cannabis use disorders in those with BD were 29.4% and were independently and significantly associated with increased suicide attempts, greater likelihood of mixed episodes and greater disability attributable to BD.", "corpus_id": 13777173, "score": 0 }, { "doc_id": "11497986", "title": "Risk factors for secondary substance use disorders in people with childhood and adolescent-onset bipolar disorder: opportunities for prevention.", "abstract": "BACKGROUND\nCompared to other mental illnesses, bipolar disorder is associated with a disproportionately high rate of substance use disorders (SUDs), and the co-occurrence is associated with significant morbidity and mortality. Early diagnosis of primary bipolar disorder may provide opportunities for SUD prevention, but little is known about the risk factors for secondary SUD among individuals with bipolar disorder. The purposes of this study were to describe the population of people with childhood and adolescent-onset primary bipolar disorder, and to identify risk factors for secondary SUD in this population.\n\n\nMETHODS\nUsing data collected from the National Comorbidity Survey Replication study, we identified 158 individuals with childhood-onset (<13 years) or adolescent-onset (13-18 years) primary bipolar disorder (I, II or subthreshold). Survival analysis was used to identify risk factors for SUD.\n\n\nRESULTS\nCompared to adolescent-onset, people with childhood-onset bipolar disorder had increased likelihoods of attention deficit hyperactivity disorder (ADHD) (adjusted odds ratio=2.81) and suicide attempt (aOR=3.61). Males were more likely than females to develop SUD, and did so at a faster rate. Hazard ratios of risk factors for SUD were: lifetime oppositional defiant disorder (2.048), any lifetime anxiety disorder (3.077), adolescent-onset bipolar disorder (1.653), and suicide attempt (15.424). SUD was not predicted by bipolar disorder type, family history of bipolar disorder, hospitalization for a mood episode, ADHD or conduct disorder.\n\n\nCONCLUSIONS\nAs clinicians struggle to help individuals with bipolar disorder, this study provides information that might be useful in identifying individuals at higher risk for SUD. Future research can examine whether targeting these risk factors may help prevent secondary SUD.", "corpus_id": 11497986, "score": 1 }, { "doc_id": "2791036", "title": "Risk for substance use disorders in youths with child- and adolescent-onset bipolar disorder.", "abstract": "OBJECTIVE\nPrevious work in adults has suggested that early-onset bipolar disorder (BPD) is associated with an elevated risk for substance use disorders (SUD). To this end, the authors assessed the risk for SUD in child- versus adolescent-onset BPD with attention to comorbid psychopathology.\n\n\nMETHOD\nAll youths (aged 13-18 years) with available structured psychiatric interviews were studied systematically. From clinic subjects (N = 333), 86 subjects with DSM-III-R BPD were identified. To evaluate the risk for SUD and BPD while attending to developmental issues, the authors stratified the BPD sample into those with child-onset BPD (< or = 12 years of age, n = 50) and those with adolescent-onset BPD (13-18 years of age, n = 36).\n\n\nRESULTS\nIn mid-adolescence, youths with adolescent-onset BPD were at significantly increased risk for SUD relative to those with child-onset BPD (39% versus 8%; p = .001). Compared with those with child-onset BPD, those with adolescent-onset BPD had 8.8 times the risk for SUD (95% confidence interval = 2.2-34.7; chi 7(2) = 9.7, p = .002). The presence of conduct disorder or other comorbid psychopathology within BPD did not account for the risk for SUD.\n\n\nCONCLUSIONS\nAdolescent-onset BPD is associated with a much higher risk for SUD than child-onset BPD, which was not accounted for by conduct disorder or other comorbid psychopathology. Youths with adolescent-onset BPD should be monitored and educated about SUD risk. The identification and treatment of manic symptomatology may offer therapeutic opportunities to decrease the risk for SUD in these high-risk youths.", "corpus_id": 2791036, "score": 1 }, { "doc_id": "31082359", "title": "Substance use disorders and suicide attempts in bipolar subtypes.", "abstract": "Bipolar disorder (BD) is associated with high rates of suicide attempt and completion. Substance use disorders (SUD) have been identified as potent risk factors for suicidal behavior in BD. However, little is known concerning differences between BD subtypes with regard to SUD as a risk factor for suicidal behavior. We studied previous suicidal behavior in adults with a major depressive episode in context of BD type I (BD-I; N=96) or BD type II (BD-II; N=42), with and without history of SUD. Logistic regressions assessed the association between SUD and suicide attempt history by BD type, and exploratory analyses examined the effects of other clinical characteristics on these relationships. SUD were associated with suicide attempt in BD-I but not BD-II, an effect not attributable to sample size differences. The higher suicide attempt rate associated with alcoholism in BD-I was mostly explained by higher aggression scores, and earlier age of BD onset increased the likelihood that alcohol use disorder would be associated with suicide attempt(s). The higher suicide attempt rate associated with other drug use disorders in BD-I was collectively explained by higher impulsivity, hostility, and aggression scores. The presence of both alcohol and drug use disorders increased odds of a history of suicide attempt in a multiplicative fashion: 97% of BD-I who had both co-morbid drug and alcohol use disorders had made a suicide attempt. A critical next question is how to target SUD and aggressive traits for prevention of suicidal behavior in BD-I.", "corpus_id": 31082359, "score": 0 }, { "doc_id": "32140119", "title": "Does recovery from substance use disorder matter in patients with bipolar disorder?", "abstract": "OBJECTIVE\nTo examine the potential impact of recovery from substance use disorder (SUD) on the course of bipolar disorder among patients diagnosed with both bipolar and substance use disorders according to DSM-IV criteria.\n\n\nMETHOD\nAs part of the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), we examined bipolar disorder status (i.e., whether the patient is recovering or recovered), role functioning, and quality of life in the first 1000 patients to enter the STEP-BD study. We compared patients with no history of SUD, current SUD, and past SUD (i.e., lifetime SUD, but no current SUD) on these parameters. Data were collected between November 1999 and April 2001.\n\n\nRESULTS\nA current clinical status of recovering or recovered from bipolar disorder was less likely among patients with current or past SUD compared to patients with no SUD (p < .002). Recovering/recovered status did not differ significantly between patients with current SUD versus past SUD. All 3 groups differed significantly on measures of role functioning as assessed by the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT), with poorest role functioning among patients with current SUD, followed by patients with past SUD (p = .0002). Patients with current or past SUD reported significantly lower quality of life as measured by the LIFE-RIFT and the Quality of Life Enjoyment and Satisfaction Questionnaire and more lifetime suicide attempts (p < .001) than patients without an SUD; patients with past versus current SUD did not differ significantly on these measures.\n\n\nCONCLUSION\nThe results suggest that patients with bipolar disorder who experience sustained remission from an SUD fare better than patients with current SUD, but not as well as subjects with no history of SUD; differences among the 3 groups appear greatest in the area of role functioning.", "corpus_id": 32140119, "score": 0 }, { "doc_id": "38617806", "title": "Clinicians’ assessments of bipolar disorder and substance abuse as predictors of suicidal behavior in acutely hospitalized psychiatric inpatients", "abstract": "BACKGROUND\nSuicide is a major risk for those with bipolar disorder, a risk amplified by comorbid substance abuse in some, but not all, previous studies. To further explore the relationships of substance abuse, suicide, and bipolarity as they present in clinical practice, we analyzed standardized clinical data from a large acute psychiatric inpatient service.\n\n\nMETHODS\nStandardized clinical evaluations of 7819 patients with diagnoses of bipolar depression (n=990), bipolar mania (n=948), unipolar depressive episode (n=3626), or schizophrenia-schizoaffective disorders (n=2255) were analyzed to evaluate the relationship between current substance-use problems, substance-induced symptoms, and a current suicide crisis, as well as lifetime suicide attempts, with logistic regressions adjusting for age, gender, and ethnicity.\n\n\nRESULTS\nAcross the combined groups, current substance-use problems were significantly associated with a lifetime suicide attempt (odds ratios [ORs] 1.6-2.5) and to a lesser degree to the admission suicide crisis (ORs 1-2.2). Among bipolar (depressed/manic) patients, but not other diagnostic groups, those with both current substance-use problems and substance-induced symptoms had even higher rates of a recent suicide crisis (ORs 1.5-3.1) and of a lifetime attempt (ORs 2.5-3.4).\n\n\nCONCLUSIONS\nIn bipolar patients, substance use disorder doubled and substance use disorder plus substance-induced symptoms tripled the suicidal risk. Implications for future research are discussed.", "corpus_id": 38617806, "score": 0 }, { "doc_id": "36414281", "title": "Suicide risk in bipolar patients: the role of co-morbid substance use disorders.", "abstract": "OBJECTIVE\nBipolar disorder is associated with a high frequency of both completed suicides and suicide attempts. The primary aim of this study was to identify clinical predictors of suicide attempts in subjects with bipolar disorder.\n\n\nMETHODS\nWe studied 336 subjects with a diagnosis of bipolar I, bipolar II, or schizoaffective disorder (bipolar type). The Structured Clinical Interview for DSM-IV (SCID-I) was administered and subsequently two expert psychiatrists established a diagnosis. Predictors of suicide attempts were examined in attempters and non-attempters.\n\n\nRESULTS\nThe lifetime rate of suicide attempts for the entire sample was 25.6%. A lifetime co-morbid substance use disorder was a significant predictor of suicide attempts: bipolar subjects with co-morbid substance use disorders (SUD) had a 39.5% lifetime rate of attempted suicide, while those without had a 23.8% rate (odds ratio = 2.09, 95% CI = 1.03-4.21, chi2 = 4.33, df = 1, p = 0.037).\n\n\nCONCLUSIONS\nLifetime co-morbid SUD were associated with a higher rate of suicide attempts in patients with bipolar disorder. This relationship may have a genetic origin and/or be explained by severity of illness and trait impulsivity.", "corpus_id": 36414281, "score": 0 }, { "doc_id": "30842638", "title": "Attempted suicide and alcoholism in bipolar disorder: clinical and familial relationships.", "abstract": "OBJECTIVE\nThis study examined the clinical and familial relationships between comorbid alcoholism and attempted suicide in affectively ill relatives of probands with bipolar I disorder.\n\n\nMETHOD\nIn 71 families ascertained for a genetic linkage study, 337 subjects with major affective disorder were assessed by using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version.\n\n\nRESULTS\nSubjects with bipolar disorder and alcoholism had a 38.4% lifetime rate of attempted suicide, whereas those without alcoholism had a 21.7% rate. Attempted suicide among subjects with bipolar disorder and alcoholism clustered in a subset of seven families. Families with alcoholic and suicidal probands had a 40.7% rate of attempted suicide in first-degree relatives with bipolar disorder, whereas other families had a 19.0% rate.\n\n\nCONCLUSIONS\nComorbid alcoholism was associated with a higher rate of attempted suicide among family members with bipolar disorder. Attempted suicide and alcoholism clustered in a subset of families. These relationships may have a genetic origin and may be mediated by intoxication, mixed states, and/or temperamental instability.", "corpus_id": 30842638, "score": 0 }, { "doc_id": "20838907", "title": "Twelve-month outcome of adolescents with bipolar disorder following first hospitalization for a manic or mixed episode.", "abstract": "OBJECTIVE\nAlthough adolescent-onset bipolar disorder is associated with significant morbidity, there have been few prospective outcome studies of this population. The aim of this study was to examine the 12-month outcome of bipolar adolescents following an initial hospitalization for a manic or mixed episode.\n\n\nMETHOD\nBipolar adolescents (N=71) were recruited during their first hospitalization for a manic or mixed episode and were evaluated using diagnostic, symptomatic, and functional assessments. Patients were also evaluated at 1, 4, 8, and 12 months after hospitalization to assess syndromic, symptomatic, and functional outcomes. Predictors of each type of outcome were identified.\n\n\nRESULTS\nKaplan-Meier estimates of the cumulative probabilities of syndromal, symptomatic, and functional recovery and syndromic recurrence during the first 12 months following initial hospitalization were 0.86, 0.43, 0.41, and 0.54, respectively. Only 35% of bipolar adolescents reported full medication adherence. Individual predictors of poor syndromic recovery included co-occurring attention deficit hyperactivity disorder (ADHD), anxiety disorders, and disruptive behavior disorders as well as nonadherence to psychotropic medication and lower socioeconomic levels. Co-occurring alcohol use disorders, treatment with antidepressants, and the absence of psychotherapeutic intervention predicted syndromic recurrence. Boys were more than twice as likely as girls to experience symptomatic recovery.\n\n\nCONCLUSIONS\nMost bipolar adolescents experienced syndromic recovery following their first hospitalization. However, rates of symptomatic and functional recoveries were much lower. Future studies examining effective pharmacological and nonpharmacological treatment strategies for bipolar youth with co-occurring disorders and investigating factors that contribute to the development of substance use disorders and treatment adherence in bipolar youth are necessary to improve outcome.", "corpus_id": 20838907, "score": 0 }, { "doc_id": "30732509", "title": "Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).", "abstract": "OBJECTIVE\nBipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined. The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder.\n\n\nMETHOD\nSubjects (N=3,750) with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were followed prospectively for up to 2 years. Prospectively observed depressive episodes were identified for this analysis. Subjects with a past or current drug or alcohol use disorder were compared with those with no history of drug or alcohol use disorders on time to recovery from depression and time until switch to a manic, hypomanic, or mixed episode.\n\n\nRESULTS\nDuring follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state.\n\n\nCONCLUSIONS\nCurrent or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study.", "corpus_id": 30732509, "score": 0 }, { "doc_id": "19613690", "title": "Clinical features, response to treatment and functional outcome of bipolar disorder patients with and without co-occurring substance use disorder: 1-year follow-up.", "abstract": "INTRODUCTION\nBipolar disorder patients (BP) with comorbid Substance Use Disorder (SUD) may present clinical features that could compromise adherence and response to pharmacological treatment. The purpose of this study was to examine clinical and psychopathological features of BP with and without comorbid SUD in a real-world setting.\n\n\nMETHODS\nThe sample was composed by 131 affective patients. Sixty-five patients were affected by Bipolar Disorder I (BP-I, 49.2%), 29 by Bipolar Disorder II (BP-II, 22.3%) and 37 by Cyclothymic Disorder (CtD, 28.5%), according to DSM-IV. Sixty-six patients were diagnosed for a comorbid SUD. All patients have been submitted to psychometric assessment with Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), Young Mania Rating Scale (YMRS), Global Assessment Scale (GAS), Social Adjustment Self-reported Scale (SASS), Quality of Life Scale (QoL), at baseline and repeated follow-up periods (1, 3, 6, 12 months).\n\n\nRESULTS\nBP comorbid for SUD were more likely diagnosed as BP-II and CtD and were less likely to present a moderate-severe manic symptomatology. Furthermore, personality disorders were more frequent in SUD patients than in non-comorbid BP. BP with SUD were not different for primary outcome measure (HDRS, HARS, YMRS, GAS) from non-comorbid BP; however, BP with SUD were significantly more impaired in social functioning (SASS) at any stage of the follow-up and poor functioning increased the risk of relapse in substance use during treatment. Finally, SUD comorbidity did not represent a risk factor for treatment drop-out, while in our sample young age, low treatment dosage and BP-I diagnosis were significantly associated with drop-out.\n\n\nDISCUSSION\nThe primary finding of this work is that BP with comorbid SUD are significantly more compromised in social functioning. Second, these patients were less likely to be diagnosed for BP-I and to present a severe manic symptomatology. Finally, we found that the diagnosis of SUD, but young age, low treatment dosage and BP-I diagnosis to be risk factors for treatment drop-out. Physicians should be alert to these differences in their clinical practice.", "corpus_id": 19613690, "score": 0 }, { "doc_id": "28280305", "title": "Presence of co-morbid substance use disorder in bipolar patients worsens their social functioning to the level observed in patients with schizophrenia", "abstract": "Bipolar disorder has been considered to have a better prognosis than schizophrenia at the very beginning of its definition. However, psychosocial functioning may vary not only because of the characteristics of the disorder, but also of co-morbid conditions, especially regarding substance use disorder (SUD). The purpose of this study was to compare the social adjustment level of patients with bipolar disorder with that observed in patients with schizophrenia, taking into account substance use disorder (SUD). Forty subjects with schizophrenia and 40 subjects with bipolar disorder, in the stable phase of the disorder, were matched for age, gender and presence of SUD (DSM-IV criteria). The social adjustment scale was completed with socio-demographic and clinical characteristics of illness. The global adaptation score of bipolar patients with SUD was poorer than bipolar patients without SUD, but was not observed as being significantly different from that of patients with schizophrenia, with or without associated SUD. Suicide attempts, poor compliance, longer hospitalisation, shorter remissions and criminal activity were also more frequently observed in the group of patients with bipolar disorder and SUD. Presence of substance use disorder seems to have a greater weight than the main diagnostic (schizophrenia versus bipolar disorder) to predict worse social adjustment and poorer outcome.", "corpus_id": 28280305, "score": 0 }, { "doc_id": "46273574", "title": "HIV risk behavior among patients with co-occurring bipolar and substance use disorders: associations with mania and drug abuse.", "abstract": "BACKGROUND\nBipolar and substance use disorders frequently co-occur, and both are associated with impulsivity, impaired judgment, and risk-taking.\n\n\nOBJECTIVES\nThis study aimed to: (1) describe the rates of HIV sexual and drug risk behaviors among patients with co-occurring bipolar and substance use disorders, (2) test whether acute mania, psychiatric severity, and drug severity independently predict HIV risk, and (3) examine the relationship between specific substance dependencies and sexual risk behaviors.\n\n\nMETHOD\nParticipants (N=101) were assessed for psychiatric diagnoses, substance abuse, and HIV risk behavior using structured clinical interviews and self-report questionnaires.\n\n\nRESULTS\nThe majority (75%) were sexually active in the past 6 months and reported high rates of sexual risk behaviors, including unprotected intercourse (69%), multiple partners (39%), sex with prostitutes (24%, men only), and sex trading (10%). In a multivariate linear regression model, recent manic episode, lower psychiatric severity, and greater drug severity were independent predictors of total HIV risk. Cocaine dependence was associated with increased risk of sex trading.\n\n\nCONCLUSIONS\nResults underscore the importance of HIV prevention for this population.", "corpus_id": 46273574, "score": 0 }, { "doc_id": "205428222", "title": "Cigarette smoking and its relationship to mood disorder symptoms and co‐occurring alcohol and cannabis use disorders following first hospitalization for bipolar disorder", "abstract": "Heffner JL, DelBello MP, Anthenelli RM, Fleck DE, Adler CM, Strakowski SM. Cigarette smoking and its relationship to mood disorder symptoms and co‐occurring alcohol and cannabis use disorders following first hospitalization for bipolar disorder. Bipolar Disord 2012: 14: 99–108. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S.", "corpus_id": 205428222, "score": 0 }, { "doc_id": "11828246", "title": "Effects of co-occurring alcohol abuse on the course of bipolar disorder following a first hospitalization for mania.", "abstract": "CONTEXT\nAlcohol-use disorders are common co-occurring conditions affecting bipolar patients, and this co-occurrence is negatively associated with outcome.\n\n\nOBJECTIVE\nThe primary goal of this study was to identify how the relative onsets of alcohol-use and bipolar disorders affect the subsequent courses of illness in patients with both conditions.\n\n\nDESIGN AND SETTING\nInception cohort at an academic medical center.\n\n\nPATIENTS\nPatients meeting criteria for type I bipolar disorder, manic or mixed, with ages of 12 to 45 years, no prior hospitalizations, and minimal prior treatment. We enrolled 144 subjects who were followed up for up to 5 years, including 27 subjects in whom the onset of an alcohol-use disorder preceded the onset of bipolar disorder (Alcohol First), 33 subjects in whom bipolar disorder onset preceded or was concurrent with the onset of alcohol abuse (Bipolar First), and 83 subjects with bipolar disorder only (No Alcohol).\n\n\nMAIN OUTCOME MEASURES\nSymptomatic recovery and recurrence of both conditions and percentage of follow-up with affective episodes and affective and alcohol-use disorder symptoms.\n\n\nRESULTS\nThe Alcohol First group was older and more likely to recover and recover more quickly than the other groups. Affective symptomatic recurrence curves were similar among groups. The Bipolar First group spent more time with affective episodes and symptoms of an alcohol-use disorder during follow-up than the Alcohol First group. Hospitalization was associated with a period of decreased alcohol abuse, although recurrence of the alcohol-use disorder was common.\n\n\nCONCLUSIONS\nThe relative age at onset of alcohol-use and bipolar disorders is associated with differences in the course of both conditions. A first hospitalization for mania is associated with a period of recovery from comorbid alcohol abuse, suggesting this posthospital time may provide an opportunity to treat this co-occurring condition.", "corpus_id": 11828246, "score": 0 }, { "doc_id": "24971153", "title": "Effects of co-occurring cannabis use disorders on the course of bipolar disorder after a first hospitalization for mania.", "abstract": "CONTEXT\nCannabis use disorders commonly co-occur in bipolar disorder; however, the effects of cannabis abuse on outcome have been minimally studied.\n\n\nOBJECTIVE\nTo identify how the sequence of the onsets of a cannabis use disorder and bipolar disorder is associated with the subsequent course of each condition.\n\n\nDESIGN\nInception cohort.\n\n\nSETTING\nAcademic medical center.\n\n\nPATIENTS\nPatients (N = 144) were studied who met criteria for bipolar I disorder (manic or mixed), were 12 to 45 years old, and had no previous hospitalizations and minimal previous treatment. Patients were followed up for up to 5 years and included 33 in whom the onset of a cannabis use disorder preceded the onset of bipolar disorder (cannabis first), 36 in whom bipolar disorder onset preceded the onset of cannabis abuse (bipolar first), and 75 with bipolar disorder only.\n\n\nMAIN OUTCOME MEASURES\nSymptomatic recovery and recurrence of both conditions and percentage of follow-up time with affective and cannabis use disorder symptoms.\n\n\nRESULTS\nThe cannabis first group exhibited better recovery than the other groups, although when adjusted for potential mediator variables these results did not persist. Cannabis use was associated with more time in affective episodes and with rapid cycling. Most cannabis use disorders remitted immediately after hospitalization, followed by rapid rates of recurrence.\n\n\nCONCLUSIONS\nThe effects of the sequence of onsets of bipolar and cannabis use disorders were less pronounced than observed in co-occurring alcohol and bipolar disorders. Aggressive drug abuse treatment immediately after a first psychiatric hospitalization might decrease rates of recurrence and new cases of cannabis use disorder in the course of bipolar disorder.", "corpus_id": 24971153, "score": 0 }, { "doc_id": "45709088", "title": "The Fifth Edition of the Addiction Severity Index.", "abstract": "The Addiction Severity Index (ASI) is 12 years old and has been revised to include a new section on family history of alcohol, drug, and psychiatric problems. New items were added in existing sections to assess route of drug administration; additional illegal activities; emotional, physical, and sexual abuse; quality of the recovery environment; and history of close personal relationships. No changes were made in the composite scoring to maintain comparability with previous editions. This article discusses the clinical and research uses of the ASI over the past 12 years, emphasizing some special circumstances that affect its administration. The article then describes the rationale for and description of the changes made in the ASI. The final section provides \"normative data\" on the composite scores and severity ratings for samples of opiate, alcohol, and cocaine abusers as well as drug abusing inmates, pregnant women, homeless men, and psychiatrically ill substance abusers.", "corpus_id": 45709088, "score": 0 }, { "doc_id": "40187001", "title": "Best estimate of lifetime psychiatric diagnosis: a methodological study.", "abstract": "It is important for genetic, epidemiologic, and nosological studies to determine accurate rates of lifetime psychiatric diagnoses in patient and nonpatient populations. As part of a case-control family study of major depression, lifetime psychiatric diagnoses were made for 1,878 individuals. Sources of information used in making diagnostic estimates included direct interview, medical records, and family history data systematically obtained from relatives. Diagnostic estimates were made by trained interviewers, experienced clinicians, and by computer program. The results indicate that it is possible to make lifetime best estimate diagnoses reliably among both interviewed and noninterviewed individuals for most diagnostic categories and that diagnoses based on interview data alone are an adequate substitute for best estimate diagnoses based on all available information in a limited number of diagnostic categories.", "corpus_id": 40187001, "score": 0 }, { "doc_id": "45442606", "title": "Predictors of first-onset substance use disorders during the prospective course of bipolar spectrum disorders in adolescents.", "abstract": "OBJECTIVE\nSubstance use disorders (SUD) are common and problematic in bipolar disorder (BP). We prospectively examined predictors of first-onset SUD among adolescents with BP.\n\n\nMETHOD\nAdolescents (12-17 years old; N = 167) in the Course and Outcome of Bipolar Youth (COBY) study fulfilling criteria for BP-I, BP-II, or operationalized BP not otherwise specified, without SUD at intake, were included. Baseline demographic, clinical, and family history variables, and clinical variables assessed during follow-up, were examined in relation to first-onset SUD. Participants were prospectively interviewed every 38.5 ± 22.2 weeks for an average of 4.25 ± 2.11 years.\n\n\nRESULTS\nFirst-onset SUD developed among 32% of subjects, after a mean of 2.7 ± 2.0 years from intake. Lifetime alcohol experimentation at intake most robustly predicted first-onset SUD. Lifetime oppositional defiant disorder and panic disorder, family history of SUD, low family cohesiveness, and absence of antidepressant treatment at intake were also associated with increased risk of SUD, whereas BP subtype was not. Risk of SUD increased with increasing number of these 6 predictors: 54.7% of subjects with 3 or more predictors developed SUD vs. 14.1% of those with fewer than 3 predictors (hazard ratio = 5.41 95% confidence interval = 2.7-11.0 p < .0001). Greater hypo/manic symptom severity in the preceding 12 weeks predicted greater likelihood of SUD onset. Lithium exposure in the preceding 12 weeks predicted lower likelihood of SUD.\n\n\nCONCLUSIONS\nThis study identifies several predictors of first-onset SUD in the COBY sample that, if replicated, may suggest targets for preventive interventions for SUD among youth with BP. Treatment-related findings are inconclusive and must be interpreted tentatively, given the limitations of observational naturalistic treatment data. There is a substantial window of opportunity between BP and SUD onset during which preventive strategies may be used.", "corpus_id": 45442606, "score": 0 }, { "doc_id": "25143728", "title": "Adolescent substance use disorder during the early stages of bipolar disorder: a prospective high-risk study.", "abstract": "BACKGROUND\nThere is a paucity of longitudinal data characterizing the relationship between substance use disorder (SUD) and the early clinical course of bipolar disorder (BD). We studied this relationship in a prospectively assessed cohort of high-risk offspring.\n\n\nMETHODS\nEligible families had one parent with confirmed BD based on SADS-L interviews and best estimate diagnostic procedure. Offspring completed KSADS-PL interviews at baseline and were reassessed prospectively. DSM-IV diagnoses were made on blind consensus review using all available information. This analysis included 211 offspring ≥12 years, and used GEE and linear mixed models to determine clinical characteristics differentiating those with compared to those without SUD, and CPH models to assess the relationship between SUD and the early stages of BD.\n\n\nRESULTS\nLifetime SUD was diagnosed in 24% of offspring; cannabis use being most common. The peak hazard of SUD was between 14 and 20 years of age. Male sex (HR 3.285; p=.0007), a prior mood disorder (HR 2.437; p=.0091) and parental history of SUD (HR 2.999; p=.0027) contributed to the risk of SUD in the offspring, while SUD predicted an increased risk of psychosis (HR 3.225; p=.0074). The estimated hazard of a major mood disorder in those offspring with compared to those without a prior SUD was almost 3-fold (HR 2.990 (p≤0.01).\n\n\nLIMITATIONS\nThe novel clinical staging model requires independent replication.\n\n\nCONCLUSIONS\nSUD is a common comorbidity arising during the early course of BD, even before the first activated episode. Further research is needed to understand causative factors and to develop effective early intervention and prevention strategies.", "corpus_id": 25143728, "score": 0 }, { "doc_id": "35462330", "title": "Post-traumatic stress disorder, depression and suicidality in inpatients with substance use disorders.", "abstract": "INTRODUCTION AND AIMS\nThe international literature suggests that traumatic events are common for patients with substance use disorders (SUDs), and are often associated with the development of post-traumatic stress disorder (PTSD) and other psychiatric comorbidities. However, limited research has been conducted among Australian SUD patients. The aim of the present study was to examine the prevalence of these disorders in a group of Australian patients admitted for detoxification.\n\n\nDESIGN AND METHODS\nData were collected from 253 inpatients using a modified version of the Composite International Diagnostic Interview, the 10-item Trauma Screening Questionnaire, the Zung Self-rating Depression Scale and questions from the PsyCheck.\n\n\nRESULTS\nApproximately 20% of inpatients experienced moderate to severe depressive symptoms, and 37% had a lifetime history of self-harm or attempted suicide. Approximately 80% of patients had experienced at least one traumatic event, most experiencing multiple traumas. The mean age of first trauma was 14years. Almost 45% of patients screened positive for current PTSD symptoms. Women were nine times more likely to have been raped and five times more likely to have been sexually molested than men. PTSD symptoms were associated with greater trauma exposure, younger age of first trauma, specific trauma types, moderate to severe depressive symptoms and a history of self-harm or attempted suicide. Despite their difficulties, patients with PTSD symptoms had high rates of retention in treatment.\n\n\nDISCUSSION AND CONCLUSIONS\nPatients entering treatment for SUDs should be assessed for PTSD, depression and suicidality. These conditions impact significantly on treatment outcomes, and require the development of appropriate treatment strategies.", "corpus_id": 35462330, "score": 0 }, { "doc_id": "23370866", "title": "Childhood trauma among individuals with co-morbid substance use and post traumatic stress disorder.", "abstract": "BACKGROUND: Little is known about the impact of childhood trauma (CT) on the clinical profile of individuals with co-occurring substance use disorder (SUD) and post traumatic stress disorder (PTSD). AIMS: To compare the clinical characteristics of individuals with SUD+PTSD who have a history of CT with SUD+PTSD individuals who have experienced trauma during adulthood only. METHOD: Data were collected on 103 individuals as part of a randomised controlled trial examining the efficacy of an integrated psychosocial treatment for SUD+PTSD. Participants were recruited from substance use treatment services, community referrals and advertising. Data were collected on demographic characteristics, substance use and treatment histories, lifetime trauma exposure, and current physical and mental health functioning. RESULTS: The vast majority (77%) of the sample had experienced at least one trauma before the age of 16, with 55% of those endorsing childhood sexual abuse. As expected individuals with a CT history, as compared to without, evidenced significantly longer duration of PTSD. Those with a CT history also had more extensive lifetime trauma exposure, an earlier age of first intoxication, and reported more severe substance use (e.g., a greater number of drug classes used in their lifetime, higher severity of dependence scores and greater number of drug treatment episodes). CONCLUSION: Individuals with co-morbid SUD+PTSD who have experienced CT present with a more severe and chronic clinical profile in relation to a number of trauma and substance use characteristics, when compared to individuals with adulthood only trauma histories. It is therefore important for SUD+PTSD treatment planning that CT be carefully assessed.", "corpus_id": 23370866, "score": 0 }, { "doc_id": "205427311", "title": "Posttraumatic stress disorder and substance use disorder in adolescent bipolar disorder.", "abstract": "OBJECTIVE\nAnxiety disorders such as posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are increasingly recognized as comorbid disorders in children with bipolar disorder (BPD). This study explores the relationship between BPD, PTSD, and SUD in a cohort of BPD and non-BPD adolescents.\n\n\nMETHODS\nWe studied 105 adolescents with BPD and 98 non-mood-disordered adolescent controls. Psychiatric assessments were made using the Kiddie Schedule for Affective Disorders and Schizophrenia-Epidemiologic Version (KSADS-E), or Structured Clinical Interview for DSM-IV (SCID) if 18 years or older. SUD was assessed by KSADS Substance Use module for subjects under 18 years, or SCID module for SUD if age 18 or older.\n\n\nRESULTS\nNine (8%) BPD subjects endorsed PTSD and nine (8%) BPD subjects endorsed subthreshold PTSD compared to one (1%) control subject endorsing full PTSD and two (2%) controls endorsing subthreshold PTSD. Within BPD subjects endorsing PTSD, seven (39%) met criteria for SUD. Significantly more SUD was reported with full PTSD than with subthreshold PTSD (chi(2) = 5.58, p = 0.02) or no PTSD (chi(2) = 6.45, p = 0.01). Within SUD, the order of onset was BPD, PTSD, and SUD in three cases, while in two cases the order was PTSD, BPD, SUD. The remaining two cases experienced coincident onset of BPD and SUD, which then led to trauma, after which they developed PTSD and worsening SUD.\n\n\nCONCLUSION\nAn increased rate of PTSD was found in adolescents with BPD. Subjects with both PTSD and BPD developed significantly more subsequent SUD, with BPD, PTSD, then SUD being the most common order of onset. Follow-up studies need to be conducted to elucidate the course and causal relationship of BPD, PTSD and SUD.", "corpus_id": 205427311, "score": 0 }, { "doc_id": "31463419", "title": "Reasons for substance use among people with psychotic disorders: method triangulation approach.", "abstract": "Substance use disorders (SUD) are common among people with psychotic disorders and are associated with many negative consequences. Understanding the reasons for substance use in this population may allow for the development of more effective prevention and intervention strategies. We examined reasons for tobacco, alcohol, or cannabis use among people with psychotic disorders. Sixty-four participants with a diagnosed psychotic disorder completed a self-report reasons for use questionnaire. A subset of eight participants completed semi-structured qualitative interviews. Both the qualitative and quantitative data indicated that reasons for use of tobacco, alcohol, and cannabis differed considerably. Tobacco was primarily used for coping motives, alcohol for social motives, and cannabis for pleasure enhancement motives. Prevention and intervention strategies targeting coexisting psychotic disorders and SUD may improve in effectiveness if they address the perceived beneficial effects of tobacco use, the strong social pressures influencing alcohol use and if they encourage cannabis users to seek alternative pleasurable activities.", "corpus_id": 31463419, "score": 0 }, { "doc_id": "30508524", "title": "Do treatment improvements in PTSD severity affect substance use outcomes? A secondary analysis from a randomized clinical trial in NIDA's Clinical Trials Network.", "abstract": "OBJECTIVE\nThe purpose of the analysis was to examine the temporal course of improvement in symptoms of posttraumatic stress disorder (PTSD) and substance use disorder among women in outpatient substance abuse treatment.\n\n\nMETHOD\nParticipants were 353 women randomly assigned to 12 sessions of either trauma-focused or health education group treatment. PTSD and substance use assessments were conducted during treatment and posttreatment at 1 week and after 3, 6, and 12 months. A continuous Markov model was fit on four defined response categories (nonresponse, substance use response, PTSD response, or global response [improvement in both PTSD and substance use]) to investigate the temporal association between improvement in PTSD and substance use symptom severity during the study's treatment phase. A generalized linear model was applied to test this relationship over the follow-up period.\n\n\nRESULTS\nSubjects exhibiting nonresponse, substance use response, or global response tended to maintain original classification; subjects exhibiting PTSD response were significantly more likely to transition to global response over time, indicating maintained PTSD improvement was associated with subsequent substance use improvement. Trauma-focused treatment was significantly more effective than health education in achieving substance use improvement, but only among those who were heavy substance users at baseline and had achieved significant PTSD reductions.\n\n\nCONCLUSIONS\nPTSD severity reductions were more likely to be associated with substance use improvement, with minimal evidence of substance use symptom reduction improving PTSD symptoms. Results support the self-medication model of coping with PTSD symptoms and an empirical basis for integrated interventions for improved substance use outcomes in patients with severe symptoms.", "corpus_id": 30508524, "score": 0 }, { "doc_id": "33031278", "title": "The spectrum of substance abuse in bipolar disorder: reasons for use, sensation seeking and substance sensitivity.", "abstract": "OBJECTIVES\nTo examine the spectrum of alcohol and substance abuse, including reasons for use, in patients with bipolar I disorder, compared with patients with substance use disorder and healthy controls, with a specific focus on the relationship between substance use, substance sensitivity, other comorbid psychiatric symptoms and traits related to sensation seeking.\n\n\nMETHODS\nThis study included 104 patients with bipolar I disorder (BPD I), of whom 57 (54.8%) met DSM-IV criteria for lifetime alcohol or substance use disorder (BPD + SUD), 35 patients with substance use disorder (SUD) and no psychiatric disorder and 50 healthy controls. Assessments included the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) and the Structured Clinical Interview for the Spectrum of Substance Use (SCI-SUBS).\n\n\nRESULTS\nPatients with BPD + SUD and SUD had significantly higher scores on the SCI-SUBS domains of self-medication, substance sensitivity and sensation seeking compared with patients with BPD and healthy controls. Reasons for substance use did not differ between patients with BPD + SUD and patients with SUD. Those most frequently cited were: improving mood; relieving tension; alleviating boredom; achieving/maintaining euphoria; and increasing energy.\n\n\nCONCLUSIONS\nRecourse to substances is associated with increased mood and anxiety symptoms, substance sensitivity, and sensation seeking among patients with BPD + SUD and SUD. Substance sensitivity and sensation seeking traits should be investigated in all patients with BPD as possible factors associated with a development of SUD, in order to warn patients of the specific risks related to improper use of medications and substances.", "corpus_id": 33031278, "score": 0 }, { "doc_id": "38012572", "title": "Reasons for substance use among adolescents with bipolar disorder.", "abstract": "We examined whether children and adolescents with bipolar disorder (BPD) \"self-medicate\" with cigarettes, alcohol, or other substances of abuse. One hundred and five adolescents with BPD and 98 controls were comprehensively assessed with a structured psychiatric diagnostic interview for psychopathology and the Drug Use Screening Inventory (DUSI) for self-medication. Thirteen control (mean ± standard deviation [SD]= 15.31 ± 1.18 years) and 27 BPD (15.30 ± 2.09 years) subjects endorsed use of one of the listed drugs in the DUSI Section A within the past year and were included in all analyses. BPD adolescents were more likely than nonmood disordered, substance-using controls to report starting to use their preferred drug for mood-altering effects. There were no differences between groups in motivation for use with respect to starting substances to sleep better or get high, or in continuing substances to change mood, sleep better, or get high. These data may contribute to increased prevention of substance use disorders and to the treatment of adolescent BPD. Further studies clarifying the characteristics of self-medication are necessary.", "corpus_id": 38012572, "score": 0 }, { "doc_id": "37016938", "title": "Impulsivity: a link between bipolar disorder and substance abuse.", "abstract": "BACKGROUND\nSubstance abuse is present in most patients with bipolar disorder and associated with poor treatment outcome and increased risk of suicide. Increased impulsivity may be a link between bipolar disorder and substance abuse.\n\n\nMETHODS\nFirst, we compared impulsivity as a stable trait (Barratt Impulsiveness Scale, BIS) and as state-dependent behavioral laboratory performance (Immediate Memory-Delayed Memory task, derived from the Continuous Performance Task) in interepisode bipolar and non-bipolar subjects with and without substance abuse. Secondly, we compared impulsivity in interepisode and manic bipolar subjects with and without substance abuse.\n\n\nRESULTS\nThe BIS scores were increased in interepisode bipolar disorder and in subjects with histories of substance abuse, and were increased further in interepisode bipolar subjects with substance abuse. Performance impulsivity was increased in subjects with substance abuse, regardless of whether they had bipolar disorder. Among subjects with bipolar disorder, after correction for age, BIS scores were increased in those with substance abuse. Performance impulsivity was increased in manic compared with interepisode subjects, regardless of substance abuse history, and was increased in interepisode subjects with substance abuse similarly to manic subjects without substance abuse. These differences could not be accounted for by age, gender, or course of illness.\n\n\nCONCLUSIONS\nTrait impulsivity is increased additively in bipolar disorder and substance abuse. Performance impulsivity is increased in interepisode bipolar disorder only if a history of substance abuse is present. This increased predisposition to impulsivity when not manic may contribute to the decrement in treatment outcome and compliance, and increased risk for suicide and aggression, in bipolar disorder with substance abuse.", "corpus_id": 37016938, "score": 0 }, { "doc_id": "15803935", "title": "Pharmacotherapy of Attention-deficit/Hyperactivity Disorder Reduces Risk for Substance Use Disorder", "abstract": "Objective. To assess the risk for substance use disorders (SUD) associated with previous exposure to psychotropic medication in a longitudinal study of boys with attention-deficit/hyperactivity disorder (ADHD). Methods. The cumulative incidence of SUD throughout adolescence was compared in 56 medicated subjects with ADHD, 19 nonmedicated subjects with ADHD, and 137 non-ADHD control subjects. Results. Unmedicated subjects with ADHD were at a significantly increased risk for any SUD at follow-up compared with non-ADHD control subjects (adjusted OR: 6.3 [1.8–21.6]). Subjects with ADHD medicated at baseline were at a significantly reduced risk for a SUD at follow-up relative to untreated subjects with ADHD (adjusted OR: 0.15 [0.04–0.6]). For each SUD subtype studied, the direction of the effect of exposure to pharmacotherapy was similar to that seen for the any SUD category. Conclusions. Consistent with findings in untreated ADHD in adults, untreated ADHD was a significant risk factor for SUD in adolescence. In contrast, pharmacotherapy was associated with an 85% reduction in risk for SUD in ADHD youth.", "corpus_id": 15803935, "score": 0 }, { "doc_id": "45939710", "title": "Cocaine receptors on dopamine transporters are related to self-administration of cocaine.", "abstract": "Although cocaine binds to several sites in the brain, the biochemical receptor mechanism or mechanisms associated with its dependence producing properties are unknown. It is shown here that the potencies of cocaine-like drugs in self-administration studies correlate with their potencies in inhibiting [3H]mazindol binding to the dopamine transporters in the rat striatum, but not with their potencies in binding to a large number of other presynaptic and postsynaptic binding sites. Thus, the cocaine receptor related to substance abuse is proposed to be the one associated with dopamine uptake inhibition.", "corpus_id": 45939710, "score": 0 } ]

{ "doc_id": "4649459", "title": "Calcium-Dependent Interaction Occurs between Slow Skeletal Myosin Binding Protein C and Calmodulin", "abstract": "Myosin binding protein C (MyBP-C) is a multi-domain protein that participates in the regulation of muscle contraction through dynamic interactions with actin and myosin. Three primary isoforms of MyBP-C exist: cardiac (cMyBP-C), fast skeletal (fsMyBP-C), and slow skeletal (ssMyBP-C). The N-terminal region of cMyBP-C contains the M-motif, a three-helix bundle that binds Ca2+-loaded calmodulin (CaM), but less is known about N-terminal ssMyBP-C and fsMyBP-C. Here, we characterized the conformation of a recombinant N-terminal fragment of ssMyBP-C (ssC1C2) using differential scanning fluorimetry, nuclear magnetic resonance, and molecular modeling. Our studies revealed that ssC1C2 has altered thermal stability in the presence and absence of CaM. We observed that site-specific interaction between CaM and the M-motif of ssC1C2 occurs in a Ca2+-dependent manner. Molecular modeling supported that the M-motif of ssC1C2 likely adopts a three-helix bundle fold comparable to cMyBP-C. Our study provides evidence that ssMyBP-C has overlapping structural determinants, in common with the cardiac isoform, which are important in controlling protein–protein interactions. We shed light on the differential molecular regulation of contractility that exists between skeletal and cardiac muscle.", "corpus_id": 4649459 }

[ { "doc_id": "5021301", "title": "Direct visualization of myosin-binding protein C bridging myosin and actin filaments in intact muscle", "abstract": "Myosin-binding protein C (MyBP-C) is a thick filament protein playing an essential role in muscle contraction, and MyBP-C mutations cause heart and skeletal muscle disease in millions worldwide. Despite its discovery 40 y ago, the mechanism of MyBP-C function remains unknown. In vitro studies suggest that MyBP-C could regulate contraction in a unique way—by bridging thick and thin filaments—but there has been no evidence for this in vivo. Here we use electron tomography of exceptionally well preserved muscle to demonstrate that MyBP-C does indeed bind to actin in intact muscle. This binding implies a physical mechanism for communicating the relative sliding between thick and thin filaments that does not involve myosin and which could modulate the contractile process.", "corpus_id": 5021301, "score": 0 }, { "doc_id": "12417984", "title": "The Myosin-binding Protein C Motif Binds to F-actin in a Phosphorylation-sensitive Manner*", "abstract": "Cardiac myosin-binding protein C (cMyBP-C) is a regulatory protein expressed in cardiac sarcomeres that is known to interact with myosin, titin, and actin. cMyBP-C modulates actomyosin interactions in a phosphorylation-dependent way, but it is unclear whether interactions with myosin, titin, or actin are required for these effects. Here we show using cosedimentation binding assays, that the 4 N-terminal domains of murine cMyBP-C (i.e. C0-C1-m-C2) bind to F-actin with a dissociation constant (Kd) of ∼10 μm and a molar binding ratio (Bmax) near 1.0, indicating 1:1 (mol/mol) binding to actin. Electron microscopy and light scattering analyses show that these domains cross-link F-actin filaments, implying multiple sites of interaction with actin. Phosphorylation of the MyBP-C regulatory motif, or m-domain, reduced binding to actin (reduced Bmax) and eliminated actin cross-linking. These results suggest that the N terminus of cMyBP-C interacts with F-actin through multiple distinct binding sites and that binding at one or more sites is reduced by phosphorylation. Reversible interactions with actin could contribute to effects of cMyBP-C to increase cross-bridge cycling.", "corpus_id": 12417984, "score": 0 }, { "doc_id": "3338545", "title": "Binding of the N-terminal fragment C0-C2 of cardiac MyBP-C to cardiac F-actin.", "abstract": "Cardiac myosin-binding protein C (cMyBP-C), a major accessory protein of cardiac thick filaments, is thought to play a key role in the regulation of myocardial contraction. Although current models for the function of the protein focus on its binding to myosin S2, other evidence suggests that it may also bind to F-actin. We have previously shown that the N-terminal fragment C0-C2 of cardiac myosin-binding protein-C (cMyBP-C) bundles actin, providing evidence for interaction of cMyBP-C and actin. In this paper we directly examined the interaction between C0-C2 and F-actin at physiological ionic strength and pH by negative staining and electron microscopy. We incubated C0-C2 (5-30μM, in a buffer containing in mM: 180 KCl, 1 MgCl(2), 1 EDTA, 1 DTT, 20 imidazole, at pH 7.4) with F-actin (5μM) for 30min and examined negatively-stained samples of the solution by electron microscopy (EM). Examination of EM images revealed that C0-C2 bound to F-actin to form long helically-ordered complexes. Fourier transforms indicated that C0-C2 binds with the helical periodicity of actin with strong 1st and 6th layer lines. The results provide direct evidence that the N-terminus of cMyBP-C can bind to F-actin in a periodic complex. This interaction of cMyBP-C with F-actin supports the possibility that binding of cMyBP-C to F-actin may play a role in the regulation of cardiac contraction.", "corpus_id": 3338545, "score": 0 }, { "doc_id": "5269759", "title": "The C0C1 fragment of human cardiac myosin binding protein C has common binding determinants for both actin and myosin.", "abstract": "The N-terminal domains of cardiac myosin binding protein C (MyBP-C) play a regulatory role in modulating interactions between myosin and actin during heart muscle contraction. Using NMR spectroscopy and small-angle neutron scattering, we have determined specific details of the interaction between the two-module human C0C1 cMyBP-C fragment and F-actin. The small-angle neutron scattering data show that C0C1 spontaneously polymerizes monomeric actin (G-actin) to form regular assemblies composed of filamentous actin (F-actin) cores decorated by C0C1, similar to what was reported in our earlier four-module mouse cMyBP-C actin study. In addition, NMR titration analyses show large intensity changes for a subset of C0C1 peaks upon addition of G-actin, indicating that human C0C1 interacts specifically with actin and promotes its assembly into filaments. During the NMR titration, peaks corresponding to cardiac-specific C0 domain are the first to be affected, followed by those from the C1 domain. No peak intensity or position changes were detected for peaks arising from the disordered proline/alanine-rich (P/A) linker connecting C0 with C1, despite previous suggestions of its involvement in binding actin. Of considerable interest is the observation that the actin-interaction \"hot-spots\" within the C0 and C1 domains, revealed in our NMR study, overlap with regions previously identified as binding to the regulatory light chain of myosin and to myosin ΔS2. Our results suggest that C0 and C1 interact with myosin and actin using a common set of binding determinants and therefore support a cMyBP-C switching mechanism between myosin and actin.", "corpus_id": 5269759, "score": 0 }, { "doc_id": "36886575", "title": "Myosin Binding Protein C Interaction with Actin", "abstract": "Myosin binding protein C (MyBPC) is a multidomain protein associated with the thick filaments of striated muscle. Although both structural and regulatory roles have been proposed for MyBPC, its interactions with other sarcomeric proteins remain obscure. The current study was designed to examine the actin-binding properties of MyBPC and to define MyBPC domain regions involved in actin interaction. Here, we have expressed full-length mouse cardiac MyBPC (cMyBPC) in a baculovirus system and shown that purified cMyBPC binds actin filaments with an affinity of 4.3 ± 1.1 μm and a 1:1 molar ratio with regard to an actin protomer. The actin binding by cMyBPC is independent of protein phosphorylation status and is not significantly affected by the presence of tropomyosin and troponin on the actin filament. In addition, cMyBPC-actin interaction is not modulated by calmodulin. To determine the region of cMyBPC that is responsible for its interaction with actin, we have expressed and characterized five recombinant proteins encoding fragments of the cMyBPC sequence. Recombinant N-terminal fragments such as C0–C1, C0–C4, and C0–C5 cosediment with actin in a linear, nonsaturable manner. At the same time, MyBPC fragments lacking either the C0–C1 or C0–C4 region bind F-actin with essentially the same properties as full-length protein. Together, our results indicate that cMyBPC interacts with actin via a single, moderate affinity site localized to the C-terminal region of the protein. In contrast, certain basic regions of the N-terminal domains of MyBPC may act as small polycations and therefore bind actin via nonspecific electrostatic interactions.", "corpus_id": 36886575, "score": 0 }, { "doc_id": "46489913", "title": "Determination of the critical residues responsible for cardiac myosin binding protein C's interactions.", "abstract": "Despite early demonstrations of myosin binding protein C's (MyBP-C) interaction with actin, different investigators have reached different conclusions regarding the relevant and necessary domains mediating this binding. Establishing the detailed structure-function relationships is needed to fully understand cMyBP-C's ability to impact on myofilament contraction as mutations in different domains are causative for familial hypertrophic cardiomyopathy. We defined cMyBP-C's N-terminal structural domains that are necessary or sufficient to mediate interactions with actin and/or the head region of the myosin heavy chain (S2-MyHC). Using a combination of genetics and functional assays, we defined the actin binding site(s) present in cMyBP-C. We confirmed that cMyBP-C's C1 and m domains productively interact with actin, while S2-MyHC interactions are restricted to the m domain. Using residue-specific mutagenesis, we identified the critical actin binding residues and distinguished them from the residues that were critical for S2-MyHC binding. To validate the structural and functional significance of these residues, we silenced the endogenous cMyBP-C in neonatal rat cardiomyocytes (NRC) using cMyBP-C siRNA, and replaced the endogenous cMyBP-C with normal or actin binding-ablated cMyBP-C. Replacement with actin binding-ablated cMyBP-C showed that the mutated protein did not incorporate into the sarcomere normally. Residues responsible for actin and S2-MyHC binding are partially present in overlapping domains but are unique. Expression of an actin binding-deficient cMyBP-C resulted in abnormal cytosolic distribution of the protein, indicating that interaction with actin is essential for the formation and/or maintenance of normal cMyBP-C sarcomeric distribution.", "corpus_id": 46489913, "score": 0 }, { "doc_id": "30097111", "title": "Cardiac myosin-binding protein C decorates F-actin: Implications for cardiac function", "abstract": "Cardiac myosin-binding protein C (cMyBP-C) is an accessory protein of striated muscle sarcomeres that is vital for maintaining regular heart function. Its 4 N-terminal regulatory domains, C0-C1-m-C2 (C0C2), influence actin and myosin interactions, the basic contractile proteins of muscle. Using neutron contrast variation data, we have determined that C0C2 forms a repeating assembly with filamentous actin, where the C0 and C1 domains of C0C2 attach near the DNase I-binding loop and subdomain 1 of adjacent actin monomers. Direct interactions between the N terminus of cMyBP-C and actin thereby provide a mechanism to modulate the contractile cycle by affecting the regulatory state of the thin filament and its ability to interact with myosin.", "corpus_id": 30097111, "score": 0 }, { "doc_id": "11452730", "title": "A Critical Function for Ser-282 in Cardiac Myosin Binding Protein-C Phosphorylation and Cardiac Function", "abstract": "Rationale: Cardiac myosin-binding protein-C (cMyBP-C) phosphorylation at Ser-273, Ser-282, and Ser-302 regulates myocardial contractility. In vitro and in vivo experiments suggest the nonequivalence of these sites and the potential importance of Ser-282 phosphorylation in modulating the protein's overall phosphorylation and myocardial function. Objective: To determine whether complete cMyBP-C phosphorylation is dependent on Ser-282 phosphorylation and to define its role in myocardial function. We hypothesized that Ser-282 regulates Ser-302 phosphorylation and cardiac function during &bgr;-adrenergic stimulation. Methods and Results: Using recombinant human C1-M-C2 peptides in vitro, we determined that protein kinase A can phosphorylate Ser-273, Ser-282, and Ser-302. Protein kinase C can also phosphorylate Ser-273 and Ser-302. In contrast, Ca2+-calmodulin-activated kinase II targets Ser-302 but can also target Ser-282 at nonphysiological calcium concentrations. Strikingly, Ser-302 phosphorylation by Ca2+-calmodulin-activated kinase II was abolished by ablating the ability of Ser-282 to be phosphorylated via alanine substitution. To determine the functional roles of the sites in vivo, three transgenic lines, which expressed cMyBP-C containing either Ser-273-Ala-282-Ser-302 (cMyBP-CSAS), Ala-273-Asp-282-Ala-302 (cMyBP-CADA), or Asp-273-Ala-282-Asp-302 (cMyBP-CDAD), were generated. Mutant protein was completely substituted for endogenous cMyBP-C by breeding each mouse line into a cMyBP-C null (t/t) background. Serine-to-alanine substitutions were used to ablate the abilities of the residues to be phosphorylated, whereas serine-to-aspartate substitutions were used to mimic the charged state conferred by phosphorylation. Compared to control nontransgenic mice, as well as transgenic mice expressing wild-type cMyBP-C, the transgenic cMyBP-CSAS(t/t), cMyBP-CADA(t/t), and cMyBP-CDAD(t/t) mice showed no increases in morbidity and mortality and partially rescued the cMyBP-C(t/t) phenotype. The loss of cMyBP-C phosphorylation at Ser-282 led to an altered &bgr;-adrenergic response. In vivo hemodynamic studies revealed that contractility was unaffected but that cMyBP-CSAS(t/t) hearts showed decreased diastolic function at baseline. However, the normal increases in cardiac function (increased contractility/relaxation) as a result of infusion of &bgr;-agonist was significantly decreased in all of the mutants, suggesting that competency for phosphorylation at multiple sites in cMyBP-C is a prerequisite for normal &bgr;-adrenergic responsiveness. Conclusions: Ser-282 has a unique regulatory role in that its phosphorylation is critical for the subsequent phosphorylation of Ser-302. However, each residue plays a role in regulating the contractile response to &bgr;-agonist stimulation.", "corpus_id": 11452730, "score": 0 }, { "doc_id": "7837521", "title": "The major myosin-binding domain of skeletal muscle MyBP-C (C protein) resides in the COOH-terminal, immunoglobulin C2 motif", "abstract": "A common feature shared by myosin-binding proteins from a wide variety of species is the presence of a variable number of related internal motifs homologous to either the Ig C2 or the fibronectin (Fn) type III repeats. Despite interest in the potential function of these motifs, no group has clearly demonstrated a function for these sequences in muscle, either intra- or extracellularly. We have completed the nucleotide sequence of the fast type isoform of MyBP-C (C protein) from chicken skeletal muscle. The deduced amino acid sequence reveals seven Ig C2 sets and three Fn type III motifs in MyBP-C. alpha-chymotryptic digestion of purified MyBP-C gives rise to four peptides. NH2-terminal sequencing of these peptides allowed us to map the position of each along the primary structure of the protein. The 28-kD peptide contains the NH2-terminal sequence of MyBP-C, including the first C2 repeat. It is followed by two internal peptides, one of 5 kD containing exclusively spacer sequences between the first and second C2 motifs, and a 95-kD fragment containing five C2 domains and three fibronectin type III motifs. The C-terminal sequence of MyBP-C is present in a 14- kD peptide which contains only the last C2 repeat. We examined the binding properties of these fragments to reconstituted (synthetic) myosin filaments. Only the COOH-terminal 14-kD peptide is capable of binding myosin with high affinity. The NH2-terminal 28-kD fragment has no myosin-binding, while the long internal 100-kD peptide shows very weak binding to myosin. We have expressed and purified the 14-kD peptide in Escherichia coli. The recombinant protein exhibits saturable binding to myosin with an affinity comparable to that of the 14-kD fragment obtained by proteolytic digestion (1/2 max binding at approximately 0.5 microM). These results indicate that the binding to myosin filaments is mainly restricted to the last 102 amino acids of MyBP-C. The remainder of the molecule (1,032 amino acids) could interact with titin, MyBP-H (H protein) or thin filament components. A comparison of the highly conserved Ig C2 domains present at the COOH- terminus of five MyBPs thus far sequenced (human slow and fast MyBP-C, human and chicken MyBP-H, and chicken MyBP-C) was used to identify residues unique to these myosin-binding Ig C2 repeats.", "corpus_id": 7837521, "score": 0 }, { "doc_id": "8634281", "title": "cAPK‐phosphorylation controls the interaction of the regulatory domain of cardiac myosin binding protein C with myosin‐S2 in an on‐off fashion", "abstract": "Myosin binding protein C is a protein of the myosin filaments of striated muscle which is expressed in isoforms specific for cardiac and skeletal muscle. The cardiac isoform is phosphorylated rapidly upon adrenergic stimulation of myocardium by cAMP‐dependent protein kinase, and together with the phosphorylation of troponin‐I and phospholamban contributes to the positive inotropy that results from adrenergic stimulation of the heart. Cardiac myosin binding protein C is phosphorylated by cAMP‐dependent protein kinase on three sites in a myosin binding protein C specific N‐terminal domain which binds to myosin‐S2. This interaction with myosin close to the motor domain is likely to mediate the regulatory function of the protein. Cardiac myosin binding protein C is a common target gene of familial hypertrophic cardiomyopathy and most mutations encode N‐terminal subfragments of myosin binding protein C. The understanding of the signalling interactions of the N‐terminal region is therefore important for understanding the pathophysiology of myosin binding protein C associated cardiomyopathy. We demonstrate here by cosedimentation assays and isothermal titration calorimetry that the myosin‐S2 binding properties of the myosin binding protein C motif are abolished by cAMP‐dependent protein kinase‐mediated tris‐phosphorylation, decreasing the S2 affinity from a K d of ≈5 μM to undetectable levels. We show that the slow and fast skeletal muscle isoforms are no cAMP‐dependent protein kinase substrates and that the S2 interaction of these myosin binding protein C isoforms is therefore constitutively on. The regulation of cardiac contractility by myosin binding protein C therefore appears to be a ‘brake‐off’ mechanism that will free a specific subset of myosin heads from sterical constraints imposed by the binding to the myosin binding protein C motif.", "corpus_id": 8634281, "score": 0 }, { "doc_id": "44780669", "title": "A molecular map of the interactions between titin and myosin-binding protein C. Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy.", "abstract": "The thick filaments of vertebrate striated muscles contain with myosin a number of accessory proteins of the intracellular immunoglobulin superfamily, which are localized in a distinct pattern of stripes 43 nm apart. The specific localization of these proteins is believed to be due partly to their interaction with the giant muscle protein titin (also called connectin), which spans the entire sarcomere and may act as a molecular ruler. We have used recombinant fragments of titin covering the thick filament region to investigate their interaction with myosin-binding protein C (MyBP-C) from skeletal and cardiac muscle. The interaction of titin and MYBP-C is directed by a subset of titin immunoglobulin domains that are specific for the C-region of the thick filament, supporting the ruler hypothesis for the myosin-binding proteins. The interaction of recombinant titin with overlapping fragments of human cardiac MyBP-C maps the titin-binding site within the C-terminal region, which is deleted in patients suffering from the chromosome-11-associated form of familial hypertrophic cardiomyopathy. This disorder is therefore likely to be the result of thick-filament misassembly by abolishing the ternary interaction of titin, myosin and MyBP-C.", "corpus_id": 44780669, "score": 0 }, { "doc_id": "20834690", "title": "The interface between MyBP-C and myosin: site-directed mutagenesis of the CX myosin-binding domain of MyBP-C", "abstract": "Myosin-binding protein-C (MyBP-C or C-protein) is a ca. 130 kDa protein present in the thick filaments of all vertebrate striated muscle. The protein contains ten domains, each of ca. 90–100 amino acids; seven are members of the IgI family of proteins, three of the fibronectin type III family. The motifs are arranged in the following order (from N- to C-terminus): Ig-Ig-Ig-Ig-Ig-Fn-Fn-Ig-Fn-Ig. The C-terminal Ig motif (domain X or CX) contains its light meromyosin-binding site. A recombinant form of CX, beginning at Met-1027, exhibits saturable binding to myosin with an affinity comparable to the C-terminal 13 kDa chymotryptic fragment of native MyBP-C. To identify the surface in CX involved in its interaction with myosin, nine site-directed mutants (R37E, K43E, N49D, E52R, D56K, R73E, R74E, G80D and R103E) were constructed. Using a new assay for assessing the binding of CX with the light meromyosin (LMM) portion of myosin, we demonstrate that recombinant CX, just as the full-length protein, is able to facilitate LMM polymerization. Moreover, we show that residues Arg-37, Glu-52, Asp-56, Arg-73, and Arg-74 are involved in this interaction with the myosin rod. All of these amino acids interact with negatively charged residues of LMM, since the mutants R37E, R73E and R74E are unable to bind myosin, whereas E52R and D56K bind myosin with higher affinity than wild-type CX. Residues Lys-43 and Arg-103 show a small but significant influence on the binding reaction; residues Asn-49 and Gly-80 seem not to be involved in this interaction. Based on these data, a model is proposed for the interaction between MyBP-C CX and myosin filaments. In this model, CX interacts with four molecules of LMM at four different sites of the binding protein, thus explaining the effects of MyBP-C on the critical concentration of myosin polymerization.", "corpus_id": 20834690, "score": 1 }, { "doc_id": "23294812", "title": "Localization of the binding site of the C-terminal domain of cardiac myosin-binding protein-C on the myosin rod.", "abstract": "cMyBP-C [cardiac (MyBP-C) myosin-binding protein-C)] is a sarcomeric protein involved both in thick filament structure and in the regulation of contractility. It is composed of eight IgI-like and three fibronectin-3-like domains (termed C0-C10). Mutations in the gene encoding cMyBP-C are a principal cause of HCM (hypertrophic cardiomyopathy). cMyBP-C binds to the LMM (light meromyosin) portion of the myosin rod via its C-terminal domain, C10. We investigated this interaction in detail to determine whether HCM mutations in beta myosin heavy chain located within the LMM portion alter the binding of cMyBP-C, and to define the precise region of LMM that binds C10 to aid in developing models of the arrangement of MyBP-C on the thick filament. In co-sedimentation experiments recombinant C10 bound full-length LMM with a K(d) of 3.52 microM and at a stoichiometry of 1.14 C10 per LMM. C10 was also shown to bind with similar affinity to LMM containing either the HCM mutations A1379T or S1776G, suggesting that these HCM mutations do not perturb C10 binding. Using a range of N-terminally truncated LMM fragments, the cMyBP-C-binding site on LMM was shown to lie between residues 1554 and 1581. Since it had been reported previously that acidic residues on myosin mediate the C10 interaction, three clusters of acidic amino acids (Glu1554/Glu1555, Glu1571/Glu1573 and Glu1578/Asp1580/Glu1581/Glu1582) were mutated in full-length LMM and the proteins tested for C10 binding. No effect of these mutations on C10 binding was however detected. We interpret our results with respect to the localization of the proposed trimeric collar on the thick filament.", "corpus_id": 23294812, "score": 0 }, { "doc_id": "21077749", "title": "A Hypertrophic Cardiomyopathy-associated MYBPC3 Mutation Common in Populations of South Asian Descent Causes Contractile Dysfunction*", "abstract": "Background: A 25-base pair deletion in the MYBPC3 gene is the most prevalent hypertrophic cardiomyopathy-associated mutation among South Asian populations. Results: Expression of mutant protein (cMyBP-CC10mut) in cultured adult rat cardiomyocytes led to improper localization and contractile dysfunction. Conclusion: cMyBP-CC10mut expression is sufficient to cause contractile dysfunction. Significance: The study sheds light on the etiology of this ethnic-specific hypertrophic cardiomyopathy mutation. Hypertrophic cardiomyopathy (HCM) results from mutations in genes encoding sarcomeric proteins, most often MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). A recently discovered HCM-associated 25-base pair deletion in MYBPC3 is inherited in millions worldwide. Although this mutation causes changes in the C10 domain of cMyBP-C (cMyBP-CC10mut), which binds to the light meromyosin (LMM) region of the myosin heavy chain, the underlying molecular mechanism causing HCM is unknown. In this study, adenoviral expression of cMyBP-CC10mut in cultured adult rat cardiomyocytes was used to investigate protein localization and evaluate contractile function and Ca2+ transients, compared with wild-type cMyBP-C expression (cMyBP-CWT) and controls. Forty-eight hours after infection, 44% of cMyBP-CWT and 36% of cMyBP-CC10mut protein levels were determined in total lysates, confirming equal expression. Immunofluorescence experiments showed little or no localization of cMyBP-CC10mut to the C-zone, whereas cMyBP-CWT mostly showed C-zone staining, suggesting that cMyBP-CC10mut could not properly integrate in the C-zone of the sarcomere. Subcellular fractionation confirmed that most cMyBP-CC10mut resided in the soluble fraction, with reduced presence in the myofilament fraction. Also, cMyBP-CC10mut displayed significantly reduced fractional shortening, sarcomere shortening, and relaxation velocities, apparently caused by defects in sarcomere function, because Ca2+ transients were unaffected. Co-sedimentation and protein cross-linking assays confirmed that C10mut causes the loss of C10 domain interaction with myosin LMM. Protein homology modeling studies showed significant structural perturbation in cMyBP-CC10mut, providing a potential structural basis for the alteration in its mode of interaction with myosin LMM. Therefore, expression of cMyBP-CC10mut protein is sufficient to cause contractile dysfunction in vitro.", "corpus_id": 21077749, "score": 0 }, { "doc_id": "25472581", "title": "Complete sequence of human fast-type and slow-type muscle myosin-binding-protein C (MyBP-C). Differential expression, conserved domain structure and chromosome assignment.", "abstract": "Myosin-binding-protein C (MyBP-C) is a myosin-associated protein of unknown function found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. Using a cDNA clone encoding the fast-type isoform of chicken MyBP-C, we screened a human fetal muscle cDNA library and isolated clones encoding the full-length human fast-type isoform of MyBP-C. cDNA clones encoding the slow-type isoform of human MyBP-C, were also isolated and fully sequenced. Northern-blot analysis demonstrated skeletal muscle-specific expression of these gene products. Using human/hamster somatic-cell hybrids, we were able to map the slow-type MyBP-C to human chromosome 12, and the fast-type MyBP-C to chromosome 19. The cDNA for human fast-type MyBP-C encodes a polypeptide of 1142 amino acids with an expected molecular mass of 128.1 kDa. Comparison of this cDNA with other members of the MyBP family reveals extensive primary-sequence conservation. Each MyBP-C contains seven immunoglobulin C2 motifs and three fibronectin type-III repeats in the arrangement C2-C2-C2-C2-C2-III-III-C2-III-C2. Regions of high identity shared by the chicken and the two human proteins are not restricted to the immunoglobulin and fibronectin motifs. Sequence comparison of all three proteins has allowed us to map a highly conserved region between the first and second C2 motifs, the only large spacer sequence present between motifs in these proteins.", "corpus_id": 25472581, "score": 0 }, { "doc_id": "23780999", "title": "The Motif of Human Cardiac Myosin-binding Protein C Is Required for Its Ca2+-dependent Interaction with Calmodulin*", "abstract": "Background: The motif of human cMyBP-C contains phosphorylation sites that regulate its interaction with myosin ΔS2. Results: The motif interacts with calmodulin in a calcium-dependent manner yet is independent of its phosphorylation state. Conclusion: Highly conserved residues toward the C-terminal end of the motif interact with calmodulin in an extended conformation. Significance: Calmodulin can link cMyBP-C with the calcium-signaling pathways in muscle. The N-terminal modules of cardiac myosin-binding protein C (cMyBP-C) play a regulatory role in mediating interactions between myosin and actin during heart muscle contraction. The so-called “motif,” located between the second and third immunoglobulin modules of the cardiac isoform, is believed to modulate contractility via an “on-off” phosphorylation-dependent tether to myosin ΔS2. Here we report a novel Ca2+-dependent interaction between the motif and calmodulin (CaM) based on the results of a combined fluorescence, NMR, and light and x-ray scattering study. We show that constructs of cMyBP-C containing the motif bind to Ca2+/CaM with a moderate affinity (KD ∼10 μm), which is similar to the affinity previously determined for myosin ΔS2. However, unlike the interaction with myosin ΔS2, the Ca2+/CaM interaction is unaffected by substitution with a triphosphorylated motif mimic. Further, Ca2+/CaM interacts with the highly conserved residues (Glu319–Lys341) toward the C-terminal end of the motif. Consistent with the Ca2+ dependence, the binding of CaM to the motif is mediated via the hydrophobic clefts within the N- and C-lobes that are known to become more exposed upon Ca2+ binding. Overall, Ca2+/CaM engages with the motif in an extended clamp configuration as opposed to the collapsed binding mode often observed in other CaM-protein interactions. Our results suggest that CaM may act as a structural conduit that links cMyBP-C with Ca2+ signaling pathways to help coordinate phosphorylation events and synchronize the multiple interactions between cMyBP-C, myosin, and actin during the heart muscle contraction.", "corpus_id": 23780999, "score": 1 }, { "doc_id": "147751", "title": "Myosin Binding Protein-C Slow Phosphorylation is Altered in Duchenne Dystrophy and Arthrogryposis Myopathy in Fast-Twitch Skeletal Muscles", "abstract": "Myosin Binding Protein-C slow (sMyBP-C), encoded by MYBPC1, comprises a family of regulatory proteins of skeletal muscles that are phosphorylated by PKA and PKC. MYBPC1 missense mutations are linked to the development of Distal Arthrogryposis-1 (DA-1). Although structure-function details for this myopathy are evolving, function is undoubtedly driven by sequence variations and post-translational modifications in sMyBP-C. Herein, we examined the phosphorylation profile of sMyBP-C in mouse and human fast-twitch skeletal muscles. We used Flexor Digitorum Brevis (FDB) isolated from young (~2-months old) and old (~14-months old) wild type and mdx mice, and human Abductor Hallucis (AH) and gastrocnemious muscles carrying the DA-1 mutations. Our results indicate both constitutive and differential phosphorylation of sMyBP-C in aged and diseased muscles. We report a 7–35% reduction in the phosphorylation levels of select sites in old wild type and young or old mdx FDB mouse muscles, compared to young wild type tissue. Similarly, we observe a 30–70% decrease in the phosphorylation levels of all PKA and PKC phospho-sites in the DA-1 AH, but not gastrocnemius, muscle. Overall, our studies show that the phosphorylation pattern of sMyBP-C is differentially regulated in response to age and disease, suggesting that phosphorylation plays important roles in these processes.", "corpus_id": 147751, "score": 1 }, { "doc_id": "42890694", "title": "Mutation in the β-hairpin of the Bordetella pertussis adenylate cyclase toxin modulates N-lobe conformation in calmodulin.", "abstract": "Bordetella pertussis, causative agent of whooping cough, produces an adenylate cyclase toxin (CyaA) that is an important virulence factor. In the host cell, the adenylate cyclase domain of CyaA (CyaA-ACD) is activated upon association with calmodulin (CaM), an EF-hand protein comprised of N- and C-lobes (N-CaM and C-CaM, respectively) connected by a flexible tether. Maximal CyaA-ACD activation is achieved through its binding to both lobes of intact CaM, but the structural mechanisms remain unclear. No high-resolution structure of the intact CaM/CyaA-ACD complex is available, but crystal structures of isolated C-CaM bound to CyaA-ACD shed light on the molecular mechanism by which this lobe activates the toxin. Previous studies using molecular modeling, biochemical, and biophysical experiments demonstrate that CyaA-ACD's β-hairpin participates in site-specific interactions with N-CaM. In this study, we utilize nuclear magnetic resonance (NMR) spectroscopy to probe the molecular association between intact CaM and CyaA-ACD. Our results indicate binding of CyaA-ACD to CaM induces large conformational perturbations mapping to C-CaM, while substantially smaller structural changes are localized primarily to helices I, II, and IV, and the metal-binding sites in N-CaM. Site-specific mutations in CyaA-ACD's β-hairpin structurally modulate N-CaM, resulting in conformational perturbations in metal binding sites I and II, while no significant structural modifications are observed in C-CaM. Moreover, dynamic light scattering (DLS) analysis reveals that mutation of the β-hairpin results in a decreased hydrodynamic radius (Rh) and reduced thermal stability in the mutant complex. Taken together, our data provide new structural insights into the β-hairpin's role in stabilizing interactions between CyaA-ACD and N-CaM.", "corpus_id": 42890694, "score": 1 }, { "doc_id": "207129073", "title": "High-throughput thermal scanning: a general, rapid dye-binding thermal shift screen for protein engineering.", "abstract": "The low stability of natural proteins often limits their use in therapeutic, industrial, and research applications. The scale and throughput of methods such as circular dichroism, fluorescence spectroscopy, and calorimetry severely limit the number of variants that can be examined. Here we demonstrate a high-throughput thermal scanning (HTTS) method for determining the approximate stabilities of protein variants at high throughput and low cost. The method is based on binding to a hydrophobic dye akin to ANS, which fluoresces upon binding to molten globules and thermal denaturation intermediates. No inherent properties of the protein, such as enzymatic activity or presence of an intrinsic fluorophore, are required. Very small sample sizes are analyzed using a real-time PCR machine, enabling the use of high-throughput purification. We show that the apparent T(M) values obtained from HTTS are approximately linearly related to those from CD thermal denaturation for a series of four-helix bundle hydrophobic core variants. We demonstrate similar results for a small set of TIM barrel variants. This inexpensive, general, and scaleable approach enables the search for conservative, stable mutants of biotechnologically important proteins and provides a method for statistical correlation of sequence-stability relationships.", "corpus_id": 207129073, "score": 1 }, { "doc_id": "23857817", "title": "A quantitative model of thermal stabilization and destabilization of proteins by ligands.", "abstract": "Equilibrium binding ligands usually increase protein thermal stability by an amount proportional to the concentration and affinity of the ligand. High-throughput screening for the discovery of drug-like compounds uses an assay based on thermal stabilization. The mathematical description of this stabilization is well developed, and the method is widely applicable to the characterization of ligand-protein binding equilibrium. However, numerous cases have been experimentally observed where equilibrium binding ligands destabilize proteins, i.e., diminish protein melting temperature by an amount proportional to the concentration and affinity of the ligand. Here, we present a thermodynamic model that describes ligand binding to the native and unfolded (denatured) protein states explaining the combined stabilization and destabilization effects. The model also explains nonsaturation and saturation effects on the protein melting temperature when the ligand concentration significantly exceeds the protein concentration. Several examples of the applicability of the model are presented, including specific sulfonamide binding to recombinant hCAII, peptide and ANS binding to the Polo-box domain of Plk1, and zinc ion binding to the recombinant porcine growth hormone. The same ligands may stabilize and destabilize different proteins, and the same proteins may be stabilized and destabilized by different ligands.", "corpus_id": 23857817, "score": 0 }, { "doc_id": "24492361", "title": "Structural Insight into Unique Cardiac Myosin-binding Protein-C Motif", "abstract": "Background: Cardiac myosin-binding protein-C is a sarcomeric assembly protein necessary for the regulation of sarcomere structure and function. Results: The cMyBP-C motif is composed of two subdomains, a largely disordered N-terminal portion and a more ordered C-terminal subdomain. Conclusion: The C-terminal subdomain is capable of forming a three-helix bundle. Significance: The three-helix bundle may provide a platform for actin binding. The structural role of the unique myosin-binding motif (m-domain) of cardiac myosin-binding protein-C remains unclear. Functionally, the m-domain is thought to directly interact with myosin, whereas phosphorylation of the m-domain has been shown to modulate interactions between myosin and actin. Here we utilized NMR to analyze the structure and dynamics of the m-domain in solution. Our studies reveal that the m-domain is composed of two subdomains, a largely disordered N-terminal portion containing three known phosphorylation sites and a more ordered and folded C-terminal portion. Chemical shift analyses, dNN(i, i + 1) NOEs, and 15N{1H} heteronuclear NOE values show that the C-terminal subdomain (residues 315–351) is structured with three well defined helices spanning residues 317–322, 327–335, and 341–348. The tertiary structure was calculated with CS-Rosetta using complete 13Cα, 13Cβ, 13C′, 15N, 1Hα, and 1HN chemical shifts. An ensemble of 20 acceptable structures was selected to represent the C-terminal subdomain that exhibits a novel three-helix bundle fold. The solvent-exposed face of the third helix was found to contain the basic actin-binding motif LK(R/K)XK. In contrast, 15N{1H} heteronuclear NOE values for the N-terminal subdomain are consistent with a more conformationally flexible region. Secondary structure propensity scores indicate two transient helices spanning residues 265–268 and 293–295. The presence of both transient helices is supported by weak sequential dNN(i, i + 1) NOEs. Thus, the m-domain consists of an N-terminal subdomain that is flexible and largely disordered and a C-terminal subdomain having a three-helix bundle fold, potentially providing an actin-binding platform.", "corpus_id": 24492361, "score": 0 }, { "doc_id": "206210450", "title": "Human cardiac myosin binding protein C: structural flexibility within an extended modular architecture.", "abstract": "New insights into the modular organization and flexibility of the N-terminal half of human cardiac myosin binding protein C (cMyBP-C) and information on the association state of the full-length protein have been deduced from a combined small-angle X-ray scattering (SAXS) and NMR study. SAXS data show that the first five immunoglobulin domains of cMyBP-C, which include those implicated in interactions with both myosin and actin, remain monodisperse and monomeric in solution and have a highly extended yet distinctively 'bent' modular arrangement that is similar to the giant elastic muscle protein titin. Analyses of the NMR and SAXS data indicate that a proline/alanine-rich linker connecting the cardiac-specific N-terminal C0 domain to the C1 domain provides significant structural flexibility at the N-terminus of the human isoform, while the modular arrangement of domains C1-C2-C3-C4 is relatively fixed. Domain fragments from the C-terminal half of the protein have a propensity to self-associate in vitro, while full-length bacterially expressed cMyBP-C forms flexible extended dimers at micromolar protein concentrations. In summary, our studies reveal that human cMyBP-C combines a distinctive modular architecture with regions of flexibility and that the N-terminal half of the protein is sufficiently extended to span the range of interfilament distances sampled within the dynamic environment of heart muscle. These structural features of cMyBP-C could facilitate its putative role as a molecular switch between actin and myosin and may contribute to modulating the transverse pliancy of the C-zone of the A-band across muscle sarcomeres.", "corpus_id": 206210450, "score": 0 }, { "doc_id": "46261452", "title": "A Highly Conserved Yet Flexible Linker Is Part of a Polymorphic Protein-Binding Domain in Myosin-Binding Protein C.", "abstract": "The nuclear magnetic resonance (NMR) structure of the tri-helix bundle (THB) of the m-domain plus C2 (ΔmC2) of myosin-binding protein C (MyBP-C) has revealed a highly flexible seven-residue linker between the structured THB and C2. Bioinformatics shows significant patterns of conservation across the THB-linker sequence, with the linker containing a strictly conserved serine in all MyBP-C isoforms. Clinically linked mutations further support the functional significance of the THB-linker region. NMR, small-angle X-ray scattering, and binding studies show the THB-linker plus the first ten residues of C2 undergo dramatic changes when ΔmC2 binds Ca2+-calmodulin, with the linker and C2 N-terminal residues contributing significantly to the affinity. Modeling of all available experimental data indicates that the THB tertiary structure must be disrupted to form the complex. These results are discussed in the context of the THB-linker and the N-terminal residues of C2 forming a polymorphic binding domain that could accommodate multiple binding partners in the dynamic sarcomere.", "corpus_id": 46261452, "score": 1 }, { "doc_id": "9776866", "title": "SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information", "abstract": "Protein structure homology modelling has become a routine technique to generate 3D models for proteins when experimental structures are not available. Fully automated servers such as SWISS-MODEL with user-friendly web interfaces generate reliable models without the need for complex software packages or downloading large databases. Here, we describe the latest version of the SWISS-MODEL expert system for protein structure modelling. The SWISS-MODEL template library provides annotation of quaternary structure and essential ligands and co-factors to allow for building of complete structural models, including their oligomeric structure. The improved SWISS-MODEL pipeline makes extensive use of model quality estimation for selection of the most suitable templates and provides estimates of the expected accuracy of the resulting models. The accuracy of the models generated by SWISS-MODEL is continuously evaluated by the CAMEO system. The new web site allows users to interactively search for templates, cluster them by sequence similarity, structurally compare alternative templates and select the ones to be used for model building. In cases where multiple alternative template structures are available for a protein of interest, a user-guided template selection step allows building models in different functional states. SWISS-MODEL is available at http://swissmodel.expasy.org/.", "corpus_id": 9776866, "score": 0 }, { "doc_id": "28678522", "title": "QMEAN: A comprehensive scoring function for model quality assessment", "abstract": "In protein structure prediction, a considerable number of alternative models are usually produced from which subsequently the final model has to be selected. Thus, a scoring function for the identification of the best model within an ensemble of alternative models is a key component of most protein structure prediction pipelines. QMEAN, which stands for Qualitative Model Energy ANalysis, is a composite scoring function describing the major geometrical aspects of protein structures. Five different structural descriptors are used. The local geometry is analyzed by a new kind of torsion angle potential over three consecutive amino acids. A secondary structure‐specific distance‐dependent pairwise residue‐level potential is used to assess long‐range interactions. A solvation potential describes the burial status of the residues. Two simple terms describing the agreement of predicted and calculated secondary structure and solvent accessibility, respectively, are also included. A variety of different implementations are investigated and several approaches to combine and optimize them are discussed. QMEAN was tested on several standard decoy sets including a molecular dynamics simulation decoy set as well as on a comprehensive data set of totally 22,420 models from server predictions for the 95 targets of CASP7. In a comparison to five well‐established model quality assessment programs, QMEAN shows a statistically significant improvement over nearly all quality measures describing the ability of the scoring function to identify the native structure and to discriminate good from bad models. The three‐residue torsion angle potential turned out to be very effective in recognizing the native fold. Proteins 2008. © 2007 Wiley‐Liss, Inc.", "corpus_id": 28678522, "score": 0 }, { "doc_id": "12766988", "title": "PDBsum additions", "abstract": "PDBsum, http://www.ebi.ac.uk/pdbsum, is a website providing numerous pictorial analyses of each entry in the Protein Data Bank. It portrays the structural features of all proteins, DNA and ligands in the entry, as well as depicting the interactions between them. The latest features, described here, include annotation of human protein sequences with their naturally occurring amino acid variants, dynamic graphs showing the relationships between related protein domain architectures, analyses of ligand binding clusters across different experimental determinations of the same protein, analyses of tunnels in proteins and new search options.", "corpus_id": 12766988, "score": 0 }, { "doc_id": "2499860", "title": "Solution structures of the C-terminal domain of cardiac troponin C free and bound to the N-terminal domain of cardiac troponin I.", "abstract": "The N-terminal domain of cardiac troponin I (cTnI) comprising residues 33-80 and lacking the cardiac-specific amino terminus forms a stable binary complex with the C-terminal domain of cardiac troponin C (cTnC) comprising residues 81-161. We have utilized heteronuclear multidimensional NMR to assign the backbone and side-chain resonances of Ca2+-saturated cTnC(81-161) both free and bound to cTnI(33-80). No significant differences were observed between secondary structural elements determined for free and cTnI(33-80)-bound cTnC(81-161). We have determined solution structures of Ca2+-saturated cTnC(81-161) free and bound to cTnI(33-80). While the tertiary structure of cTnC(81-161) is qualitatively similar to that observed free in solution, the binding of cTnI(33-80) results mainly in an opening of the structure and movement of the loop region between helices F and G. Together, these movements provide the binding site for the N-terminal domain of cTnI. The putative binding site for cTnI(33-80) was determined by mapping amide proton and nitrogen chemical shift changes, induced by the binding of cTnI(33-80), onto the C-terminal cTnC structure. The binding interface for cTnI(33-80), as suggested from chemical shift changes, involves predominantly hydrophobic interactions located in the expanded hydrophobic pocket. The largest chemical shift changes were observed in the loop region connecting helices F and G. Inspection of available TnC sequences reveals that these residues are highly conserved, suggesting a common binding motif for the Ca2+/Mg2+-dependent interaction site in the TnC/TnI complex.", "corpus_id": 2499860, "score": 0 }, { "doc_id": "24534700", "title": "An interplay between protein disorder and structure confers the Ca2+ regulation of striated muscle.", "abstract": "The troponin (Tn) complex regulates the thin filament of striated muscle by transducing [Ca2+] fluctuations into conformational changes. These changes propagate to tropomyosin (Tm), which then assumes a new disposition with respect to actin, reversibly exposing actin's binding sites for the thick filament motor-ATPase (myosin). To date, the structural biology of thin filament regulation has been studied in the context of two equilibrium states corresponding to high (contraction-activated) and low (contraction-inhibited) sarcomeric [Ca2+]. New electron micrographic reconstructions of the thin filament have resolved Tn, actin, and Tm in high and low [Ca2+] states, integrating high-resolution structures of the Tn core, actin, and Tm. The resultant picture of thin filament regulation does not resolve all of the functionally significant portions of troponin I (TnI) or troponin C (TnC). Those regions of Tn have been shown (using NMR relaxation spectroscopy) to undergo conformational fluctuations, rationalizing the absence of these regions from micrograph-based reconstructions. The disordered portions of Tn are, to date, being interpreted within a canonical structure-activity paradigm. Here we present a new mechanism for the regulation of Tn having explicit descriptions of the kinetic pathways of activation and inhibition. Our thesis is that the intrinsic disorder of TnI is mechanistically significant. As the coupling of folding to binding has been shown to confer an inherent kinetic advantage (known as flycasting activity), our thesis accounts for TnI's conformational heterogeneity and known structure-activity relationships in a parsimonious fashion. We integrate recent NMR structures of the C-terminus of TnI and NMR observations of the conformational dynamics of the Tn complex into high-resolution models of the thin filament. Ways of evaluating the mechanism are discussed. The novel conceptual framework presented here prompts new hypotheses regarding the mechanism of pH sensitivity and of pathogenic mutations in troponin.", "corpus_id": 24534700, "score": 0 }, { "doc_id": "18138342", "title": "Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1.", "abstract": "Distal arthrogryposis type I (DA1) is a disorder characterized by congenital contractures of the hands and feet for which few genes have been identified. Here we describe a five-generation family with DA1 segregating as an autosomal dominant disorder with complete penetrance. Genome-wide linkage analysis using Affymetrix GeneChip Mapping 10K data from 12 affected members of this family revealed a multipoint LOD(max) of 3.27 on chromosome 12q. Sequencing of the slow-twitch skeletal muscle myosin binding protein C1 (MYBPC1), located within the linkage interval, revealed a missense mutation (c.706T>C) that segregated with disease in this family and causes a W236R amino acid substitution. A second MYBPC1 missense mutation was identified (c.2566T>C)(Y856H) in another family with DA1, accounting for an MYBPC1 mutation frequency of 13% (two of 15). Skeletal muscle biopsies from affected patients showed type I (slow-twitch) fibers were smaller than type II fibers. Expression of a green fluorescent protein (GFP)-tagged MYBPC1 construct containing WT and DA1 mutations in mouse skeletal muscle revealed robust sarcomeric localization. In contrast, a more diffuse localization was seen when non-fused GFP and MYBPC1 proteins containing corresponding MYBPC3 amino acid substitutions (R326Q, E334K) that cause hypertrophic cardiomyopathy were expressed. These findings reveal that the MYBPC1 is a novel gene responsible for DA1, though the mechanism of disease may differ from how some cardiac MYBPC3 mutations cause hypertrophic cardiomyopathy.", "corpus_id": 18138342, "score": 0 }, { "doc_id": "27537216", "title": "Phosphorylation modulates the mechanical stability of the cardiac myosin-binding protein C motif.", "abstract": "Cardiac myosin-binding protein C (cMyBP-C) is a thick-filament-associated protein that modulates cardiac contractility through interactions of its N-terminal immunoglobulin (Ig)-like C0-C2 domains with actin and/or myosin. These interactions are modified by the phosphorylation of at least four serines located within the motif linker between domains C1 and C2. We investigated whether motif phosphorylation alters its mechanical properties by characterizing force-extension relations using atomic force spectroscopy of expressed mouse N-terminal cMyBP-C fragments (i.e., C0-C3). Protein kinase A phosphorylation or serine replacement with aspartic acids did not affect persistence length (0.43 ± 0.04 nm), individual Ig-like domain unfolding forces (118 ± 3 pN), or Ig extension due to unfolding (30 ± 0.38 nm). However, phosphorylation did significantly decrease the C0-C3 mean contour length by 24 ± 2 nm. These results suggest that upon phosphorylation, the motif, which is freely extensible in the nonphosphorylated state, adopts a more stable and/or different structure. Circular dichroism and dynamic light scattering data for shorter expressed C1-C2 fragments with all four serines replaced by aspartic acids confirmed that the motif did adopt a more stable structure that was not apparent in the nonphosphorylated motif. These biophysical data provide both a mechanical and structural basis for cMyBP-C regulation by motif phosphorylation.", "corpus_id": 27537216, "score": 0 }, { "doc_id": "26655785", "title": "Modulation of cardiac troponin C-cardiac troponin I regulatory interactions by the amino-terminus of cardiac troponin I.", "abstract": "Multidimensional heteronuclear magnetic resonance studies of the cardiac troponin C/troponin I(1-80)/troponin I(129-166) complex demonstrated that cardiac troponin I(129-166), corresponding to the adjacent inhibitory and regulatory regions, interacts with and induces an opening of the cardiac troponin C regulatory domain. Chemical shift perturbation mapping and (15)N transverse relaxation rates for intact cardiac troponin C bound to either cardiac troponin I(1-80)/troponin I(129-166) or troponin I(1-167) suggested that troponin I residues 81-128 do not interact strongly with troponin C but likely serve to modulate the interaction of troponin I(129-166) with the cardiac troponin C regulatory domain. Chemical shift perturbations due to troponin I(129-166) binding the cardiac troponin C/troponin I(1-80) complex correlate with partial opening of the cardiac troponin C regulatory domain previously demonstrated by distance measurements using fluorescence methodologies. Fluorescence emission from cardiac troponin C(F20W/N51C)(AEDANS) complexed to cardiac troponin I(1-80) was used to monitor binding of cardiac troponin I(129-166) to the regulatory domain of cardiac troponin C. The apparent K(d) for cardiac troponin I(129-166) binding to cardiac troponin C/troponin I(1-80) was 43.3 +/- 3.2 microM. After bisphosphorylation of cardiac troponin I(1-80) the apparent K(d) increased to 59.1 +/- 1.3 microM. Thus, phosphorylation of the cardiac-specific N-terminus of troponin I reduces the apparent binding affinity of the regulatory domain of cardiac troponin C for cardiac troponin I(129-166) and provides further evidence for beta-adrenergic modulation of troponin Ca(2+) sensitivity through a direct interaction between the cardiac-specific amino-terminus of troponin I and the cardiac troponin C regulatory domain.", "corpus_id": 26655785, "score": 0 }, { "doc_id": "30653156", "title": "Magnesium-calcium exchange in cardiac troponin C bound to cardiac troponin I.", "abstract": "Understanding the process of Ca(2+)/Mg(2+)exchange during muscle excitation and relaxation is fundamental to elucidating the mechanism of Ca(2+)-regulated muscle contraction. During the resting phase, the C-domain of cardiac troponin C may be occupied by either Ca(2+)or Mg(2+). Here, complexes of recombinant cardiac troponin C(81-161) and the N terminus of cardiac troponin I, representing residues 33-80, were generated in the presence of saturating Mg(2+). Heteronuclear multi-dimensional nuclear magnetic resonance experiments were used to obtain backbone assignments of the Mg(2+)-loaded complex. In the presence of cardiac troponin I, the affinity of site IV for Mg(2+)is increased. Comparison of Mg(2+)and Ca(2+)-loaded complexes reveals that chemical shift differences are primarily localized to metal-binding sites III and IV, defining positions within these sites that have distinct Ca(2+)/Mg(2+)conformations. The observed transition from the Mg(2+)-loaded to Ca(2+)-loaded form demonstrates that sites III and IV fill simultaneously with Ca(2+)displacing Mg(2+). However, even in the absence of excess Ca(2+), Mg(2+)does not readily displace Ca(2+)in the isolated binary complex. Thus, the Mg(2+)-loaded conformer may only represent a small fraction of the total cardiac troponin C found in the sarcomere.", "corpus_id": 30653156, "score": 0 }, { "doc_id": "39912831", "title": "Phosphorylation-induced distance change in a cardiac muscle troponin I mutant.", "abstract": "Phosphorylation of two adjacent serine residues in the unique N-terminal extension of cardiac muscle troponin I (cTnI) is known to decrease the Ca2+-sensitivity of cardiac myofilaments. To probe the structural significance of the N-terminal extension, we have constructed two cTnI mutants each containing a single cysteine: (1) a full-length cTnI mutant (S5C/C81I/C98S) and (2) a truncated cTnI mutant (S9C/C50I/C67S) in which the N-terminal 32 amino acid residues were deleted. We determined the apparent binding constants for the complex formation between IAANS-labeled cardiac troponin C (cTnC) and the two cTnI mutants. The affinities of the cTnC for the truncated cTnI mutant were: (1) 1.5 x 10(6) M(-1) in EGTA, (2) 28.9 x 10(6) M(-1) in Mg2+, and (3) 87.5 x 10(6) M(-1) in Mg2+ + Ca2+. These binding constants were approximately 1.4-fold smaller than the corresponding values obtained with the full-length cTnI mutant, suggesting a very small contribution of the N-terminal extension to the binding of cTnI to cTnC. Cys-5 in the full-length cTnI mutant was labeled with IAANS, and the distribution of the separation between this site and Trp-192 was determined by analysis of the efficiency of fluorescence resonance energy transfer from Trp-192 to IAANS. The following mean distances were obtained with the unphosphorylated full-length mutant: 44.4 A (cTnI alone), 48.3 A (cTnI + cTnC), 46.3 A (cTnI + cTnC in Mg2+), and 51.6 A (cTnI + cTnC in Mg2+ + Ca2+). The corresponding values of the mean distance determined with the phosphorylated full-length cTnI mutant were 35.8, 36.6, 34.8, and 37.3 A. The phosphorylation of cTnI reduced the half-width of the distribution from 9.5 to 3.7 A. Similar but less pronounced decreases of the half-widths were also observed with the phosphorylated cTnI complexed with cTnC in different ionic conditions. Thus, phosphorylation of cTnI resulted in a decrease of 9-12 A in the mean distance between the sites located at the N- and C-terminal portion of cTnI. Our results indicate that phosphorylation elicits a change in the conformation of cTnI which underlies the basis of the phosphorylation-induced modulation of cTnI activity.", "corpus_id": 39912831, "score": 0 }, { "doc_id": "25661979", "title": "In Vivo and in Vitro Analysis of Cardiac Troponin I Phosphorylation*", "abstract": "Adrenergic stimulation induces positive changes in cardiac contractility and relaxation. Cardiac troponin I is phosphorylated at different sites by protein kinase A and protein kinase C, but the effects of these post-translational modifications on the rate and extent of contractility and relaxation during β-adrenergic stimulation in the intact animal remain obscure. To investigate the effect(s) of complete and chronic cTnI phosphorylation on cardiac function, we generated transgenic animals in which the five possible phosphorylation sites were replaced with aspartic acid, mimicking a constant state of complete phosphorylation (cTnI-AllP). We hypothesized that chronic and complete phosphorylation of cTnI might result in increased morbidity or mortality, but complete replacement with the transgenic protein was benign with no detectable pathology. To differentiate the effects of the different phosphorylation sites, we generated another mouse model, cTnI-PP, in which only the protein kinase A phosphorylation sites (Ser23/Ser24) were mutated to aspartic acid. In contrast to the cTnIAllP, the cTnI-PP mice showed enhanced diastolic function under basal conditions. The cTnI-PP animals also showed augmented relaxation and contraction at higher heart rates compared with the nontransgenic controls. Nuclear magnetic resonance amide proton/nitrogen chemical shift analysis of cardiac troponin C showed that, in the presence of cTnI-AllP and cTnI-PP, the N terminus exhibits a more closed conformation, respectively. The data show that protein kinase C phosphorylation of cTnI plays a dominant role in depressing contractility and exerts an antithetic role on the ability of protein kinase A to increase relaxation.", "corpus_id": 25661979, "score": 0 }, { "doc_id": "34926857", "title": "Modulation of cardiac troponin C function by the cardiac-specific N-terminus of troponin I: influence of PKA phosphorylation and involvement in cardiomyopathies.", "abstract": "The cardiac-specific N-terminus of cardiac troponin I (cTnI) is known to modulate the activity of troponin upon phosphorylation with protein kinase A (PKA) by decreasing its Ca(2+) affinity and increasing the relaxation rate of the thin filament. The molecular details of this modulation have not been elaborated to date. We have established that the N-terminus and the switch region of cTnI bind to cNTnC [the N-domain of cardiac troponin C (cTnC)] simultaneously and that the PKA signal is transferred via the cTnI N-terminus modulating the cNTnC affinity toward cTnI(147-163) but not toward Ca(2+). The K(d) of cNTnC for cTnI(147-163) was found to be 600 microM in the presence of cTnI(1-29) and 370 microM in the presence of cTn1(1-29)PP, which can explain the difference in muscle relaxation rates upon the phosphorylation with PKA in experiments with cardiac fibers. In the light of newly found mutations in cNTnC that are associated with cardiomyopathies, the important role played by the cTnI N-terminus in the development of heart disorders emerges. The mutants studied, L29Q (the N-domain of cTnC containing mutation L29Q) and E59D/D75Y (the N-domain of cTnC containing mutation E59D/D75Y), demonstrated unchanged Ca(2+) affinity per se and in complex with the cTnI N-terminus (cTnI(1-29) and cTnI(1-29)PP). The affinity of L29Q and E59D/D75Y toward cTnI(147-163) was significantly perturbed, both alone and in complex with cTnI(1-29) and cTnI(1-29)PP, which is likely to be responsible for the development of malfunctions.", "corpus_id": 34926857, "score": 0 }, { "doc_id": "21025276", "title": "NMR analysis of cardiac troponin C‐troponin I complexes: effects of phosphorylation", "abstract": "Phosphorylation of the cardiac specific amino‐terminus of troponin I has been demonstrated to reduce the Ca2+ affinity of the cardiac troponin C regulatory site. Recombinant N‐terminal cardiac troponin I proteins, cardiac troponin I(33–80), cardiac troponin I(1–80), cardiac troponin I(1–80)DD and cardiac troponin I(1–80)pp, phosphorylated by protein kinase A, were used to form stable binary complexes with recombinant cardiac troponin C. Cardiac troponin I(1–80)DD, having phosphorylated Ser residues mutated to Asp, provided a stable mimetic of the phosphorylated state. In all complexes, the N‐terminal domain of cardiac troponin I primarily makes contact with the C‐terminal domain of cardiac troponin C. The non‐phosphorylated cardiac specific amino‐terminus, cardiac troponin I(1–80), was found to make additional interactions with the N‐terminal domain of cardiac troponin C.", "corpus_id": 21025276, "score": 0 }, { "doc_id": "30202307", "title": "Cardiac myosin binding protein c phosphorylation is cardioprotective", "abstract": "Cardiac myosin binding protein C (cMyBP-C) has three phosphorylatable serines at its N terminus (Ser-273, Ser-282, and Ser-302), and the residues' phosphorylation states may alter thick filament structure and function. To examine the effects of cMyBP-C phosphorylation, we generated transgenic mice with cardiac-specific expression of a cMyBP-C in which the three phosphorylation sites were mutated to aspartic acid, mimicking constitutive phosphorylation (cMyBP-CAllP+). The allele was bred into a cMyBP-C null background (cMyBP-C(t/t)) to ensure the absence of endogenous dephosphorylated cMyBP-C. cMyBP-CAllP+ was incorporated normally into the cardiac sarcomere and restored normal cardiac function in the null background. However, subtle changes in sarcomere ultrastructure, characterized by increased distances between the thick filaments, indicated that phosphomimetic cMyBP-C affects thick–thin filament relationships, and yeast two-hybrid data and pull-down studies both showed that charged residues in these positions effectively prevented interaction with the myosin heavy chain. Confirming the physiological relevance of these data, the cMyBP-CAllP+:(t/t) hearts were resistant to ischemia–reperfusion injury. These data demonstrate that cMyBP-C phosphorylation functions in maintaining thick filament spacing and structure and can help protect the myocardium from ischemic injury.", "corpus_id": 30202307, "score": 0 }, { "doc_id": "10301958", "title": "Cardiac myosin binding protein-C restricts intrafilament torsional dynamics of actin in a phosphorylation-dependent manner", "abstract": "We have determined the effects of myosin binding protein-C (MyBP-C) and its domains on the microsecond rotational dynamics of actin, detected by time-resolved phosphorescence anisotropy (TPA). MyBP-C is a multidomain modulator of striated muscle contraction, interacting with myosin, titin, and possibly actin. Cardiac and slow skeletal MyBP-C are known substrates for protein kinase-A (PKA), and phosphorylation of the cardiac isoform alters contractile properties and myofilament structure. To determine the effects of MyBP-C on actin structural dynamics, we labeled actin at C374 with a phosphorescent dye and performed TPA experiments. The interaction of all three MyBP-C isoforms with actin increased the final anisotropy of the TPA decay, indicating restriction of the amplitude of actin torsional flexibility by 15–20° at saturation of the TPA effect. PKA phosphorylation of slow skeletal and cardiac MyBP-C relieved the restriction of torsional amplitude but also decreased the rate of torsional motion. In the case of fast skeletal MyBP-C, its effect on actin dynamics was unchanged by phosphorylation. The isolated C-terminal half of cardiac MyBP-C (C5–C10) had effects similar to those of the full-length protein, and it bound actin more tightly than the N-terminal half (C0–C4), which had smaller effects on actin dynamics that were independent of PKA phosphorylation. We propose that these MyBP-C-induced changes in actin dynamics play a role in the functional effects of MyBP-C on the actin–myosin interaction.", "corpus_id": 10301958, "score": 0 }, { "doc_id": "23137552", "title": "Unique single molecule binding of cardiac myosin binding protein-C to actin and phosphorylation-dependent inhibition of actomyosin motility requires 17 amino acids of the motif domain.", "abstract": "Cardiac myosin binding protein-C (cMyBP-C) has 11 immunoglobulin or fibronectin-like domains, C0 through C10, which bind sarcomeric proteins, including titin, myosin and actin. Using bacterial expressed mouse N-terminal fragments (C0 through C3) in an in vitro motility assay of myosin-generated actin movement and the laser trap assay to assess single molecule actin-binding capacity, we determined that the first N-terminal 17 amino acids of the cMyBP-C motif (the linker between C1 and C2) contain a strong, stereospecific actin-binding site that depends on positive charge due to a cluster of arginines. Phosphorylation of 4 serines within the motif decreases the fragments' actin-binding capacity and actomyosin inhibition. Using the laser trap assay, we observed individual cMyBP-C fragments transiently binding to a single actin filament with both short (~20 ms) and long (~300 ms) attached lifetimes, similar to that of a known actin-binding protein, α-actinin. These experiments suggest that cMyBP-C N-terminal domains containing the cMyBP-C motif tether actin filaments and provide one mechanism by which cMyBP-C modulates actomyosin motion generation, i.e. by imposing an effective viscous load within the sarcomere.", "corpus_id": 23137552, "score": 0 }, { "doc_id": "27561479", "title": "Roles of phosphorylation of myosin binding protein‐C and troponin I in mouse cardiac muscle twitch dynamics", "abstract": "A normal heart increases its contractile force with increasing heart rate. Although calcium handling and myofibrillar proteins have been implicated in maintaining this positive force–frequency relationship (FFR), the exact mechanisms by which it occurs have not been addressed. In this study, we have developed an analytical method to define the calcium–force loop data, which characterizes the function of the contractile proteins in response to calcium that is independent of the calcium handling proteins. Results demonstrate that increasing the stimulation frequency causes increased force production per unit calcium concentration and decreased frequency‐dependent calcium sensitivity during the relaxation phase. We hypothesize that phosphorylation of myosin binding protein‐C (MyBP‐C) and troponin I (TnI) acts coordinately to change the rates of force generation and relaxation, respectively. To test this hypothesis, we performed simultaneous calcium and force measurements on stimulated intact mouse papillary bundles before and after inhibition of MyBP‐C and TnI phosphorylation using the calcium/calmodulin kinase II (CaMK2) inhibitor autocamtide‐2 related inhibitory peptide, or the protein kinase A (PKA) inhibitor 14–22 amide. CaMK2 inhibition reduced both MyBP‐C and TnI phosphorylation and decreased active force without changing the magnitude of the [Ca2+]i transient. This reduced the normalized change in force per change in calcium by 19–39%. Data analyses demonstrated that CaMK2 inhibition changed the myofilament characteristics via a crossbridge feedback mechanism. These results strongly suggest that the phosphorylation of  MyBP‐C and TnI contributes significantly to the rates of force development and relaxation.", "corpus_id": 27561479, "score": 0 }, { "doc_id": "26876853", "title": "Myosin binding protein-C slow is a novel substrate for protein kinase A (PKA) and C (PKC) in skeletal muscle.", "abstract": "Myosin Binding Protein-C slow (MyBP-C slow), a family of thick filament-associated proteins, consists of four alternatively spliced forms, namely variants 1-4. Variants 1-4 share common structures and sequences; however, they differ in three regions: variants 1 and 2 contain a novel 25-residue long insertion at the extreme NH(2)-terminus, variant 3 carries an 18-amino acid long segment within immunoglobulin (Ig) domain C7, and variant 1 contains a unique COOH-terminus consisting of 26-amino acids, while variant 4 does not possess any of these insertions. Variants 1-4 are expressed in variable amounts among skeletal muscles, exhibiting different topographies and potentially distinct functions. To date, the regulatory mechanisms that modulate the activities of MyBP-C slow are unknown. Using an array of proteomic approaches, we show that MyBP-C slow comprises a family of phosphoproteins. Ser-59 and Ser-62 are substrates for PKA, while Ser-83 and Thr-84 are substrates for PKC. Moreover, Ser-204 is a substrate for both PKA and PKC. Importantly, the levels of phosphorylated skeletal MyBP-C proteins (i.e., slow and fast) are notably increased in mouse dystrophic muscles, even though their overall amounts are significantly decreased. In brief, our studies are the first to show that the MyBP-C slow subfamily undergoes phosphorylation, which may regulate its activities in normalcy and disease.", "corpus_id": 26876853, "score": 0 }, { "doc_id": "2497073", "title": "GPS 2.1: enhanced prediction of kinase-specific phosphorylation sites with an algorithm of motif length selection.", "abstract": "As the most important post-translational modification of proteins, phosphorylation plays essential roles in all aspects of biological processes. Besides experimental approaches, computational prediction of phosphorylated proteins with their kinase-specific phosphorylation sites has also emerged as a popular strategy, for its low-cost, fast-speed and convenience. In this work, we developed a kinase-specific phosphorylation sites predictor of GPS 2.1 (Group-based Prediction System), with a novel but simple approach of motif length selection (MLS). By this approach, the robustness of the prediction system was greatly improved. All algorithms in GPS old versions were also reserved and integrated in GPS 2.1. The online service and local packages of GPS 2.1 were implemented in JAVA 1.5 (J2SE 5.0) and freely available for academic researches at: http://gps.biocuckoo.org.", "corpus_id": 2497073, "score": 0 }, { "doc_id": "6896960", "title": "Isoform-specific Interaction of the Myosin-binding Proteins (MyBPs) with Skeletal and Cardiac Myosin Is a Property of the C-terminal Immunoglobulin Domain*", "abstract": "Full-length cDNAs encoding chicken and human skeletal MyBP-H and MyBP-C have been isolated and sequenced (1–5). All are members of a protein family with repetitive immunoglobulin C2 and fibronectin type III motifs. The myosin binding domain was mapped to a single immunoglobulin motif in cardiac MyBP-C and skeletal MyBP-H. Limited α-chymotryptic digestion of cardiac MyBP-C generated three peptides, similar in relative mobility to those of skeletal MyBP-C: ∼100, 40, and 15 kDa. Tryptic digestion of MyBP-H yielded two peptides: ∼50 and 14 kDa. Partial amino acid sequences proved that the 15- and 14-kDa fragments are located at the C termini of cardiac MyBP-C and skeletal MyBP-H, respectively. Only the 14- and 15-kDa peptides bound to myosin. Thus, the myosin binding site in all three proteins resides within an homologous, C-terminal immunoglobulin domain. Binding reactions (2) between the skeletal and cardiac MyBPs and corresponding myosin isoforms demonstrated saturable binding of theMyBP proteins and their C-terminal peptides to myosin, but there are higher limiting stoichiometries with the homologous isoform partners. Evidence is presented indicating that MyBP-H and -C compete for binding to a discrete number of sites in myosin filaments.", "corpus_id": 6896960, "score": 0 }, { "doc_id": "43304039", "title": "Structural evidence for the interaction of C-protein (MyBP-C) with actin and sequence identification of a possible actin-binding domain.", "abstract": "C-protein (MyBP-C) is a myosin-binding protein that is usually seen in two sets of seven to nine positions in the C-zones in each half of the vertebrate striated muscle A-band. Skeletal muscle C-protein is a modular structure containing ten sub-domains (C1 to C10) of which seven are immunoglobulin-type domains and three (C6, C7 and C9) are fibronectin-like domains. Cardiac muscle C-protein has an extra N-terminal domain (C0) and also some sequence insertions, one of which provides phosphorylation sites. It is conceivable that C-protein has both a structural and regulatory role within the sarcomere. The precise mode of binding of C-protein to the myosin filament has not been determined. However, detailed ultrastructural studies have suggested that C-protein, which binds to myosin, can give rise to a longer periodicity (about 435A) than the intrinsic myosin filament repeat of 429A. The reason for this has remained a puzzle for over 25 years. Here we show by modelling and computation that the presence of this longer periodicity could be explained if the myosin-binding part of C-protein binds to myosin with the expected 429A repeat, but if there are systematic interactions of the N-terminal end of C-protein with the neighbouring actin filaments in the hexagonal lattice of filaments in the A-band. We also show that if they occur these interactions would probably only arise in defined muscle states. Further analysis of the MyBP-C sequence identifies a possible actin-binding domain in the Pro-Ala-rich sequence found at the N terminus of skeletal MyBP-C and between domains C0 and C1 in the cardiac sequence.", "corpus_id": 43304039, "score": 0 }, { "doc_id": "1336010", "title": "In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament.", "abstract": "In the 20 years since the discovery of the first mutation linked to familial hypertrophic cardiomyopathy (HCM), an astonishing number of mutations affecting numerous sarcomeric proteins have been described. Among the most prevalent of these are mutations that affect thick filament binding proteins, including the myosin essential and regulatory light chains and cardiac myosin binding protein (cMyBP)-C. However, despite the frequency with which myosin binding proteins, especially cMyBP-C, have been linked to inherited cardiomyopathies, the functional consequences of mutations in these proteins and the mechanisms by which they cause disease are still only partly understood. The purpose of this review is to summarize the known disease-causing mutations that affect the major thick filament binding proteins and to relate these mutations to protein function. Conclusions emphasize the impact that discovery of HCM-causing mutations has had on fueling insights into the basic biology of thick filament proteins and reinforce the idea that myosin binding proteins are dynamic regulators of the activation state of the thick filament that contribute to the speed and force of myosin-driven muscle contraction. Additional work is still needed to determine the mechanisms by which individual mutations induce hypertrophic phenotypes.", "corpus_id": 1336010, "score": 0 }, { "doc_id": "16776699", "title": "NMRPipe: A multidimensional spectral processing system based on UNIX pipes", "abstract": "SummaryThe NMRPipe system is a UNIX software environment of processing, graphics, and analysis tools designed to meet current routine and research-oriented multidimensional processing requirements, and to anticipate and accommodate future demands and developments. The system is based on UNIX pipes, which allow programs running simultaneously to exchange streams of data under user control. In an NMRPipe processing scheme, a stream of spectral data flows through a pipeline of processing programs, each of which performs one component of the overall scheme, such as Fourier transformation or linear prediction. Complete multidimensional processing schemes are constructed as simple UNIX shell scripts. The processing modules themselves maintain and exploit accurate records of data sizes, detection modes, and calibration information in all dimensions, so that schemes can be constructed without the need to explicitly define or anticipate data sizes or storage details of real and imaginary channels during processing. The asynchronous pipeline scheme provides other substantial advantages, including high flexibility, favorable processing speeds, choice of both all-in-memory and disk-bound processing, easy adaptation to different data formats, simpler software development and maintenance, and the ability to distribute processing tasks on multi-CPU computers and computer networks.", "corpus_id": 16776699, "score": 0 } ]

{ "doc_id": "17199635", "title": "Marjolin's ulcers: theories, prognostic factors and their peculiarities in spina bifida patients", "abstract": "BackgroundDue to improved care, more and more children born with spina bifida in rural Kenya are surviving into adulthood. This improved survival has led to significant challenges in their lifestyles, especially the need to ensure pressure ulcer prevention and treatment. Malignant degeneration of pressure ulcers in spina bifida patients is very rare. The author describes the clinical presentation of two pressure ulcer carcinomas that are at variance from classical descriptions.Materials and methodsAn internet/Medline/PubMed search of English literature for theories on Marjolin's ulcer evolution and prognostic features of Marjolin's ulcers was performed.A chart review of two young adults with spina bifida who had presented to the author's hospital between 2004 and August 2010 with chronic pressure ulcers found to be Marjolin's ulcers on histo-pathological examination was performed, and the clinical features are reported.ResultsThe two ulcers appeared clinically benign: one was a deep ulcer, while the other was shallow; both had normal, benign-appearing edges, and a foul smelling discharge. The two ulcers were surrounded by induration and multiple communicating sinuses, with no evidence of chronic osteomyelitis. The internet search revealed a total of nine theories on Marjolin's ulcer development, as well as seven clinical and four histological prognostic features.DiscussionThe multifactorial theory, a coalescence of a number of proposed theories, best explains the evolution of Marjolin's ulcers. Poor prognostic features include pressure ulcer carcinomas, lesions and location in the lower limbs/trunks, all present in the two patients making their prognosis dim: this is despite the surgical margins being clear of tumor. Benign appearance, induration and presence of multiple communicating sinuses are features that have not been previously described as presenting features of pressure ulcers carcinomas.ConclusionThere is need for spina bifida patients and their guardians/caretakers to receive a close follow-up throughout life; health education focused on pressure ulcer prevention as well as early treatment of pressure ulcers when they occur, will avert the development of Marjolin's ulcers, and save lives.", "corpus_id": 17199635 }

[ { "doc_id": "10536320", "title": "Marjolin's ulcer: a review and reevaluation of a difficult problem.", "abstract": "The formation of an epidermoid carcinoma in nonhealing scar tissue, a Marjolin's ulcer, is a well described neoplasm. These lesions are, however, frequently overlooked and often inadequately treated. This paper reviews six cases of scar-tissue carcinoma. All lesions were secondary to various kinds of burns. Four of the Marjolin's ulcers were well-differentiated squamous cell carcinomas. One was a moderately differentiated squamous cell carcinoma, and one was a malignant melanoma. The average age at presentation was 59 years, and the mean interval from time of burn injury to appearance of neoplasm was 36.8 years. The lesions varied in anatomic location and involved the upper extremities, lower extremities, and scalp. In addition to the case studies, this paper reviews the literature and provides a logical treatment plan for a patient with a Marjolin's ulcer. Because these lesions can be very aggressive, a well thought-out treatment plan is necessary to optimize care and assure patient survival.", "corpus_id": 10536320, "score": 1 }, { "doc_id": "68284336", "title": "Marjolin's ulcer arising in a burn scar.", "abstract": "Abstract Marjolin's ulcer-a term used to describe a malignancy arising in chronic ulcers of the skin, sinuses, scar tissue, and especially burns scars-occurs in two forms: an acute variant in which the malignant changes occur within a year of injury, and a chronic form in which the injury may precede the malignancy by decades. Illustrating the more common chronic form, we present the case of a 32-year old Haitian woman with an extensive squamous cell carcinoma arising from a burn scar on the dorsum of her right hand, with a review of the literature pertaining to burn scar carcinoma.", "corpus_id": 68284336, "score": 1 }, { "doc_id": "8048607", "title": "THE EXPERIMENTAL DISCLOSURE OF LATENT NEOPLASTIC CHANGES IN TARRED SKIN", "abstract": "A carcinogenic tar applied to rabbit skin renders many more epidermal cells neoplastic than ever declare themselves by forming tumors. They may be present in large numbers and persist for a considerable time after brief tarring, yet give rise to no growths unless encouraged. The stimulus of wound healing will suffice to make some of them multiply and form tumors. No evidence has been obtained, in experiments specifically directed to the point, that the cells which tar renders neoplastic respond in this way because they are possessed of peculiarities not shared by the rest of the normal epithelium. The fact that non-specific stimulation (as e.g. wound healing) may act as the deciding influence in tumor formation brings out the need for a sharp distinction between the forces which induce neoplastic change and those which determine, or prevent, its realization in terms of a tumor. The distinction is vital to the appraisal of the many carcinogenic substances worked with nowadays. The ability of tumor cells to lie latent for long periods and respond to non-carcinogenic stimulation by multiplying into growths provides an explanation of those clinical instances in which cancer appears rapidly after acute injury to tissue that had seemed normal.", "corpus_id": 8048607, "score": 1 }, { "doc_id": "37314799", "title": "A New Concept in the Management of Marjolin's Ulcers", "abstract": "Marjolin's ulcers have a grave prognosis, especially when regional nodes are involved. Recent studies suggest such cancers are in an immunologically privileged sites due to the dense scar tissue. The prognosis has been shown to be much worse for tumors not having a round cell infiltrate prior to surgery, as in Marjolin's ulcers. The use of topical 5-fluorouracil (5-FU) induces a round cell infiltrate. Three case reports of large Marjolin's ulcers are presented which were first treated with topical 5-FU. Radical ablative surgery was avoided in these patients with a successful outcome.", "corpus_id": 37314799, "score": 1 }, { "doc_id": "46738893", "title": "HLA DR4 is associated with the development of multiple basal cell carcinomas and malignant melanoma.", "abstract": "An association between HLA DR4 and the development of multiple basal cell carcinomas (BCC) and malignant melanoma (MM) was detected in southern Australia. There were highly significant differences in HLA DR frequencies between patients with multiple BCCs and MM and matched patients with multiple BCCs only. These findings suggest that hereditary factors associated with the HLA system influence what types of multiple skin cancers people develop.", "corpus_id": 46738893, "score": 1 }, { "doc_id": "34605001", "title": "Deletion of the p53 gene in a patient with aggressive burn scar carcinoma.", "abstract": "BACKGROUND\nAggressive squamous cell carcinoma (SCC) is known to occur in scars that develop after a burn injury, especially in the underdeveloped areas of the world where care is lacking. Because most SCC are associated with abnormalities in tumor suppressor genes, particularly p53, we postulated that similar mechanisms may underlie the development of burn-associated SCC.\n\n\nMETHODS\nWe analyzed tissue DNA from a patient who died from an aggressive SCC in a burn scar for evidence of p53 gene abnormalities by polymerase chain reaction and immunohistochemical staining for p53 protein.\n\n\nRESULTS\nUsing polymerase chain reaction, the p53 gene could not be detected in DNA from the patient's cancer. The p53 protein was also undetectable by immunohistochemical staining.\n\n\nCONCLUSION\nThese studies indicate that there was a homozygous deletion of the p53 gene in this burn-related carcinoma. Further studies of other patients may lead to new understanding of this cancer, explain in part the usual aggressive behavior, and lead to new methods of prevention and treatment.", "corpus_id": 34605001, "score": 1 }, { "doc_id": "28141966", "title": "Marjolin ulcers: secondary carcinomas in chronic wounds.", "abstract": "Marjolin ulcers are malignant tumors arising in chronic wounds. Strictly defined, they include carcinomas that transform from the chronic open wounds of pressure sores or burn scars. They behave aggressively and have a propensity for local recurrence and lymph node metastases. A retrospective study was done at a single institution identifying six individuals who had chronic wound ulcers that underwent malignant transformation into a carcinoma. Sinus tract degeneration in osteomyelitis was not included. The average latency time between ulcer formation and documentation of a malignancy was 30 years. All wounds were about the pelvis or flank. Major oncologic surgical procedures were done in an attempt to eradicate the cancer. High-grade tumors had positive lymph node metastases, portending a grave prognosis. All four individuals with nodal metastases eventually died of systemic disease. Early recognition and proper staging offers the best chance for cure.", "corpus_id": 28141966, "score": 0 }, { "doc_id": "26023402", "title": "Marjolin’s Ulcers in sub-Saharan Africa", "abstract": "BackgroundCutaneous malignancies are considered rare among Africans. Trauma, its sequelae, and other chronic non-healing wounds are known to predispose to malignant degeneration. Not much is known of the demographics of Marjolin’s ulcers in sub-Saharan Africa.MethodsPathology records on patients suspected to have Marjolin’s ulcers submitted to the Pathology Department were extracted from a database of 75,124 specimens. A review of the English literature on Marjolin’s ulcers from Nigeria, a sub-Saharan country, was also performed.ResultsOf 210 specimens from suspected Marjolin’s ulcers, 167 records had a histological diagnosis of malignancy, with a male to female ratio of 1:1.4, and a mean age of 48 years (range: 4–97 years). There were 163 (97.6%) squamous cell carcinomas, 3 (1.8%) sarcomas, and 1 (0.6%) malignant melanoma. Burn scars, chronic ulcers, osteomyelitis, and “other” ulcers constituted 82 (49%), 70 (42%), 9 (5.4%), and 6 (3.6%), respectively. Subjects in six sub-Saharan Marjolin’s ulcer studies had a mean age between 36 and 42 years, with a mean latent period 16 years.ConclusionsMarjolin’s ulcers in sub-Saharan African have a shorter latent period, and they occur in younger patients. Provision of early stable wound cover is essential for prevention of malignant degeneration of scars, while early appropriate intervention is crucial in the treatment of chronic ulcers.", "corpus_id": 26023402, "score": 1 }, { "doc_id": "36234542", "title": "Squamous-cell carcinoma complicating chronic osteomyelitis.", "abstract": "Treatment of carcinomatous degeneration in patients with chronic osteomyelitis requires differentiation between benign, penetrating epithelioma and invading, low-grade squamous-cell carcinoma. Although most lesions are low grade, analysis of the case histories of twenty-three patients treated at the Mayo Clinic indicates that these tumors do metastasize. When malignant-appearing epithelium invading bone is identified, ablative surgery is indicated. Inadequate surgical treatment resulted in the deaths of two patients in our series. Routine regional lymphadenectomy at the time of amputation seems unnecessary. Regional lymphadenopathy persisting for six to twelve weeks after amputation warrants surgical intervention. With prompt, aggressive surgical treatment, the prognosis for patients with squamous-cell carcinoma in an osteomyelitic cavity is good.", "corpus_id": 36234542, "score": 0 }, { "doc_id": "24202438", "title": "Marjolin's ulcers arising in burn scars.", "abstract": "Epidermoid carcinoma in nonhealing scar tissue, known as Marjolin's ulcer, is not uncommon and is thought to behave in a more aggressive fashion than those from other causes. Between 1982 and 1997, 56 patients with Marjolin's ulcer were treated at our center, Ege University Medical School, Izmir, Turkey. All lesions were secondary to various kinds of burns. Forty of these patients could be followed up 5 years or more. These 40 patients' medical records were reviewed retrospectively.", "corpus_id": 24202438, "score": 0 }, { "doc_id": "46169581", "title": "Prognostic and therapeutic use of microstaging of cutaneous squamous cell carcinoma of the trunk and extremities", "abstract": "Cutaneous squamous cell carcinomas (SCC) arising in actinically damaged skin, unassociated with chronic inflammation or injury, are generally regarded as nonaggressive lesions. These tumors occasionally recur or metastasize, however, as do de novo SCC. The authors reviewed 63 patients with cutaneous SCC of the trunk or extremities, excluding lesions that developed in known high risk settings, in order to explore the potential of histologic microstaging as a prognostic indicator. Fiftyfour patients (86%) were free of recurrence following primary surgical therapy. Nine patients (14%) had either local recurrence or metastases; five of these (8% of the entire series) died of their tumors. Tumor behavior correlated best with the level of dermal invasion and the vertical tumor thickness. All tumors that recurred were 4 mm or more thick and involved the deep half of the dermis or deeper structures. All tumors that proved fatal were at least 10 mm in maximum thickness, and the four lethal lesions that could be evaluated for level of invasion extended into subcutaneous tissue or deeper structures. The thickness and level of invasion of cutaneous SCC appear to represent important prognostic factors and may be relevant indicators for wide field resection and/or elective lymph node dissection.", "corpus_id": 46169581, "score": 0 }, { "doc_id": "10569251", "title": "Burn scar carcinoma: Diagnosis and Management", "abstract": "background. The term Marjolin ulcer is now synonymous with malignant transformation of chronic ulcers, sinus tracts, and burn scars. objective. To illustrate the importance of incisional or excisional biopsies in cases of suspected burn scar carcinoma. methods. Case report and review of the literature. results. Multiple punch biopsies were negative while a complete excision revealed the diagnosis of squamous cell carcinoma. conclusion. Because of the focal nature of malignant change in burn scars, incisional or excisional biopsy should be performed.", "corpus_id": 10569251, "score": 0 } ]

{ "doc_id": "38770821", "title": "The TERT promoter mutation incidence is modified by germline TERT rs2736098 and rs2736100 polymorphisms in hepatocellular carcinoma", "abstract": "Telomerase activation via induction of the catalytic component telomerase reverse transcriptase (TERT) plays essential roles in malignant transformation. TERT promoter-activating mutations were recently identified as a novel mechanism to activate telomerase in hepatocellular carcinoma (HCC) and many other malignancies. In addition, single nucleotide polymorphisms (SNPs) in the TERT rs2736098 and rs2736100 are significantly associated with cancer susceptibility. It is currently unclear whether different germline TERT variants modify TERT promoter mutations. Here we analyzed the TERT promoter status and genotyped the TERT SNPs at rs2736098 and rs2736100 in patients with HCC. Thirty percent of HCCs harbored TERT promoter mutations and there was a significant difference in rs2736098 and rs2736100 genotypes between wt and mutant TERT promoter-bearing HCC tumors (P = 0.007 and 0.018, respectively). For rs2736100, the cancer risk genotype CC was significantly associated with a reduced incidence of TERT promoter mutations compared to AA + AC variants [Odds ratio (OR): 0.181, 95% Confidence interval (CI): 0.0543–0.601, P = 0.004]. The rs2736098_CT genotype was significantly associated with the TERT promoter mutation-positive tumors compared to the TT genotype (OR: 5.391, 95% CI: 1.234–23.553, P = 0.025). These differences in genotype distribution did not differ between patients with a wt TERT promoter and controls. The presence of TERT promoter mutations was not associated with clinico-pathological variables. Taken together, the germline TERT genetic background may significantly affect the onset of TERT promoter mutations in HCCs, which provides a better understanding of HCC-related TERT promoter mutations and telomerase regulation in cancer.", "corpus_id": 38770821 }

[ { "doc_id": "7867443", "title": "Molecular alterations in hepatocellular carcinoma associated with hepatitis B and hepatitis C infections", "abstract": "Chronic infections with hepatitis B (HBV) and hepatitis C viruses (HCV) are the leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Both viruses encode multifunctional regulatory proteins activating several oncogenic pathways, which induce accumulation of multiple genetic alterations in the infected hepatocytes. Gene mutations in HBV- and HCV-induced HCCs frequently impair the TP53, Wnt/b-catenin, RAS/RAF/MAPK kinase and AKT/mTOR pathways, which represent important anti-cancer targets. In this review, we highlight the molecular mechanisms underlying the pathogenesis of primary liver cancer, with particular emphasis on the host genetic variations identified by high-throughput technologies. In addition, we discuss the importance of genetic alterations, such as mutations in the telomerase reverse transcriptase (TERT) promoter, for the diagnosis, prognosis, and tumor stratification for development of more effective treatment approaches.", "corpus_id": 7867443, "score": 1 }, { "doc_id": "22809130", "title": "Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.", "abstract": "Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years, there has been a clear delineation of the landscape of genetic alterations in HCC, including high-level DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), as well as homozygous deletions in chromosome 9 (CDKN2A). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in preneoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25%-30% of HCC patients, that, in addition to low-frequency mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated pathways in HCC. Conceptually, some of these changes behave as prototypic oncogenic addiction loops, being ideal biomarkers for specific therapeutic approaches. Data from genomic profiling enabled a proposal of HCC in 2 major molecular clusters (proliferation and nonproliferation), with differential enrichment in prognostic signatures, pathway activation and tumor phenotype. Translation of these discoveries into specific therapeutic decisions is an unmet medical need in this field.", "corpus_id": 22809130, "score": 0 }, { "doc_id": "25457422", "title": "Regulation of the human catalytic subunit of telomerase (hTERT).", "abstract": "Over the past decade, there has been much interest in the regulation of telomerase, the enzyme responsible for maintaining the integrity of chromosomal ends, and its crucial role in cellular immortalization, tumorigenesis, and the progression of cancer. Telomerase activity is characterized by the expression of the telomerase reverse transcriptase (TERT) gene, suggesting that TERT serves as the major limiting agent for telomerase activity. Recent discoveries have led to characterization of various interactants that aid in the regulation of human TERT (hTERT), including numerous transcription factors; further supporting the pivotal role that transcription plays in both the expression and repression of telomerase. Several studies have suggested that epigenetic modulation of the hTERT core promoter region may provide an additional level of regulation. Although these studies have provided essential information on the regulation of hTERT, there has been ambiguity of the role of methylation within the core promoter region and the subsequent binding of various activating and repressive agents. As a result, we found it necessary to consolidate and summarize these recent developments and elucidate these discrepancies. In this review, we focus on the co-regulation of hTERT via transcriptional regulation, the presence or absence of various activators and repressors, as well as the epigenetic pathways of DNA methylation and histone modifications.", "corpus_id": 25457422, "score": 0 }, { "doc_id": "2959406", "title": "Human Telomerase and Its Regulation", "abstract": "SUMMARY The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.", "corpus_id": 2959406, "score": 0 }, { "doc_id": "16313766", "title": "Cancer-Specific Telomerase Reverse Transcriptase (TERT) Promoter Mutations: Biological and Clinical Implications", "abstract": "The accumulated evidence has pointed to a key role of telomerase in carcinogenesis. As a RNA-dependent DNA polymerase, telomerase synthesizes telomeric DNA at the end of linear chromosomes, and attenuates or prevents telomere erosion associated with cell divisions. By lengthening telomeres, telomerase extends cellular life-span or even induces immortalization. Consistent with its functional activity, telomerase is silent in most human normal somatic cells while active only in germ-line, stem and other highly proliferative cells. In contrast, telomerase activation widely occurs in human cancer and the enzymatic activity is detectable in up to 90% of malignancies. Recently, hotspot point mutations in the regulatory region of the telomerase reverse transcriptase (TERT) gene, encoding the core catalytic component of telomerase, was identified as a novel mechanism to activate telomerase in cancer. This review discusses the cancer-specific TERT promoter mutations and potential biological and clinical significances.", "corpus_id": 16313766, "score": 1 }, { "doc_id": "42306672", "title": "TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection.", "abstract": "INTRODUCTION\nMutation in the core promoter of the telomerase reverse transcriptase (TERT) gene was determined to be a frequent event in malignant melanoma and other cancers. However, the role of TERT promoter mutation in hepatocellular carcinomas (HCCs) remains largely unknown.\n\n\nMETHODS\nGenomic DNA samples from the tumor tissue of 195 HCCs were analyzed for TERT promoter mutation at 2 hotspots (-124 and -146 bp from the ATG start site, g.1,295,228 and g.1,295,250, respectively) through direct sequencing.\n\n\nRESULTS\nThe TERT promoter mutation was identified in 57 of the 195 HCCs (29.2%) and was associated with old age (P = 0.0122), presence of anti-hepatitis C (HCV; P = 0.0048), and absence of hepatitis B surface antigen (HBsAg; P = 0.0007). However, the TERT promoter mutation did not correlate with serum α-fetoprotein levels, liver cirrhosis, tumor size, tumor grade, tumor stage, early tumor recurrence, β-catenin mutation or p53 mutation. A multivariate analysis confirmed that the absence of hepatitis B infection is an independent factor associated with TERT promoter mutation. Furthermore, among HCC patients infected with hepatitis C, those with concomitant hepatitis B infection exhibited infrequent TERT promoter mutation (P = 0.0435). Remarkably, patients presenting with TERT promoter mutation-positive and -negative HCCs exhibited similar disease-free and overall survival rates.\n\n\nCONCLUSIONS\nOur study indicated that the TERT promoter mutation frequently occurred in HCV-associated HCCs. The absence of Hepatitis B infection was significantly associated with the TERT promoter mutation. These findings suggest that various etiological factors may be involved in differing mechanisms to preserve telomeres during the carcinogenesis of HCCs.", "corpus_id": 42306672, "score": 0 }, { "doc_id": "34864999", "title": "Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features", "abstract": "Background and AimsGenetic alterations in specific genes are critical events in carcinogenesis and hepatocellular carcinoma (HCC) progression. However, the genetic alterations responsible for HCC development, progression, and survival are unclear.MethodsWe investigated the essential difference in genetic alterations between HCC and adjacent non-HCC tissues using next-generation sequencing technology.ResultsWe found recurrent mutations in several genes such as telomerase reverse transcriptase (TERT; 65 % of the total 104 HCCs), TP53 (38 %), CTNNB1 (30 %), AXIN1 (2 %), PTEN (2 %), and CDKN2A (2 %). TERT promoter mutations were associated with older age (p = 0.005), presence of hepatitis C virus (HCV) infection (p = 0.003), and absence of hepatitis B virus (HBV) infection (p < 0.0001). In hepatitis B surface antigen (HBs Ag)-positive HCC without TERT promoter mutations, HBV integration into TERT locus was found in 47 % patients and was mutually exclusive to TERT promoter mutations. Most (89 %) HBV integrants were in the HBx region. TP53 mutations were associated with HBV infection (p = 0.0001) and absence of HCV infection (p = 0.002). CTNNB1 mutations were associated with absence of HBV infection (p = 0.010). Moreover, TERT promoter mutation was significantly associated with shorter disease-free survival (p = 0.005) and poor overall survival (p = 0.024).ConclusionsGene alterations in TERT promoter, TP53, CTNNB1, and HBV integration were closely associated with HCC development, and mutations in TERT promoter are related to poor prognosis. These results are useful for understanding the underlying mechanism of hepatocarcinogenesis, diagnosis, and predicting outcomes of patients with HCC.", "corpus_id": 34864999, "score": 0 }, { "doc_id": "9435492", "title": "TERT promoter mutations in primary liver tumors.", "abstract": "Next-generation sequencing has drawn the genetic landscape of hepatocellular carcinoma and several signaling pathways are altered at the DNA level in tumors: Wnt/β-catenin, cell cycle regulator, epigenetic modifier, histone methyltransferase, oxidative stress, ras/raf/map kinase and akt/mtor pathways. Hepatocarcinogenesis is a multistep process starting with the exposure to different risk factors, followed by the development of a chronic liver disease and cirrhosis precede in the vast majority of the cases the development of HCC. Several lines of evidence have underlined the pivotal role of telomere maintenance in both cirrhosis and HCC pathogenesis. TERT promoter mutations were identified as the most frequent genetic alterations in hepatocellular carcinoma with an overall frequency around 60%. Moreover, in cirrhosis, TERT promoter mutations are observed at the early steps of hepatocarcinogenesis since they are recurrently identified in low-grade and high-grade dysplastic nodules. In contrast, acquisition of genomic diversity through mutations of classical oncogenes and tumor suppressor genes (TP53, CTNNB1, ARID1A…) occurred only in progressed HCC. In normal liver, a subset of HCC can derived from the malignant transformation of hepatocellular adenoma (HCA). In HCA, CTNNB1 mutations predispose to transformation of HCA in HCC and TERT promoter mutations are required in most of the cases as a second hit for a full malignant transformation. All these findings have refined our knowledge of HCC pathogenesis and have pointed telomerase as a target for tailored therapy in the future.", "corpus_id": 9435492, "score": 0 }, { "doc_id": "34068857", "title": "Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis", "abstract": "Genetic determinants of the early steps of carcinogenesis on cirrhosis are still poorly understood. We aimed to evaluate the occurrence of telomerase reverse transcriptase (TERT) promoter mutations in the transformation of cirrhotic nodules into hepatocellular carcinoma (HCC). We analyzed a series of 268 liver samples, including 96 nodules developed in 58 patients with cirrhosis and 114 additional cirrhosis. All samples were screened for TERT promoter mutations, and in 31 nodules, for 10 genes recurrently mutated in HCC. Immunohistochemistry (IHC) analyses were performed for glypican 3, glutamine synthase, and heat shock protein 70. Six liver pathologists reviewed all the samples. Among The 96 nodules, 88 were firmly diagnosed as low‐grade dysplastic nodules (LGDNs; 32 cases), high‐grade dysplastic nodules (HGDNs; 16 cases), early HCC (eHCC; 23 cases), or small and progressed HCC in 17 cases. The agreement between the initial diagnosis from pathological report and the final expert consensus report was moderate for the diagnosis of benign versus malignant nodules (weighted kappa = 0.530). TERT promoter mutations were highly related to the step‐wise hepatocarcinogenesis because mutations were identified in 6% of LGDNs, 19% of HGDNs, 61% of eHCCs, and 42% of small and progressed HCC. TERT promoter mutation is the most frequent molecular alteration in eHCC given that the IHC criteria for diagnosis of malignancy were found in only 39% of the cases. TERT promoter mutation was also the earliest genetic alteration because mutations in 10 other genes were only identified in 28% of the small and progressed HCC. Conclusion: Frequency of TERT promoter mutations rapidly increases during the different steps of the transformation of premalignant lesions into HCC on cirrhosis. Consequently, somatic TERT promoter mutation is a new biomarker predictive of transformation of premalignant lesions into HCC. (Hepatology 2014;60:1982–1991)", "corpus_id": 34068857, "score": 1 }, { "doc_id": "62778996", "title": "Corrigendum: High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions", "abstract": "Somatic mutations activating telomerase reverse-trancriptase promoter were recently identified in several tumour types. Here we identify frequent similar mutations in human hepatocellular carcinomas (59%), cirrhotic preneoplastic macronodules (25%) and hepato-cellular adenomas with malignant transformation in hepatocellular carcinomas (44%). In hepatocellular tumours, telomerase reverse-transcripase-and CTNNB1-activating mutations are significantly associated. Moreover, preliminary data suggest that telomerase reverse-trancriptase promoter mutations can increase the expression of telomerase transcript. In conclusion, telomerase reverse-trancriptase promoter mutation is the earliest recurrent genetic event identified in cirrhotic preneoplastic lesions so far and is also the most frequent genetic alteration in hepatocellular carcinomas, arising from both the cirrhotic or non-cirrhotic liver.", "corpus_id": 62778996, "score": 1 }, { "doc_id": "18087614", "title": "Tumor specific mutations in TERT promoter and CTNNB1 gene in hepatitis B and hepatitis C related hepatocellular carcinoma", "abstract": "Recurrent somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene and in the exon 3 of CTNNB1 gene have been recognized as common events in hepatocellular carcinoma (HCC) with variable frequencies depending on etiology and geographical region. We have analyzed TERT promoter and CTNNB1 gene mutations in 122 cases of hepatitis B (HBV) and hepatitis C (HCV) related HCCs, in 7 cases of cholangiocarcinoma (CC) and hepatocholangiocarcinoma (HCC-CC) as well as in autologous cirrhotic tissues. Overall, 50.4% and 26% of HCC as well as 14.3% and none of CC and HCC-CC were mutated in TERT promoter and in CTNNB1 exon 3, respectively. TERT and CTNNB1 mutations were found more frequently in HCV related (53.6% and 26.4%, respectively) than HBV related (41.7% and 16.7%, respectively) HCCs and coexisted in 57.6% of CTNNB1 mutated tumors. Mutations in TERT and CTNNB1 were not associated with the functional promoter polymorphism rs2853669. No mutations were detected in the 129 non-HCC cirrhotic tissues. In conclusion, mutations in TERT promoter and in CTNNB1 gene represent specific cancer signatures in the pathogenesis of viral related HCC and could be promising early biomarkers as well as targets for tailored therapies.", "corpus_id": 18087614, "score": 1 }, { "doc_id": "16405378", "title": "Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma", "abstract": "Telomerase reverse transcriptase (TERT) promoter mutations are among the most frequent noncoding somatic mutations in multiple cancers, including hepatocellular carcinoma (HCC). The clinical and pathological implications of TERT promoter mutations in hepatitis B virus (HBV)-associated HCC have not been resolved. To investigate TERT promoter mutations, protein expression, and their clinical-pathological implications, we sequenced the TERT promoter region for hotspot mutations in HCC tissues and performed immunostaining for TERT protein expression from HBV-associated HCC in Chinese patients. Of 276 HCC tumor DNA samples sequenced, 85 (31%) carried TERT promoter mutations. TERT promoter mutations were more frequent in those with low α-fetoprotein (AFP) serum levels (p = 0.03), advanced age (p = 0.04), and in those lacking HCC family history (p = 0.02), but were not correlated with HCC stages and grades. TERT protein levels were higher in HCC (n = 28) compared to normal liver tissues (n = 8) (p =0.001), but did not differ between mutated and non-mutated tumor tissues. In conclusion, TERT promoter mutations are common somatic mutations in HCC of Han Chinese with HBV infection. Detection of TERT promoter mutations in those with low levels of AFP may aid diagnosis of HCC with atypical presentation.", "corpus_id": 16405378, "score": 0 }, { "doc_id": "16254762", "title": "TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations", "abstract": "The telomerase reverse transcriptase (TERT) gene rs2736100_C allele has recently been shown to be associated with an increased risk for myeloproliferative neoplasms (MPNs) among Caucasians. However, it is unknown if this association is present in other ethnical populations and whether rs2736100 allele frequencies mirror the incidence of MPNs in a population. Here we genotyped TERT rs2736100 variants in 126 Swedish and 101 Chinese MPN patients and their age-, sex-, and ethnically-matched healthy controls. Healthy Chinese adults had a higher frequency of the A allele and lower frequencies of the C allele compared to Swedish counterparts (57.4 vs 47.0 % for A, 42.6 vs 53.0 % for C, P = 0.006). Both Swedish and Chinese patients harbored significantly higher C allele frequency than their controls (62.7 vs 53.0 % and 57.4 vs 42.6 % for Swedish and Chinese, respectively, P = 0.004). Swedes and Chinese bearing the CC genotype had a significantly increased risk of MPN compared to AA carriers (OR = 2.47; 95 % CI: 1.33–4.57, P = 0.003, for Swedes, and OR = 3.45; 95 % CI: 1.52–7.85, P = 0.005, for Chinese). Further analyses showed that rs2736100_CC was associated with robustly enhanced risk in males only (CC vs AA, OR = 5.11; 95 % CI: 2.19–11.92, P < 0.0001). The CC-carrying MPN patients exhibited significantly higher TERT expression than patients with the AC genotype. Collectively, the rs2736100_C is a risk allele for MPNs in Swedish and Chinese males, and the lower incidence of MPNs in the Chinese population is correlated with a lower rs2736100_C risk allele frequency.", "corpus_id": 16254762, "score": 1 }, { "doc_id": "9659266", "title": "TERT promoter mutations in renal cell carcinomas and upper tract urothelial carcinomas", "abstract": "TERT promoter mutations are identified in many malignancies including bladder cancer (BC) and upper tract urothelial carcinoma (UTUC). In contrast, no mutations were found in renal cell carcinoma (RCC) as reported in a recent study. Because the mutant TERT promoter in urine DNA was recently tested as a marker for BC, it is important to ascertain whether these mutations are truly absent in RCCs. Here we determined TERT promoter mutations in 109 patients with RCC and 14 patients with UTUC. The mutations were found in 9/96 (9.3%) clear cell RCC (ccRCC) tumors and 1/8 (13%) chromophobe RCC tumors. Among ccRCC patients, the mutation was correlated with the advanced stages and metastasis, and higher TERT expression. Among UTUCs, the mutation was detected in tumors from 3/5 (60%) patients with renal pelvic cancer and 1/9 (11%) patients with ureter cancer. The mutation was also detected in 1 of 4 urine samples from patients with mutation+ UTUC. Collectively, TERT promoter mutations do occur in RCCs and are associated with aggressive disease. The mutation is more frequent in renal pelvic cancer. Thus, the mutant TERT promoter found in urine may come from not only BC, but also RCC or UTUC.", "corpus_id": 9659266, "score": 0 }, { "doc_id": "5874923", "title": "Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis.", "abstract": "BACKGROUND\nSeveral recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer.\n\n\nMETHODS\nA systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as \"strong,\" \"moderate,\" and \"weak\" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association.\n\n\nRESULTS\nEighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types.\n\n\nCONCLUSIONS\nTo our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans.", "corpus_id": 5874923, "score": 0 }, { "doc_id": "19312520", "title": "TERT rs2736098 polymorphism and cancer risk: results of a meta-analysis.", "abstract": "OBJECTIVE\nSeveral studies have demonstrated associations between the TERT rs2736098 single nucleotide polymorphisms (SNPs) and susceptibility to cancer development. However, there are conflicting results. A systematic meta-analysis was therefore performed to establish the cancer risk associated with the polymorphism.\n\n\nMETHODS\nIn this meta-analysis, a total of 6 case-control studies, including 5,567 cases and 6,191 controls, were included. Crude odds ratios with 95% confidence intervals were used to assess the strength of associations in several genetic models.\n\n\nRESULTS\nOur results showed no association reaching the level of statistical significance for overall risk. Interestingly, in the stratified analyses (subdivided by ethnicity), significantly increased risks were found in the Asian subgroup which indicates the TERT rs2736098 polymorphism may have controversial involvement in cancer susceptibility.\n\n\nCONCLUSIONS\nOverall, this meta-analysis indicates that the TERT rs2736098 polymorphism may have little involvement in cancer susceptibility.", "corpus_id": 19312520, "score": 0 }, { "doc_id": "205355914", "title": "Genome-wide association study identifies five susceptibility loci for glioma", "abstract": "To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 × 10−17), 8q24.21 (rs4295627, CCDC26; P = 2.34 × 10−18), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 × 10−15), 20q13.33 (rs6010620, RTEL1; P = 2.52 × 10−12) and 11q23.3 (rs498872, PHLDB1; P = 1.07 × 10−8). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.", "corpus_id": 205355914, "score": 0 }, { "doc_id": "15697955", "title": "The association between the TERT rs2736100 AC genotype and reduced risk of upper tract urothelial carcinomas in a Han Chinese population", "abstract": "Upper tract urothelial carcinomas (UTUCs) are originated from urothelium, and consist of renal pelvic carcinomas (RPCs) and ureter carcinomas (UCs). Most UTUCs have already become invasive when diagnosed and there is thus a need to identify high-risk populations for preventive intervention. Recent evidence has accumulated supporting common single nucleotide polymorphisms (SNPs) to be associated with increased risk of various malignancies. However, little is known about susceptibility loci in relation to UTUC development. We genotyped telomerase reverse transcriptase (TERT) rs2736100 variants, the SNP associated with a risk of multiple-types of cancer, in patients with UTUC (n = 212) and evaluated the relationship between the rs2736100 and UTUC risk by comparing to 289 healthy controls. Neither AA nor CC genotypes differed significantly between cases and controls, while the AC-carriers were associated with a reduced risk of UTUC compared to the homozygous AA (OR = 0.583; 95% CI: 0.388 − 0.875; P = 0.012) or AA + CC genotypes (0.613; 95% CI: 0.428 − 0.879; P = 0.010). Further analyses showed that the AC variant conferred a lower risk for early stage UTUCs or those with a wt TERT promoter. When UTUCs were sub-grouped into UCs and RPCs, the AC genotype still predicts a significantly lower risk for UC (P = 0.045, OR = 0.597, 95% CI: 0.370 − 0.963), while at a border line significance for RPC (P = 0.055, OR = 0.597, 95% CI: 0.324 − 0.976). Collectively, the rs2736100 AC variant predicts a reduced risk to develop UTUC.", "corpus_id": 15697955, "score": 0 }, { "doc_id": "1037860", "title": "hTERT rs2736098 genetic variants and susceptibility of hepatocellular carcinoma in the Chinese population: a case-control study.", "abstract": "BACKGROUND\nThe human telomerase reverse transcriptase (hTERT) gene encodes the catalytic subunit of telomerase, which mediates pleiotropic effects, including the regulation of senescence and proliferation and plays an important role in carcinogenesis. This study attempts to clarify the genetic predisposition to hepatocellular carcinoma (HCC), focusing on the hTERT gene rs2736098 polymorphism.\n\n\nMETHOD\nFour hundred patients with HCC and 400 non-cancer controls were genotyped to elucidate the potential association between hTERT rs2736098 polymorphism and HCC risks.\n\n\nRESULTS\nCompared with the controls, the patients with HCC had a lower frequency of G/G genotype (33.3% vs 44.3%, P=0.001) and a higher frequency of G/A (51.5% vs 39.5%, P=0.001). Allele genotypic frequencies in the patients differed from those of the controls (P=0.040). The data of this study rs2736098[A] allele contributed significantly to HCC risk in female patients (OR=1.78, 95% CI, 1.17-2.72, P=0.007), patients with HCV infection (OR=2.89, 95% CI, 1.08-7.70, P=0.031), non-drinker patients (OR=1.32, 95% CI, 1.06-1.65, P=0.015), and patients not affected by HBV (OR=1.77, 95% CI, 1.30-2.40, P<0.001).\n\n\nCONCLUSIONS\nrs2736098[A] may be an independent hereditary parameter in HCC, but some risk factors would cover up the association by more powerful hepatocarcinogenesis. These results are important guidance for further studies in detecting HCC-associated single nucleotide polymorphisms.", "corpus_id": 1037860, "score": 1 }, { "doc_id": "11410872", "title": "The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms", "abstract": "The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms", "corpus_id": 11410872, "score": 0 }, { "doc_id": "21957586", "title": "hTERT Cancer Risk Genotypes Are Associated With Telomere Length", "abstract": "Telomere biology is associated with cancer initiation and prognosis. Collected data suggest that blood cell telomere length (TL) can change over time, which may be related to development of common disorders, such as cardiovascular diseases and cancer. Recently, single nucleotide polymorphisms in the region of the human telomerase reverse transcriptase (hTERT) gene were associated with various malignancies, including glioma, lung and urinary bladder cancer, and telomerase RNA gene hTERC genotypes were recently linked to TL. In the present study a hypothetical association between identified genotypes in hTERT and hTERC genes and TL were investigated. We analyzed 21 polymorphisms, covering 90% of the genetic variance, in the hTERT gene, two genetic variants in hTERC, and relative TL(RTL) at average age 50 and 60 in 959 individuals with repeated blood samples. Mean RTL at age 60 was associated with four genetic variants of the hTERT gene (rs2736100, rs2853672, rs2853677, and rs2853676), two of which reported to be associated with cancer risk. Two alleles (rs12696304, rs16847897) near the hTERC gene were confirmed as also being associated with RTL at age 60. Our data suggest that hTERT and hTERC genotypes have an impact on TL of potential relevance and detectable first at higher ages, which gives us further insight to the complex regulation of TL. Genet. Epidemiol. 36:368–372, 2012. © 2012 Wiley Periodicals, Inc.", "corpus_id": 21957586, "score": 0 }, { "doc_id": "205346672", "title": "Lung cancer susceptibility locus at 5p15.33", "abstract": "We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 × 10−7 and P = 4 × 10−6) and replicated by the independent study series (P = 7 × 10−5 and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.", "corpus_id": 205346672, "score": 0 }, { "doc_id": "13964564", "title": "The TERT variant rs2736100 is associated with colorectal cancer risk", "abstract": "Background:Polymorphic variation at the 5p15.33 (TERT–CLPTM1L) locus is associated with the risk of many cancers but a relationship with colorectal cancer (CRC) risk has yet to be defined.Methods:We used data from six genome-wide association studies (GWAS) of CRC, linkage disequilibrium mapping and imputation, to examine the relationship between 73 single-nucleotide polymorphisms at 5p15.33 and CRC risk in detail.Results:rs2736100, which localises to intron 2 of TERT, provided the strongest evidence of an association with CRC (P=2.28 × 10−4). The association was also shown in an independent series of 10 047 CRC cases and 6918 controls (P=0.02). A meta-analysis of all seven studies (totalling 16 039 cases, 16 430 controls) provided increased evidence of association (P=2.49 × 10−5; per allele odds ratio=1.07). The association of rs2736100 on CRC risk was shown to be independent of 15 low-penetrance variants previously identified.Conclusion:The rs2736100 association demonstrates an influence of variation at 5p15.33 on CRC risk and further evidence that the 5p15.33 (TERT–CLPTM1L) locus has pleiotropic effects (reflecting generic or lineage-specific effects) on cancer risk.", "corpus_id": 13964564, "score": 0 }, { "doc_id": "21914849", "title": "Genetic variations on chromosomes 5p15 and 15q25 and bladder cancer risk: findings from the Los Angeles-Shanghai bladder case-control study.", "abstract": "Genome-wide association studies have associated common variations at chromosomes 5p15 and 15q25 with lung cancer risk. The 5p15 locus has also been associated with increased bladder cancer risk in a recent report. The 15q25 locus has been associated with nicotine dependence and self-reported number of cigarettes smoked per day in some studies and it was proposed that its association with lung cancer may be mediated through differences in smoking behavior. Here, we investigated the roles of variations at 5p15 (rs401681, rs402710, rs2736098 and rs2736100) and 15q25 (rs1051730 and rs8034191) in bladder cancer etiology in two case-control studies conducted separately in Los Angeles County, CA, USA (498 cases and 588 controls) and in Shanghai, China (506 cases and 530 controls). We replicated the association between the 5p15 locus and bladder cancer among non-Hispanic whites (NHW) in Los Angeles [for rs2736100, per C allele odds ratio (OR) = 1.23; 95% confidence interval (CI), 1.02-1.48; P = 0.029] and among Chinese in Shanghai (OR = 1.22; 95% CI, 1.02-1.47; P = 0.033). Both rs1051730 and rs8034191 at 15q25 were rare among Chinese. Among NHW, a significant association was found between rs8034191 and bladder cancer which persisted after adjustment for cigarette smoking status, number of cigarettes smoked per day and number of years of smoking (per C allele OR = 1.26; 95% CI, 1.04-1.54; P = 0.017). Our results support 5p15 and 15q25 as susceptibility regions for bladder cancer risk.", "corpus_id": 21914849, "score": 0 }, { "doc_id": "24549232", "title": "Multiple variants of TERT and CLPTM1L constitute risk factors for lung adenocarcinoma.", "abstract": "Recent studies have shown that 5p15.33 is one of the chromosomal regions that is most consistently altered in lung cancer; common variants that are located in this region have been genotyped in various populations. However, the genetic contribution of these variants to carcinogenesis is relatively unknown. A clinic-based case-control study in Shanghai was undertaken on 196 patients with lung cancer and 229 healthy individuals. TERT rs2736100 and CLPTM1L rs401681 and rs402710 were genotyped using the ABI TaqMan Allelic Discrimination assay. For rs2736100, the G variant and the GG genotype were more frequent, whereas the TT genotype was less frequent in patients with lung adenocarcinoma than in controls. The CT genotype at rs401681 was more common and the TT genotype was rare in patients, and the differences were significant between lung adenocarcinoma patients and controls. This was also true for rs402710. Moreover, the frequency of the GGCTCT haplotype was higher and the TTTTTT frequency was lower in patients, especially those with lung adenocarcinoma. Aberrant linkage disequilibrium among the three SNPs was found in patients with lung adenocarcinoma. We conclude that multiple variants at 5p15.33 contribute to susceptibility to lung adenocarcinoma.", "corpus_id": 24549232, "score": 0 }, { "doc_id": "403398", "title": "Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer", "abstract": "TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10−7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10−8) and BRCA1 mutation carrier (P = 1.1 × 10−5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10−14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10−15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10−12) and BRCA1 mutation carrier (P = 1.6 × 10−14) breast and invasive ovarian (P = 1.3 × 10−11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.", "corpus_id": 403398, "score": 0 }, { "doc_id": "8790161", "title": "TERT Polymorphism rs2736100-C Is Associated with EGFR Mutation–Positive Non–Small Cell Lung Cancer", "abstract": "Purpose: EGF receptor (EGFR) mutation–positive (EGFRmut+) non–small cell lung cancer (NSCLC) may be a unique orphan disease. Previous studies suggested that the telomerase reverse transcriptase (TERT) gene polymorphism is associated with demographic and clinical features strongly associated with EGFR mutations, for example, adenocarcinoma histology, never-smoking history, and female gender. We aim to test the association between TERT polymorphism and EGFRmut+ NSCLC. Experimental Design: We conducted a genetic association study in Chinese patients with NSCLC (n = 714) and healthy controls (n = 2,520), between the rs2736100 polymorphism and EGFRmut+ NSCLC. We further tested the association between the EGFR mutation status and mean leukocyte telomere length (LTL). The potential function of rs2736100 in lung epithelial cells was also explored. Results: The rs2736100-C allele was significantly associated with EGFRmut+ NSCLC [OR, 1.52; 95% confidence interval (CI), 1.28–1.80; P = 1.6 × 10−6] but not EGFRmut− NSCLC (OR = 1.07, 95% CI, 0.92–1.24, P = 0.4). While patients with NSCLC as a whole have significantly longer LTL than healthy controls (P ≤ 10−13), the EGFRmut+ patients have even longer LTL than EGFRmut− patients (P = 0.008). Meanwhile, rs2736100 was significantly associated with TERT mRNA expression in both normal and tumor lung tissues. All results remained significant after controlling for age, gender, smoking status, and histology (P < 0.05 for all tests). Moreover, the rs2736100 DNA sequence has an allele-specific affinity to nuclear proteins extracted from lung epithelial cells, which led to an altered enhancer activity of the sequence in vitro. Conclusions: Our study suggests that telomerase and telomere function may be essential for carcinogenesis of EGFRmut+ NSCLC. Further investigation for the underlying mechanism is warranted. Clin Cancer Res; 21(22); 5173–80. ©2015 AACR.", "corpus_id": 8790161, "score": 1 }, { "doc_id": "9169599", "title": "Co-occurrence of Myeloproliferative Neoplasms and Solid Tumors Is Attributed to a Synergism Between Cytoreductive Therapy and the Common TERT Polymorphism rs2736100", "abstract": "Background: The germline telomerase reverse transcriptase (TERT) rs2736100_C variant was identified as a susceptibility factor for a variety of solid tumors and recently for myeloproliferative neoplasms (MPN). Methods: LightCycler melting curve analysis was applied to detect risk alleles of TERT rs2736100_C and Janus kinase 2 (JAK2) rs12343867_C tagging 46/1 haplotype in 584 BCR-ABL1–negative MPN, 308 acute, and 86 chronic myeloid leukemia (AML and CML) patients and 400 healthy individuals. Results: TERT rs2736100_C showed an increased allele frequency in BCR-ABL1–negative MPN patients compared with controls (62.7%±2.8% vs. 48.8%±3.5%, P < 0.0001) regardless of molecular background or disease type, but not in CML or AML. Combined TERT and JAK2 hetero- or homozygosity conferred even higher risk for classic MPN. Common complications (thrombosis, myelofibrosis, or leukemia) were not associated with the TERT variant; however, adverse survival was noted in TERT variant carrier polycythemia vera patients. MPN patients with the TERT CC genotype had a higher probability (44.4%) to die from solid tumors compared with TERT AC/AA individuals (5.3%; P = 0.004). TERT rs2736100_C carriers had increased risk of solid tumors independently from cytoreductive treatment [3.08 (1.03–9.26), P = 0.045]. Conclusions: TERT rs2736100_C polymorphism predisposes to the development of BCR-ABL1–negative MPN with the co-occurrence of solid tumors, especially with the usage of cytoreductive treatment. Impact: The high frequency of TERT variant in the classic MPN population highlights the importance of the avoidance of long-term cytoreductive treatment in MPN patients. Cancer Epidemiol Biomarkers Prev; 25(1); 98–104. ©2015 AACR.", "corpus_id": 9169599, "score": 0 }, { "doc_id": "32477740", "title": "Sequence variants at the TERT-CLPTM1L locus associate with many cancer types", "abstract": "The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 × 10−12). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 × 10−8) and urinary bladder, prostate and cervix cancer (ORs = 1.07−1.31, all P < 4 × 10−4). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 × 10−4). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.", "corpus_id": 32477740, "score": 0 }, { "doc_id": "206544787", "title": "Highly Recurrent TERT Promoter Mutations in Human Melanoma", "abstract": "Promoter Mutations and Cancer Cancer genome sequencing projects have highlighted the pathogenic role of recurrent mutations within the protein-coding regions of genes. Now, two studies suggest that the scope of mutations in human tumors extends to gene regulatory regions. In a study of 70 melanomas, Huang et al. (p. 957, published online 24 January) found that 71% harbored one of two specific mutations in the promoter region of TERT, the gene coding for the catalytic subunit of telomerase, the enzyme that caps chromosome ends. Independently, Horn et al. (p. 959, published online 24 January) identified a disease-segregating germline mutation in the TERT promoter in a family predisposed to melanoma and found additional TERT promoter mutations in a high percentage of sporadic melanomas and melanoma cell lines. The mutations in both studies generated new binding sites for specific transcription factors and, in reporter assays, caused an increase in transcription. A large fraction of human melanomas harbor mutations in sequences that regulate the expression of telomerase. Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.", "corpus_id": 206544787, "score": 0 }, { "doc_id": "16942691", "title": "The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer", "abstract": "A mutant promoter's partner in crime Telomerase is an enzyme that maintains the ends of chromosomes. TERT, the gene coding for the enzyme's catalytic subunit, is not expressed in healthy somatic cells, but its expression is reactivated in the majority of human cancers. The resultant high levels of telomerase help cancer cells survive and multiply. Recurrent mutations in the promoter region of TERT are associated with high telomerase levels in multiple cancer types. Bell et al. show that a specific transcription factor called GABP is selectively recruited to the mutant form of the TERT promoter, which activates TERT gene expression Science, this issue p. 1036 Cancer-associated mutations in the promoter of the telomerase gene allow increased activation by transcription factor binding. Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBMs), harbor highly recurrent TERT promoter mutations of unknown function but specific to two nucleotide positions. We identified the functional consequence of these mutations in GBMs to be recruitment of the multimeric GA-binding protein (GABP) transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression in multiple cancers.", "corpus_id": 16942691, "score": 0 }, { "doc_id": "31779470", "title": "TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA", "abstract": "The telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have been found in many malignancies, including in thyroid carcinomas. However, it is unclear how early these mutations occur in thyroid tumorigenesis.", "corpus_id": 31779470, "score": 0 }, { "doc_id": "2634428", "title": "TERT promoter mutations rather than methylation are the main mechanism for TERT upregulation in adult gliomas", "abstract": "observed TERT upregulation in some tumors without mutations in the hotspots. A small subset of tumors had neither TERT nor ATRX mutations [9]. Recently, it has been reported that DNA hypermethylation of the TERT promoter is a common finding in pediatric brain tumors and associated with TERT upregulation [2]. Hypermethylation of the TERT CpG island has been linked to increased expression levels in other cancers [2, 4, 5]. We, therefore, studied the association between TERT methylation and TERT mRNA levels to investigate the possibility that DNA methylation serves as an alternative mechanism for TERT upregulation in adult gliomas. Eighty-eight adult gliomas samples with known TERT promoter mutation status suitable for mRNA expression analysis, 43 of which had mutations, were examined in this study. TERT mRNA expression of 88 tumors including 48 primary glioblastomas that have previously been investigated was analyzed as described [1]. The methylation status of three regions within the CpG island (Regions 1–3; Fig. 1a), including the region methylated in pediatric tumors (Region 1) and the region that contains the two mutation hotspots (Region 3), was assessed by pyrosequencing of the PCR products amplified from bisulfitemodified genomic DNA. The methylation status was represented either as the mean methylation levels of all CpGs in each region or as a dichotomous variable (hypermethylated or unmethylated) at each region using the cut-off value of 15 % according to Castelo-Branco et al. [2]. More detailed information is available in Supplementary Materials and Methods. There was no significant difference in the mean methylation levels or the frequency of hypermethylated tumors in any of the regions between tumors of the different histological subtypes (astrocytic tumor, oligodendroglial tumor and glioblastoma), or between those with and without Telomere lengthening (TL) is mandatory for infinite proliferation of many cancer cells. This is generally achieved either by telomerase activation or in some cases by telomerase-independent alternative lengthening of telomeres (ALT) [3]. Recently, recurrent mutations at two hotspots termed C228T and C250T in the promoter region of TERT, a catalytic subunit of telomerase, have been reported in various types of cancers [1, 6, 7, 9, 12]. These mutations result in upregulation of TERT expression [1, 7], which is required for telomerase activation [11]. TERT promoter mutations are particularly common in adult gliomas [1, 9]. It is also known that a subset of astrocytomas harbors mutations of ATRX, which could lead to ALT [10]. We have previously shown that glioblastomas with TERT mutation had TERT mRNA upregulation [1]. We have also", "corpus_id": 2634428, "score": 0 }, { "doc_id": "6603881", "title": "The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas", "abstract": "Telomerase activation through induction of its catalytic component telomerase reverse transcriptase (TERT) expression is essential for malignant transformation. TERT promoter mutations namely C228T and C250T that stimulate TERT transcription and telomerase activation have recently been identified in many human malignancies. We thus determined these mutations and their biological and clinical implications in thyroid carcinomas in the present study. The TERT promoter was sequenced in 10 thyroid cancer cell lines and 144 tumors from 20 patients with anaplastic thyroid carcinoma (ATC), 51 with papillary thyroid carcinoma (PTC), 36 with follicular thyroid carcinoma (FTC), and 37 with medullary thyroid carcinoma (MTC). We identified C228T or C250T mutation in 6/8 of ATC cell lines, as well as in tumor tissue from 10/20, 13/51, 8/36 and 0/37 patients with ATC, PTC, FTC and MTC, respectively. In PTC patients, these mutations were exclusively present in the group with age >45 years (P<0.0001), and highly correlated shorter telomeres (P<0.0001) and distant metastasis (P=0.028). The previous radioactivity exposure did not induce the mutation. The presence of C228T or C250T was an independent predictor associated with shorter disease-related survival (DRS) in the entire cohort (P<0.0001), as well as among patients >45 years (P=0.021). ATC patients carrying the mutation survived shorter than those without mutations, although not statistically significant (P=0.129). The TERT promoter mutation was associated with overall survival (P=0.038) and DRS (P=0.058) of FTC patients. Taken together, age- and shorter telomere-dependent TERT promoter mutations occur frequently in follicular cell-derived thyroid carcinoma (ATC, PTC and FTC) but not in parafollicular cell-originated MTC, and may serve as a marker for aggressive disease and poor outcome.", "corpus_id": 6603881, "score": 0 }, { "doc_id": "25639199", "title": "Genetic variation in TERT and TERC and human leukocyte telomere length and longevity: a cross‐sectional and longitudinal analysis", "abstract": "Telomerase is of key importance for telomere maintenance, and variants of the genes encoding its major subunits, telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), are candidates for interindividual variation in telomere length. Recently, the two SNPs rs3772190 and rs12696304 in the TERC locus were reported to be associated with leukocyte telomere length (LTL) in two genome‐wide association studies, while one haplotype of TERT (rs2853669, rs2736098, rs33954691, and rs2853691) has been reported to be associated with both LTL and longevity in a candidate gene study. In this study, we investigated the two TERC and four TERT SNPs in middle‐aged, old, and oldest‐old Danes (58–100 years) and their association with LTL (n = 864) and longevity (n = 1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest‐old and 736 middle‐aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross‐sectional and a longitudinal approach. Applying an additive model, we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coefficient = −0.08, P = 0.011) and in male rs12696304 G carriers (regression coefficient = −0.13, P = 0.014). No TERT variations showed association. Moreover, the A allele of rs3772190 (TERC) was found to be associated with longevity [hazard rate (AG + AA) = 1.31, P = 0.006]. No associations with longevity were observed for the TERT SNPs or haplotypes. Our study, thus, indicates that TERC is associated with both LTL and longevity in humans.", "corpus_id": 25639199, "score": 0 }, { "doc_id": "16558402", "title": "Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome.", "abstract": "BACKGROUND\nHotspot mutations in the promoter of the gene coding for telomerase reverse transcriptase (TERT) have been described and proposed to activate gene expression.\n\n\nOBJECTIVES\nTo investigate TERT mutation frequency, spectrum, association with expression and clinical outcome, and potential for detection of recurrences in urine in patients with urothelial bladder cancer (UBC).\n\n\nDESIGN, SETTING, AND PARTICIPANTS\nA set of 111 UBCs of different stages was used to assess TERT promoter mutations by Sanger sequencing and TERT messenger RNA (mRNA) expression by reverse transcription-quantitative polymerase chain reaction. The two most frequent mutations were investigated, using a SNaPshot assay, in an independent set of 184 non-muscle-invasive and 173 muscle-invasive UBC (median follow-up: 53 mo and 21 mo, respectively). Voided urine from patients with suspicion of incident UBC (n=174), or under surveillance after diagnosis of non-muscle-invasive UBC (n=194), was tested using a SNaPshot assay.\n\n\nOUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS\nAssociation of mutation status with age, sex, tobacco, stage, grade, fibroblast growth factor receptor 3 (FGFR3) mutation, progression-free survival, disease-specific survival, and overall survival.\n\n\nRESULTS AND LIMITATIONS\nIn the two series, 78 of 111 (70%) and 283 of 357 (79%) tumors harbored TERT mutations, C228T being the most frequent substitution (83% for both series). TERT mutations were not associated with clinical or pathologic parameters, but were more frequent among FGFR3 mutant tumors (p=0.0002). There was no association between TERT mutations and mRNA expression (p=0.3). Mutations were not associated with clinical outcome. In urine, TERT mutations had 90% specificity in subjects with hematuria but no bladder tumor, and 73% in recurrence-free UBC patients. The sensitivity was 62% in incident and 42% in recurrent UBC. A limitation of the study is its retrospective nature.\n\n\nCONCLUSIONS\nSomatic TERT promoter mutations are an early, highly prevalent genetic event in UBC and are not associated with TERT mRNA levels or disease outcomes. A SNaPshot assay in urine may help to detect UBC recurrences.", "corpus_id": 16558402, "score": 0 }, { "doc_id": "31586630", "title": "Comprehensive mutation analysis of the TERT promoter in bladder cancer and detection of mutations in voided urine.", "abstract": "The link between telomere maintenance and telomerase activation has long been studied in cancer cells, but the process by which telomerase becomes activated has remained elusive. A mechanism by which some tumour cells maintain telomerase expression was uncovered by analysis of the promoter region of the telomerase reverse transcriptase (TERT) gene. Two studies reported frequent (approximately 70%) somatic mutation in the TERT promoter in melanoma [1,2] at positions 124 base pairs (bp) (G > A; C > T on the opposite strand) and 146 bp (G > A; C > T on the opposite strand) upstream from the ATG translation start codon. These mutations create consensus binding motifs for E-twenty six (ETS)/ternary complex factor (TCF) transcription factors (GGA[A/T] or CCGGAA) leading to increased TERT promoter activity. One of these studies also reported mutations at 124 bp (G > A) in three of three bladder tumour-derived cell lines [2] and two subsequent studies of relatively small numbers of bladder tumours reported mutations at the same sites. We aimed to perform comprehensive mutation analysis of the TERT core promoter in a large number of bladder cancer samples to assess clinicopathologic associations and to detect mutations in voided urine [3,4]. SNaPshot assays (Life Technologies Corp., Carlsbad, CA, USA) are sensitive, low-cost, high-throughput assays [5] suitable for detection of hotspot mutations. We designed a SNaPshot assay to detect mutations at hotspot positions 124 bp and 146 bp. This was tested on three bladder tumour–derived cell lines with 124 bp G > A mutations [2], one melanoma cell line with 146 bp G > A [2], normal human urothelial cells (NHUC), and 17 hTERT-immortalised NHUC (TERT-NHUC) cell lines. The expected mutations were detected in the tumour cell lines and not in NHUC or TERT-NHUC (Supplemental Fig. 1). Mutations were confirmed by Sanger sequencing (Supplemental Fig. 1). We then screened 44 additional cell lines and 262 tumours. Thirty-seven cell lines carried mutations at 124 bp (G > A) and three at 146 bp (G > A) (Table 1 and Supplemental Table 1). In tumours, mutations were identified at 124 bp (G > A) in 165 samples and at 146 bp (G > A) in 32 samples (Table 1 and Supplemental Table 2). In addition,", "corpus_id": 31586630, "score": 0 }, { "doc_id": "11817960", "title": "The genetic difference between Western and Chinese urothelial cell carcinomas: infrequent FGFR3 mutation in Han Chinese patients", "abstract": "Urothelial cell carcinoma (UCC) includes urothelial bladder carcinoma (UBC), renal pelvic carcinoma (RPC) and ureter carcinoma (UC), and its incidence varies dependent on geographical areas and tumor locations, which indicates different oncogenic mechanisms and/or different genetic susceptibility/environment exposure. The activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene and telomerase reverse transcriptase (TERT) promoter are the most frequent genetic events in UCCs. These mutations have clinical utilities in UCC initial diagnostics, prognosis, recurrence monitoring and management. However, the vast majority of the results are obtained from studies of UCC patients in Western countries, and little has been known about these in Han Chinese patients. In the present study, we screened the FGFR3 gene and TERT promoter for mutations in 116 UBC, 91 RPC and 115 UC tumors from Han Chinese patients by using Sanger Sequencing. TERT promoter mutations occurred at a high frequency in these UCC patients, comparable with that seen in Western patients, however, the FGFR3 mutation was surprisingly lower, only 9.4% for UBCs, 8.8% for RPCs and 2.6% for UCs, respectively. Taken together, the FGFR3 gene is an infrequent target in the pathogenesis of Han Chinese UCCs, and its mutation detection and targeted therapy have limited clinical utility in these patients. Our results underscore the need for extensive characterization of cancer genomes from diverse patient populations, thereby contributing to precision medicine for cancer treatment and prevention.", "corpus_id": 11817960, "score": 0 }, { "doc_id": "39492059", "title": "TERT promoter mutations and TERT mRNA but not FGFR3 mutations are urinary biomarkers in Han Chinese patients with urothelial bladder cancer.", "abstract": "The TERT promoter and FGFR3 gene mutations are two of the most common genetic events in urothelial bladder cancer (UBC), and these mutation assays in patient urine have been shown to be promising biomarkers for UBC diagnosis and surveillance. These results were obtained mainly from studies of patients with UBC in Western countries, and little is known about such information in Han Chinese patients with UBC. In the present study, we addressed this issue by analyzing tumors from 182 Han Chinese patients with UBC and urine samples from 102 patients for mutations in the TERT promoter and FGFR3 and TERT mRNA expression in tumors and/or urine. TERT promoter and FGFR3 mutations were identified in 87 of 182 (47.8%) and 7 of 102 (6.7%) UBC cases, respectively. In 46 urine samples from patients with TERT promoter mutation-carrying tumors, the mutant promoter was detected in 24 (52%) prior to operation and disappeared in most examined urine samples (80%) taken 1 week after operation. TERT mRNA was detected in urine derived from 46 of 49 patients (94%) that was analyzed before operation independently of the presence of TERT promoter mutations. Collectively, FGFR3 mutations occur at a very low rate in Han Chinese UBC and cannot serve as diagnostic markers for Chinese patients. Han Chinese patients with UBC have relatively low TERT promoter mutation frequency compared with patients in Western countries, and simultaneous detection of both mutant TERT promoter and TERT mRNA improves sensitivity and specificity of urine-based diagnosis.", "corpus_id": 39492059, "score": 0 }, { "doc_id": "23194930", "title": "TERT Promoter Mutations in Familial and Sporadic Melanoma", "abstract": "Promoter Mutations and Cancer Cancer genome sequencing projects have highlighted the pathogenic role of recurrent mutations within the protein-coding regions of genes. Now, two studies suggest that the scope of mutations in human tumors extends to gene regulatory regions. In a study of 70 melanomas, Huang et al. (p. 957, published online 24 January) found that 71% harbored one of two specific mutations in the promoter region of TERT, the gene coding for the catalytic subunit of telomerase, the enzyme that caps chromosome ends. Independently, Horn et al. (p. 959, published online 24 January) identified a disease-segregating germline mutation in the TERT promoter in a family predisposed to melanoma and found additional TERT promoter mutations in a high percentage of sporadic melanomas and melanoma cell lines. The mutations in both studies generated new binding sites for specific transcription factors and, in reporter assays, caused an increase in transcription. A large fraction of human melanomas harbor mutations in sequences that regulate the expression of telomerase. Cutaneous melanoma occurs in both familial and sporadic forms. We investigated a melanoma-prone family through linkage analysis and high-throughput sequencing and identified a disease-segregating germline mutation in the promoter of the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomerase. The mutation creates a new binding motif for Ets transcription factors and ternary complex factors (TCFs) near the transcription start and, in reporter gene assays, caused up to twofold increase in transcription. We then screened the TERT promoter in sporadic melanoma and observed recurrent ultraviolet signature somatic mutations in 125 of 168 (74%) of human cell lines derived from metastatic melanomas, 45 of 53 corresponding metastatic tumor tissues (85%), and 25 of 77 (33%) primary melanomas. The majority of those mutations occurred at two positions in the TERT promoter and also generated binding motifs for Ets/TCF transcription factors.", "corpus_id": 23194930, "score": 0 }, { "doc_id": "21391374", "title": "hTERT genetic variation in depression.", "abstract": "BACKGROUND\nTelomeres are protective DNA-protein complexes forming the chromosome ends. TL differs between tissues. Shorter telomere length (TL) in blood leukocytes (LTL) has been associated with major depression, and with previous exposure to childhood adversity. TL studies on non-invasively sampled salivary DNA are less common. Telomerase, with its catalytic subunit hTERT, counteracts telomere shortening. Reduced telomerase activity associates with depression-like behavior in mice. Recently, the minor allele of the hTERT polymorphism rs2736100 was associated with shorter LTL among primarily healthy individuals. We hypothesized that (i) TL in saliva DNA is shortened in adults with a history of depression, and that (ii) rs2736100 is implicated in depression and depressive episodes in bipolar disorder type 1 (BD1).\n\n\nMETHODS\nIndividuals with a history of depression and those without (controls) were identified using self-reported questionnaires from a well-characterized population-based cohort. Clinical BD1 patients were diagnosed by specialized psychiatrists. Saliva TL was measured in age-matched depressed individuals and controls (n=662) using qRT-PCR. rs2736100 was genotyped in 436 depressed individuals, 1590 controls, and 368 BD1 patients.\n\n\nRESULTS\nSaliva TL was shorter in depressed individuals compared to controls. The rs2736100 minor allele was associated with depression among those without experience of childhood adversity, and with number of depressive episodes in BD1 patients responding well to lithium.\n\n\nLIMITATION\nPsychopathological symptoms were recorded at two time points only, 3 and 6 years prior to DNA sampling.\n\n\nCONCLUSIONS\nThis is the first report on hTERT genetic variation in mood disorder. It proposes that genetic variation in hTERT may influence the susceptibility to depression.", "corpus_id": 21391374, "score": 0 } ]

{ "doc_id": "119678075", "title": "Discreteness of silting objects and t‐structures in triangulated categories", "abstract": "We introduce the notion of ST-pairs of triangulated subcategories, a prototypical example of which is the pair of the bound homotopy category and the bound derived category of a finite-dimensional algebra. For an ST-pair $(\\C,\\D)$, we construct an order-preserving map from silting objects in $\\C$ to bounded $t$-structures on $\\D$ and show that the map is bijective if and only if $\\C$ is silting-discrete if and only if $\\D$ is $t$-discrete. Based on a work of Qiu and Woolf, the above result is applied to show that if $\\C$ is silting-discrete then the stability space of $\\D$ is contractible. This is used to obtain the contractibility of the stability spaces of some Calabi--Yau triangulated categories associated to Dynkin quivers.", "corpus_id": 119678075 }

[ { "doc_id": "14358154", "title": "On t-structures and torsion theories induced by compact objects", "abstract": "Abstract First, we show that a compact object C in a triangulated category, which satisfies suitable conditions, induces a t-structure. Second, in an abelian category we show that a complex P · of small projective objects of term length two, which satisfies suitable conditions, induces a torsion theory. In the case of module categories, using a torsion theory, we give equivalent conditions for P · to be a tilting complex. Finally, in the case of artin algebras, we give a one-to-one correspondence between tilting complexes of term length two and torsion theories with certain conditions.", "corpus_id": 14358154, "score": 0 }, { "doc_id": "120951810", "title": "Homological and Homotopical Aspects of Torsion Theories", "abstract": "Introduction Torsion pairs in abelian and triangulated categories Torsion pairs in pretriangulated categories Compactly generated torsion pairs in triangulated categories Hereditary torsion pairs in triangulated categories Torsion pairs in stable categories Triangulated torsion(-free) classes in stable categories Gorenstein categories and (co)torsion pairs Torsion pairs and closed model structures (Co)torsion pairs and generalized Tate-Vogel cohomology Nakayama categories and Cohen-Macaulay cohomology Bibliography Index.", "corpus_id": 120951810, "score": 0 }, { "doc_id": "115173344", "title": "Weight structures vs. $t$-structures; weight filtrations, spectral sequences, and complexes (for motives and in general)", "abstract": "In this paper we introduce a new notion of a weight structure (w) for a triangulated category C; this notion is an important natural counterpart to the notion of t-structures. This allows to generalize certain results of the previous paper [11] to a large class of triangulated categories and functors. The heart of w is an additive Hw C; there are no non-trivial C-distinguished triangles in Hw. We prove that a weight structure defines Postnikov towers for any X2 ObjC (whose \"factors\" are X i 2 ObjHw); these towers are canonical and functorial \"up to zero cohomology\". For any (co)homological functor H : C! A (A is abelian) we construct a weight spectral sequence T : H(X i [j]) =) H(X[i+j]); it is canonical and functorial starting from E2. This spectral sequences specializes to the usual weight spectral sequences for \"classical\" realizations of (Voevodsky’s) motives and to the Atiyah-Hirzebruch sequence in topology. We prove that K0(C) = K0(Hw) in the bounded case if Hw is idempotent complete. Under certain restrictions, we prove a similar equality for K0(EndC). We define a canonical conservative weakly exact functor t from C to a certain weak category of complexes Kw(Hw).", "corpus_id": 115173344, "score": 0 }, { "doc_id": "195218165", "title": "Auslander–Buchweitz Context and Co-t-structures", "abstract": "We show that the relative Auslander–Buchweitz context on a triangulated category $\\mathcal{T}$ coincides with the notion of co-t-structure on certain triangulated subcategory of $\\mathcal{T}$ (see Theorem 3.8). In the Krull–Schmidt case, we establish a bijective correspondence between co-t-structures and cosuspended, precovering subcategories (see Theorem 3.11). We also give a characterization of bounded co-t-structures in terms of relative homological algebra. The relationship between silting classes and co-t-structures is also studied. We prove that a silting class ω induces a bounded non-degenerated co-t-structure on the smallest thick triangulated subcategory of $\\mathcal{T}$ containing ω. We also give a description of the bounded co-t-structures on $\\mathcal{T}$ (see Theorem 5.10). Finally, as an application to the particular case of the bounded derived category ${\\mathbf{D}^b}(\\mathcal{H}),$ where $\\mathcal{H}$ is an abelian hereditary category which is Hom-finite, Ext-finite and has a tilting object (see Happel and Reiten, Math Z 232:559–588, 1999), we give a bijective correspondence between finite silting generator sets ω = add (ω) and bounded co-t-structures (see Theorem 6.7).", "corpus_id": 195218165, "score": 0 }, { "doc_id": "119686091", "title": "Realisation functors in tilting theory", "abstract": "Derived equivalences and t-structures are closely related. We use realisation functors associated to t-structures in triangulated categories to establish a derived Morita theory for abelian categories with a projective generator or an injective cogenerator. For this purpose we develop a theory of (non-compact, or large) tilting and cotilting objects that generalises the preceding notions in the literature. Within the scope of derived Morita theory for rings we show that, under some assumptions, the realisation functor is a derived tensor product. This fact allows us to approach a problem by Rickard on the shape of derived equivalences. Finally, we apply the techniques of this new derived Morita theory to show that a recollement of derived categories is a derived version of a recollement of abelian categories if and only if there are tilting or cotilting t-structures glueing to a tilting or a cotilting t-structure. As a further application, we answer a question by Xi on a standard form for recollements of derived module categories for finite dimensional hereditary algebras.", "corpus_id": 119686091, "score": 0 }, { "doc_id": "17939514", "title": "Almost complete cluster tilting objects in generalized higher cluster categories", "abstract": "We study higher cluster tilting objects in generalized higher cluster categories arising from dg algebras of higher Calabi-Yau dimension. Taking advantage of silting mutations of Aihara-Iyama, we obtain a class of $m$-cluster tilting objects in generalized $m$-cluster categories. For generalized $m$-cluster categories arising from strongly ($m+2$)-Calabi-Yau dg algebras, by using truncations of minimal cofibrant resolutions of simple modules, we prove that each almost complete $m$-cluster tilting $P$-object has exactly $m+1$ complements with periodicity property. This leads us to the conjecture that each liftable almost complete $m$-cluster tilting object has exactly $m+1$ complements in generalized $m$-cluster categories arising from $m$-rigid good completed deformed preprojective dg algebras.", "corpus_id": 17939514, "score": 0 }, { "doc_id": "119178093", "title": "Three kinds of mutation", "abstract": "For a finite dimensional hereditary algebra, we consider: exceptional sequences in the category of finite dimensional modules, silting objects in the bounded derived category, and m-cluster tilting objects in the m-cluster category. There are mutation operations on both the set of m-cluster tilting objects and the set of exceptional sequences. It is also possible to define a mutation operation for silting objects. We compare these three different notions of mutation.", "corpus_id": 119178093, "score": 0 }, { "doc_id": "117924058", "title": "Silting reduction and Calabi--Yau reduction of triangulated categories", "abstract": "It is shown that the silting reduction $\\ct/\\thick\\cp$ of a triangulated category $\\ct$ with respect to a presilting subcategory $\\cp$ can be realized as a certain subfactor category of $\\ct$, and that there is a one-to-one correspondence between the set of (pre)silting subcategories of $\\ct$ containing $\\cp$ and the set of (pre)silting subcategories of $\\ct/\\thick\\cp$. This is analogous to a result for Calabi-Yau reduction. This result is applied to show that Amiot-Guo-Keller's construction of $d$-Calabi-Yau triangulated categories with $d$-cluster-tilting objects takes silting reduction to Calabi-Yau reduction.", "corpus_id": 117924058, "score": 1 }, { "doc_id": "2716821", "title": "Discrete derived categories II: the silting pairs CW complex and the stability manifold", "abstract": "Discrete derived categories were studied initially by Vossieck [‘The algebras with discrete derived category’, J. Algebra 243 (2001) 168–176] and later by Bobinski, Geis and Skowronski [‘Classification of discrete derived categories’, Cent. Eur. J. Math. 2 (2004) 19–49]. In this article, we define the CW complex of silting pairs for a triangulated category and show that it is contractible in the case of discrete derived categories. We provide an explicit embedding from the silting CW complex into the stability manifold. By work of Qiu and Woolf [‘Contractible stability spaces and faithful braid group actions’, Preprint, 2014, arXiv:1407.5986], there is a deformation retract of the stability manifold onto the silting pairs CW complex. We obtain that the space of stability conditions of discrete derived categories is contractible.", "corpus_id": 2716821, "score": 0 }, { "doc_id": "119712674", "title": "Universal localizations via silting", "abstract": "Abstract We show that silting modules are closely related with localizations of rings. More precisely, every partial silting module gives rise to a localization at a set of maps between countably generated projective modules and, conversely, every universal localization, in the sense of Cohn and Schofield, arises in this way. To establish these results, we further explore the finite-type classification of tilting classes and we use the morphism category to translate silting modules into tilting objects. In particular, we prove that silting modules are of finite type.", "corpus_id": 119712674, "score": 0 }, { "doc_id": "15519035", "title": "SILTING OBJECTS, SIMPLE-MINDED COLLECTIONS, t-STRUCTURES AND CO-t-STRUCTURES FOR FINITE-DIMENSIONAL ALGEBRAS", "abstract": "Bijective correspondences are established between (1) silting objects, (2) simple- minded collections, (3) bounded t-structures with length heart and (4) bounded co-t-structures. These correspondences are shown to commute with mutations. The results are valid for finite- dimensional non-positive differential graded algebras, in particular for finite dimensional alge- bras. A concrete example is given to illustrate how these correspondences help to compute the space of Bridgeland's stability conditions. MSC 2010 classification: 16E35, 16E45, 18E30.", "corpus_id": 15519035, "score": 1 }, { "doc_id": "1215706", "title": "Stability conditions on triangulated categories", "abstract": "This paper introduces the notion of a stability condition on a triangulated category. The motivation comes from the study of Dirichlet branes in string theory, and especially from M.R. Douglas's notion of $\\Pi$-stability. From a mathematical point of view, the most interesting feature of the definition is that the set of stability conditions $\\Stab(\\T)$ on a fixed category $\\T$ has a natural topology, thus defining a new invariant of triangulated categories. After setting up the necessary definitions I prove a deformation result which shows that the space $\\Stab(\\T)$ with its natural topology is a manifold, possibly infinite-dimensional.", "corpus_id": 1215706, "score": 0 }, { "doc_id": "119380219", "title": "STABILITY CONDITIONS AND QUANTUM DILOGARITHM IDENTITIES FOR DYNKIN QUIVERS", "abstract": "Abstract We study the fundamental groups of the exchange graphs for the bounded derived category D ( Q ) of a Dynkin quiver Q and the finite-dimensional derived category D ( Γ N Q ) of the Calabi–Yau-N Ginzburg algebra associated to Q. In the case of D ( Q ) , we prove that its space of stability conditions (in the sense of Bridgeland) is simply connected. As an application, we show that the Donaldson–Thomas type invariant associated to Q can be calculated as a quantum dilogarithm function on its exchange graph. In the case of D ( Γ N Q ) , we show that the faithfulness of the Seidel–Thomas braid group action (which is known for Q of type A or N = 2 ) implies the simply connectedness of the space of stability conditions.", "corpus_id": 119380219, "score": 0 }, { "doc_id": "120181154", "title": "Wakamatsu tilting modules", "abstract": "Abstract We study a generalization of tilting modules to modules of possibly infinite projective dimension, introduced by Wakamatsu in [J. Algebra 114 (1988) 106–114]. In particular, we characterize these modules in terms of suitable subcategories of finitely generated modules and in terms of cotorsion theories.", "corpus_id": 120181154, "score": 0 }, { "doc_id": "46738815", "title": "Discrete triangulated categories", "abstract": "We introduce and study several homological notions which generalise the discrete derived categories of D. Vossieck. As an application, we show that Vossieck discrete algebras have this property with respect to all bounded t-structures. We give many examples of triangulated categories regarding these notions.", "corpus_id": 46738815, "score": 0 }, { "doc_id": "959310", "title": "On differential graded categories", "abstract": "Differential graded categories enhance our understanding of triangulated categories\nappearing in algebra and geometry. In this survey, we review their foundations and report on\nrecent work by Drinfeld, Dugger�Shipley, Toen, Toen�Vaquie, and others.", "corpus_id": 959310, "score": 1 }, { "doc_id": "12641428", "title": "Derived equivalences from mutations of quivers with potential", "abstract": "Abstract We show that Derksen–Weyman–Zelevinsky's mutations of quivers with potential yield equivalences of suitable 3-Calabi–Yau triangulated categories. Our approach is related to that of Iyama–Reiten and ‘Koszul dual’ to that of Kontsevich–Soibelman. It improves on previous work by Vitoria. In Appendix A, the first-named author studies pseudo-compact derived categories of certain pseudo-compact dg algebras.", "corpus_id": 12641428, "score": 1 }, { "doc_id": "10682282", "title": "Generators and representability of functors in commutative and noncommutative geometry", "abstract": "We give a sufficient condition for an Ext-finite triangulated category to be saturated. Saturatedness means that every contravariant cohomological functor of finite type to vector spaces is representable. The condition consists in existence of a strong generator. We prove that the bounded derived categories of coherent sheaves on smooth proper commutative and noncommutative varieties have strong generators, hence saturated. In contrast the similar category for a smooth compact analytic surface with no curves is not saturated.", "corpus_id": 10682282, "score": 0 }, { "doc_id": "119127812", "title": "Dimensions of triangulated categories", "abstract": "We define a dimension for a triangulated category. We prove a representability Theorem for a class of functors on finite dimensional triangulated categories. We study the dimension of the bounded derived category of an algebra or a scheme and we show in particular that the bounded derived category of coherent sheaves over a variety has a finite dimension.", "corpus_id": 119127812, "score": 1 }, { "doc_id": "50735301", "title": "Weight structures and simple dg modules for positive dg algebras", "abstract": "Using techniques due to Dwyer-Greenlees-Iyengar we construct weight structures in triangulated categories generated by compact objects. We apply our result to show that, for a dg category whose homology vanishes in negative degrees and is semi-simple in degree 0, each simple module over the homology lifts to a dg module which is unique up to isomorphism in the derived category. This allows us, in certain situations, to deduce the existence of a canonical t-structure on the perfect derived category of a dg algebra. From this, we can obtain a bijection between hearts of t-structures and sets of so-called simple-minded objects for some dg algebras (including Ginzburg algebras associated to quivers with potentials). In three appendices, we elucidate the relation between Milnor colimits and homotopy colimits and clarify the construction of t-structures from sets of compact objects in triangulated categories as well as the construction of a canonical weight structure on the unbonded derived category of a non positive dg category.", "corpus_id": 50735301, "score": 0 }, { "doc_id": "54217785", "title": "Relative singularity categories I: Auslander resolutions", "abstract": "Abstract Let R be an isolated Gorenstein singularity with a non-commutative resolution A = End R ( R ⊕ M ) . In this paper, we show that the relative singularity category Δ R ( A ) of A has a number of pleasant properties, such as being Hom-finite. Moreover, it determines the classical singularity category D s g ( R ) of Buchweitz and Orlov as a certain canonical quotient category. If R has finite CM type, which includes for example Kleinian singularities, then we show the much more surprising result that D s g ( R ) determines Δ R ( Aus ( R ) ) , where Aus ( R ) is the corresponding Auslander algebra. The proofs of these results use dg algebras, A ∞ Koszul duality, and the new concept of dg Auslander algebras, which may be of independent interest.", "corpus_id": 54217785, "score": 0 }, { "doc_id": "17697133", "title": "Categorical resolution of singularities", "abstract": "Abstract Building on the concept of a smooth DG algebra we define the notion of a smooth derived category. We then propose the definition of a categorical resolution of singularities. Our main example is the derived category D ( X ) of quasi-coherent sheaves on a scheme X. We prove that D ( X ) has a canonical categorical resolution if the base field is perfect and X is a separated scheme of finite type with a dualizing complex.", "corpus_id": 17697133, "score": 0 }, { "doc_id": "14540263", "title": "Cluster algebras II: Finite type classification", "abstract": "This paper continues the study of cluster algebras initiated in math.RT/0104151. Its main result is the complete classification of the cluster algebras of finite type, i.e., those with finitely many clusters. This classification turns out to be identical to the Cartan-Killing classification of semisimple Lie algebras and finite root systems, which is intriguing since in most cases, the symmetry exhibited by the Cartan-Killing type of a cluster algebra is not at all apparent from its geometric origin. \nThe combinatorial structure behind a cluster algebra of finite type is captured by its cluster complex. We identify this complex as the normal fan of a generalized associahedron introduced and studied in hep-th/0111053 and math.CO/0202004. Another essential combinatorial ingredient of our arguments is a new characterization of the Dynkin diagrams.", "corpus_id": 14540263, "score": 0 }, { "doc_id": "125725765", "title": "Stability conditions on CYN categories associated to An-quivers and period maps", "abstract": "In this paper, we study the space of stability conditions on a certain N- Calabi-Yau (CYN) category associated to an An-quiver. Recently, Bridgeland and Smith constructed stability conditions on some CY3 categories from meromorphic quadratic differentials with simple zeros. Generalizing their results to higher dimen- sional Calabi-Yau categories, we describe the space of stability conditions as the universal cover of the space of polynomials of degree n + 1 with simple zeros. In particular, central charges of stability conditions on CYN categories are constructed as the periods of quadratic differentials with zeros of order N −2 which are associated to polynomials.", "corpus_id": 125725765, "score": 0 } ]

{ "doc_id": "7942208", "title": "Practice Variation in Spontaneous Breathing Trial Performance and Reporting", "abstract": "Background. Spontaneous breathing trials (SBTs) are standard of care in assessing extubation readiness; however, there are no universally accepted guidelines regarding their precise performance and reporting. Objective. To investigate variability in SBT practice across centres. Methods. Data from 680 patients undergoing 931 SBTs from eight North American centres from the Weaning and Variability Evaluation (WAVE) observational study were examined. SBT performance was analyzed with respect to ventilatory support, oxygen requirements, and sedation level using the Richmond Agitation Scale Score (RASS). The incidence of use of clinical extubation criteria and changes in physiologic parameters during an SBT were assessed. Results. The majority (80% and 78%) of SBTs used 5 cmH2O of ventilator support, although there was variability. A significant range in oxygenation was observed. RASS scores were variable, with RASS 0 ranging from 29% to 86% and 22% of SBTs performed in sedated patients (RASS < −2). Clinical extubation criteria were heterogeneous among centres. On average, there was no change in physiological variables during SBTs. Conclusion. The present study highlights variation in SBT performance and documentation across and within sites. With their impact on the accuracy of outcome prediction, these results support efforts to further clarify and standardize optimal SBT technique.", "corpus_id": 7942208 }

[ { "doc_id": "27198715", "title": "Respiratory weakness is associated with limb weakness and delayed weaning in critical illness*", "abstract": "Objective:Although critical illness neuromyopathy might interfere with weaning from mechanical ventilation, its respiratory component has not been investigated. We designed a study to assess the level of respiratory muscle weakness emerging during the intensive care unit stay in mechanically ventilated patients and to examine the correlation between respiratory and limb muscle strength and the specific contribution of respiratory weakness to delayed weaning. Design:Prospective observational study. Setting:Two medical, one surgical, and one medicosurgical intensive care units in two university hospitals and one university- affiliated hospital. Patients:A total of 116 consecutive patients were enrolled after ≥7 days of mechanical ventilation. Interventions:None. Measurements and Main Results:Maximal inspiratory and expiratory pressures and vital capacity were measured via the tracheal tube on the first day of return to normal consciousness. Muscle strength was measured using the Medical Research Council score. After standardized weaning, successful extubation was defined as the day from which mechanical ventilatory support was no longer required within the next 15 days. The median value (interquartile range) of maximal inspiratory pressure was 30 (20–40) cm H2O, maximal expiratory pressure was 30 (20–50) cm H2O, and vital capacity was 11.1 (6.3–19.8) mL/kg. Maximal inspiratory pressure, maximal expiratory pressure, and vital capacity were significantly correlated with the Medical Research Council score. The median time (interquartile range) from awakening to successful extubation was 6 (1–17) days. Low maximal inspiratory pressure (hazard ratio, 1.86; 95% confidence interval, 1.07–3.23), maximal expiratory pressure (hazard ratio, 2.18; 95% confidence interval, 1.44–3.84), and Medical Research Council score (hazard ratio, 1.96; 95% confidence interval, 1.27–3.02) were independent predictors of delayed extubation. Septic shock before awakening was significantly associated with respiratory weakness (odds ratio, 3.17; 95% confidence interval, 1.17–8.58). Conclusions:Respiratory and limb muscle strength are both altered after 1 wk of mechanical ventilation. Respiratory muscle weakness is associated with delayed extubation and prolonged ventilation. In our study, septic shock is a contributor to respiratory weakness.", "corpus_id": 27198715, "score": 0 }, { "doc_id": "20162523", "title": "Epidemiology and outcomes of ventilator-associated pneumonia in a large US database.", "abstract": "OBJECTIVES\nTo evaluate risk factors for ventilator-associated pneumonia (VAP), as well as its influence on in-hospital mortality, resource utilization, and hospital charges.\n\n\nDESIGN\nRetrospective matched cohort study using data from a large US inpatient database.\n\n\nPATIENTS\nPatients admitted to an ICU between January 1998 and June 1999 who received mechanical ventilation for > 24 h.\n\n\nMEASUREMENTS\nRisk factors for VAP were examined using crude and adjusted odds ratios (AORs). Cases of VAP were matched on duration of mechanical ventilation, severity of illness on admission (predicted mortality), type of admission (medical, surgical, trauma), and age with up to three control subjects. Mortality, resource utilization, and billed hospital charges were then compared between cases and control subjects.\n\n\nRESULTS\nOf the 9,080 patients meeting study entry criteria, VAP developed in 842 patients (9.3%). The mean interval between intubation, admission to the ICU, hospital admission, and the identification of VAP was 3.3 days, 4.5 days, and 5.4 days, respectively. Identified independent risk factors for the development of VAP were male gender, trauma admission, and intermediate deciles of underlying illness severity (on admission) [AOR, 1.58, 1.75, and 1.47 to 1.70, respectively]. Patients with VAP were matched with 2,243 control subjects without VAP. Hospital mortality did not differ significantly between cases and matched control subjects (30.5% vs 30.4%, p = 0.713). Nevertheless, patients with VAP had a significantly longer duration of mechanical ventilation (14.3 +/- 15.5 days vs 4.7 +/- 7.0 days, p < 0.001), ICU stay (11.7 +/- 11.0 days vs 5.6 +/- 6.1 days, p < 0.001), and hospital stay (25.5 +/- 22.8 days vs 14.0 +/- 14.6 days, p < 0.001). Development of VAP was also associated with an increase of > $40,000 USD in mean hospital charges per patient ($104,983 USD +/- $91,080 USD vs $63,689 USD+/- $75,030 USD, p < 0.001).\n\n\nCONCLUSIONS\nThis retrospective matched cohort study, the largest of its kind, demonstrates that VAP is a common nosocomial infection that is associated with poor clinical and economic outcomes. While strategies to prevent the occurrence of VAP may not reduce mortality, they may yield other important benefits to patients, their families, and hospital systems.", "corpus_id": 20162523, "score": 0 }, { "doc_id": "2367460", "title": "Risk factors for and economic implications of prolonged ventilation after cardiac surgery.", "abstract": "OBJECTIVE\nThe study's objective was to identify predictors of prolonged ventilation and assess clinical and cost implications in patients undergoing cardiac surgery.\n\n\nMETHODS\nPatients undergoing cardiac surgery were classified as (1) ventilated less than 96 hours or (2) ventilated 96 hours or more. Multivariate modeling was used to identify predictors of prolonged ventilation and to ascertain the impact of prolonged ventilation on in-hospital mortality and bed occupancy costs and 5-year survival.\n\n\nRESULTS\nA total of 7553 patients were studied; 197 (2.6%) had prolonged ventilation. Median ventilation times were 8 and 192 hours, and in-hospital mortality was 1.0% and 22.2% in the control and prolonged ventilation groups, respectively (P < .001). In-hospital mortality remained higher in the prolonged ventilation group after adjustment and when comparing propensity-matched patients (odds ratio 8.06; 95% confidence interval [CI] 4.27-15.2; P < .001 for propensity-matched groups). Independent predictors of prolonged ventilation were as follows: older age, New York Heart Association class, ejection fraction less than 50%, creatinine greater than 200 micromol/L, multiple valve replacements, aortic procedures, operative priority, reoperation for bleeding, inotropes, and preoperative intra-aortic balloon pump. Five-year survival was lower in the prolonged ventilation group (56.1% [95% CI 46.6%-64.6%] vs 88.8% [95% CI 87.9%-89.6%]) also after adjustment for imbalances and when comparing propensity-matched patients (hazard ratio 2.39; 95% CI 1.75-3.27; P < .001 for propensity-matched groups). Mean bed occupancy costs were 14,286 dollars (95% CI 12,731 dollars-15,690 dollars) and 2761 dollars (95% CI 2705 dollars-2814 dollars) in the prolonged ventilation and control groups, respectively (P < .001).\n\n\nCONCLUSION\nProlonged ventilation is associated with high in-hospital mortality and costs, and poor 5-year survival. Identified predictors of prolonged ventilation might help to optimize the clinical management of these patients.", "corpus_id": 2367460, "score": 0 }, { "doc_id": "71485187", "title": "A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation", "abstract": "Abstract Background. The traditional predictors of the outcome of weaning from mechanical ventilation — minute ventilation (VE) and maximal inspiratory pressure (P1max) — are frequently inaccurate. We developed two new indexes: the first quantitates rapid shallow breathing as the ratio of respiratory frequency to tidal volume (f/VT), and the second is termed CROP, because it integrates thoracic compliance, respiratory ṟate, arterial oxygenation, and P1max. Methods. The threshold values for each index that discriminated best between a successful and an unsuccessful outcome of weaning were determined in 36 patients, and the predictive accuracy of these values was then tested prospectively in an additional 64 patients. Sensitivity and specificity were calculated, and the data were also analyzed with receiver-operating-characteristic (ROC) curves, in which the proportions of true positive results and false positive results are plotted against each other for a number of threshold values of an index; the area...", "corpus_id": 71485187, "score": 0 }, { "doc_id": "46529423", "title": "Effect of failed extubation on the outcome of mechanical ventilation.", "abstract": "OBJECTIVE\nTo examine medical outcomes associated with reintubation for extubation failure after discontinuation of mechanical ventilation.\n\n\nDESIGN\nProspective cohort study of consecutive intubated medical ICU patients who underwent a trial of extubation at a tertiary-care teaching hospital. The failed extubation group consisted of all patients reintubated within 72 h or within 7 days (if continuous ICU care had been required) of extubation. All others were considered to be successfully extubated. Study end points included hospital death vs survival, the number of days spent in the ICU and in the hospital after the onset of mechanical ventilation, the likelihood of requiring > or = 7 or > or = 14 days of ICU care after extubation, and the need for transfer to either a long-term care or rehabilitation facility among the survivors.\n\n\nRESULTS\nOf 289 intubated patients, 247 (85%) were successfully extubated, and 42 (15%) required reintubation for failed extubation (time to reintubation 1.5+/-0.2 days). Reintubation for extubation failure resulted in 12 additional days of mechanical ventilation. When compared with successfully extubated patients, reintubated patients were more likely to die in the hospital (43% vs 12%; p<0.0001), spend more time in the ICU (21.2+/-2.8 days vs 4.5+/-0.6 days; p<0.001) and in the hospital (30.5+/-3.3 days vs 16.3+/-1.2 days; p<0.001) after extubation, and require transfer to a long-term care or rehabilitation facility (38% vs 21%; p<0.05). Using multiple logistic regression, extubation failure was an independent predictor for death and the need for transfer to a long-term care facility. Compared with those successfully extubated, patients who failed extubation were seven times (p<0.0001) more likely to die, 31 times (p<0.0001) more likely to spend > or = 14 days in the ICU after extubation, and six times (p<0.001) more likely to need transfer to a long-term care or rehabilitation facility if they survived.\n\n\nCONCLUSION\nAfter adjusting for severity of illness and comorbid conditions, extubation failure had a significant independent association with increased risk for death, prolonged ICU stay, and transfer to a long-term care or rehabilitation facility. Extubation failure may serve as an additional independent marker of severity of illness. Alternatively, poor outcomes may be etiologically related to extubation failure. If the latter proves to be the case, identifying patients at risk for poor outcomes from extubation failure and instituting alternative care practices may reduce mortality, duration of ICU stay, and need for transfer to a long-term care facility.", "corpus_id": 46529423, "score": 0 }, { "doc_id": "25765441", "title": "Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Spanish Lung Failure Collaborative Group.", "abstract": "The duration of spontaneous breathing trials before extubation has been set at 2 h in research studies, but the optimal duration is not known. We conducted a prospective, multicenter study involving 526 ventilator-supported patients considered ready for weaning, to compare clinical outcomes for trials of spontaneous breathing with target durations of 30 and 120 min. Of the 270 and 256 patients in the 30- and 120-min trial groups, respectively, 237 (87.8%) and 216 (84.8%), respectively, completed the trial without distress and were extubated (p = 0.32); 32 (13.5%) and 29 (13.4%), respectively, of these patients required reintubation within 48 h. The percentage of patients who remained extubated for 48 h after a spontaneous breathing trial did not differ in the 30- and 120-min trial groups (75.9% versus 73.0%, respectively, p = 0.43). The 30- and 120-min trial groups had similar within-unit mortality rates (13 and 9%, respectively) and in-hospital mortality rates (19 and 18%, respectively). Reintubation was required in 61 (13.5%) patients, and these patients had a higher mortality (20 of 61, 32.8%) than did patients who tolerated extubation (18 of 392, 4.6%) (p < 0.001). Neither measurements of respiratory frequency, heart rate, systolic blood pressure, and oxygen saturation during the trial, nor other functional measurements before the trial discriminated between patients who required reintubation from those who tolerated extubation. In conclusion, after a first trial of spontaneous breathing, successful extubation was achieved equally effectively with trials targeted to last 30 and 120 min.", "corpus_id": 25765441, "score": 1 }, { "doc_id": "22494758", "title": "Daily cost of an intensive care unit day: The contribution of mechanical ventilation*", "abstract": "Objective:To quantify the mean daily cost of intensive care, identify key factors associated with increased cost, and determine the incremental cost of mechanical ventilation during a day in the intensive care unit. Design:Retrospective cohort analysis using data from NDCHealth’s Hospital Patient Level Database. Setting:A total of 253 geographically diverse U.S. hospitals. Patients:The study included 51,009 patients ≥18 yrs of age admitted to an intensive care unit between October 1, 2002, and December 31, 2002. Interventions:None. Measurements and Main Results:Days of intensive care and mechanical ventilation were identified using billing data, and daily costs were calculated as the sum of daily charges multiplied by hospital-specific cost-to-charge ratios. Cost data are presented as mean (±sd). Incremental daily cost of mechanical ventilation was calculated using log-linear regression, adjusting for patient and hospital characteristics. Approximately 36% of identified patients were mechanically ventilated at some point during their intensive care unit stay. Mechanically ventilated patients were older (63.5 yrs vs. 61.7 yrs, p < .0001) and more likely to be male (56.1% vs. 51.8%, p < 0.0001), compared with patients who were not mechanically ventilated, and required mechanical ventilation for a mean duration of 5.6 days ± 9.6. Mean intensive care unit cost and length of stay were $31,574 ± 42,570 and 14.4 days ± 15.8 for patients requiring mechanical ventilation and $12,931 ± 20,569 and 8.5 days ± 10.5 for those not requiring mechanical ventilation. Daily costs were greatest on intensive care unit day 1 (mechanical ventilation, $10,794; no mechanical ventilation, $6,667), decreased on day 2 (mechanical ventilation:, $4,796; no mechanical ventilation, $3,496), and became stable after day 3 (mechanical ventilation, $3,968; no mechanical ventilation, $3,184). Adjusting for patient and hospital characteristics, the mean incremental cost of mechanical ventilation in intensive care unit patients was $1,522 per day (p < .001). Conclusions:Intensive care unit costs are highest during the first 2 days of admission, stabilizing at a lower level thereafter. Mechanical ventilation is associated with significantly higher daily costs for patients receiving treatment in the intensive care unit throughout their entire intensive care unit stay. Interventions that result in reduced intensive care unit length of stay and/or duration of mechanical ventilation could lead to substantial reductions in total inpatient cost.", "corpus_id": 22494758, "score": 0 }, { "doc_id": "2004016", "title": "Predicting success in weaning from mechanical ventilation.", "abstract": "We identified 65 observational studies of weaning predictors that had been reported in 70 publications. After grouping predictors with similar names but different thresholds, the following predictors met our relevance criteria: heterogeneous populations, 51; COPD patients, 21; and cardiovascular ICU patients, 45. Many variables were of no use in predicting the results of weaning. Moreover, few variables had been studied in > 50 patients or had results presented to generate estimates of predictive power. For stepwise reductions in mechanical support, the most promising predictors were a rapid shallow breathing index (RSBI) < 65 breaths/min/L (measured using the ventilator settings that were in effect at the time that the prediction was made) and a pressure time product < 275 cm H2O/L/s. The pooled likelihood ratios (LRs) were 1.1 (95% confidence interval [CI], 0.95 to 1.28) for a respiratory rate [RR] of < 38 breaths/min and 0.32 (95% CI, 0.06 to 1.71) for an RR of > 38 breaths/min, which indicate that an RR of < 38 breaths/min leaves the probability of successful weaning virtually unchanged but that a value of > 38 breaths/min leads to a small reduction in the probability of success in weaning the level of mechanical support. For trials of unassisted breathing, the most promising weaning predictors include the following: RR; RSBI; a product of RSBI and occlusion pressure < 450 cm H2O breaths/min/L; maximal inspiratory pressure (PImax) < 20 cm H2O; and a knowledge-based system for adjusting pressure support. Pooled results for the power of a positive test result for both RR and RSBI were limited (highest LR, 2.23), while the power of a negative test result was substantial (ie, LR, 0.09 to 0.23). Summary data suggest a similar predictive power for RR and RSBI. In the prediction of successful extubation, an RR of < 38 breaths/min (sensitivity, 88%; specificity, 47%), an RSBI < 100 or 105 breaths/min/L (sensitivity, 65 to 96%; specificity, 0 to 73%), PImax, and APACHE (acute physiology and chronic health evaluation) II scores that are obtained at hospital admission appear to be the most promising. After pooling, two variables appeared to have some value. An RR of > 38 breaths/min and an RSBI of > 100 breaths/min/L appear to reduce the probability of successful extubation, and PImax < 0.3, for which the pooled LR is 2.23 (95% CI, 1.15 to 4.34), appears to marginally increase the likelihood of successful extubation. Judging by areas under the receiver operator curve for all variables, none of these variables demonstrate more than modest accuracy in predicting weaning outcome. Why do most of these tests perform so poorly? The likely explanation is that clinicians have already considered the results when they choose patients for trials of weaning.", "corpus_id": 2004016, "score": 0 }, { "doc_id": "205180683", "title": "Pressure support versus T-tube for weaning from mechanical ventilation in adults.", "abstract": "BACKGROUND\nMechanical ventilation is important in caring for patients with critical illness. Clinical complications, increased mortality, and high costs of health care are associated with prolonged ventilatory support or premature discontinuation of mechanical ventilation. Weaning refers to the process of gradually or abruptly withdrawing mechanical ventilation. The weaning process begins after partial or complete resolution of the underlying pathophysiology precipitating respiratory failure and ends with weaning success (successful extubation in intubated patients or permanent withdrawal of ventilatory support in tracheostomized patients).\n\n\nOBJECTIVES\nTo evaluate the effectiveness and safety of two strategies, a T-tube and pressure support ventilation, for weaning adult patients with respiratory failure that required invasive mechanical ventilation for at least 24 hours, measuring weaning success and other clinically important outcomes.\n\n\nSEARCH METHODS\nWe searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6); MEDLINE (via PubMed) (1966 to June 2012); EMBASE (January 1980 to June 2012); LILACS (1986 to June 2012); CINAHL (1982 to June 2012); SciELO (from 1997 to August 2012); thesis repository of CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) (http://capesdw.capes.gov.br/capesdw/) (August 2012); and Current Controlled Trials (August 2012).We reran the search in December 2013. We will deal with any studies of interest when we update the review.\n\n\nSELECTION CRITERIA\nWe included randomized controlled trials (RCTs) that compared a T-tube with pressure support (PS) for the conduct of spontaneous breathing trials and as methods of gradual weaning of adult patients with respiratory failure of various aetiologies who received invasive mechanical ventilation for at least 24 hours.\n\n\nDATA COLLECTION AND ANALYSIS\nTwo authors extracted data and assessed the methodological quality of the included studies. Meta-analyses using the random-effects model were conducted for nine outcomes. Relative risk (RR) and mean difference (MD) or standardized mean difference (SMD) were used to estimate the treatment effect, with 95% confidence intervals (CI).\n\n\nMAIN RESULTS\nWe included nine RCTs with 1208 patients; 622 patients were randomized to a PS spontaneous breathing trial (SBT) and 586 to a T-tube SBT. The studies were classified into three categories of weaning: simple, difficult, and prolonged. Four studies placed patients in two categories of weaning. Pressure support ventilation (PSV) and a T-tube were used directly as SBTs in four studies (844 patients, 69.9% of the sample). In 186 patients (15.4%) both interventions were used along with gradual weaning from mechanical ventilation; the PS was gradually decreased, twice a day, until it was minimal and periods with a T-tube were gradually increased to two and eight hours for patients with difficult and prolonged weaning. In two studies (14.7% of patients) the PS was lowered to 2 to 4 cm H2O and 3 to 5 cm H2O based on ventilatory parameters until the minimal PS levels were reached. PS was then compared to the trial with the T-tube (TT).We identified 33 different reported outcomes in the included studies; we took 14 of them into consideration and performed meta-analyses on nine. With regard to the sequence of allocation generation, allocation concealment, selective reporting and attrition bias, no study presented a high risk of bias. We found no clear evidence of a difference between PS and TT for weaning success (RR 1.07, 95% CI 0.97 to 1.17, 9 studies, low quality of evidence), intensive care unit (ICU) mortality (RR 0.81, 95% CI 0.53 to 1.23, 5 studies, low quality of evidence), reintubation (RR 0.92, 95% CI 0.66 to 1.26, 7 studies, low quality evidence), ICU and long-term weaning unit (LWU) length of stay (MD -7.08 days, 95% CI -16.26 to 2.1, 2 studies, low quality of evidence) and pneumonia (RR 0.67, 95% CI 0.08 to 5.85, 2 studies, low quality of evidence). PS was significantly superior to the TT for successful SBTs (RR 1.09, 95% CI 1.02 to 1.17, 4 studies, moderate quality of evidence). Four studies reported on weaning duration, however we were unable to combined the study data because of differences in how the studies presented their data. One study was at high risk of other bias and four studies were at high risk for detection bias. Three studies reported that the weaning duration was shorter with PS, and in one study the duration was shorter in patients with a TT.\n\n\nAUTHORS' CONCLUSIONS\nTo date, we have found evidence of generally low quality from studies comparing pressure support ventilation (PSV) and with a T-tube. The effects on weaning success, ICU mortality, reintubation, ICU and LWU length of stay, and pneumonia were imprecise. However, PSV was more effective than a T-tube for successful spontaneous breathing trials (SBTs) among patients with simple weaning. Based on the findings of single trials, three studies presented a shorter weaning duration in the group undergoing PS SBT, however a fourth study found a shorter weaning duration with a T-tube.", "corpus_id": 205180683, "score": 0 }, { "doc_id": "20554187", "title": "Protocolized vs. non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients: Cochrane review protocol.", "abstract": "AIM\nThis paper is a report of the protocol for a review to identify, critically appraise and synthesize the best current evidence supporting the use of weaning protocols compared to non-protocolized practice in liberating patients from mechanical ventilation.\n\n\nBACKGROUND\nPatients experiencing difficulty in weaning require a longer hospital stay and have higher morbidity and mortality. Consequently, efforts to reduce weaning time are desirable to reduce the duration of ventilation and related complications. Standardized weaning protocols are safe and effective in reducing the time spent on mechanical ventilation.Notwithstanding, the evidence supporting their use in practice is inconsistent. The discordant results of studies may reflect the fact that protocols vary in composition and are implemented in different environments by various healthcare providers.\n\n\nDESIGN\nThe objectives of this review are to compare the total duration of mechanical ventilation between patients weaned using protocols vs. non-protocolized practice; to ascertain differences between protocolized and non-protocolized weaning with regards to mortality, adverse events, quality of life, weaning duration, ICU and hospital stay; and to explore variation in outcomes by the type of ICU, the type of protocol and approach to delivering the protocol. We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL, ISI Web of Science and LILACS. In addition, we will endeavour to identify unpublished data and contact first authors of studies included in the review to obtain information on unpublished studies or work in progress.\n\n\nCONCLUSION\nThis review will provide much needed direction for healthcare professionals in intensive care in terms of both research and practice.", "corpus_id": 20554187, "score": 1 }, { "doc_id": "20291545", "title": "Multicenter implementation of a consensus-developed, evidence-based, spontaneous breathing trial protocol*", "abstract": "Objective:Evidence-based practice recommendations abound, but implementation is often unstructured and poorly audited. We assessed the ability of a peer network to implement an evidence-based best practice protocol and to measure patient outcomes. Design:Consensus definition of spontaneous breathing trial followed by implementation in eight academic medical centers. Setting:Six medical, two surgical, and two combined medical/surgical adult intensive care units among eight academic medical centers. Study Population:Patients initiating mechanical ventilation through an endotracheal tube during a 12-wk interval formed the study population. Interventions:Adoption and implementation of a common spontaneous breathing trial protocol across multiple intensive care units. Measurements and Main Results:Seven hundred five patients had 3,486 safety screens for conducting a spontaneous breathing trial; 2072 (59%) patients failed the safety screen. Another 379 (11%) patients failed a 2-min tolerance screen and 1,122 (34%) patients had a full 30–120 min spontaneous breathing trial performed. Seventy percent of eligible patients were enrolled. Only 55% of passing spontaneous breathing trials resulted in liberation from mechanical ventilatory support before another spontaneous breathing trial was performed. Conclusions:Peer networks can be effective in promoting and implementing evidence-based best practices. Implementation of a best practice (spontaneous breathing trial) may be necessary for, but by itself insufficient to achieve, consistent and timely liberation from ventilator support.", "corpus_id": 20291545, "score": 1 }, { "doc_id": "8513561", "title": "Weaning from mechanical ventilation: a model for extubation", "abstract": "Objective: To develop a model able to determine the right time for extubation and to validate its performance.¶Design: A prospective clinical study.¶Setting: 14-bed medical intensive care unit in a university hospital.¶Patients: 101 patients (37 women/64 men) ventilated over more than 48 h (mean 10.4 ± 10.3 days) and considered ready to be weaned by the medical team (February 1996–February 1998).¶Methods: This study included two series: a development series with 53 patients and a validation series with 48 patients. Before extubation, a weaning test was performed measuring tidal volume (VT), respiratory rate (f), f/VT ratio, minute ventilation, vital capacity (VC) and maximum inspiratory and expiratory pressures (MIP and MEP). The success of extubation was assessed after 48 h. Receiver operating characteristic (ROC) curves allowed the analysis of the discriminating power of each parameter. Threshold values were determined using the Youden's index. To create the best predictive model, we performed a multiple logistic regression analysis. To assess the calibration and the discrimination of the model, the Hosmer-¶Lemeshow goodness-of-fit test and area under ROC curves (AUC) were adopted.¶Measurements and results: In a development series, 60 tests were carried out with 38 successful extubations and 22 extubation failures. The multivariate analysis found three significant variables: VC (threshold value = 635 ml), f/VT ratio (threshold value = 88 breaths/min.l) and MEP (threshold value = 28 cmH2O). The validation cohort included 59 tests (38 successes and 21 failures). The validation series shows a good discrimination (AUC = 0.855 ± 0.059) and calibration (goodness-of-fit test C: p = 0.224) of the model.¶Conclusion: VC together with the ¶f/VT ratio and MEP offer accurate prediction of early extubation.", "corpus_id": 8513561, "score": 0 }, { "doc_id": "28933964", "title": "Extubation and the myth of \"minimal ventilator settings\".", "abstract": "the foundation of improvement. Ann Intern Med 1998;128:1004–1009. 4. Collins FS. Re-engineering translational science: the time is right. Sci Transl Med 2011;3:1–6. 5. National Institutes of Health. The CRADA initiative [Internet; accessed 2011 Sept 15]. Available from: http://www.ott.nih.gov/cradas/model_ agree.aspx 6. National Institutes of Health. The TRND initiative [Internet; accessed 2011 Sept 15]. Available from: http://trend.nih.gov/ 7. Innovative Medicines Initiative [Internet; accessed 2011 Sept 15]. Available from: http://www.imi-europe.org/ 8. Foundation for the NIH [Internet; accessed 2011 Sept 15]. Available from: http://www.fnih.org/support/foundation/research-partnership 9. Glass B. The ethical basis of science. Science 1965;150:1254–1261. 10. Hyatt HH. Protecting the medical commons: who is responsible? N Engl J Med 1975;293:235–241. 11. Petak SM, Coble YD, Duick DS, Gonzales-Campoy JM, Hodgson SF, Lefferts JD, Williams FA, Zeiger MZ. American Association of Clinical Endocrinologists and American College of Endocrinology: position statement on physician/industry relationships. Endocr Pract 2009;15:289. 12. Levinsky NG. Non-financial conflicts of interest in research. N Engl J Med 2002;347:759–761. 13. Beecher HK. Ethics and clinical research. N Engl J Med 1966;274:1354– 1360. 14. MacIntyre A. After virtue: a study in moral theory, 3rd ed. Notre Dame, IN: University of Notre Dame Press; 2007.", "corpus_id": 28933964, "score": 0 }, { "doc_id": "205541553", "title": "Comparisons of predictive performance of breathing pattern variability measured during T-piece, automatic tube compensation, and pressure support ventilation for weaning intensive care unit patients from mechanical ventilation*", "abstract": "Objective:To investigate the influence of different ventilatory supports on the predictive performance of breathing pattern variability for extubation outcomes in intensive care unit patients. Design and Setting:A prospective measurement of retrospectively analyzed breathing pattern variability in a medical center. Patients:Sixty-eight consecutive and ready-for-weaning patients were divided into success (n = 45) and failure (n = 23) groups based on their extubation outcomes. Measurements:Breath-to-breath analyses of peak inspiratory flow, total breath duration, tidal volume, and rapid shallow breathing index were performed for three 30-min periods while patients randomly received T-piece, 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure, and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure trials. Coefficient of variations and data dispersion (standard descriptor values SD1 and SD2 of the Poincaré plot) were analyzed to serve as breathing pattern variability indices. Main Results:Under all three trials, breathing pattern variability in extubation failure patients was smaller than in extubation success patients. Compared to the T-piece trial, 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure decreased the ability of certain breathing pattern variability indices to discriminate extubation success from extubation failure. The areas under the receiver operating characteristic curve of these breathing pattern variability indices were: T-piece (0.73–0.87) > 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure (0.60–0.79) > 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure (0.53–0.76). Analysis of the classification and regression tree indicated that during the T-piece trial, a SD1 of peak inspiratory flow >3.36 L/min defined a group including all extubation success patients. Conversely, the combination of a SD1 of peak inspiratory flow ≤3.36 L/min and a coefficient of variations of rapid shallow breathing index ≤0.23 defined a group of all extubation failure patients. The decision strategies using SD1 of peak inspiratory flow and coefficient of variations of rapid shallow breathing index measured during 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure trials achieved a less clear separation of extubation failure from extubation success. Conclusions:Since 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure reduce the predictive performance of breathing pattern variability, breathing pattern variability measurement during the T-piece trial is the best choice for predicting extubation outcome in intensive care unit patients patients.", "corpus_id": 205541553, "score": 0 }, { "doc_id": "21000379", "title": "Mechanical ventilator weaning protocols driven by nonphysician health-care professionals: evidence-based clinical practice guidelines.", "abstract": "Health-care professionals (HCPs) can provide protocol-based care that has a measurable impact on critically ill patients beyond their liberation from mechanical ventilation (MV). Randomized controlled trials have demonstrated that protocols for liberating patients from MV driven by nonphysician HCPs can reduce the duration of MV. The structure and features of protocols should be adapted from published protocols to incorporate patient-specific needs, clinician preferences, and institutional resources. As a general approach, shortly after patients demonstrate that their condition has been stabilized on the ventilator, a spontaneous breathing trial (SBT) is safe to perform and is indicated. Ventilator management strategies for patients who fail a trial of spontaneous breathing include the following: (1) consideration of all remediable factors (such as electrolyte derangements, bronchospasm, malnutrition, patient positioning, and excess secretions) to enhance the prospects of successful liberation from MV; (2) use of a comfortable, safe, and well-monitored mode of MV (such as pressure support ventilation); and (3) repeating a trial of spontaneous breathing on the following day. For patients who pass the SBT, the decision to extubate must be guided by clinical judgment and objective data to minimize the risk of unnecessary reintubations and self-extubations. Protocols should not represent rigid rules but, rather, guides to patient care. Moreover, the protocols may evolve over time as clinical and institutional experience with them increases. Useful protocols aim to safely and efficiently liberate patients from MV, reducing unnecessary or harmful variations in approach.", "corpus_id": 21000379, "score": 1 }, { "doc_id": "10168105", "title": "Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation.", "abstract": "OBJECTIVE\nTo compare a practice of protocol-directed sedation during mechanical ventilation implemented by nurses with traditional non-protocol-directed sedation administration.\n\n\nDESIGN\nRandomized, controlled clinical trial.\n\n\nSETTING\nMedical intensive care unit (19 beds) in an urban teaching hospital.\n\n\nPATIENTS\nPatients requiring mechanical ventilation (n = 321).\n\n\nINTERVENTIONS\nPatients were randomly assigned to receive either protocol-directed sedation (n = 162) or non-protocol-directed sedation (n = 159).\n\n\nMEASUREMENTS AND MAIN RESULTS\nThe median duration of mechanical ventilation was 55.9 hrs (95% confidence interval, 41.0-90.0 hrs) for patients managed with protocol-directed sedation and 117.0 hrs (95% confidence interval, 96.0-155.6 hrs) for patients receiving non-protocol-directed sedation. Kaplan-Meier analysis demonstrated that patients in the protocol-directed sedation group had statistically shorter durations of mechanical ventilation than patients in the non-protocol-directed sedation group (chi-square = 7.00, p = .008, log rank test; chi-square = 8.54, p = .004, Wilcoxon's test; chi-square = 9.18, p = .003, -2 log test). Lengths of stay in the intensive care unit (5.7+/-5.9 days vs. 7.5+/-6.5 days; p = .013) and hospital (14.0+/-17.3 days vs. 19.9+/-24.2 days; p < .001) were also significantly shorter among patients in the protocol-directed sedation group. Among the 132 patients (41.1%) receiving continuous intravenous sedation, those in the protocol-directed sedation group (n = 66) had a significantly shorter duration of continuous intravenous sedation than those in the non-protocol-directed sedation group (n = 66) (3.5+/-4.0 days vs. 5.6+/-6.4 days; p = .003). Patients in the protocol-directed sedation group also had a significantly lower tracheostomy rate compared with patients in the non-protocol-directed sedation group (10 of 162 patients [6.2%] vs. 21 of 159 patients [13.2%], p = .038).\n\n\nCONCLUSIONS\nThe use of protocol-directed sedation can reduce the duration of mechanical ventilation, the intensive care unit and hospital lengths of stay, and the need for tracheostomy among critically ill patients with acute respiratory failure.", "corpus_id": 10168105, "score": 0 }, { "doc_id": "23236975", "title": "The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation.", "abstract": "STUDY OBJECTIVE\nTo determine whether the use of continuous i.v. sedation is associated with prolongation of the duration of mechanical ventilation.\n\n\nDESIGN\nProspective observational cohort study.\n\n\nSETTING\nThe medical ICU of Barnes-Jewish Hospital, a university-affiliated urban teaching hospital.\n\n\nPATIENTS\nTwo hundred forty-two consecutive ICU patients requiring mechanical ventilation.\n\n\nINTERVENTIONS\nPatient surveillance and data collection.\n\n\nMEASUREMENTS AND RESULTS\nThe primary outcome measure was the duration of mechanical ventilation. Secondary outcome measures included ICU and hospital lengths of stay, hospital mortality, and acquired organ system derangements. A total of 93 (38.4%) mechanically ventilated patients received continuous i.v. sedation while 149 (61.6%) patients received either bolus administration of i.v. sedation (n=64) or no i.v. sedation (n=85) following intubation. The duration of mechanical ventilation was significantly longer for patients receiving continuous i.v. sedation compared with patients not receiving continuous i.v. sedation (185+/-190 h vs 55.6+/-75.6 h; p<0.001). Similarly, the lengths of intensive care (13.5+/-33.7 days vs 4.8+/-4.1 days; p<0.001) and hospitalization (21.0+/-25.1 days vs 12.8+/-14.1 days; p<0.001) were statistically longer among patients receiving continuous i.v. sedation. Multiple linear regression analysis, adjusting for age, gender, severity of illness, mortality, indication for mechanical ventilation, use of chemical paralysis, presence of a tracheostomy, and the number of acquired organ system derangements, found the adjusted duration of mechanical ventilation to be significantly longer for patients receiving continuous i.v. sedation compared with patients who did not receive continuous i.v. sedation (148 h [95% confidence interval: 121, 175 h] vs 78.7 h [95% confidence interval: 68.9, 88.6 h]; p<0.001).\n\n\nCONCLUSION\nWe conclude from these preliminary observational data that the use of continuous i.v. sedation may be associated with the prolongation of mechanical ventilation. This study suggests that strategies targeted at reducing the use of continuous i.v. sedation could shorten the duration of mechanical ventilation for some patients. Prospective randomized clinical trials, using well-designed sedation guidelines and protocols, are required to determine whether patient-specific outcomes (eg, duration of mechanical ventilation, patient comfort) can be improved compared with conventional sedation practices.", "corpus_id": 23236975, "score": 0 }, { "doc_id": "25492453", "title": "Sedation Interruption in Mechanically Ventilated Critically Ill Patients Cared for With a Sedation Protocol A Randomized Controlled Trial", "abstract": "Sangeeta Mehta, MD Lisa Burry, PharmD Deborah Cook, MD Dean Fergusson, PhD Marilyn Steinberg, RN John Granton, MD Margaret Herridge, MD Niall Ferguson, MD John Devlin, PharmD Maged Tanios, MD Peter Dodek, MD Robert Fowler, MD Karen Burns, MD Michael Jacka, MD Kendiss Olafson, MD Yoanna Skrobik, MD Paul Hébert, MD Elham Sabri, MSc Maureen Meade, MD for the SLEAP Investigators and the Canadian Critical Care Trials Group", "corpus_id": 25492453, "score": 0 }, { "doc_id": "2812585", "title": "The Ventilator Discontinuation Process: An Expanding Evidence Base", "abstract": "The ventilator discontinuation process is an essential component of overall ventilator management. Undue delay leads to excess stay, iatrogenic lung injury, unnecessary sedation, and even higher mortality. On the other hand, premature withdrawal can lead to muscle fatigue, dangerous gas exchange impairment, loss of airway protection, and also a higher mortality. Continued ventilator dependence can be a result of persistent illness or can be a result of poor management. It is obviously important for the clinician to be able to assess both of these issues. An evidence-based task force has recommended regular assessments focusing on the causes of ventilator dependence, regular assessments for evidence of disease stability/reversal, use of regular spontaneous breathing trials (SBTs) as the primary assessment tool for ventilator discontinuation potential, use of separate assessments to evaluate the need for an artificial airway in patients tolerating the SBT, and the use of comfortable, interactive ventilator modes (that do not need to be “weaned”) in between regular SBTs. More recent developments have focused on the importance of linking sedation reduction protocols to ventilator discontinuation protocols. Patients with repeated SBT failures are often considered to require prolonged mechanical ventilation (PMV). These patients often receive tracheostomies and are probably better managed with more gradual reductions in support and gradually lengthened spontaneous breathing periods. PMV patients have a high 1-year mortality, and many may ultimately require lifelong support. This evidence base is growing, but the earlier guidelines are standing the test of time. Indeed, practice patterns are evolving in accordance with them. Nevertheless, there is still room for improvement, and further clinical studies, especially in the patient requiring PMV, are needed.", "corpus_id": 2812585, "score": 1 }, { "doc_id": "11611726", "title": "Bedside criteria for discontinuation of mechanical ventilation.", "abstract": "The purpose of this study was to determine bedside criteria for discontinuation of mechanical ventilation. The resting minute ventilation (MV), maximal voluntary ventilation (MVV) and peak negative pressure on maximal inspiration (PNP) were studied in 100 consecutive patients receiving assisted ventilation. Seventysix patients (Group 1) had MV less than 10 L/min and could double the MV with an MVV maneuver. All Group 1 patients could have mechanical ventilation discontinued. Seventeen patients (Group 2) could not double their resting MV with an MVV maneuver and required further ventilatory assistance. Seven patients (Group 3) could not double their resting MV with an MVV maneuver but did not require further mechanical ventilation. Patients whose PNP was greater than 30 cm H2O less than atmospheric were always able to have mechanical ventilation discontinued. The ease with which these measurements can be performed at the bedside and their high degree of predictability make them useful in acute respiratory care.", "corpus_id": 11611726, "score": 0 }, { "doc_id": "21137642", "title": "Predicting 3-day and 7-day outcomes of weaning from mechanical ventilation.", "abstract": "OBJECTIVE\nTo determine the correlation of acute physiology and chronic health evaluation (APACHE) II score and various weaning indexes (WIs) with 3- and 7-day weaning outcomes.\n\n\nDESIGN\nProspective, observational.\n\n\nSETTING\nThe medical ICU of a teaching, urban hospital.\n\n\nMETHODS\nThe study included 118 adults referred for weaning from mechanical ventilation (MV). Critical care physicians, critical care nurses, and respiratory care practitioners were asked to predict whether it would take < or =3 days, 4 to 7 days, or > or =8 days to wean each patient from MV. The WIs and APACHE II scores were measured or calculated. The causes of respiratory failure, the duration of MV before initiating weaning assessment, and the 3- and 7-day weaning outcomes were obtained. Significance was set at p<0.05.\n\n\nRESULTS\nThe most common causes of respiratory failure were pneumonia (38 cases) and acute exacerbation of COPD (29 cases). Fifty-seven patients (48%) were successfully weaned from MV within 3 days of weaning assessment, and 67 (57%) were weaned within 7 days. The percentages of correct prediction of 3-day weaning outcome by critical care physicians, critical care nurses, and respiratory care practitioners were 64%, 62%, and 59%, respectively; for 7-day weaning outcome, 60%, 64%, and 58%, respectively. The successfully weaned groups had significantly lower APACHE II scores and higher maximal inspiratory pressures than the unsuccessfully weaned (failure) groups. There were no significant differences between the two groups for the remaining indexes, including rapid shallow breathing, dynamic compliance, static compliance, spontaneous respiratory rate, and the ratio of PaO2 to the fraction of inspired oxygen.\n\n\nCONCLUSIONS\nThe overall severity of illness as assessed by APACHE II score correlates better with 3- and 7-day weaning outcome than the published WIs.", "corpus_id": 21137642, "score": 0 }, { "doc_id": "27355561", "title": "Diagnostic accuracy of the rapid shallow breathing index to predict a successful spontaneous breathing trial outcome in mechanically ventilated patients with chronic obstructive pulmonary disease.", "abstract": "OBJECTIVE\nTo evaluate the diagnostic accuracy of 2 threshold values (105 breaths per minute [bpm]/L and 130 bpm/L) of the rapid shallow breathing index (RSBI) to predict a successful weaning trial outcome in a homogenous group of patients with chronic obstructive pulmonary disease (COPD).\n\n\nMETHODS\nA consecutive population of patients with COPD who were intubated for hypercapnic respiratory failure during a 2-year period were studied prospectively. RSBI was measured by 2 investigators at minute 5 of the T-piece trial, whereas 2 other physicians evaluated the 30 minute T-piece trial as successful or unsuccessful, according to clinical criteria.\n\n\nRESULTS\nOf 64 patients with COPD (53 male, 11 female) who constituted the study population, 42 patients (35 male, 7 female; aged 70 ± 9.2 years) completed the spontaneous breathing trial (SBT) and remained clinically stable (group 1). The remaining 22 patients (18 male, 4 female; aged 71.9 ± 4.7 years) had to return to ventilatory support by the end of the SBT because of clinical deterioration (group 2). The 2 threshold values that were evaluated had low specificity (38.1% for < 105 bpm/L and 66.7% for < 130 bpm/L), low sensitivity (63.6% for < 105 bpm/L and 54.5% for < 130 bpm/L), and low diagnostic accuracy (46.8% for < 105 bpm/L and 65.6% for < 130 bpm/L) in predicting a successful T-piece trial outcome.\n\n\nCONCLUSION\nRSBI measured early during an SBT cannot accurately predict the successful outcome of a T-piece trial in a homogenous population of patients with COPD.", "corpus_id": 27355561, "score": 0 }, { "doc_id": "19734596", "title": "Tidal volume maintenance during weaning with pressure support.", "abstract": "Ventilation was measured in 31 difficult-to-wean patients while pressure support (PS) was reduced by 5 cm H2O every 20 min. Weaning had to be aborted in 14 of 31 patients (Group F) because they met predefined distress criteria. The remaining 17 patients who were able to complete the \"weaning test\" (Group S) had larger static respiratory compliances (Cstat = 0.08 +/- 0.02 versus 0.05 +/- 0.01 L/cm H2O, p < or = 0.05) and a lower dead space to tidal volume ratio (0.55 +/- 0.05 versus 0.64 +/- 0.06, p < or = 0.05). Group S patients had a larger tidal volume (VT) than did those of Group F at most PS settings. The groups differed with respect to VT maintenance during PS withdrawal (p < 0.01). In Group S, VT fell exponentially with machine support and stabilized at PS levels between 5 and 10 cm H2O. In contrast, Group F patients defended VT at higher PS settings but were unable to maintain VT during distress. Ventilatory response parameters such as the rapid shallow breathing index were of limited value in predicting weaning outcome and yielded receiver operator curve area values between 0.66 and 0.82 over the range of PS settings tested. We conclude that the gradual withdrawal of machine support does not facilitate the recognition of impending respiratory failure.", "corpus_id": 19734596, "score": 0 }, { "doc_id": "195644", "title": "Do heart and respiratory rate variability improve prediction of extubation outcomes in critically ill patients?", "abstract": "IntroductionProlonged ventilation and failed extubation are associated with increased harm and cost. The added value of heart and respiratory rate variability (HRV and RRV) during spontaneous breathing trials (SBTs) to predict extubation failure remains unknown.MethodsWe enrolled 721 patients in a multicenter (12 sites), prospective, observational study, evaluating clinical estimates of risk of extubation failure, physiologic measures recorded during SBTs, HRV and RRV recorded before and during the last SBT prior to extubation, and extubation outcomes. We excluded 287 patients because of protocol or technical violations, or poor data quality. Measures of variability (97 HRV, 82 RRV) were calculated from electrocardiogram and capnography waveforms followed by automated cleaning and variability analysis using Continuous Individualized Multiorgan Variability Analysis (CIMVA™) software. Repeated randomized subsampling with training, validation, and testing were used to derive and compare predictive models.ResultsOf 434 patients with high-quality data, 51 (12%) failed extubation. Two HRV and eight RRV measures showed statistically significant association with extubation failure (P <0.0041, 5% false discovery rate). An ensemble average of five univariate logistic regression models using RRV during SBT, yielding a probability of extubation failure (called WAVE score), demonstrated optimal predictive capacity. With repeated random subsampling and testing, the model showed mean receiver operating characteristic area under the curve (ROC AUC) of 0.69, higher than heart rate (0.51), rapid shallow breathing index (RBSI; 0.61) and respiratory rate (0.63). After deriving a WAVE model based on all data, training-set performance demonstrated that the model increased its predictive power when applied to patients conventionally considered high risk: a WAVE score >0.5 in patients with RSBI >105 and perceived high risk of failure yielded a fold increase in risk of extubation failure of 3.0 (95% confidence interval (CI) 1.2 to 5.2) and 3.5 (95% CI 1.9 to 5.4), respectively.ConclusionsAltered HRV and RRV (during the SBT prior to extubation) are significantly associated with extubation failure. A predictive model using RRV during the last SBT provided optimal accuracy of prediction in all patients, with improved accuracy when combined with clinical impression or RSBI. This model requires a validation cohort to evaluate accuracy and generalizability.Trial registrationClinicalTrials.gov NCT01237886. Registered 13 October 2010.", "corpus_id": 195644, "score": 0 }, { "doc_id": "1844245", "title": "Extubation outcome after spontaneous breathing trials with T-tube or pressure support ventilation. The Spanish Lung Failure Collaborative Group.", "abstract": "A 2-h T-tube trial of spontaneous breathing was used in selecting patients ready for extubation and discontinuation of mechanical ventilation. However, some doubt remains as to whether it is the most appropriate method of performing a spontaneous breathing trial. We carried out a prospective, randomized, multicenter study involving patients who had received mechanical ventilation for more than 48 h and who were considered by their physicians to be ready for weaning according to clinical criteria and standard weaning parameters. Patients were randomly assigned to undergo a 2-h trial of spontaneous breathing in one of two ways: with a T-tube system or with pressure support ventilation of 7 cm H2O. If a patient had signs of poor tolerance at any time during the trial, mechanical ventilation was reinstituted. Patients without these features at the end of the trial were extubated. Of the 246 patients assigned to the T-tube group, 192 successfully completed the trial and were extubated; 36 of them required reintubation. Of the 238 patients in the group receiving pressure support ventilation, 205 were extubated and 38 of them required reintubation. The percentage of patients who remained extubated after 48 h was not different between the two groups (63% T-tube, 70% pressure support ventilation, p = 0.14). The percentage of patients falling the trial was significantly higher when the T-tube was used (22 versus 14%, p = 0.03). Clinical evolution during the trial was not different in patients reintubated and successfully extubated. ICU mortality among reintubated patients was significantly higher than in successfully extubated patients (27 versus 2.6%, p < 0.001). Spontaneous breathing trials with pressure support or T-tube are suitable methods for successful discontinuation of ventilator support in patients without problems to resume spontaneous breathing.", "corpus_id": 1844245, "score": 0 }, { "doc_id": "24167275", "title": "Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial", "abstract": "BACKGROUND\nApproaches to removal of sedation and mechanical ventilation for critically ill patients vary widely. Our aim was to assess a protocol that paired spontaneous awakening trials (SATs)-ie, daily interruption of sedatives-with spontaneous breathing trials (SBTs).\n\n\nMETHODS\nIn four tertiary-care hospitals, we randomly assigned 336 mechanically ventilated patients in intensive care to management with a daily SAT followed by an SBT (intervention group; n=168) or with sedation per usual care plus a daily SBT (control group; n=168). The primary endpoint was time breathing without assistance. Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00097630.\n\n\nFINDINGS\nOne patient in the intervention group did not begin their assigned treatment protocol because of withdrawal of consent and thus was excluded from analyses and lost to follow-up. Seven patients in the control group discontinued their assigned protocol, and two of these patients were lost to follow-up. Patients in the intervention group spent more days breathing without assistance during the 28-day study period than did those in the control group (14.7 days vs 11.6 days; mean difference 3.1 days, 95% CI 0.7 to 5.6; p=0.02) and were discharged from intensive care (median time in intensive care 9.1 days vs 12.9 days; p=0.01) and the hospital earlier (median time in the hospital 14.9 days vs 19.2 days; p=0.04). More patients in the intervention group self-extubated than in the control group (16 patients vs six patients; 6.0% difference, 95% CI 0.6% to 11.8%; p=0.03), but the number of patients who required reintubation after self-extubation was similar (five patients vs three patients; 1.2% difference, 95% CI -5.2% to 2.5%; p=0.47), as were total reintubation rates (13.8%vs 12.5%; 1.3% difference, 95% CI -8.6% to 6.1%; p=0.73). At any instant during the year after enrolment, patients in the intervention group were less likely to die than were patients in the control group (HR 0.68, 95% CI 0.50 to 0.92; p=0.01). For every seven patients treated with the intervention, one life was saved (number needed to treat was 7.4, 95% CI 4.2 to 35.5).\n\n\nINTERPRETATION\nOur results suggest that a wake up and breathe protocol that pairs daily spontaneous awakening trials (ie, interruption of sedatives) with daily spontaneous breathing trials results in better outcomes for mechanically ventilated patients in intensive care than current standard approaches and should become routine practice.", "corpus_id": 24167275, "score": 0 }, { "doc_id": "26185923", "title": "Predictors of extubation outcome in patients who have successfully completed a spontaneous breathing trial.", "abstract": "BACKGROUND\nAfter patients recovering from respiratory failure have successfully completed a spontaneous breathing trial (SBT), clinicians must determine whether an artificial airway is still required. We hypothesized that cough strength and the magnitude of endotracheal secretions affect extubation outcomes.\n\n\nMETHODS\nWe conducted a prospective study of 91 adult patients treated in medical-cardiac ICUs who were recovering from respiratory failure, had successfully completed an SBT, and were about to be extubated. A number of demographic and physiologic parameters were recorded with the patient receiving full ventilatory support and during the SBT, just prior to extubation. Cough strength on command was measured with a semiobjective scale of 0 to 5, and the magnitude of endotracheal secretions was measured as none, mild, moderate, or abundant by a single observer. In addition, patients were asked to cough onto a white card held 1 to 2 cm from the endotracheal tube; if secretions were propelled onto the card, it was termed a positive white card test (WCT) result. All patients were then extubated from T-piece or continuous positive airway pressure breathing trials. If 72 h elapsed and patients did not require reintubation, they were defined as successfully extubated.\n\n\nRESULTS\nNinety-one patients with a mean (+/- SE) age of 65.2 +/- 1.6 years, ICU admission APACHE (acute physiology and chronic health evaluation) II score of 17.7 +/- 0.7, and duration of mechanical ventilation of 5.0 +/- 0.5 days were studied over 100 extubations. Sixteen patients could not be extubated, and 2 patients underwent two unsuccessful extubation attempts, for a total of 18 unsuccessful extubations. Age, severity of illness, duration of mechanical ventilation, oxygenation, rapid shallow breathing index, and vital signs during SBTs did not differ between patients with successful extubations vs patients with unsuccessful extubations. The WCT result was highly correlated with cough strength. Patients with weak (grade 0 to 2) coughs were four times as likely to have unsuccessful extubations, compared to those with moderate-to-strong (grade 3 to 5) coughs (risk ratio [RR], 4.0; 95% confidence interval [CI],1.8 to 8.9). Patients with moderate-to-abundant secretions were more than eight times as times as likely to have unsuccessful extubations as those with no or mild secretions (RR, 8.7; 95% CI, 2.1 to 35.7). Patients with negative WCT results were three times as likely to have unsuccessful extubations as those with positive WCT results (RR, 3.0; 95% CI, 1.3 to 6.7). Poor cough strength and endotracheal secretions were synergistic in predicting extubation failure (Rothman synergy index, 3.7; RR, 31.9; 95% CI, 4.5 to 225.3). Patients with PaO(2)/fraction of inspired oxygen (P:F) ratios of 120 to 200 (receiving mechanical ventilation) were not less likely to be successfully extubated than those with P:F ratios of > 200, but those with hemoglobin levels < or = 10 g/dL were more than five times as likely to have unsuccessful extubations as those with hemoglobin levels > 10 g/dL.\n\n\nCONCLUSIONS\nAfter patients recovering from respiratory failure have successfully completed an SBT, factors affecting airway competence, such as cough strength and amount of endotracheal secretions, may be important predictors of extubation outcomes. Also, a majority (89%) of medically ill patients with P:F ratios of 120 to 200 (four of five patients with P:F ratios from 120 to 150), values sometimes used to preclude weaning, were extubated successfully.", "corpus_id": 26185923, "score": 0 }, { "doc_id": "5735905", "title": "Risk factors for extubation failure in patients following a successful spontaneous breathing trial.", "abstract": "BACKGROUND\nTo assess the factors associated with reintubation in patients who had successfully passed a spontaneous breathing trial.\n\n\nMETHODS\nWe used logistic regression and recursive partitioning analyses of prospectively collected clinical data from adults admitted to ICUs of 37 hospitals in eight countries, who had undergone invasive mechanical ventilation for > 48 h and were deemed ready for extubation.\n\n\nRESULTS\nExtubation failure occurred in 121 of the 900 patients (13.4%). The logistic regression analysis identified the following associations with reintubation: rapid shallow breathing index (RSBI) [odds ratio (OR), 1.009 per unit; 95% confidence interval (CI), 1.003 to 1.015]; positive fluid balance (OR, 1.70; 95% CI, 1.15 to 2.53); and pneumonia as the reason for initiating mechanical ventilation (OR, 1.77; 95% CI, 1.10 to 2.84). The recursive partitioning analysis allowed the separation of patients into different risk groups for extubation failure: (1) RSBI of > 57 breaths/L/min and positive fluid balance (OR, 3.0; 95% CI, 1.8 to 4.8); (2) RSBI of < 57 breaths/L/min and pneumonia as reason for mechanical ventilation (OR, 2.0; 95% CI, 1.1 to 3.6); (3) RSBI of > 57 breaths/L/min and negative fluid balance (OR, 1.4; 95% CI, 0.8 to 2.5); and (4) RSBI of < 57 breaths/L/min (OR, 1 [reference value]).\n\n\nCONCLUSIONS\nAmong routinely measured clinical variables, RSBI, positive fluid balance 24 h prior to extubation, and pneumonia at the initiation of ventilation were the best predictors of extubation failure. However, the combined predictive ability of these variables was weak.", "corpus_id": 5735905, "score": 0 }, { "doc_id": "22787358", "title": "Protocol weaning of mechanical ventilation in medical and surgical patients by respiratory care practitioners and nurses: effect on weaning time and incidence of ventilator-associated pneumonia.", "abstract": "STUDY OBJECTIVES\n(1) To determine the effect of a single ventilator management protocol (VMP) used in medical and surgical ICUs on the duration of mechanical ventilation. (2) To determine the effect of a VMP on the incidence of ventilator-associated pneumonia (VAP).\n\n\nDESIGN\nProspective, randomized, controlled study.\n\n\nSETTING\n: University medical center.\n\n\nPATIENTS\nThree hundred eighty-five patients receiving mechanical ventilation between June 1997 and May 1998.\n\n\nINTERVENTIONS\nA respiratory care practitioner- and registered nurse-driven VMP.\n\n\nRESULTS\nIntervention and control groups were comparable with respect to age, sex, severity of illness and injury, and duration of respiratory failure at the time of randomization. The duration of mechanical ventilation for patients was decreased from a median of 124 h for the control group to 68 h in the VMP group (p = 0.0001). Thirty-one total instances of VAP were noted. Twelve patients in the surgical control group had VAP, compared with 5 in the surgical VMP group (p = 0.061). The impact of the VMP on VAP frequency was less for medical patients. Mortality and ventilator discontinuation failure rates were similar between control and VMP groups.\n\n\nCONCLUSIONS\nA VMP designed for multidisciplinary use was effective in reducing duration of mechanical ventilatory support without any adverse effects on patient outcome. The VMP was also associated with a decrease in incidence of VAP in trauma patients. These results, in conjunction with prior studies, suggest that VMPs are highly effective means of improving care, even in university ICUs.", "corpus_id": 22787358, "score": 0 }, { "doc_id": "37058647", "title": "Improved extubation rates and earlier liberation from mechanical ventilation with implementation of a daily spontaneous-breathing trial protocol.", "abstract": "BACKGROUND\nDaily spontaneous-breathing trials (SBTs) are promulgated as the best method for assessing readiness for discontinuation of mechanical ventilation. SBT protocols have also been shown to improve outcomes as opposed to wild-type implementation of daily SBT recommendations. Here we determine whether implementation of a mandatory, protocol-driven daily SBT on all ventilated patients in the ICU improves extubation rates and accelerates liberation from mechanical ventilation.\n\n\nSTUDY DESIGN\nA daily 30-minute SBT protocol was introduced into an academic surgical ICU in July 2005 and followed through September 2006. Decisions about next steps (continued mechanical support versus liberation) after each trial were recorded. Owing to the low liberation rate, physicians began (in January 2006) recording the reasons for continuing mechanical ventilation after a passing SBT. Differences in patient outcomes were compared for the first and last 8 weeks of the study period, corresponding to similar times in the academic and calendar years.\n\n\nRESULTS\nFour hundred eighty-eight patients experienced 547 mechanical ventilation episodes from July 2005 to September 2006. A total of 2,835 safety evaluations for SBTs were completed. Rate of extubations of passing patients after the first 8 weeks of implementation (n = 73 patients) was 27% (35 extubations of 131 passed trials). This rate improved in the last 8 weeks to 42% (42 of 101) (p < 0.02) (n = 57 patients). Reintubation rate was similar at 6% for the first 8 weeks and 8% for the final 8 weeks (p = 0.65), including self-extubations.\n\n\nCONCLUSIONS\nImplementation of a daily SBT protocol resulted in improvement of extubation rates during the year of implementation without a change in the reintubation rate. Requesting that physicians enumerate reasons for continuing mechanical ventilation in the face of a passing breathing trial was associated with a sustained improvement in extubation rate.", "corpus_id": 37058647, "score": 0 } ]

{ "doc_id": "210168662", "title": "Genetic analysis of male Hungarian Conquerors: European and Asian paternal lineages of the conquering Hungarian tribes", "abstract": "According to historical sources, ancient Hungarians were made up of seven allied tribes and the fragmented tribes that split off from the Khazars, and they arrived from the Eastern European steppes to conquer the Carpathian Basin at the end of the ninth century AD. Differentiating between the tribes is not possible based on archaeology or history, because the Hungarian Conqueror artifacts show uniformity in attire, weaponry, and warcraft. We used Y-STR and SNP analyses on male Hungarian Conqueror remains to determine the genetic source, composition of tribes, and kin of ancient Hungarians. The 19 male individuals paternally belong to 16 independent haplotypes and 7 haplogroups (C2, G2a, I2, J1, N3a, R1a, and R1b). The presence of the N3a haplogroup is interesting because it rarely appears among modern Hungarians (unlike in other Finno-Ugric-speaking peoples) but was found in 37.5% of the Hungarian Conquerors. This suggests that a part of the ancient Hungarians was of Ugric descent and that a significant portion spoke Hungarian. We compared our results with public databases and discovered that the Hungarian Conquerors originated from three distant territories of the Eurasian steppes, where different ethnicities joined them: Lake Baikal-Altai Mountains (Huns/Turkic peoples), Western Siberia-Southern Urals (Finno-Ugric peoples), and the Black Sea-Northern Caucasus (Caucasian and Eastern European peoples). As such, the ancient Hungarians conquered their homeland as an alliance of tribes, and they were the genetic relatives of Asiatic Huns, Finno-Ugric peoples, Caucasian peoples, and Slavs from the Eastern European steppes.", "corpus_id": 210168662 }

[ { "doc_id": "1359107", "title": "Comparison of maternal lineage and biogeographic analyses of ancient and modern Hungarian populations.", "abstract": "The Hungarian language belongs to the Finno-Ugric branch of the Uralic family, but Hungarian speakers have been living in Central Europe for more than 1000 years, surrounded by speakers of unrelated Indo-European languages. In order to study the continuity in maternal lineage between ancient and modern Hungarian populations, polymorphisms in the HVSI and protein coding regions of mitochondrial DNA sequences of 27 ancient samples (10th-11th centuries), 101 modern Hungarian, and 76 modern Hungarian-speaking Sekler samples from Transylvania were analyzed. The data were compared with sequences derived from 57 European and Asian populations, including Finno-Ugric populations, and statistical analyses were performed to investigate their genetic relationships. Only 2 of 27 ancient Hungarian samples are unambiguously Asian: the rest belong to one of the western Eurasian haplogroups, but some Asian affinities, and the genetic effect of populations who came into contact with ancient Hungarians during their migrations are seen. Strong differences appear when the ancient Hungarian samples are analyzed according to apparent social status, as judged by grave goods. Commoners show a predominance of mtDNA haplotypes and haplogroups (H, R, T), common in west Eurasia, while high-status individuals, presumably conquering Hungarians, show a more heterogeneous haplogroup distribution, with haplogroups (N1a, X) which are present at very low frequencies in modern worldwide populations and are absent in recent Hungarian and Sekler populations. Modern Hungarian-speaking populations seem to be specifically European. Our findings demonstrate that significant genetic differences exist between the ancient and recent Hungarian-speaking populations, and no genetic continuity is seen.", "corpus_id": 1359107, "score": 0 }, { "doc_id": "13217908", "title": "Y‐Chromosome Analysis of Ancient Hungarian and Two Modern Hungarian‐Speaking Populations from the Carpathian Basin", "abstract": "The Hungarian population belongs linguistically to the Finno‐Ugric branch of the Uralic family. The Tat C allele is an interesting marker in the Finno‐Ugric context, distributed in all the Finno‐Ugric‐speaking populations, except for Hungarians. This question arises whether the ancestral Hungarians, who settled in the Carpathian Basin, harbored this polymorphism or not. 100 men from modern Hungary, 97 Szeklers (a Hungarian‐speaking population from Transylvania), and 4 archaeologically Hungarian bone samples from the 10th century were studied for this polymorphism. Among the modern individuals, only one Szekler carries the Tat C allele, whereas out of the four skeletal remains, two possess the allele. The latter finding, even allowing for the low sample number, appears to indicate a Siberian lineage of the invading Hungarians, which later has largely disappeared.", "corpus_id": 13217908, "score": 1 }, { "doc_id": "4099313", "title": "Genetic structure of the early Hungarian conquerors inferred from mtDNA haplotypes and Y-chromosome haplogroups in a small cemetery", "abstract": "We applied ancient DNA methods to shed light on the origin of ancient Hungarians and their relation to modern populations. Hungarians moved into the Carpathian Basin from the Eurasian Pontic steppes in the year 895 AD as a confederation of seven tribes, but their further origin remains obscure. Here, we present 17 mtDNA haplotypes and four Y-chromosome haplogroups, which portray the genetic composition of an entire small cemetery of the first generation Hungarians. Using novel algorithms to compare these mitochondrial DNA haplogroups with other ancient and modern Eurasian data, we revealed that a significant portion of the Hungarians probably originated from a long ago consolidated gene pool in Central Asia-South Siberia, which still persists in modern Hungarians. Another genetic layer of the early Hungarians was obtained during their westward migrations by admixing with various populations of European origin, and an important component of these was derived from the Caucasus region. Most of the modern populations, which are genetically closest relatives of ancient Hungarians, today speak non-Indo-European languages. Our results contribute to our understanding of the peopling of Europe by providing ancient DNA data from a still genetically poorly studied period of medieval human migrations.", "corpus_id": 4099313, "score": 0 }, { "doc_id": "54165415", "title": "Correction: Mitogenomic data indicate admixture components of Central-Inner Asian and Srubnaya origin in the conquering Hungarians", "abstract": "[This corrects the article DOI: 10.1371/journal.pone.0205920.].", "corpus_id": 54165415, "score": 1 }, { "doc_id": "23742103", "title": "Probable ancestors of Hungarian ethnic groups: an admixture analysis", "abstract": "The history of Hungary starts in the 9th century with the arrival of the Magyars in the Carpathian Basin. They spoke, like modern Hungarians, an Uralic language belonging to the Finno‐Ugric language group. Their original composition probably included Iranian and Turkish people, while other populations were already present in the territory (Avars, Slavs, Germans). Some of the Hungarian ethnic groups claim to be descendants of ancient Magyars settlers (such as the Örség), others of Huns, Turks or Iranians. We collected and compared the previously published gene frequencies of eight ethnic groups and seven hypothetical ancestral populations, including Uralics, applying a model of admixture. The results, most of which confirm historical hypotheses or the oral tradition, show that only one ethnic group (Örség) highly resembles the Uralic population.", "corpus_id": 23742103, "score": 0 }, { "doc_id": "46261606", "title": "MtDNA polymorphism in the Hungarians: comparison to three other Finno-Ugric-speaking populations.", "abstract": "Mitochondrial DNA sequence variation as well as restriction site polymorphisms were examined in 437 individuals from four Finno-Ugric-speaking populations. These included the Hungarians (Budapest region and the Csángós from Hungary and Romania), the Finns and two Saami groups from northeastern Finland (Inari Saami and Skolt Saami), and the Erzas from central Russia. The mtDNA data obtained in this study were combined with our previous data on Y chromosomal variation for eight different loci in these populations. The genetic variation observed among the Hungarians resembled closely that found in other European populations. The Hungarians could not be distinguished from the neighboring populations (e.g., the Austrians) any more than from their Finno-Ugric linguistic relatives.", "corpus_id": 46261606, "score": 0 }, { "doc_id": "205676493", "title": "MtDNA and Y chromosome polymorphisms in Hungary: inferences from the palaeolithic, neolithic and Uralic influences on the modern Hungarian gene pool", "abstract": "Magyars imposed their language on Hungarians but seem not to have affected their genetic structure. To better investigate this point, we analysed some mtDNA and Y chromosome polymorphisms in a sample of the Hungarian Palóc who, for historical reasons, could have retained genetic traces of Magyars more than other groups. In addition, we examined a mixed sample from Budapest. About 100 individuals were tested for the markers defining all the European and Asian mtDNA haplogroups and about 50 individuals for some Y chromosome markers, namely the 12f2 and 49a,f/TaqI RFLPs, the YAP insertion, the microsatellites YCAIIa, YCAIIb, DYS19 and the Asian 50f2/C deletion. In the mtDNA analysis only two subjects belonged to the Asian B and M haplogroups. The Y chromosome analyses showed: that the Palóc differed from the Budapest sample by the absence of YAP+ allele and by the DYS19 allele distribution; that the proto-European 49a,f Ht 15 and the neolithic 12f2–8Kb were rather uncommon in both groups; that there is a high prevalence of the 49a,f Ht 11 and the YCAII a5–b1; and that the Asian 50f2/C deletion is absent. These results suggest that the influence of Magyars on the Hungarian gene pool has been very low through both females and males and the Hungarian language could be an example of cultural dominance. Alternative explanations are discussed. An expansion centred on YAP−; 49a,f Ht 11 is revealed by the median network based on compound haplotypes. 49a,f Ht 11 could represent either a paleolithic marker of eastern Europe which underwent expansion after the last glacial period, or a marker of the more recent spread of the Yamnaia culture from southern Ukraine.", "corpus_id": 205676493, "score": 0 }, { "doc_id": "52313426", "title": "Genes reveal traces of common recent demographic history for most of the Uralic-speaking populations", "abstract": "BackgroundThe genetic origins of Uralic speakers from across a vast territory in the temperate zone of North Eurasia have remained elusive. Previous studies have shown contrasting proportions of Eastern and Western Eurasian ancestry in their mitochondrial and Y chromosomal gene pools. While the maternal lineages reflect by and large the geographic background of a given Uralic-speaking population, the frequency of Y chromosomes of Eastern Eurasian origin is distinctively high among European Uralic speakers. The autosomal variation of Uralic speakers, however, has not yet been studied comprehensively.ResultsHere, we present a genome-wide analysis of 15 Uralic-speaking populations which cover all main groups of the linguistic family. We show that contemporary Uralic speakers are genetically very similar to their local geographical neighbours. However, when studying relationships among geographically distant populations, we find that most of the Uralic speakers and some of their neighbours share a genetic component of possibly Siberian origin. Additionally, we show that most Uralic speakers share significantly more genomic segments identity-by-descent with each other than with geographically equidistant speakers of other languages. We find that correlated genome-wide genetic and lexical distances among Uralic speakers suggest co-dispersion of genes and languages. Yet, we do not find long-range genetic ties between Estonians and Hungarians with their linguistic sisters that would distinguish them from their non-Uralic-speaking neighbours.ConclusionsWe show that most Uralic speakers share a distinct ancestry component of likely Siberian origin, which suggests that the spread of Uralic languages involved at least some demic component.", "corpus_id": 52313426, "score": 0 }, { "doc_id": "40143312", "title": "Genetic relationships of Asians and Northern Europeans, revealed by Y-chromosomal DNA analysis.", "abstract": "We have identified a new T-->C transition on the human Y chromosome. C-allele chromosomes have been found only in a subset of the populations from Asia and northern Europe and reach their highest frequencies in Yakut, Buryats, and Finns. Examination of the microsatellite haplotypes of the C-allele chromosomes suggests that the mutation occurred recently in Asia. The Y chromosome thus provides both information about population relationships in Asia and evidence for a substantial paternal genetic contribution of Asians to northern European populations such as the Finns.", "corpus_id": 40143312, "score": 1 }, { "doc_id": "17408437", "title": "Y-SNP L1034: limited genetic link between Mansi and Hungarian-speaking populations", "abstract": "Genetic studies noted that the Hungarian Y-chromosomal gene pool significantly differs from other Uralic-speaking populations. Hungarians show very limited or no presence of haplogroup N-Tat, which is frequent among other Uralic-speaking populations. We proposed that some genetic links need to be observed between the linguistically related Hungarian and Mansi populations.This is the first attempt to divide haplogroup N-Tat into subhaplogroups by testing new downstream SNP markers L708 and L1034. Sixty Northern Mansi samples were collected in Western Siberia and genotyped for Y-chromosomal haplotypes and haplogroups. We found 14 Mansi and 92 N-Tat samples from 7 populations. Comparative results showed that all N-Tat samples carried the N-L708 mutation. Some Hungarian, Sekler, and Uzbek samples were L1034 SNP positive, while all Mongolians, Buryats, Khanty, Finnish, and Roma samples yielded a negative result for this marker. Based on the above, L1034 marker seems to be a subgroup of N-Tat, which is typical for Mansi and Hungarian-speaking ethnic groups so far. Based on our time to most recent common ancestor data, the L1034 marker arose 2,500 years before present. The overall frequency of the L1034 is very low among the analyzed populations, thus it does not necessarily mean that proto-Hungarians and Mansi descend from common ancestors. It does provide, however, a limited genetic link supporting language contact. Both Hungarians and Mansi have much more complex genetic population history than the traditional tree-based linguistic model would suggest.", "corpus_id": 17408437, "score": 0 }, { "doc_id": "10107799", "title": "A study of the Bodrogköz population in north-eastern Hungary by Y chromosomal haplotypes and haplogroups", "abstract": "We have determined the distribution of Y chromosomal haplotypes and haplogroups in population samples from one of the most important areas in north-eastern Hungary from many villages in the Bodrogköz. The Bodrogköz region was chosen due to its isolated nature, because this area was a moorland encircled by the Tisza, Bodrog, and Latorca Rivers and inhabitants of this part of Hungary escaped from both Tatar and Ottoman invasions, which decimated the post-Hungarian Conquest populations in many parts of the country. Furthermore, in the first half of the tenth century, this region served as the Palatial Centre and burial grounds of the Hungarian tribes. It has thus been assumed that the present population in this area is likely to be more similar to the population that lived in the Conquest period. We analysed male-specific markers, 23 Y-STRs and more than 30 Y-SNPs, that reflect the past and recent genetic history. We found that the general haplogroup distribution of the samples showed high genetic similarity to non-Bodrogköz Hungarians and neighbouring populations, despite its sheltered location and historical record. We were able to classify the Y-chromosomal haplogroups into four large groups based on STR mutation events: pre-Roman/Roman ancient lineage, Finno-Ugric speakers arriving into the Carpathian Basin, Migration period admixture, and post-Hungarian Conquest admixture. It is clear that a significantly larger database with deep haplogroup resolution, including ancient DNA data, is required to strengthen this research.", "corpus_id": 10107799, "score": 0 }, { "doc_id": "163164504", "title": "Y-chromosomal connection between Hungarians and geographically distant populations of the Ural Mountain region and West Siberia", "abstract": "Hungarians who live in Central Europe today are one of the westernmost Uralic speakers. Despite of the proposed Volga-Ural/West Siberian roots of the Hungarian language, the present-day Hungarian gene pool is highly similar to that of the surrounding Indo-European speaking populations. However, a limited portion of specific Y-chromosomal lineages from haplogroup N, sometimes associated with the spread of Uralic languages, link modern Hungarians with populations living close to the Ural Mountain range on the border of Europe and Asia. Here we investigate the paternal genetic connection between these spatially separated populations. We reconstruct the phylogeny of N3a4-Z1936 clade by using 33 high-coverage Y-chromosomal sequences and estimate the coalescent times of its sub-clades. We genotype close to 5000 samples from 46 Eurasian populations to show the presence of N3a4-B539 lineages among Hungarians and in the populations from Ural Mountain region, including Ob-Ugric-speakers from West Siberia who are geographically distant but linguistically closest to Hungarians. This sub-clade splits from its sister-branch N3a4-B535, frequent today among Northeast European Uralic speakers, 4000–5000 ya, which is in the time-frame of the proposed divergence of Ugric languages.", "corpus_id": 163164504, "score": 0 }, { "doc_id": "37204852", "title": "Application of the iPLEXTM Gold SNP genotyping method for the analysis of Amerindian ancient DNA samples: Benefits for ancient population studies", "abstract": "Important developments in the matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) technique have generated new perspectives regarding SNP genotyping, which are particularly promising for ancient population‐based studies. The main aim of the present study was to investigate the application of a MALDI‐TOF MS‐based SNP genotyping technique, called iPLEX® Gold, to analyze Amerindian ancient DNA samples. The first objective was to test the sensitivity of the method, which is recommended for DNA quantities between 10 and 5 ng, for ancient biological samples containing DNA molecules that were degraded and present in minute quantities. The second objective was to detail the advantages of this technique for studies on ancient populations. Two multiplexes were designed, allowing the major Amerindian mitochondrial and Y haplogroups to be determined simultaneously. This analysis has never been described before. Results demonstrated the reliability and accuracy of the method; data were obtained for both mitochondrial and nuclear DNA using picogram (pg) quantities of nucleic acid. This technique has the advantages of both MS and minisequencing techniques; thus, it should be included in the protocols for future ancient DNA studies.", "corpus_id": 37204852, "score": 0 }, { "doc_id": "43084340", "title": "Median-joining networks for inferring intraspecific phylogenies.", "abstract": "Reconstructing phylogenies from intraspecific data (such as human mitochondrial DNA variation) is often a challenging task because of large sample sizes and small genetic distances between individuals. The resulting multitude of plausible trees is best expressed by a network which displays alternative potential evolutionary paths in the form of cycles. We present a method (\"median joining\" [MJ]) for constructing networks from recombination-free population data that combines features of Kruskal's algorithm for finding minimum spanning trees by favoring short connections, and Farris's maximum-parsimony (MP) heuristic algorithm, which sequentially adds new vertices called \"median vectors\", except that our MJ method does not resolve ties. The MJ method is hence closely related to the earlier approach of Foulds, Hendy, and Penny for estimating MP trees but can be adjusted to the level of homoplasy by setting a parameter epsilon. Unlike our earlier reduced median (RM) network method, MJ is applicable to multistate characters (e.g., amino acid sequences). An additional feature is the speed of the implemented algorithm: a sample of 800 worldwide mtDNA hypervariable segment I sequences requires less than 3 h on a Pentium 120 PC. The MJ method is demonstrated on a Tibetan mitochondrial DNA RFLP data set.", "corpus_id": 43084340, "score": 0 }, { "doc_id": "7624568", "title": "Comprehensive mutation analysis of 17 Y-chromosomal short tandem repeat polymorphisms included in the AmpFlSTR® Yfiler® PCR amplification kit", "abstract": "The Y-chromosomal short tandem repeat (Y-STR) polymorphisms included in the AmpFlSTR® Yfiler® polymerase chain reaction amplification kit have become widely used for forensic and evolutionary applications where a reliable knowledge on mutation properties is necessary for correct data interpretation. Therefore, we investigated the 17 Yfiler Y-STRs in 1,730–1,764 DNA-confirmed father–son pairs per locus and found 84 sequence-confirmed mutations among the 29,792 meiotic transfers covered. Of the 84 mutations, 83 (98.8%) were single-repeat changes and one (1.2%) was a double-repeat change (ratio, 1:0.01), as well as 43 (51.2%) were repeat gains and 41 (48.8%) repeat losses (ratio, 1:0.95). Medians from Bayesian estimation of locus-specific mutation rates ranged from 0.0003 for DYS448 to 0.0074 for DYS458, with a median rate across all 17 Y-STRs of 0.0025. The mean age (at the time of son’s birth) of fathers with mutations was with 34.40 (±11.63) years higher than that of fathers without ones at 30.32 (±10.22) years, a difference that is highly statistically significant (p < 0.001). A Poisson-based modeling revealed that the Y-STR mutation rate increased with increasing father’s age on a statistically significant level (α = 0.0294, 2.5% quantile = 0.0001). From combining our data with those previously published, considering all together 135,212 meiotic events and 331 mutations, we conclude for the Yfiler Y-STRs that (1) none had a mutation rate of >1%, 12 had mutation rates of >0.1% and four of <0.1%, (2) single-repeat changes were strongly favored over multiple-repeat ones for all loci but 1 and (3) considerable variation existed among loci in the ratio of repeat gains versus losses. Our finding of three Y-STR mutations in one father–son pair (and two pairs with two mutations each) has consequences for determining the threshold of allelic differences to conclude exclusion constellations in future applications of Y-STRs in paternity testing and pedigree analyses.", "corpus_id": 7624568, "score": 0 }, { "doc_id": "6265129", "title": "The phylogenetic and geographic structure of Y-chromosome haplogroup R1a", "abstract": "R1a-M420 is one of the most widely spread Y-chromosome haplogroups; however, its substructure within Europe and Asia has remained poorly characterized. Using a panel of 16 244 male subjects from 126 populations sampled across Eurasia, we identified 2923 R1a-M420 Y-chromosomes and analyzed them to a highly granular phylogeographic resolution. Whole Y-chromosome sequence analysis of eight R1a and five R1b individuals suggests a divergence time of ∼25 000 (95% CI: 21 300–29 000) years ago and a coalescence time within R1a-M417 of ∼5800 (95% CI: 4800–6800) years. The spatial frequency distributions of R1a sub-haplogroups conclusively indicate two major groups, one found primarily in Europe and the other confined to Central and South Asia. Beyond the major European versus Asian dichotomy, we describe several younger sub-haplogroups. Based on spatial distributions and diversity patterns within the R1a-M420 clade, particularly rare basal branches detected primarily within Iran and eastern Turkey, we conclude that the initial episodes of haplogroup R1a diversification likely occurred in the vicinity of present-day Iran.", "corpus_id": 6265129, "score": 1 }, { "doc_id": "19900060", "title": "Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows", "abstract": "We present here a new version of the Arlequin program available under three different forms: a Windows graphical version (Winarl35), a console version of Arlequin (arlecore), and a specific console version to compute summary statistics (arlsumstat). The command‐line versions run under both Linux and Windows. The main innovations of the new version include enhanced outputs in XML format, the possibility to embed graphics displaying computation results directly into output files, and the implementation of a new method to detect loci under selection from genome scans. Command‐line versions are designed to handle large series of files, and arlsumstat can be used to generate summary statistics from simulated data sets within an Approximate Bayesian Computation framework.", "corpus_id": 19900060, "score": 0 }, { "doc_id": "28609578", "title": "Global distribution of Y-chromosome haplogroup C reveals the prehistoric migration routes of African exodus and early settlement in East Asia", "abstract": "The regional distribution of an ancient Y-chromosome haplogroup C-M130 (Hg C) in Asia provides an ideal tool of dissecting prehistoric migration events. We identified 465 Hg C individuals out of 4284 males from 140 East and Southeast Asian populations. We genotyped these Hg C individuals using 12 Y-chromosome biallelic markers and 8 commonly used Y-short tandem repeats (Y-STRs), and performed phylogeographic analysis in combination with the published data. The results show that most of the Hg C subhaplogroups have distinct geographical distribution and have undergone long-time isolation, although Hg C individuals are distributed widely across Eurasia. Furthermore, a general south-to-north and east-to-west cline of Y-STR diversity is observed with the highest diversity in Southeast Asia. The phylogeographic distribution pattern of Hg C supports a single coastal ‘Out-of-Africa’ route by way of the Indian subcontinent, which eventually led to the early settlement of modern humans in mainland Southeast Asia. The northward expansion of Hg C in East Asia started ∼40 thousand of years ago (KYA) along the coastline of mainland China and reached Siberia ∼15 KYA and finally made its way to the Americas.", "corpus_id": 28609578, "score": 0 }, { "doc_id": "1496488", "title": "Investigating the Prehistory of Tungusic Peoples of Siberia and the Amur-Ussuri Region with Complete mtDNA Genome Sequences and Y-chromosomal Markers", "abstract": "Evenks and Evens, Tungusic-speaking reindeer herders and hunter-gatherers, are spread over a wide area of northern Asia, whereas their linguistic relatives the Udegey, sedentary fishermen and hunter-gatherers, are settled to the south of the lower Amur River. The prehistory and relationships of these Tungusic peoples are as yet poorly investigated, especially with respect to their interactions with neighbouring populations. In this study, we analyse over 500 complete mtDNA genome sequences from nine different Evenk and even subgroups as well as their geographic neighbours from Siberia and their linguistic relatives the Udegey from the Amur-Ussuri region in order to investigate the prehistory of the Tungusic populations. These data are supplemented with analyses of Y-chromosomal haplogroups and STR haplotypes in the Evenks, Evens, and neighbouring Siberian populations. We demonstrate that whereas the North Tungusic Evenks and Evens show evidence of shared ancestry both in the maternal and in the paternal line, this signal has been attenuated by genetic drift and differential gene flow with neighbouring populations, with isolation by distance further shaping the maternal genepool of the Evens. The Udegey, in contrast, appear quite divergent from their linguistic relatives in the maternal line, with a mtDNA haplogroup composition characteristic of populations of the Amur-Ussuri region. Nevertheless, they show affinities with the Evenks, indicating that they might be the result of admixture between local Amur-Ussuri populations and Tungusic populations from the north.", "corpus_id": 1496488, "score": 0 }, { "doc_id": "26101254", "title": "Testing Central and Inner Asian admixture among contemporary Hungarians.", "abstract": "Historically, the Carpathian Basin was the final destination for many nomadic peoples who migrated westward from Inner and Central Asia towards Europe. Proto-Hungarians (Steppe Magyars) were among those who came from the East, the Eurasian Steppe in the early middle ages. In order to detect the paternal genetic contribution from nomadic Steppe tribes, we tested 966 samples from Central Asian (Uzbekistan, Kazakhstan), Inner Asian (Mongolians and Buryats in Mongolia) and Hungarian-speaking European (Hungarian, Sekler and Csango) populations. We constructed median-joining networks of certain haplogroups in Hungarian-speaking European, and Altaic-speaking Central and Inner Asian populations. We estimated that the possible paternal genetic contribution from the above described populations among contemporary Hungarian speaking populations ranged between 5% and 7.4%. It is lowest among Hungarians from Hungary (5.1%), while higher among Hungarian-speaking groups in Romania, notably Sekler (7.4%) and Csango (6.3%). However, these results represent only an upper limit. Actual Central/Inner Asian admixture might be somewhat lower as some of the related lineages may have come from a common third source. The main haplogroups responsible for the Central/Inner Asian admixture among Hungarians are J2*-M172 (xM47, M67, M12), J2-L24, R1a-Z93; Q-M242 and E-M78. Earlier studies showed very limited Uralic genetic influence among Hungarians, and based on the present study, Altaic/Turkic genetic contribution is also not significant, although significantly higher than the Uralic one. The conclusion of this study is that present-day Hungarian speakers are genetically very similar to neighbouring populations, isolated Hungarian speaking groups having relatively higher presence of Central and Inner Asian genetic elements. At the same time, the reliable historical and genetic conclusions require an extension of the study to a significantly larger database with deep haplogroup resolution, including ancient DNA data.", "corpus_id": 26101254, "score": 0 }, { "doc_id": "20536258", "title": "Human Y Chromosome Haplogroup N: A Non-trivial Time-Resolved Phylogeography that Cuts across Language Families.", "abstract": "The paternal haplogroup (hg) N is distributed from southeast Asia to eastern Europe. The demographic processes that have shaped the vast extent of this major Y chromosome lineage across numerous linguistically and autosomally divergent populations have previously been unresolved. On the basis of 94 high-coverage re-sequenced Y chromosomes, we establish and date a detailed hg N phylogeny. We evaluate geographic structure by using 16 distinguishing binary markers in 1,631 hg N Y chromosomes from a collection of 6,521 samples from 56 populations. The more southerly distributed sub-clade N4 emerged before N2a1 and N3, found mostly in the north, but the latter two display more elaborate branching patterns, indicative of regional contrasts in recent expansions. In particular, a number of prominent and well-defined clades with common N3a3'6 ancestry occur in regionally dissimilar northern Eurasian populations, indicating almost simultaneous regional diversification and expansion within the last 5,000 years. This patrilineal genetic affinity is decoupled from the associated higher degree of language diversity.", "corpus_id": 20536258, "score": 1 }, { "doc_id": "402639", "title": "Y-chromosome diversity in the Kalmyks at the ethnical and tribal levels", "abstract": "The Mongolic-speaking Kalmyks currently inhabiting the steppes of the Volga region have Central Asian ancestry and are organized into the tribal groups. The genetic relationships among these tribes and their origin have remained obscure. We analyzed 17 short tandem repeat and 44 binary polymorphisms of Y-chromosome in 426 individuals mainly from three major tribes of the Kalmyks (the Torguuds, Dörwöds and Khoshuuds). Among these tribes, the Dörwöds and Torguuds, as well as the Kalmyks collectively as an ethnic group, showed relatively close genetic affinities to each other and to the Mongols and Altaian Kazakhs, whereas the Khoshuuds were clearly separated from all of them, gathering with the Manchu, Tibetans or Evenks (depending on the algorithm used to calculate genetic distances). The genetic results also indicate that paternal gene flow from East Europeans to the Kalmyks is very little, despite their cohabitation in the North Caspian Steppe during the last 380 years. The occurrence of unique cluster of N1c-Tat haplotypes in the Khoshuuds, which dates to about 340 years and is likely to have East European ancestry, is considered as a result of interethnic contacts occurred soon after the appearance of the Kalmyk tribes in the Volga-Ural region.", "corpus_id": 402639, "score": 0 }, { "doc_id": "13785575", "title": "Y-chromosomal STR haplotypes in Kalmyk population samples.", "abstract": "Seventeen Y-chromosomal short tandem repeats (STRs), DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, GATA-H4, DYS448, DYS456, DYS458, DYS635 were typed in DNA samples from the Kalmyk population (n=99). The population is characterized by a high proportion of duplicated DYS19 alleles and deletions of the locus DYS448 on the background of the Central Asian haplogroup C*. AMOVA analysis reveals a close vicinity to Mongolian and Kazakh populations and large genetic distance to geographical neighbours from Russia, Ukraine and the Caucasus.", "corpus_id": 13785575, "score": 0 }, { "doc_id": "90948814", "title": "Excavated DNA from Two Khazar Burials", "abstract": "To understand a biological tribal affiliation (in terms of Y-chromosomal haplogroups, subclades, and haplotypes) of two excavated Khazar bone remains in the lower Don region in the south of Russia, we have extracted and analyzed their DNA and showed that both belonged to haplogroup R1a and its subclade Z93. The pattern could be considered typically “Turkic”, and not a Jewish DNA lineage. Their haplotypes were also identified and reported here. The haplotypes indicate that both Khazars were unrelated to each other in a sense that their common ancestor lived as long as 1500 - 2500 years earlier than them, in the middle of the II millennium BC—beginning of the I millennium BC, during typically Scythian times or somewhat earlier. Their haplotypes are unrelated to well-known Jewish haplotypes of haplogroup R1a.", "corpus_id": 90948814, "score": 0 }, { "doc_id": "19006303", "title": "A major Y-chromosome haplogroup R1b Holocene era founder effect in Central and Western Europe", "abstract": "The phylogenetic relationships of numerous branches within the core Y-chromosome haplogroup R-M207 support a West Asian origin of haplogroup R1b, its initial differentiation there followed by a rapid spread of one of its sub-clades carrying the M269 mutation to Europe. Here, we present phylogeographically resolved data for 2043 M269-derived Y-chromosomes from 118 West Asian and European populations assessed for the M412 SNP that largely separates the majority of Central and West European R1b lineages from those observed in Eastern Europe, the Circum-Uralic region, the Near East, the Caucasus and Pakistan. Within the M412 dichotomy, the major S116 sub-clade shows a frequency peak in the upper Danube basin and Paris area with declining frequency toward Italy, Iberia, Southern France and British Isles. Although this frequency pattern closely approximates the spread of the Linearbandkeramik (LBK), Neolithic culture, an advent leading to a number of pre-historic cultural developments during the past ≤10 thousand years, more complex pre-Neolithic scenarios remain possible for the L23(xM412) components in Southeast Europe and elsewhere.", "corpus_id": 19006303, "score": 0 }, { "doc_id": "13941125", "title": "Parallel evolution of genes and languages in the Caucasus region.", "abstract": "We analyzed 40 single nucleotide polymorphism and 19 short tandem repeat Y-chromosomal markers in a large sample of 1,525 indigenous individuals from 14 populations in the Caucasus and 254 additional individuals representing potential source populations. We also employed a lexicostatistical approach to reconstruct the history of the languages of the North Caucasian family spoken by the Caucasus populations. We found a different major haplogroup to be prevalent in each of four sets of populations that occupy distinct geographic regions and belong to different linguistic branches. The haplogroup frequencies correlated with geography and, even more strongly, with language. Within haplogroups, a number of haplotype clusters were shown to be specific to individual populations and languages. The data suggested a direct origin of Caucasus male lineages from the Near East, followed by high levels of isolation, differentiation, and genetic drift in situ. Comparison of genetic and linguistic reconstructions covering the last few millennia showed striking correspondences between the topology and dates of the respective gene and language trees and with documented historical events. Overall, in the Caucasus region, unmatched levels of gene-language coevolution occurred within geographically isolated populations, probably due to its mountainous terrain.", "corpus_id": 13941125, "score": 0 }, { "doc_id": "129893942", "title": "Haplogroup R1a, Its Subclades and Branches in Europe During the Last 9,000 Years", "abstract": "This study identifies and describes 38 branches of the haplogroup R1a STR haplotypes which currently exist in Europe or which migrated from Europe to areas in the east, south, and southeast between 6000 and 4500 years before the present (ybp). The study is based on 2471 haplotypes which have been tested for either 67- or 111-markers; it essentially creates a unified robust system, which assembles dozens of R1a-SNPs and thousands of STRs and assigned haplotypes to branches, some of which do not have SNP assignments as yet. The assembled system consists of base (deduced ancestral) haplotypes, one for each STR branch and for each SNP-assigned subclade, each with its characteristic (ancestral) set of alleles, arranged in the chronological space from ~ 9000 ybp to 1300 ybp. We found that the most ancient R1a subclades (R1a1-M198- and R1a1a-M198+/M417-) bearers of which currently live in Europe (the present day haplotypes are scattered between England and the Balkans) appeared in Europe at least 7300 ybp, and possibly 9000 ybp. R1a’s three principal downstream subclades, L664 (North-Western branch), Z93 (South-Eastern branch), and Z283 (Eurasian branch), split from their common European ancestor at about the same time, around 7000 - 6000 ybp. L664 apparently stayed in North-Western Europe; its lineage recovered and began expanding ~ 4575 ybp. The Z93 subclade began to expand during the Aryan migrations, on the Aryan's journey to India and the Middle East in the 3rd-2nd millennia BC. The Z283 subclade split ~ 5500 ybp into three branches. One of them, Z280 (the Central Eurasian branch) moved east to the Russian Plain in 4800 - 4600 ybp, and formed at least 16 sub-branches there and in the course of the later westward repopulation of Europe in the 1st millennium BC – 1st millennium CE. Some of the older branches, like the Russian Plain branch, largely stayed in the present Russia-Ukraine-Belarus-Poland- Baltic countries region, and were described by early historians as the Scythians, Antes, Veneti, and a multitude of different proto-Slavic tribes (though many of them belonged to haplogroups other than R1a, primarily I1 and I2). Those R1a branches which are “older” than 3000 years, such as the Russian Plain branch (4600 ybp), the Western Eurasian (4300 ybp), and the Balto-Carpathian (4300 ybp), did not move en mass to Europe but stayed behind at the Russian Plain. In the middle of 1st millennium CE, the time of the collapse of the Roman Empire, multiple migrations of R1a were taking place eastward and westward; these migrations gradually formed the current landscape of R1a in Europe. All 38 branches and their datings are listed in the Appendix of this paper; current distribution maps are shown in the body of the paper.", "corpus_id": 129893942, "score": 0 }, { "doc_id": "53980214", "title": "DNA profiling of Hungarian King Béla III and other skeletal remains originating from the Royal Basilica of Székesfehérvár", "abstract": "A few decades after the collapse of the Avar Khaganate (c. 822 AD), Hungarian invaders conquered the Carpathian Basin (c. 862–895 AD). The first Hungarian ruling dynasty, the Árpáds played an important role in European history during the Middle Ages. King Béla III (1172–1196) was one of the most significant rulers of the dynasty. He also consolidated Hungarian dominance over the Northern Balkans. The provostry church of the Virgin Mary (commonly known as the Royal Basilica of Székesfehérvár) played a prominent role as a coronation church and burial place of medieval Hungarian kings. The basilica’s building and graves had been destroyed over the centuries. The only royal graves that remained intact were those of King Béla III and his first spouse, Anna of Antioch. These graves were discovered in 1848. We defined the autosomal STR (short tandem repeat) fingerprints of the royal couple and eight additional individuals (two females and six males) found in the Royal Basilica. These results revealed no evidence of first-degree relationship between any of the investigated individuals. Y-chromosomal STR profiles were also established for all the male skeletons. Based upon the Y-chromosomal data, one male skeleton showed an obvious patrilineal relationship to King Béla III. A database search uncovered an existing Y-chromosomal haplotype, which had a single-repeat difference compared to that of King Béla. It was discovered in a person living in an area close to Hungary. This current male line is probably related paternally to the Árpád Dynasty. The control region of the mitochondrial DNA was determined in the royal couple and in the remains of the inferred relative. The mitochondrial results excluded sibling relationship between the King and the patrilineal relative. In summary, we successfully defined a Y-chromosomal profile of King Béla III, which can serve as a reference for the identification of further remains and disputed living descendants of the Árpád Dynasty. Among the examined skeletons, we discovered an Árpád member, whose exact affiliation, however, has not yet been established.", "corpus_id": 53980214, "score": 0 }, { "doc_id": "21833053", "title": "Nuclear and mitochondrial DNA analysis of a 2,000-year-old necropolis in the Egyin Gol Valley of Mongolia.", "abstract": "DNA was extracted from the skeletal remains of 62 specimens excavated from the Egyin Gol necropolis, in northern Mongolia. This burial site is linked to the Xiongnu period and was used from the 3rd century b.c. to the 2nd century a.d. Three types of genetic markers were used to determine the genetic relationships between individuals buried in the Egyin Gol necropolis. Results from analyses of autosomal and Y chromosome short tandem repeats, as well as mitochondrial DNA, showed close relationships between several specimens and provided additional background information on the social organization within the necropolis as well as the funeral practices of the Xiongnu people. To the best of our knowledge, this is the first study using biparental, paternal, and maternal genetic systems to reconstruct partial genealogies in a protohistoric necropolis.", "corpus_id": 21833053, "score": 0 }, { "doc_id": "39995385", "title": "A western Eurasian male is found in 2000-year-old elite Xiongnu cemetery in Northeast Mongolia.", "abstract": "We analyzed mitochondrial DNA (mtDNA), Y-chromosome single nucleotide polymorphisms (Y-SNP), and autosomal short tandem repeats (STR) of three skeletons found in a 2,000-year-old Xiongnu elite cemetery in Duurlig Nars of Northeast Mongolia. This study is one of the first reports of the detailed genetic analysis of ancient human remains using the three types of genetic markers. The DNA analyses revealed that one subject was an ancient male skeleton with maternal U2e1 and paternal R1a1 haplogroups. This is the first genetic evidence that a male of distinctive Indo-European lineages (R1a1) was present in the Xiongnu of Mongolia. This might indicate an Indo-European migration into Northeast Asia 2,000 years ago. Other specimens are a female with mtDNA haplogroup D4 and a male with Y-SNP haplogroup C3 and mtDNA haplogroup D4. Those haplogroups are common in Northeast Asia. There was no close kinship among them. The genetic evidence of U2e1 and R1a1 may help to clarify the migration patterns of Indo-Europeans and ancient East-West contacts of the Xiongnu Empire. Artifacts in the tombs suggested that the Xiongnu had a system of the social stratification. The West Eurasian male might show the racial tolerance of the Xiongnu Empire and some insight into the Xiongnu society.", "corpus_id": 39995385, "score": 0 }, { "doc_id": "23457453", "title": "Ancient DNA from nomads in 2500-year-old archeological sites of Pengyang, China", "abstract": "Six human remains (dating ∼2500 years ago) were excavated from Pengyang, China, an area occupied by both ancient nomadic and farming people. The funerary objects found with these remains suggested they were nomads. To further confirm their ancestry, we analyzed both the maternal lineages and paternal lineages of the ancient DNA. From the mitochondrial DNA, six haplotypes were identified as three haplogroups: C, D4 and M10. The haplotype-sharing populations and phylogenetic analyses revealed that these individuals were closely associated with the ancient Xiongnu and modern northern Asians. Single-nucleotide polymorphism analysis of Y chromosomes from four male samples that were typed as haplogroup Q indicated that these people had originated in Siberia. These results show that these ancient people from Pengyang present a close genetic affinity to nomadic people, indicating that northern nomads had reached the Central Plain area of China nearly 2500 years ago.", "corpus_id": 23457453, "score": 0 }, { "doc_id": "13670282", "title": "137 ancient human genomes from across the Eurasian steppes", "abstract": "For thousands of years the Eurasian steppes have been a centre of human migrations and cultural change. Here we sequence the genomes of 137 ancient humans (about 1× average coverage), covering a period of 4,000 years, to understand the population history of the Eurasian steppes after the Bronze Age migrations. We find that the genetics of the Scythian groups that dominated the Eurasian steppes throughout the Iron Age were highly structured, with diverse origins comprising Late Bronze Age herders, European farmers and southern Siberian hunter-gatherers. Later, Scythians admixed with the eastern steppe nomads who formed the Xiongnu confederations, and moved westward in about the second or third century bc, forming the Hun traditions in the fourth–fifth century ad, and carrying with them plague that was basal to the Justinian plague. These nomads were further admixed with East Asian groups during several short-term khanates in the Medieval period. These historical events transformed the Eurasian steppes from being inhabited by Indo-European speakers of largely West Eurasian ancestry to the mostly Turkic-speaking groups of the present day, who are primarily of East Asian ancestry.Sequences of 137 ancient and 502 modern human genomes illuminate the population history of the Eurasian steppes after the Bronze Age and document the replacement of Indo-European speakers of West Eurasian ancestry by Turkic-speaking groups of East Asian ancestry.", "corpus_id": 13670282, "score": 0 }, { "doc_id": "16326890", "title": "Human evolution in Siberia: from frozen bodies to ancient DNA", "abstract": "BackgroundThe Yakuts contrast strikingly with other populations from Siberia due to their cattle- and horse-breeding economy as well as their Turkic language. On the basis of ethnological and linguistic criteria as well as population genetic studies, it has been assumed that they originated from South Siberian populations. However, many questions regarding the origins of this intriguing population still need to be clarified (e.g. the precise origin of paternal lineages and the admixture rate with indigenous populations). This study attempts to better understand the origins of the Yakuts by performing genetic analyses on 58 mummified frozen bodies dated from the 15th to the 19th century, excavated from Yakutia (Eastern Siberia).ResultsHigh quality data were obtained for the autosomal STRs, Y-chromosomal STRs and SNPs and mtDNA due to exceptional sample preservation. A comparison with the same markers on seven museum specimens excavated 3 to 15 years ago showed significant differences in DNA quantity and quality. Direct access to ancient genetic data from these molecular markers combined with the archaeological evidence, demographical studies and comparisons with 166 contemporary individuals from the same location as the frozen bodies helped us to clarify the microevolution of this intriguing population.ConclusionWe were able to trace the origins of the male lineages to a small group of horse-riders from the Cis-Baïkal area. Furthermore, mtDNA data showed that intermarriages between the first settlers with Evenks women led to the establishment of genetic characteristics during the 15th century that are still observed today.", "corpus_id": 16326890, "score": 0 } ]

{ "doc_id": "55225611", "title": "Flux Prediction in Direct Contact Membrane Distillation", "abstract": "Membrane distillation (MD) is a potential mean of water desalination. MD is a thermally driven desalination technology that has been employed in four basic configurations. One of these configuration is Direct Contact Membrane Distillation (DCMD). In DCMD, both hot and cold solution is maintained in direct contact with micro porous hydrophobic membrane material. Heat and mass transfer analysis was performed on DCMD. Based on Kinetic theory of gas, the performance of different models of membrane permeability (coefficient) was investigated under different DCMD operating parameters (feed temperature, coolant temperature and feed flow rate). Knudsen number provides the guideline in identifying the type of model of mass transfer to be considered under any given experimental conditions. Results revealed that for a given pore size under the same simulation and experimental conditions, Transition (Knudsen- Molecular diffusion) type of flow model predictions is in good agreement with the experimental results. Hence the best model to be consider for flux prediction in DCMD. The effect of membrane pore size was also studied. Results showed that permeate flux increases with increase in pore size up to the critical pore condition where the flux prediction remain constant (unchanged).", "corpus_id": 55225611 }

[ { "doc_id": "97585678", "title": "Membrane distillation - a theoretical study of evaporation through microporous membranes", "abstract": "Abstract Membrane distillation is a process in which, for example, water in a heated salt solution, evaporates through a porous membrane. The vapour condenses on a coolant surface on the other side of the membrane. The two liquid streams, the salt solution and the condensate, are separated by a highly porous hydrophobic membrane. Surface tension forces withhold liquids from the pores and prevent contact between the two liquids. The temperature difference, causing a corresponding vapour pressure difference across the membrane, provides the driving force of the membrane distillation process. Evaporation will occur at the solution surface if the vapour pressure on the solution side is greater than the vapour pressure at the condensate surface. Vapours then diffuse through the pores to the cooler surface, where they condense. The dependence of mass and heat transport upon different process and membrane parameters involved in membrane distillation has been investigated theoretically.", "corpus_id": 97585678, "score": 0 }, { "doc_id": "107392157", "title": "Membrane distillation : principles and applications", "abstract": "Modern membrane engineering is critical to the development of process-intensification strategies and to the stimulation of industrial growth. \"Membrane Distillation (MD)\" is a broad reference that covers specific information on membranes available and methods for MD membrane preparation and characterization. The book offers an introduction to the terminology and fundamental concepts as well as a historical review of MD development. Commercial membranes used in MD as well as laboratory-made membranes, including emerging membranes, are described in detail and illustrated by a number of clear and instructive schematic drawings and images. This is a comprehensive review on the development of MD membranes, MD modules, MD membrane characterization, MD configurations, applications in different areas and theoretical models. It offers an introduction to the terminology and fundamental concepts associated with MD as well as an historical review of MD development. It provides a description of commercial membranes used in MD as well as laboratory-made membranes, including emerging membranes.", "corpus_id": 107392157, "score": 1 }, { "doc_id": "13885422", "title": "Membrane-distillation desalination: Status and potential", "abstract": "Abstract This paper presents an assessment of membrane distillation (MD) based on the available state of the art and on ourpreliminary analysis. The process has many desirable properties such as low energy consumption, ability to use low temperature heat, compactness, and perceivably more immunity to fouling than other membrane processes. Within the tested range, the operating parameters of conventional MD configurations have the following effects:(1) the permeate fluxes can significantly be improved by increasing the hot feed temperature (increasing the temperature from 50 to 70°C increases the flux by more than three-fold), and by reducing the vapor/air gap (reducing the vapor air gap thickness from 5 to 1 mm increase the flux 2.3-fold); (2) the mass flow rate of the feed solution has a smaller effect: increasing it three-fold increases the flux by about 1.3-fold; (3) the concentration of the solute has slight effect: increasing the concentration by more than five-fold decreases the flux by just 1.15-fold; (4) the cold side conditions have a lower effect (about half) on the flux than the hot side; (5) the coolant mass flow rate has a negligible effect; (6) the coolant temperature has a lower effect than the mass flow rate of the hot solution. Fouling effects, membranes used, energy consumption, system applications and configurations, and very approximate cost estimates are presented. The permeate fluxes obtained by the different researchers seem to disagree by an order of magnitude, and better experimental work is needed.", "corpus_id": 13885422, "score": 0 }, { "doc_id": "96577334", "title": "Microporous polypropylene and polyethylene hollow fiber membranes. Part 3. Experimental studies on membrane distillation for desalination", "abstract": "Three polypropylene (PP) and one polyethylene (PE) microporous hollow-fiber membranes were used in direct contact membrane distillation (DCMD) and vacuum membrane distillation (VMD) for the desalination of simulated seawater. The influence of feed temperature and feed flow on distillate pure water flux was investigated. The comparison of the PP and PE membranes in DCMD and VMD was carried out. It was found that the water flux increased with the feed temperature and feed flow in both DCMD and VMD. The data also showed that, compared with the PP membranes, higher water flux could be obtained by using PE membranes in both the DCMD and VMD processes.", "corpus_id": 96577334, "score": 0 }, { "doc_id": "101028899", "title": "Multiscale Modeling of Membrane Distillation: Some Theoretical Considerations", "abstract": "First, it is shown that the effective thickness of the membrane is the sum of the actual thickness, k0/UL, and λC/(UL) where k0 is the thermal conductivity of the membrane matrix, λ is the latent of vaporization of water, C is a parameter (defined as flux per unit thickness of membrane per unit of temperature driving force), and UL is a coefficient combining the heat-transfer coefficients on the feed side and the permeate side film. For typical conditions, the sum of the additional terms exceeds 100 μm, which clearly shows that the flux is not inversely proportional to membrane thickness. Also, to a first approximation, the thermal efficiency is independent of membrane thickness. This work and the development of an overall mass-transfer coefficient for direct contact membrane distillation build upon the pioneering work of Giulio Sarti. Second, a reassessment of the traditional method for combining the Knudsen diffusion coefficient and the molecular diffusion coefficient suggests that the traditional sum o...", "corpus_id": 101028899, "score": 0 }, { "doc_id": "14026609", "title": "Experimental study of desalination using direct contact membrane distillation: a new approach to flux enhancement", "abstract": "Abstract New membrane distillation configurations and a new membrane module were investigated to improve water desalination. The performances of three hydrophobic microporous membranes were evaluated under vacuum enhanced direct contact membrane distillation (DCMD) with a turbulent flow regime and with a feed water temperature of only 40 °C. The new configurations provide reduced temperature polarization effects due to better mixing and increased mass transport of water due to higher permeability through the membrane and due to a total pressure gradient across the membrane. Comparison with previously reported results in the literature reveals that mass transport of water vapors is substantially improved with the new approach. The performance of the new configuration was investigated with both NaCl and synthetic sea salt feed solutions. Salt rejection was greater than 99.9% in almost all cases. Salt concentrations in the feed stream had only a minor effect on water flux. The economic aspects of the enhanced DCMD process are briefly discussed and comparisons are made with the reverse osmosis (RO) process for desalination.", "corpus_id": 14026609, "score": 1 }, { "doc_id": "140171275", "title": "Advances in Membrane Distillation for Water Desalination and Purification Applications", "abstract": "Membrane distillation is a process that utilizes differences in vapor pressure to permeate water through a macro-porous membrane and reject other non-volatile constituents present in the influent water. This review considers the fundamental heat and mass transfer processes in membrane distillation, recent advances in membrane technology, module configurations, and the applications and economics of membrane distillation, and identifies areas that may lead to technological improvements in membrane distillation as well as the application characteristics required for commercial deployment.", "corpus_id": 140171275, "score": 0 }, { "doc_id": "97698271", "title": "Heat and mass transfer in membrane distillation", "abstract": "Abstract Equations for heat and mass transfer in membrane distillation (MD) have been developed and tested experimentally. The concept of temperature polarisation is introduced and shown to be important in the interpretation of experimental results. Vapour transport through the membranes tested is reasonably described by combined Knudsen and molecular diffusion. The significance of temperature polarisation in the design and operation of large-scale MD modules is discussed, and hollow fibre and tubular systems shown to be potentially the most effective.", "corpus_id": 97698271, "score": 0 }, { "doc_id": "53362941", "title": "Identification of material and physical features of membrane distillation membranes for high performance desalination", "abstract": "In this paper, the performances of various membranes were assessed in Direct Contact Membrane Distillation (DCMD) under different feed velocities and inlet temperatures. The membranes studied included a polyvinylidenefluoride (PVDF) microfiltration membrane with a non-woven support layer, a polytetrafluoroethylene (PTFE) microfiltration membrane with a non-woven support layer, and three MD membranes made from PTFE of different pore size and all with a structured scrim support layer. The results showed that distillation using PTFE membranes produced much higher flux than that of the PVDF microfiltration membrane at the same operational conditions, and the support layer affected not only the flux, but also the energy efficiency (0.51–0.24). The results also show that increasing the velocity of the feed and its inlet temperature increased the flux, but the rate of flux increase diminishes at high velocities. The mass transfer coefficient improved for thinner support and active layer membranes, leading to fluxes as high as 46 L m−2 h−1 at 80 °C. The heat transfer characteristics were found to be superior for the open scrim backed membranes compared to the non-woven support membranes, resulting in significantly greater thermal efficiency for the scrim backed membranes.", "corpus_id": 53362941, "score": 0 }, { "doc_id": "95094723", "title": "Study of Asymmetric Polarization in Direct Contact Membrane Distillation", "abstract": "Abstract The objective of this study was to analyze the polarization phenomena in each side of a microporous hydrophobic membrane using a direct contact membrane distillation process. Experiments were conducted with distilled water and sodium chloride aqueous solutions as feeds. Different flow rates and temperatures at both membrane sides were employed. Thefeed and permeate temperature polarization coefficients as well as thefeed and permeate vapor pressure polarization coefficients were defined and evaluated. Two methods: a velocity extrapolation method and a semiempirical method that considers the heat and mass transfer empirical correlations, were used. It was proved that there is an asymmetric polarization in direct contact membrane distillation.", "corpus_id": 95094723, "score": 0 }, { "doc_id": "96101722", "title": "Factors affecting flux in membrane distillation", "abstract": "Abstract This paper summarises a model of the Direct Contact Membrane Distillation (MD) process. The factors affecting flux are shown to be film heat transfer, membrane ‘thermal’ permeability, the partial pressure of air within the pores and the presence of solute in the feed. Solute effects mainly influence vapour pressure and film transfer coefficients. Deaeration significantly increases gas phase permeability, but the effect on flux is modest due to increased temperature polarisation. MD of salt and sucrose solutions at concentrations up to 25 and 30% respectively give fluxes of 60 to 70% of that for a pure water feed. The flux reduction for salt is largely due to vapour pressure reduction, and for sucrose is due to increased viscosity.", "corpus_id": 96101722, "score": 0 }, { "doc_id": "98143734", "title": "Gas and vapour transport through microporous membranes. II. Membrane distillation", "abstract": "Abstract Experimental membrane distillation (MD) fluxes were increased by up to 50% by deaeration. A new theoretical model shows that under these conditions, membrane permeability increased by around seven-fold, but temperature polarisation decreased the thermal driving force by five-fold. Greater flux increases are predicted using higher film heat transfer coefficients. Heat loss by conduction across the membrane was shown to decrease with deaeration. Results indicate that the membrane is rarely the controlling resistance and that future developments should be towards improved MD modules rather than specialised MD membranes.", "corpus_id": 98143734, "score": 0 }, { "doc_id": "98623351", "title": "Membrane distillation: A comprehensive review", "abstract": "article i nfo Membrane Distillation (MD) is a thermally-driven separation process, in which only vapour molecules trans- fer through a microporous hydrophobic membrane. The driving force in the MD process is the vapour pres- sure difference induced by the temperature difference across the hydrophobic membrane. This process has various applications, such as desalination, wastewater treatment and in the food industry. This review addresses membrane characteristics, membrane-related heat and mass transfer concepts, fouling and the effects of operating condition. State of the art research results in these different areas will be pre- sented and discussed.", "corpus_id": 98623351, "score": 0 }, { "doc_id": "5382602", "title": "Modelling mass transport through a porous partition: Effect of pore size distribution", "abstract": "Abstract Direct contact membrane distillation process has been studied using microporous polytetrafluoroethylene and polyvinylidene fluoride membranes. The membranes were characterized in terms of their non-wettability, pore size distribution and porosity. The mean pore sizes and pore size distributions were obtained by means of wet/dry flow method. The mean pore size and the effective porosity of the membranes were also determined from the gas permeation test. A theoretical model that considers the pore size distribution together with the gas transport mechanisms through the membrane pores was developed for this process. The contribution of each mass transport mechanism was analyzed. It was found that both membranes have pore size distributions in the Knudsen region and in the transition between Knudsen and ordinary diffusion region. The transition region was the major contribution to mass transport. The predicted water vapor permeability of the membranes were compared with the experimental ones. The effect of considering pore size distribution instead of mean pore size to predict the water vapor permeability of the membranes was investigated.", "corpus_id": 5382602, "score": 1 }, { "doc_id": "97506196", "title": "Effect of pore size distribution and air flux on mass transport in direct contact membrane distillation", "abstract": "Abstract The concept of mass transfer regions within the membranes was introduced to study the mass transport in membrane distillation processes. Mass transfer model for direct contact membrane distillation (DCMD) was derived to examine the influence of pore size distribution and air fluxes on water vapor fluxes across the membranes. The pore size distributions of the membranes were determined by field emission scanning electron microscopy (FESEM) and the image analysis program. DCMD experiments with pure water were carried out under laminar and turbulent flow conditions so as to compare the experimental results with the predictions. The calculation results showed that Knudsen and transition regions were found in the membranes studied, while the transition region was the major contribution to mass transport. The model including the effect of pore size distribution and air fluxes predicted water fluxes with the average discrepancy 5% of the experimental results. The mass transfer analysis indicated that the influence of pore size distribution and air fluxes on water fluxes was insignificant. Therefore, the mass transfer model with the assumptions of air trapped in membrane pores and single pore size is adequate to describe mass transport in DCMD. The concept of mass transfer regions was also applied to analyze the effect of pore size distribution on flux in vacuum membrane distillation and gas permeation.", "corpus_id": 97506196, "score": 1 }, { "doc_id": "96671859", "title": "Direct contact membrane distillation mechanism for high concentration NaCl solutions", "abstract": "Abstract Using high concentration NaCl aqueous solutions, direct contact membrane distillation (DCMD) experiments are implemented in this work where water fluxes are measured at different feed/permeation temperatures, feed concentrations and flow rates. The results under the experimental conditions show that (1) water fluxes decrease as concentrations of NaCl solutions increase; (2) when concentrations of NaCl solutions are above 25%, water fluxes decrease sharply; (3) when concentrations of NaCl solutions are up to saturation, water fluxes gradually approach steady levels. Variations of membrane-fouling resistance are found to result in the above observations. Analysis also shows that concentrations of NaCl solutions, operation temperatures and flow rates can affect the speed of membrane fouling. Among them, the concentration is the most important factor. In this work, a new model is also proposed which takes membrane resistance, concentration polarization resistance and membrane fouling resistance all into consideration. Model predictions show good agreement with the experimental results.", "corpus_id": 96671859, "score": 0 }, { "doc_id": "98777750", "title": "Mass transfer mechanisms and transport resistances in direct contact membrane distillation process", "abstract": "Abstract The objective of the present work was to investigate the mass transport and fouling mechanism of direct contact membrane distillation (DCMD) process. The experiments were performed on a flat sheet module using pure water and humic acid solution as feeds. The membrane employed was hydrophobic PVDF of pore size 0.22 μm. The mass transfer models based on Dusty gas model were applied to fit the flux data and the pressure blocking filtration laws were employed to explain the membrane fouling. The results showed that molecular diffusion was the most suitable model for predicting fluxes of both laminar and turbulent flow. Fouling of the membrane by humic acid aggregates can be described by cake filtration model. The transport resistance of the feed boundary layer was higher than other resistances, and fouling resistance increased significantly with time.", "corpus_id": 98777750, "score": 0 }, { "doc_id": "119735792", "title": "An experimentally optimized model for heat and mass transfer in direct contact membrane distillation", "abstract": "Membrane distillation (MD), a thermally driven process involving hydrophobic micro-porous membranes has gained widespread interest in academic research and is set to become an alternative solution to other membrane separation processes such as reverse osmosis (RO). Although extensive experimental studies have been carried out since the 1980s [1,2], clear understanding of the heat and mass transport phenomena has yet to be established. This manuscript presents experimental results of direct contact membrane distillation (DCMD) with de-ionized water and aqueous salt solutions of NaCl with concentration levels of up to 15 ppt as feed together with an experimentally optimized and validated model for the prediction of the permeate flux in DCMD for GE Aspire Membrane QL 833 (GE Energy). Different heat transfer prediction methods in combination with the three different forms of the Dusty Gas model for mass transport were used in the comparison of our experimental data in the laminar and turbulent flow regimes under steady-state conditions. The comparison between experimental and predicted results confirmed our expectation that the Knudsen-molecular diffusion transition model yielded the best prediction. We have also identified, based on the comparison of the data, the most accurate heat transfer correlation for the laminar and turbulent flow regimes, taking into account the experimental and permeate prediction uncertainties to optimally address the heat and mass transport equations used in DCMD studies. Hence, it is highly recommended that these heat transfer correlations and the Knudsen-molecular mass transport equation be used in the prediction of heat and mass transfer for flat sheet DCMD experiments.", "corpus_id": 119735792, "score": 1 }, { "doc_id": "95161087", "title": "Temperature and concentration polarization in membrane distillation of aqueous salt solutions", "abstract": "Abstract In this paper we have studied water transport in membrane distillation using a flat PTFE membrane. Experiments have been carried out with water and aqueous solutions of NaCl as feed. The effects of temperature and concentration polarization on the reduction of vapour pressure differences across the membrane with regard to the vapour pressure differences corresponding to the bulk phases which are separated by the membrane, are evaluated. A coefficient which measures this reduction has been introduced. This coefficient and the temperature polarization coefficient coincide when water is used as feed, but they are more and more different when the salt concentration of feed increases. The measured flux results and the calculated polarization results are discussed for different temperatures, recirculation rates and solution concentrations.", "corpus_id": 95161087, "score": 0 }, { "doc_id": "94991309", "title": "Transport analysis of an Air Gap Membrane Distillation (AGMD) process", "abstract": "Abstract Membrane distillation (MD) desalination is an emerging technology for fresh water production. This process incorporates phase change and transport of vapour through a hydrophobic membrane caused by vapour pressure across the membrane. The results from experimental studies and the one-dimensional transport analyses of the heat and mass transfer processes on an air gap MD (AGMD) unit are presented in this paper. The effects of different operating variables including feed and coolant temperatures, air gap, membrane support mesh size, feed concentration and feed and coolant flow rates were investigated. Mass transport through membrane, membrane support, air gap and condensation on the coolant plate has been analysed and expression for global mass transfer coefficient has been derived. The maximum distillate flux achieved was 5.11 kg m−2 h−1 at a feed temperature of 60°C, coolant temperature of 10°C and an air gap of 2.5 mm. Feed temperature and air gap width were found to have significant influence o...", "corpus_id": 94991309, "score": 0 } ]

{ "doc_id": "14523977", "title": "Using a community-based definition of poverty for targeting poor households for premium subsidies in the context of a community health insurance in Burkina Faso", "abstract": "BackgroundOne of the biggest challenges in subsidizing premiums of poor households for community health insurance is the identification and selection of these households. Generally, poverty assessments in developing countries are based on monetary terms. The household is regarded as poor if its income or consumption is lower than a predefined poverty cut-off. These measures fail to recognize the multi-dimensional character of poverty, ignoring community members’ perception and understanding of poverty, leaving them voiceless and powerless in the identification process. Realizing this, the steering committee of Nouna’s health insurance devised a method to involve community members to better define ‘perceived’ poverty, using this as a key element for the poor selection. The community-identified poor were then used to effectively target premium subsidies for the insurance scheme.MethodsThe study was conducted in the Nouna’s Health District located in northwest Burkina Faso. Participants in each village were selected to take part in focus-group discussions (FGD) organized in 41 villages and 7 sectors of Nouna’s town to discuss criteria and perceptions of poverty. The discussions were audio recorded, transcribed and analyzed in French using the software NVivo 9.ResultsFrom the FGD on poverty and the subjective definitions and perceptions of the community members, we found that poverty was mainly seen as scarcity of basic needs, vulnerability, deprivation of capacities, powerlessness, voicelessness, indecent living conditions, and absence of social capital and community networks for support in times of need. Criteria and poverty groups as described by community members can be used to identify poor who can then be targeted for subsidies.ConclusionPolicies targeting the poorest require the establishment of effective selection strategies. These policies are well-conditioned by proper identification of the poor people. Community perceptions and criteria of poverty are grounded in reality, to better appreciate the issue. It is crucial to take these perceptions into account in undertaking community development actions which target the poor. For most community-based health insurance schemes with limited financial resources, using a community-based definition of poverty in the targeting of the poorest might be a less costly alternative.", "corpus_id": 14523977 }

[ { "doc_id": "195330459", "title": "Poverty Reduction and Sustainable Development", "abstract": "The prominent place of the chapter on poverty in the Johannesburg Plan of Implementation (JPI) is totally in keeping with the priority given to poverty reduction in the development thinking of the international community of today. The Johannesburg process did not lead to any new insights or new commitments in the fight against poverty. Section one sets out a factual comparison of the poverty chapters in Rio's Agenda 21 (AG21) and in the JPI. Section two reviews the conceptual links between poverty reduction and sustainable development, since poverty is used both as a dependent and as an independent variable. This analysis shows a shift in the function of growth as related to environmental protection. Section three explores the ‘naturalization’ of development thinking in its economic and social dimensions and shows how this affects the policy options for social protection. I also explain how social and environmental sustainability have become elements of risk management and how are both aimed at conflict prevention and enhanced growth. Finally, in section four three lines of action are suggested to enhance the emergence of a socially meaningful sustainable development agenda that, ideally, would make poverty reduction strategies redundant.", "corpus_id": 195330459, "score": 0 }, { "doc_id": "156852455", "title": "The MDGs and Beyond", "abstract": "‘Development’ has come to mean the MDGs for many — policy-makers in particular. In this chapter we look at the evolution of the meaning of development and its relationship with the MDGs.1 We draw on recent conceptual discussions regarding the evolving notion of ‘well-being’ (as opposed to poverty, deprivation and ‘ill-being’) and ask what it adds and what it might contribute to a post-2015 future.", "corpus_id": 156852455, "score": 0 }, { "doc_id": "13706573", "title": "How are we doing on poverty and hunger reduction? A new measure of country performance", "abstract": "The paper presents a new composite indicator - the poverty and hunger index (PHI) - to measure countries' performance toward achieving millennium development goal No.1 (MDG1) on halving poverty and hunger by 2015. Building on the statistical structure of the human development index, the PHI combines all five official MDG1 indicators, thereby generating insights on a country's net progress towards its own goal, as opposed to progress measured by a single yardstick. Nonparametric analysis on the PHI components provides further evidence on the nature of the relationship between poverty and hunger measures, while cross-country results show significant variance in progress between and within regions. An extension of the PHI allows for consideration of the rate of progress made by each country in its own terms; that is, based on where it needs to be to attain all 5 MDG1 targets by 2015. Countries needing priority attention are identified, as well as areas for future research and recommendations for post-2015 initiatives.", "corpus_id": 13706573, "score": 0 }, { "doc_id": "154700399", "title": "LONGITUDINAL MEASURES OF POVERTY: ACCOUNTING FOR INCOME AND ASSETS OVER TIME", "abstract": "This paper uses data from the Survey of Income and Program Participation to estimate durations of poverty spells and to determine whether temporarily poor families have sufficient assets to cover the shortfall of their incomes below poverty—their personal poverty gaps. If poverty is measured using monthly rather than annual income data, four times as many persons enter poverty, but most spells are short: the median duration is between four and six months. More than one‐third of all poverty spells are eliminated if financial assets are used to fill poverty gaps, but remaining poverty spells are longer. Separate estimates are made for the elderly and for families with children.", "corpus_id": 154700399, "score": 0 }, { "doc_id": "10081881", "title": "Relative or absolute poverty lines : a new approach", "abstract": "When measuring poverty over time analysts must choose the value of the income elasticity of the poverty line, which essentially determines whether an absolute or relative poverty line is being used. The choice of this parameter is ultimately a value judgement but this paper suggests an approach which has some empirical basis. Borrowing from the life-style and deprivation approach to poverty various dimensions of poverty and deprivation are identified and the income elasticity of these items is used as the income elasticity of the poverty line. Data from the 1987 and 1994 Irish Household Budget Surveys suggest an upper bound of 0.7 for this parameter. Poverty measures using a number of values of the income elasticity of the poverty line are presented and test statistics are presented to determine whether observed differences in poverty measures are statistically significant.", "corpus_id": 10081881, "score": 0 }, { "doc_id": "154426788", "title": "Dealing with Poverty and Income Distribution Issues in Developing Countries: Cross-Regional Experiences", "abstract": "The paper deals with the major empirical poverty and income distribution issues in the context of developing countries. To focus attention it starts with a simple poverty decomposition framework where a change in poverty is shown to be the sum of a change due to economic growth and a change due to income distribution. It is shown that when the poverty line is a function of mean income, the elasticity of the poverty line with respect to income plays an important role in determining the size of the change due to growth. Using a recent set of data on income distribution for developing countries, the paper then looks at income inequality and poverty in three developing regions (Latin America, Asia and Sub-Saharan Africa). Empirical results on the Kuznets curve, initial inequality, and growth and adjustment and poverty are reported and policy implications are drawn. Copyright 1998 by Oxford University Press.", "corpus_id": 154426788, "score": 0 }, { "doc_id": "154827150", "title": "Roles of income and equality in poverty reduction: recent cross-country evidence", "abstract": "This paper uses a reasonable model and recent cross-country data to study empirically the effects of income and equality on poverty. Three main points are noted. First, the estimates show highly significant roles of income and equality in poverty reduction, and the effects of increased income and lower inequality are both substantial. Second, the elasticity of poverty with respect to inequality is substantially larger than that relative to income. Third, the estimates suggest a 'growth elasticity' of poverty that is much smaller than the values used in almost every study. Therefore, most of the well-known and influential recent research seems to have overstated the impact of income growth on poverty alleviation by de-emphasising the role of inequality, to which poverty is highly responsive, and by using an income (growth) elasticity of poverty that is much larger than what seems reasonable. Copyright © 2007 John Wiley & Sons, Ltd.", "corpus_id": 154827150, "score": 0 }, { "doc_id": "154122290", "title": "Experienced Poverty and Income Poverty in Mexico: A Subjective Well-Being Approach", "abstract": "Summary This paper uses a life-satisfaction conception of well-being to define experienced poverty. Based on a domains-of-life approach, it shows that experienced poverty is a broader concept than income poverty and that they lead to substantial dissonance in the classification of persons as poor. It is argued that experienced poverty better captures the complexity of being human. It is shown that raising the income received by persons does not automatically translate into greater well-being. It states that public policy should be concerned not only about getting people out of income poverty, but also about placing them in a life-satisfying situation.", "corpus_id": 154122290, "score": 0 }, { "doc_id": "154919549", "title": "Poverty Comparisons with Absolute Poverty Lines Estimated from Survey Data", "abstract": "The objective of measuring poverty is usually to make comparisons over time or between two or more groups. Common statistical inference methods are used to determine whether an apparent difference in measured poverty is statistically significant. Studies of relative poverty have long recognized that when the poverty line is calculated from sample survey data, both the variance of the poverty line and the variance of the welfare metric contribute to the variance of the poverty estimate. In contrast, studies using absolute poverty lines have ignored the poverty line variance, even when the poverty lines are estimated from sample survey data. Including the poverty line variance could either reduce or increase the precision of poverty estimates, depending on the specific characteristics of the data. This paper presents a general procedure for estimating the standard error of poverty measures when the poverty line is estimated from survey data. Based on bootstrap methods, the approach can be used for a wide range of poverty measures and methods for estimating poverty lines. The method is applied to recent household survey data from Mozambique. When the sampling variance of the poverty line is taken into account, the estimated standard errors of Foster–Greer–Thorbecke and Watts poverty measures increase by 15–30 percent at the national level, with considerable variability at lower levels of aggregation.", "corpus_id": 154919549, "score": 0 }, { "doc_id": "153804009", "title": "Unidimensional and multidimensional fuzzy poverty measures: New approach", "abstract": "the analysis of deprivation is usually seen as a unidimensional condition. However, recently it is considered to be a multidimensional one. A useful tool for such analysis is to view deprivation as a degree providing a quantitative expression to its intensity for individuals. Such fuzzy conceptualisation has been widely adopted in poverty and deprivation research. This paper aims to further develop and refine this strand of research. First, we re-examine two aspects introduced by the use of fuzzy measures, as opposed to conventional poor/non-poor dichotomous measures, namely the choice of membership functions and the rules to manipulate, resulting fuzzy sets. Secondly, we propose fuzzy monetary and non-monetary measures with the membership functions of poor and non-poor. An application based on individual well-being data from Tunisian households in 1990 is presented to illustrate use of one of the proposed concept.", "corpus_id": 153804009, "score": 0 }, { "doc_id": "153678242", "title": "Using Non-Monetary Deprivation Indicators to Analyze Poverty and Social Exclusion: Lessons from Europe?.", "abstract": "Non-monetary indicators of deprivation are now widely used in studying poverty in Europe. While measuring financial resources remains central, having reliable information about material deprivation adds to the ability to capture poverty and social exclusion. Non-monetary indicators can help improve the identification of those experiencing poverty and understand how it comes about. They are most productively used when multidimensionality is explicitly taken into account, both in framing the question and in empirical application. While serious methodological and measurement issues remain to be addressed, material deprivation indicators allow for new insights in making poverty comparisons across countries and analyzing changes over time. © 2010 by the Association for Public Policy Analysis and Management.", "corpus_id": 153678242, "score": 0 }, { "doc_id": "5523935", "title": "Theories of Poverty: A Comparative Analysis", "abstract": "Many poverty authors point out that the various ways poverty is conceptualized and measured are very crucial because different poverty measures tend to capture different people as poor. The main focus of this research is to review the theoretical and empirical research on theories of poverty, poverty measures and outcomes. Subsequently, we discuss conceptual framework of the different poverty measures.", "corpus_id": 5523935, "score": 0 }, { "doc_id": "144048444", "title": "Voices from the bottom", "abstract": "Despite many years of poverty eradication programs in numerous countries, 25% of the world's population continues to live in poverty. In the light of this global crisis, it is clear that anti-poverty strategies have not been as successful as they should have been. This paper argues that continuing poverty may be related in part to the fact that policies developed to alleviate the problem are mainly based on monetary definitions developed by ‘experts’, rather than by the poor themselves. Thus this paper will demonstrate that expert definitions invariably neglect the more qualitative aspects and experiences of poverty. In contrast, it is argued here that the poor are the ‘real’ poverty experts and their voices should be included in the definition of poverty and the formulation of solutions. While there is increasing recognition of this latter approach in developing nations, often taking a human needs perspective, this response is only in its infancy in Australia. After a discussion of the conceptualisation of human needs, this paper reports on a small pilot study that presents the voices of 10 disadvantaged men, identifying what poverty is for them in Melbourne", "corpus_id": 144048444, "score": 1 }, { "doc_id": "154279136", "title": "Multidimensional Poverty and Material Deprivation with Discrete Data", "abstract": "We propose a characterization of a popular index of multidimensional poverty which, as a special case, generates a measure of material deprivation. This index is the weighted sum of the functioning failures. The important feature of the variables that may be relevant for poverty assessments is that they are discrete in nature. Thus, poverty measures based on continuous variables are not suitable in this setting and the assumption of a discrete domain is mandatory. We apply the measure to European Union member states where the concept of material deprivation was initiated and illustrate how its recommendations differ from those obtained from poverty measures based exclusively on income considerations.", "corpus_id": 154279136, "score": 0 }, { "doc_id": "153350292", "title": "The Multidimensional Poverty Assessment Tool: a new framework for measuring rural poverty", "abstract": "The Multidimensional Poverty Assessment Tool (MPAT) measures fundamental dimensions of rural poverty in order to support poverty-alleviation efforts in the less developed world. This article's primary purpose is to introduce MPAT and describe its theoretical rationale. It begins with an overview of the importance of creating enabling environments for rural poverty alleviation before describing MPAT's purpose and structure. The article goes on to address some of the advantages and shortcomings of surveys and indicators as means of measuring poverty, and concludes with a few caveats on using MPAT, and a focus on its added value to practitioners and academics.", "corpus_id": 153350292, "score": 0 }, { "doc_id": "1335056", "title": "Multidimensional Poverty Index", "abstract": "A person is multidimensionally poor if she/he is deprived in one third or more (means 33% or more) of the weighted indicators (out of the ten indicators). Those who are deprived in one half or more of the weighted indicators are considered living in extreme multidimensional poverty. MPI is significant as it recognizes poverty from different dimensions compared to the conventional methodology that measures poverty only from the income or monetary terms.", "corpus_id": 1335056, "score": 0 }, { "doc_id": "140956632", "title": "Perceptions of Poverty and Wealth in Western and Post-Communist Countries", "abstract": "This paper analyzes the felt legitimacy of poverty and wealth in the United States, West Germany, The Netherlands, Hungary, the Czech Republic, and Russia. Several theories on poverty and wealth perception are discussed; of these, dominant ideology theory has been the most influential. This theory can predict the existence not only of a legitimizing ideology in a society, but also of challenging beliefs that incumbents of specific social positions hold. It is argued that poverty and wealth perceptions are more complex, however, involving at least three latent dimensions. Using data from the International Social Justice Project it is demonstrated that, regarding poverty, individuals distinguish between merited, unmerited, and fatalistic types of poverty. Merited poverty is poverty brought about by the individual's own doing or not doing, unmerited poverty is due to forces external to the individual, whereas fatalistic explanations attribute poverty to ascribed properties of the individual. For wealth also there are three causally relevant factors: in addition to merited und unmerited ones, a social capital factor that sees social contacts as a source for determining economic success. Using a structural equation approach and its group comparison option for comparing countries, the different explanations of poverty and wealth are translated into specific measurement models. Testing simultaneously with linear regression models show how preferences for particular explanations are shaped by stratification-related experiences and by the social position of an observer.", "corpus_id": 140956632, "score": 0 }, { "doc_id": "144143689", "title": "Development as Happiness: The Subjective Perception of Happiness and UNDP’s Analysis of Poverty, Wealth and Development", "abstract": "This paper examines to what extent the concept of happiness is complementary to the United Nations Development Program's (UNDP) human development approach in the evaluation of poverty, wealth and development. The deconstruction of UNDP's discourse on and its measurement of these concepts show that its perspective is highly arbitrary. Poverty is exclusively defined as lack and state of ill-being, inferior to wealth regarded as a state of abundance and well-being. Development then becomes a teleological process trying to promote well-being through abundance. Yet, this external perspective of UNDP on well-being is questioned by the subjective perception of the individuals themselves. Happiness studies—which define happiness as the degree to which an individual judges the overall quality of his life-as-a-whole favorably—prove that higher levels of UNDP's development indicators are not necessarily better for subjective well-being. Despite methodological and conceptual problems, happiness studies discover that the individuals' perception of poverty, wealth and development can differ considerably from UNDP's perspective. Increased income, better objective health and higher levels of education do not automatically lead to greater happiness. Furthermore, additional dimensions essential for human happiness are detected by the research, yet not taken into account by UNDP. A country ranking comparison between the two approaches confirms the different visions of well-being. The integration of a happiness indicator in its analysis of poverty, wealth and development is thus indispensable for UNDP in order to correct its analytical and also practical approach to development.", "corpus_id": 144143689, "score": 0 }, { "doc_id": "154006029", "title": "Perceptions of Poverty in Japan: Constructing an Image of Relative Poverty Contrasted Against an Image of Extreme Poverty", "abstract": "ABSTRACT Japan is now ranked as the country with the second highest ratio of relative poverty second only to the U.S. However, according to the results of our research, most Japanese people do not understand what relative poverty is. The only image they have of poverty is that of extreme poverty, which is based on media portrayals and influenced by their memories of the desperate conditions in Japan after World War II. This perception is manipulated in order to gain public acceptance of “welfare reform” and destruction of the economic safety net in the conservative political arena. Thus there is a critical and urgent need to discuss and construct a clear concept of relative poverty using understandable language accessible to Japanese people.", "corpus_id": 154006029, "score": 0 }, { "doc_id": "16078179", "title": "Participatory rural appraisal (PRA): Challenges, potentials and paradigm", "abstract": "Abstract Much of the spread of participatory rural appraisal (PRA) as an emerging family of approaches and methods has been lateral, South–South, through experiential learning and changes in behavior, with different local applications. Rapid spread has made quality assurance a concern, with dangers from “instant fashion”, rushing, formalism and ruts. Promising potentials include farmers' own farming systems research, alternatives to questionaire surveys, monitoring, evaluation and lateral spread by local people, empowerment of the poorer and weaker, and policy review. Changes in personal behavior and attitudes, and in organizational cultures, are implied. PRA parallels and resonates with paradigm shifts in the social and natural sciences, business management, and development thinking, supporting decentralization, local diversity, and personal responsibility.", "corpus_id": 16078179, "score": 1 }, { "doc_id": "153661918", "title": "Targeting the poor using community information", "abstract": "Abstract Governments and aid agencies target transfers to the poor, but audits to deter the rich are costly. This paper analyzes how community information can improve targeting. If each community is given a hard budget constraint, then targeting costs can be substantially reduced by asking recipients to make reports about each other. Audits are threatened in the event of a disagreement but never carried out in equilibrium. This scheme is immune to collusion.", "corpus_id": 153661918, "score": 1 }, { "doc_id": "25945615", "title": "Using community wealth ranking to identify the poor for subsidies: a case study of community-based health insurance in Nouna, Burkina Faso.", "abstract": "Access to health-care is low in developing countries. Poor people are less likely to seek care than those who are better off. Community-based health insurance (CBI) aims to improve healthcare utilisation by removing financial barriers, unfortunately CBI has been less effective in securing equity than expected. Poor people, who probably require greater protection from catastrophic health expenses, are less likely to enrol in such schemes. Therefore, it is important to implement targeted interventions so that the most in need are not left out. CBI has been offered to a district in Burkina Faso, comprising 7762 households in 41 villages and the district capital of Nouna since 2004. Community wealth ranking (CWR) was used in 2007 to identify the poorest quintile of households who were subsequently offered insurance at half the usual premium rate. The CWR is easy to implement and requires minimal resources such as interviews with local informants. As used in this study, the agreement between the key informants was more (37.5%) in the villages than in Nouna town (27.3%). CBI management unit only received nine complaints from villagers who considered that some households had been wrongly identified. Among the poorest, the annual enrolment increased from 18 households (1.1%) in 2006 to 186 (11.1%) in 2007 after subsidies. CWR is an alternative methodology to identify poor households and was found to be more cost and time efficient compared to other methods. It could be successfully replicated in low-income countries with similar contexts. Moreover, targeted subsidies had a positive impact on enrolment.", "corpus_id": 25945615, "score": 1 }, { "doc_id": "154378181", "title": "Perceptions of poverty among poor livestock keepers in Kenya: a discourse analysis approach", "abstract": "The paper examines perceptions of poverty among poor livestock keepers in Kenya. The study utilized discourse analysis techniques to evaluate community values towards the poor. The results demonstrated that most study participants viewed poverty as a process rather than a permanent state. The findings also highlighted the differences between the rich and the poor in terms of capabilities. When the results were compared with a wealth ranking exercise, two types of bias were noted. First, wealth-ranking exercises may not be targeting those who are the most needy. Second, projects and programmes may be viewed as assisting those who are responsible for their own poverty. Copyright © 2001 John Wiley & Sons, Ltd.", "corpus_id": 154378181, "score": 0 }, { "doc_id": "8678712", "title": "Identifying Welfare Effects from Subjective Questions", "abstract": "The authors argue that the welfare inferences drawn from subjective answers to questions on qualitative surveys are clouded by concerns about the structure of measurement errors and how latent psychological factors influence observed respondent characteristics. They propose a panel data model to high-quality panel data for Russia for 1994-96, they find that some results widely reported in past studies of subjective well-being appear to be robust but others do not. Household income, for example, is a highly significant predictor of self-rated economic welfare; per capita income is a weaker predictor. Ill health and loss of a job reduce self-reported economic welfare; per capita income is a weaker predictor. Ill health and loss of a job reduce self-reported economic welfare, but demographic effects are weak at a given current income. And the effects of unemployment is not robust. Returning to work does not restore a sense of welfare unless there is an income gain. The results imply that even transient unemployment brings the feeling of a permanent welfare loss, suggesting that high unemployment benefits do not attract people out of work but do discourage a return to work.", "corpus_id": 8678712, "score": 0 }, { "doc_id": "55264350", "title": "How Relevant is Targeting to the Success of an Antipoverty Program?", "abstract": "Policy-oriented discussions often assume that better targeting implies larger impacts on poverty or more cost-effective interventions for fighting poverty. The literature on the economics of targeting warns against that assumption, but evidence has been scarce and the lessons from the literature have often been ignored by practitioners. This paper shows that standard measures of targeting performance are uninformative or even deceptive about the impacts on poverty, and cost-effectiveness in reducing poverty, of a large cash transfer program in China. The results suggest that in program design and evaluation, it will be better to focus directly on the program's outcomes for poor people than to rely on prevailing measures of targeting.", "corpus_id": 55264350, "score": 0 }, { "doc_id": "23574638", "title": "Determinants of children's nutritional status in Kenya: evidence from Demographic and Health Surveys.", "abstract": "This paper uses a pooled sample of the 1998 and 2003 Demographic and Health Survey data sets for Kenya to analyse the determinants of children's nutritional status. We investigate the impact of child, parental, household and community characteristics on children's height and on the probability of stunting. Descriptive and econometric analysis, augmented by policy simulations, is employed to achieve the objectives of the study. In estimation, we control for sample design and possible heterogeneity arising from unobserved community characteristics correlated with children's nutritional status and its determinants. The key findings are that boys suffer more malnutrition than girls, and children of multiple births are more likely to be malnourished than singletons. The results further indicate that maternal education is a more important determinant of children's nutritional status than paternal education. Household assets are also important determinants of children's nutritional status but nutrition improves at a decreasing rate with assets. The use of public health services, more-so modern contraceptives, is also found to be an important determinant of child nutritional status. Policy simulations affirm the potential role of parental, household and community characteristics in reducing long-term malnutrition in Kenya and suggest that the correct policy mix would make a substantial reduction in the current high levels of malnutrition. Our findings suggest that, if Kenya is to achieve her strategic health objectives and millennium development target of reducing the prevalence of malnutrition, strategies for poverty alleviation, promotion of post secondary education for women and provision of basic preventive health care are critical concerns that need to be addressed. Copyright 2009 The author 2008. Published by Oxford University Press on behalf of the Centre for the Study of African Economies. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org, Oxford University Press.", "corpus_id": 23574638, "score": 0 }, { "doc_id": "8676925", "title": "Community concepts of poverty: an application to premium exemptions in Ghana’s National Health Insurance Scheme", "abstract": "BackgroundPoverty is multi dimensional. Beyond the quantitative and tangible issues related to inadequate income it also has equally important social, more intangible and difficult if not impossible to quantify dimensions. In 2009, we explored these social and relativist dimension of poverty in five communities in the South of Ghana with differing socio economic characteristics to inform the development and implementation of policies and programs to identify and target the poor for premium exemptions under Ghana’s National Health Insurance Scheme.MethodsWe employed participatory wealth ranking (PWR) a qualitative tool for the exploration of community concepts, identification and ranking of households into socioeconomic groups. Key informants within the community ranked households into wealth categories after discussing in detail concepts and indicators of poverty.ResultsCommunity defined indicators of poverty covered themes related to type of employment, educational attainment of children, food availability, physical appearance, housing conditions, asset ownership, health seeking behavior, social exclusion and marginalization. The poverty indicators discussed shared commonalities but contrasted in the patterns of ranking per community.ConclusionThe in-depth nature of the PWR process precludes it from being used for identification of the poor on a large national scale in a program such as the NHIS. However, PWR can provide valuable qualitative input to enrich discussions, development and implementation of policies, programs and tools for large scale interventions and targeting of the poor for social welfare programs such as premium exemption for health care.", "corpus_id": 8676925, "score": 1 }, { "doc_id": "154625172", "title": "The complexities of rural poverty in sub‐Saharan Africa", "abstract": "Abstract Rural poverty is an endemic problem in sub‐Saharan Africa, with the region faring very badly on most of the common poverty indicators. After drawing a contrast with the position in South Asia the paper considers the problem from the local level. It is argued, however, that while the manifestations are local, the causes and the potential remedies are found in the nature of linkages with the wider national and international economies. A framework is adopted to illustrate the complexity of linkage effects. The value of the framework is then demonstrated by considering the success of Machakos District (Kenya) in transforming a weak area into one which has shown distinctive signs of improvement as a result of the expansion of its external linkages and the consequent strengthening of its own local economy.", "corpus_id": 154625172, "score": 0 }, { "doc_id": "153403309", "title": "Attacking Poverty: but what happened to urban poverty and development?", "abstract": "This paper reviews Attacking Poverty with regard to its treatment of urban poverty. The central argument is that urbanization and urban poverty are increasingly important but are largely ignored in the report. Thus the dynamics of urban poverty are overlooked and the subsequent policy suggestions are subsequently weakened. The report's emphasis on empowerment misses the historically progressive nature of urbanization as a social force. Copyright © 2001 John Wiley & Sons, Ltd.", "corpus_id": 153403309, "score": 0 }, { "doc_id": "153874594", "title": "Rural poverty in India: a regional analysis", "abstract": "Abstract This paper identifies the regional pattern of rural poverty in India, for the first time using consumer expenditure data for areal units smaller than the states. Further, it differs from existing studies in that poverty has been measured by using regional poverty lines, based on regional food habits and prices. The application of regional poverty lines, it is believed, has revealed a more accurate distribution pattern of rural poverty than in previous studies. The regional analysis exposes the fact that, even in a largely poor country, there are distinct regional concentrations of poverty, reflecting large regional differences in real incomes. The heaviest concentration of poverty is in the north-eastern and central plateau country, while the most prosperous regions are largely in the north-west. The regression analysis indicates that irrigation use, family size and size of holding exert a negative influence on poverty and landlessness positive.", "corpus_id": 153874594, "score": 0 }, { "doc_id": "154397398", "title": "Regional poverty lines, poverty profiles, and targeting", "abstract": "The most labour-intensive task in building a poverty profile consists in the estimation of the poverty lines. Does it matter whether poverty lines are estimated for the urban and rural sectors as a whole or by geographical area within each sector? Using a decomposition of the Gini index of inequality in poverty measures, it is shown that it does, but not too much in Bangladesh.", "corpus_id": 154397398, "score": 0 }, { "doc_id": "152461363", "title": "The Spatial Dimension of Welfare and Poverty : Lessons from a Regional Targeting Program in Indonesia", "abstract": "This paper examines the spatial dimension of welfare and poverty in Indonesia and explores the effective policy interventions to remedy the regional economic disparity which was most vividly shown during the recent economic crisis. The econometric estimations confirm the existence of a spatial poverty trap, where poverty persists for generations. The inclusion of the placement of Impres Desa Tertingal (IDT) implemented during 1994–96 suggests that the regional targeting programme could fail to achieve its policy goal when the empowerment of local communities is insufficient. It is suggested that full–scale decentralization could remedy the targeting policy failure. \n \n \n \nJEL classification: O15; O18; R15", "corpus_id": 152461363, "score": 0 }, { "doc_id": "145581075", "title": "An understanding of poverty from those who are poor", "abstract": "Participatory research in the study of poverty invites those living in difficult circumstances to participate in an analysis of their own livelihood situation. A participatory poverty assessment was facilitated with a small group of women who are members of a food co-operative in Niagara Falls, Canada and who live in poverty. The women explored together issues of well-being, the stress of living in poverty, the role of the social assistance system in shaping their lives and community attitudes. Important themes which emerged included an emphasis on social relationships, the impact of the pervasive scrutiny of the social assistance bureaucracy, the importance of community good will and the possibilities for community action. This article discusses the contribution of local knowledge to an understanding of poverty as well as the limitations of participation in changing social policy.", "corpus_id": 145581075, "score": 0 }, { "doc_id": "73634216", "title": "Pro-poor tourism: putting poverty at the heart of the tourism agenda.", "abstract": "This paper examines how tourism affects the livelihoods of the poor and how positive impacts can be enhanced. In doing so, it assesses the relevance of tourism to the poverty agenda, and the factors that encourage or constrain economic participation of the poor in the industry. In conclusion it outlines strategies for promoting pro-poor tourism.", "corpus_id": 73634216, "score": 0 }, { "doc_id": "154598469", "title": "Overcoming the ‘value‐action gap’ in environmental policy: Tensions between national policy and local experience", "abstract": "Abstract This paper is concerned with debates over the implementation of sustainability objectives. In particular, it focuses on policies that address the ‘value‐action gap’ in environmental policy. Using evidence from the author's research connected with the UK Going for Green Sustainable Communities Project in Huntingdonshire, the paper highlights the tensions between national policies that are based on an ‘information deficit’ model of participation, and local research and experience that posits a more complex relationship between individuals and institutions. While this suggests the need to develop more differentiated policies based on the restructuring of socioeconomic and political institutions, the paper warns against knee‐jerk calls for more local, community or public participation which simply replace one set of generalised appeals with another. The paper concludes that greater emphasis must be placed on the negotiation of partnerships that are more sensitive to local diversity, and which involve...", "corpus_id": 154598469, "score": 0 }, { "doc_id": "143057713", "title": "Perception and response to the challenge of poverty and environmental resource degradation in rural Nigeria: Case study from the Niger Delta", "abstract": "Abstract Much of environmental analyses has focused on national and global issues rather than on local areas and underprivileged people whose voices often remain largely unheard. This paper attempts an appraisal of the environmental concerns and resource values of the poor living in difficult and degraded environment in rural Nigeria. In the study, 831 respondents validated the nature of environmental problems and priorities in relation to their experiences within the community. The results show that the poor are environmentally rational but often handicapped in doing the right thing. While most respondents have a holistic and long-term view of the environmental implications of natural resource use, a host of sustainable traditional environmental resource conservation measures previously embraced by communities have been abandoned in order to meet the exigencies of short-term survival. The self- and socio-economic survival goals, rather than the community and the ‘common good’, appear to form the predominant contexts for the individual's environmental thinking and decision-making. Resource scarcity, declining yields and associated inflation/high cost of living were seen as the major signs of resource degradation. The study demonstrates the need for a proper understanding of natural resource issues drawing not only on scientific and economic evaluations but also on community-centered approaches. Finally, social justice and fairness to communities was established to be critical to sustainable development in poor areas; resources must be harnessed such that they contribute directly to community asset building to improve socio-economic activities and protect the environment.", "corpus_id": 143057713, "score": 0 }, { "doc_id": "157400478", "title": "Voices of the Poor: Poverty and Social Capital in Tanzania", "abstract": "Environmentally and Socially Sustainable Development Studies and Monographs Series 20. This study describes the practices and processes of participatory methods that tap the knowledge the poor have about their own reality. The Participatory Poverty Assessment uses methods to measure and facilitate \"\"listening to the poor.\"\" Participatory tools show how the poor view poverty, inflation, and other economic and social trends. In addition, the study established the high economic returns to village social capital, measured by density of groups with particular characteristics.", "corpus_id": 157400478, "score": 0 }, { "doc_id": "9490817", "title": "Targeting the Poor: Evidence from a Field Experiment in Indonesia", "abstract": "This paper reports an experiment in 640 Indonesian villages on three approaches to target the poor: proxy-means tests (PMT), where assets are used to predict consumption; community targeting, where villagers rank everyone from richest to poorest; and a hybrid. Defining poverty based on PPP$2 per-capita consumption, community targeting and the hybrid perform somewhat worse in identifying the poor than PMT, though not by enough to significantly affect poverty outcomes for a typical program. Elite capture does not explain these results. Instead, communities appear to apply a different concept of poverty. Consistent with this finding, community targeting results in higher satisfaction.", "corpus_id": 9490817, "score": 0 }, { "doc_id": "166706211", "title": "Community strategic visioning as a method to define and address poverty: an analysis from select rural Montana communities.", "abstract": "Community strategic visioning is a citizen-based planning process in which diverse sectors of a community collectively determine a future state and coordinate a plan of action. Twenty-one communities in rural Montana participated in a multi-phase poverty reduction program that culminated in a community strategic vision process. Research on this process was guided by alternative definitions of poverty and place attachment literature. Results from the qualitative survey data show many descriptions of poverty outside of traditional economic definitions and illustrations on the significance of place. Implications and recommendations on the use of visioning in other contexts in Extension are discussed.", "corpus_id": 166706211, "score": 0 }, { "doc_id": "15222854", "title": "Understanding enrolment in community health insurance in sub-Saharan Africa: a population-based case-control study in rural Burkina Faso.", "abstract": "OBJECTIVE\nTo identify factors associated with decision to enrol in a community health insurance (CHI) scheme.\n\n\nMETHODS\nWe conducted a population-based case-control study among 15 communities offered insurance in 2004 in rural Burkina Faso. For inclusion in the study, we selected all 154 enrolled (cases) and a random sample of 393 non-enrolled (controls) households. We used unconditional logistic regression (applying Huber-White correction to account for clustering at the community level) to explore the association between enrolment status and a set of household head, household and community characteristics.\n\n\nFINDINGS\nMultivariate analysis revealed that enrolment in CHI was associated with Bwaba ethnicity, higher education, higher socioeconomic status, a negative perception of the adequacy of traditional care, a higher proportion of children living within the household, greater distance from the health facility, and a lower level of socioeconomic inequality within the community, but not with household health status or previous household health service utilization.\n\n\nCONCLUSION\nOur study provides evidence that the decision to enrol in CHI is shaped by a combination of household head, household, and community factors. Policies aimed at enhancing enrolment ought to act at all three levels. On the basis of our findings, we discuss specific policy recommendations and highlight areas for further research.", "corpus_id": 15222854, "score": 0 }, { "doc_id": "41978713", "title": "\"To enrol or not to enrol?\": A qualitative investigation of demand for health insurance in rural West Africa.", "abstract": "In spite of the fact that feeble levels of participation have long been identified as a major constraint to the successful long-term implementation of community-based health insurance (CBI) in low-income countries, evidence on determinants of enrolment in CBI is still lacking. The application of econometric modelling has provided a partial answer to the question, but on its own it has proved to be insufficient to guide policy making. This paper aims to fill this gap in knowledge using qualitative research methods. In-depth interviews with 32 household heads were conducted in the Nouna Health District, Burkina Faso, West Africa to assess determinants of enrolment in a newly established CBI scheme. The findings highlight that factors previously neglected in the literature, such as institutional rigidities and socio-cultural practices, play an important role in shaping the decision to enrol. The discussion of the findings focuses on the policy implications, offering concrete recommendations to maximise enrolment, within and beyond Burkina Faso.", "corpus_id": 41978713, "score": 0 }, { "doc_id": "4182559", "title": "The feasibility of community-based health insurance in Burkina Faso.", "abstract": "To ensure the acceptability of community-based insurance (CBI) by the community and its sustainability, a feasibility study of CBI was conducted in Burkina Faso, including preference for benefit package of CBI, costing of health services, costing of the benefit package and willingness-to-pay (WTP) for the package. Qualitative methods were used to collect information about preferences for the benefit package. Cost per unit health services, health demand obtained from household survey and physician-judged health needs were used to estimate the cost of the benefit package. The bidding game method was used to elicit household head's WTP for the package. We found that there were strong preferences for inclusion of high-cost healthservices such as operation, essential drugs and consultation fees in the benefit package. It is estimated that the cost of the package per capita was 1673 CFA (demand-based) and 9630 CFA (need-based), including 58% government subsidies (euro 1 = 655 CFA). The average household head with eight household members agreed to pay from 7500 (median) to 9769 CFA (mean) to join the CBI for his/her household. The WTP results were influenced by household characteristics, such as location, household size and age composition. Under certain assumptions (household as the enrolment unit, median household head's WTP as premium for the average household, 50% enrolment rate), it would be feasible to run CBI in Nouna, Burkina Faso if enrolees' health demand did not increase by more than 28% or if the underwriting of the initial losses was covered by extra funds.", "corpus_id": 4182559, "score": 0 }, { "doc_id": "144959529", "title": "Perceptions of Risk, Vulnerability, and Disease Prevention in Rural Burkina Faso: Implications for Community-Based Health Care and Insurance", "abstract": "This paper examines local discourse on perceived risk and vulnerability among rural and semiurban populations in Kossi Province in the northwest of Burkina Faso. Focus group data are presented to elucidate this discourse in a number of risk domains. Local notions of disease prevention are exemplified with respect to malaria, diarrhea, and vaccine-preventable diseases. Quantitative measures on perceived severity and perceived personal vulnerability, assessed using culturally adapted scaling methods and relating to a list of selected risks, are presented. Implications of the complex local discourse on uncertainty and vulnerability with respect to community-centered development efforts such as community-based health care and insurance are explored.", "corpus_id": 144959529, "score": 0 }, { "doc_id": "205087866", "title": "Drop-out analysis of community-based health insurance membership at Nouna, Burkina Faso.", "abstract": "OBJECTIVES\nThis study aims to identify the reasons why enrolled people decide not to renew their membership in following years.\n\n\nMETHODS\nHousehold survey is used to collect information on the factors influencing dropping out from community-based health insurance (CBI). Information from CBI agency databank is used to describe the general situation of enrolment and drop-out.\n\n\nRESULTS\nSince the launch of CBI the enrolment rate has been low ranging from 5.2% to 6.3%. The drop-out rate, however, has been high ranging from 30.9% to 45.7%. It is found, by the multivariate analysis, that female household head, higher age or lower education of a household head, lower number of illness episodes in the past three months, fewer children or elderly in a household, poor perceived health care quality, less seeking care in the past month positively effected on drop-out, increasing the rate. However, the household six-month expenditure and the distance to the contracted health facility did not have the hypothesised sign. In contrast, a higher household expenditure and a shorter distance to the contracted health facility increased the drop-out.\n\n\nCONCLUSIONS\nHigh drop-out rates endanger the sustainability of CBI not only because they reduce the size of the insurance pool, but also because they bear a negative impact on further enrolment and drop-out. The drop-out rate in the scheme of the Nouna Health District, Burkina Faso, is very high. The reasons for drop-out may be related to affordability, health-needs and health demand, quality of care, household head and household characteristics. This study represents a valuable attempt towards further increasing the sustainability of CBI schemes, by understanding not what motivates people to first enrol in CBI, but what motivates them to renew membership year after year.", "corpus_id": 205087866, "score": 0 }, { "doc_id": "15601787", "title": "Community-Based Targeting Mechanisms for Social Safety Nets: A Critical Review", "abstract": "This paper interprets case studies, and theory on community involvement in beneficiary selection, and benefit delivery for social safety nets. Several considerations should be carefully balanced in assessing the advantages of using community groups as targeting agents. First, benefits from utilizing local information, and social capital may be eroded by costly rent-seeking. Second, the potential improvement in targeting criteria from incorporating local notions of deprivation, must be tempered by the possibility of program capture by local elites, and by the possibility that local preferences are not pro-poor. Third, performance may be undermined by unforeseen strategic targeting by local communities in response to national funding, and evaluation criteria, or by declines in political support.", "corpus_id": 15601787, "score": 0 }, { "doc_id": "54912746", "title": "Socioeconomic stratification by wealth ranking: Is it valid?☆", "abstract": "Abstract This paper validates a Rapid Rural Appraisal wealth-ranking technique using standard socioeconomic indicators from a household survey in rural Bangladesh. Key informants stratified 1,637 households into three wealth groups according to a number of broad criteria and a questionnaire was subsequently administered to each household. Health, demographic and economic variables derived from the questionnaire were found to differ significantly according to wealth group. Analysis supports the construct validity and empirical validity of the wealth-ranking technique as a means of stratifying households by socioeconomic status. The requirements for external validity, as assessed through the comparison of findings with similar studies elsewhere in South Asia, are also satisfied.", "corpus_id": 54912746, "score": 0 }, { "doc_id": "74329051", "title": "Focus group discussion: a tool for health and medical research", "abstract": "Focus group discussion is a research methodology in which a small group of participants gather to discuss a specified topic or an issue to generate data. The main characteristic of a focus group is the interaction between the moderator and the group, as well as the interaction between group members. The objective is to give the researcher an understanding of the participants’ perspective on the topic in discussion. Focus groups are rapidly gaining popularity in health and medical research. This paper presents a general introduction of the use of focus groups as a research tool within the context of health research, with the intention of promoting its use among researchers in healthcare. A detailed methodology for the conduct of focus groups and analysis of focus group data are discussed. The potentials and limitations of this qualitative research technique are also highlighted.", "corpus_id": 74329051, "score": 0 }, { "doc_id": "27827901", "title": "Focus groups for qualitative research.", "abstract": "Introduction Focus Groups as Qualitative Method The Uses of Focus Groups Planning and Research Design for Focus Groups Conducting and Analyzing Focus Groups Additional Possibilities Conclusions", "corpus_id": 27827901, "score": 0 }, { "doc_id": "15830985", "title": "Community and anti-poverty targeting", "abstract": "The standard theory of anti-poverty targeting assumes individual incomes cannot be observed, but statistical properties of income distribution in broadly defined groups are known. ‘Indicator targeting’ rules are then derived for the forms of transfers conditioned on group membership of individuals. In this literature the motivating notion of a ‘group’ is purely statistical, even when it is groups such as localities and ethnicities. We focus instead on groups which are ‘communities’, meaning thereby collections of individuals who have access to community-specific public goods, from which non-members are excluded. Such differential access constitutes a source of inequality among poor individuals belonging to different communities, which is not captured by monetary earnings. We show that this formulation of what constitutes a group changes many of the basic results of the indicator targeting literature. Optimal targeting for poverty alleviation leads to seemingly paradoxical rules, such as targeting transfers to the community that is richer. Total wealth of non-poor members of a community and its distribution both become relevant for specifying optimal indicator targeting rules. In addition, a poverty measure that is sensitive to the community identities of poor individuals, yet defined on nominal incomes, may be incompatible with some of the basic axioms in the standard literature on poverty measurement.", "corpus_id": 15830985, "score": 0 }, { "doc_id": "142728209", "title": "'I keep myself clean...at least when you see me, you don't know I am poor': student experiences of poverty in South African higher education", "abstract": "There is little research exploring poverty amongst university students, which renders poverty on university campuses invisible. This study aims to begin to understand experiences and constructions of poverty among university students. The qualitative study design uses open-ended, in-depth interviews in which four students from a university in the Western Cape were interviewed. The findings suggest that poor students use multiple strategies to circumvent the psychological distress associated with poverty and to disguise their poverty. They reflect complex and seemingly contradictory views of poverty as an individually and structurally created burden when they simultaneously take responsibility for their poverty but also attribute it to structural factors. Despite this, participants expressed resilience and hope for a better future, championing education as the 'way out' of their current situation. The findings suggest that more qualitative research is needed in this area as it holds implications for student retention, access to university and drop-out rates in higher education, areas which are core to transformation in South African higher education. Some recommendations about individual and interpersonal interventions that may supplement collective or macro-level interventions are made.", "corpus_id": 142728209, "score": 0 }, { "doc_id": "154274252", "title": "Tourism and Poverty Reduction: An Interpretation by the Poor of Elmina, Ghana", "abstract": "Over the past decade, academic research into the use of tourism as a contributor to poverty reduction has grown considerably; however, there are few insights on how the poor perceive the connections between poverty and tourism. Based upon interpretive and participatory fieldwork with the poor of Elmina in Ghana, this paper explores their understanding and constructions of poverty and how they comprehend tourism as a provider of alternative livelihood opportunities. It emerged that poverty is understood as a multi-dimensional construct, including low and irregular incomes, depletion of natural resources, a lack of access to social assets and educational opportunities, and denial of meaningful participation in society. At a time of structural readjustment in Elmina's economy, the potential of tourism to enhance livelihoods and reduce poverty is high, but remains hindered by major barriers to entrepreneurship development and employment within the sector, which is worsened by the lack of access to credit, exclusion from decision-making, poor skills and excessive bureaucracy. It became evident that a focus on the use of tourism for macroeconomic gains will not necessarily benefit the poor. They need to be included in tourism policy and practice, not only as a target group, but also in participatory mechanisms to ensure the appropriate use of tourism for poverty reduction. It is argued that it is only through a better understanding of poor people's experiences of poverty, that tourism can be used more meaningfully as a strategy for its alleviation.", "corpus_id": 154274252, "score": 0 }, { "doc_id": "153869823", "title": "The Face of Chronic Poverty in Uganda from the Poor’s Perspective: constraints and opportunities", "abstract": "This paper examines the factors influencing chronic poverty in Uganda from the perspective of the poor. The findings are based on participatory poverty assessments conducted in 23 urban and 57 rural sites covering 21 districts. The paper examines: the view of the poor on the definitions of chronic poverty, the types of people who are chronically poor and why; opportunities and constraints for moving out of poverty; the effects of government policies; and suggestions for improvements. The findings suggest that the factors driving and maintaining poverty often are transmitted inter-generationally, and certain categories of people, such as the disabled, women and refugees, are more vulnerable than others. Also, ineffective local governance and government policies seem to prevent the chronically poor from escaping the poverty trap.", "corpus_id": 153869823, "score": 0 }, { "doc_id": "26562027", "title": "Poor People in Rich Nations: The United States in Comparative Perspective", "abstract": "Cross-national comparisons can teach lessons about antipoverty policy. While all nations value low poverty, high levels of economic self-reliance and equality of opportunity for younger persons, they differ dramatically in the extent to which they reach these goals. Nations also exhibit differences in the extent to which working age adults mix economic self-reliance (earned incomes), family support and government support to avoid poverty. We begin by reviewing international concepts and measures of poverty. The Luxembourg Income Study (LIS) database contains the information needed to construct comparable poverty measures for more than 30 nations. It allows comparisons of the level and trend of poverty and inequality across several nations, along with considerable detail on the sources of market incomes and public policies that shape these outcomes. We will highlight the different relationships between antipoverty policy and outcomes among several countries, and consider the implications of our analysis for research and for antipoverty policy in the United States. In doing so, we will draw on a growing body of evidence that evaluates antipoverty programs in a cross-national context.", "corpus_id": 26562027, "score": 0 }, { "doc_id": "150979919", "title": "Participatory poverty assessment : incorporating poor people's perspectives into poverty assessment work", "abstract": "A foundation stone of the World Bank's sharpened poverty strategy is to conduct Country Poverty Assessments in all borrowing countries within the next two years. These assessments have the following principal elements: a poverty profile (which analyses the depth, social and cultural nature, gender disparities and geographic spread of poverty); a review of current government policies relating to poverty; an analysis of pertinent public expenditures and institutions; an overview of nongovernmental organizations and community-based organizations working toward the alleviation of poverty; an analysis of the safety nets (both government programs and sociocultural mechanisms) in place; and based on the above a suggested country strategy of priority measures the government should take to reduce poverty. This paper proposes to supplement conventional poverty assesments with an effort to involve key groups of vulnerable people, among them women and members of indigenous communities and racial and ethnic minority goups.", "corpus_id": 150979919, "score": 0 }, { "doc_id": "6855851", "title": "Validity of rapid estimates of household wealth and income for health surveys in rural Africa", "abstract": "STUDY OBJECTIVE To test the validity of proxy measures of household wealth and income that can be readily implemented in health surveys in rural Africa. DESIGN Data are drawn from four different integrated household surveys. The assumptions underlying the choice of wealth proxy are described, and correlations with the true value are assessed in two different settings. The expenditure proxy is developed and then tested for replicability in two independent datasets representing the same population. SETTING Rural areas of Mali, Malawi, and Côte d'Ivoire (two national surveys). PARTICIPANTS Random sample of rural households in each setting (n=275, 707, 910, and 856, respectively). MAIN RESULTS In both Mali and Malawi, the wealth proxy correlated highly (r⩾0.74) with the more complex monetary value method. For rural areas of Côte d'Ivoire, it was possible to generate a list of just 10 expenditure items, the values of which when summed correlated highly with expenditures on all items combined (r=0.74, development dataset,r=0.72, validation dataset). Total household expenditure is an accepted alternative to household income in developing country settings. CONCLUSIONS It is feasible to approximate both household wealth and expenditures in rural African settings without dramatically lengthening questionnaires that have a primary focus on health outcomes.", "corpus_id": 6855851, "score": 0 }, { "doc_id": "151231025", "title": "Измерение И Анализ Бедности [Poverty Measurement and Analysis]", "abstract": "This chapter offers a primer on poverty, inequality, and vulnerability analysis and a guide to resources on this topic. It is written for decision makers who want to define the type of information they need to monitor poverty reduction and make appropriate policy decisions and for the technical experts in charge of the analysis. The chapter takes a broad look at tools for analysis and provides a brief introduction to each topic. It also outlines why certain information is essential in policymaking and how this information can be generated. This unpublished version of the paper in Russian was translated from an English version published in the World Bank's Poverty Reduction Strategy Sourcebook.", "corpus_id": 151231025, "score": 0 }, { "doc_id": "154256836", "title": "Poverty and basic needs fulfilment in Africa during structural change: Evidence from Cote d'Ivoire", "abstract": "Abstract Much attention is given in the literature to the evolution of social indicators during periods of structural adjustment and economic reform. This paper argues that these processes are not distribution-neutral from the point of view of basic needs fulfilment and that hence the focus should not be on aggregate indicators but on the distribution of beneficiaries of social services, and changes in this distribution. Evidence is presented for Cote d'Ivoire during the second half of the 1980s—a period of intense structural change—which shows that the poorest absorbed the bulk of the decline in basic needs fulfilment as a result of structural change. This was the case for almost all aspects of basic needs and occurred regardless of the overall trend in the social indicators.", "corpus_id": 154256836, "score": 0 }, { "doc_id": "145010855", "title": "The basic needs approach: Overcoming the poverty of homo oeconomicus", "abstract": "Abstract A major issue in the controversy surrounding the Basic Needs Approach to economic development concerns the difficulty of identifying a universal set of basic needs which is capable of cross-cultural application. It is argued that the apparent conceptual infeasibility of the Basic Needs Approach stems from prominent deficiencies in our current stock of economic, political and ethical paradigms, particularly with respect to the image of humans embodied in the notion of Homo oeconomicus . Recent advances in sociobiology and neurobiology provide an adequate foundation for a concept of universal basic human needs, and a proposed typology of basic needs is suggested.", "corpus_id": 145010855, "score": 0 }, { "doc_id": "56067366", "title": "Basic Needs: Some Unsettled Questions", "abstract": "Abstract Though the large basic needs literature has clarified some issues related to anti-poverty strategies, it has also raised others. This paper identifies some of these unsettled questions: (1) who is to determine basic needs? (2) do basic needs refer to the conditions for a full, long and healthy life or to a specific bundle of goods and services that are deemed to provide opportunity for these conditions? (3) what is the purpose of participation? what form should it take? how does a right to participate (if it exists) relate to the political/administrative structures necessary for efficient implementation of basic needs approach? (4) what is the relationship between the redistribution approach to development and the basic needs approach? does the basic needs approach require fundamental systemic change, or is it a palliative? (5) what is the relation between meeting basic needs as an end in itself and as an instrument for developing human resources? (6) in what manner should international support for basic needs approaches be mobilized? (7) what is the relation between poverty eradication and reducing income inequalities?", "corpus_id": 56067366, "score": 0 } ]

{ "doc_id": "4026192", "title": "Inducible Arginase 1 Deficiency in Mice Leads to Hyperargininemia and Altered Amino Acid Metabolism", "abstract": "Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver arginase isoform, arginase 1 (ARG1), which is the final step in the urea cycle for detoxifying ammonia. ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing “floxed” Arg1 mice with CreERT2 mice. The resulting mice (Arg-Cre) die about two weeks after tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1 mRNA, protein and liver arginase activity, and exhibited symptoms of hyperammonemia. Plasma amino acid analysis revealed pronounced hyperargininemia and significant alterations in amino acid and guanidino compound metabolism, including increased citrulline and guanidinoacetic acid. Despite no alteration in ornithine levels, concentrations of other amino acids such as proline and the branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of hyperargininemia. This model should prove useful for exploring potential treatment options of ARG1 deficiency.", "corpus_id": 4026192 }

[ { "doc_id": "13616975", "title": "The human arginases and arginase deficiency", "abstract": "Arginase is the final enzyme in the urea cycle. Its deficiency is the least frequently described disorder of this cycle. It results primarily in elevated blood arginine, and less frequently in either persistent or acute elevations in blood ammonia. This appears to be due to a second arginase locus, expressed primarily in the kidney, which can be recruited to compensate, in part, for the deficiency of liver arginase. The liver arginase gene structure permitted study of the molecular pathology of patients with the disorder and the results of these studies and the inferences about the protein structure are presented. The conserved regions among all arginases allowed the cloning of AII, the second arginase isoform. It has been localized to the mitochondrion and is thought to be involved in ornithine biosynthesis. It shares the major conserved protein sequences, and structural features of liver arginase gene are also conserved. When AI and AII from various species are compared, it appears that the two diverged some time prior to the evolution of amphibians. The evidence for the role of AII in nitric oxide and polyamine metabolism is presented and this appears consonant with the data on the tissue distribution.", "corpus_id": 13616975, "score": 1 }, { "doc_id": "38021990", "title": "Human type II arginase: sequence analysis and tissue-specific expression.", "abstract": "A full-length cDNA encoding type II arginase was isolated from a human kidney cDNA library and its sequence compared to those of vertebrate type I arginases as well as to arginases of bacteria, fungi and plants. The predicted sequence of human type II arginase is 58% identical to the sequence of human type I arginase but is 71% identical to the sequence of Xenopus type II arginase, suggesting that duplication of the arginase gene occurred before mammals and amphibians diverged. Seven residues known to be essential for activity were found to be conserved in all arginases. Type II arginase mRNA was detected in virtually all human and mouse RNA samples tested whereas type I arginase mRNA was found only in liver. At least five mRNA species hybridizing to type II arginase cDNA were found in the human RNA samples whereas only a single type II arginase mRNA species was found in the mouse. This raises the possibility that the multiple type II arginase mRNAs in humans arise from differential RNA processing or usage of alternative promoters.", "corpus_id": 38021990, "score": 0 }, { "doc_id": "32430605", "title": "Cloning and characterization of the human type II arginase gene.", "abstract": "There are two forms of arginase in humans, both catalyzing the hydrolysis of arginine to ornithine and urea. Recent studies in animal models and in Type I arginase-deficient patients suggest that Type II arginase is inducible and may play an important role in the regulation of extra-urea cycle arginine metabolism by modulating cellular arginine concentrations. We PCR amplified and cloned the human Type II arginase gene, the first nonliver arginase gene reported in mammals. While sequence homology to Type I arginase, arginase activity data, and immunoprecipitation with an anti-AII antibody confirm the identity of this gene, Northern blot analysis demonstrates its differential expression in the brain, prostate, and kidney. Type II arginase may be an important part of the arginine regulatory system affecting nitric oxide synthase, arginine decarboxylase, kyotorphin synthase, and arginine-glycine transaminase activities and polyamine and proline biosynthesis.", "corpus_id": 32430605, "score": 0 }, { "doc_id": "21529396", "title": "Arginase deficiency manifesting delayed clinical sequelae and induction of a kidney arginase isozyme", "abstract": "Deficiency of liver arginase (AI) is characterized clinically by hyperargininemia, progressive mental impairment, growth retardation, spasticity, and periodic episodes of hyperammonemia. The rarest of the inborn errors of urea cycle enzymes, it has been considered the least life-threatening, by virtue of the typical absence of catastrophic neonatal hyperammonemia and its compatibility with a longer life span. This has been attributed to the persistence of some ureagenesis in these patients through the activity of a second isozyme of arginase (AII) located predominantly in the kidney. We have treated a number of arginase-deficient patients into young adulthood. While they are severely retarded and wheelchairbound, their general medical care has been quite tractable. Recently, however, two of the oldest (M.U., age 20, and M.O., age 22) underwent rapid deterioration, ending in hyperammonemic coma and death, precipitated by relatively minor viral respiratory illnesses inducing a catabolic state with increased endogenous nitrogen load. In both cases, postmortem examination revealed severe global cerebral edema and aspiration pneumonia. Enzyme assays confirmed the absence of AI activity in the livers of both patients. In contrast, AII activity (identified by its different cation cofactor requirements and lack of precipitation with anti-AI antibody) was markedly elevated in kidney tissues, 20-fold in M.O. and 34-fold in M.U. Terminal plasma arginine (1500μmol/1) and ammonia (1693 mmol/1) levels of M.U. were substantially higher than those of M.O. (348μmol/1 and 259μmol/1, respectively). By Northern blot analysis, AI mRNA was detected in M.O.'s liver but not in M.U.'s; similarly, anti-AI crossreacting material was observed by Western blot in M.O. only. These findings indicate that, despite their more longlived course, patients with arginase deficiency remain vulnerable to the same catastrophic events of hyperammonemia that patients with other urea cycle disorders typically suffer in infancy. Further, unlike those other disorders, an attempt is made to compensate for the primary enzyme deficiency by induction of another isozyme in a different tissue. Such substrate-stimulated induction of an enzyme may be unique in a medical genetics setting and raises novel options for eventual gene therapy of this disorder.", "corpus_id": 21529396, "score": 1 }, { "doc_id": "34180378", "title": "Hyperargininemia due to liver arginase deficiency.", "abstract": "The urea cycle is a series of six reactions necessary to rid the body of the nitrogen generated by the metabolism, primarily of amino acids, from the diet or released as the result of endogenous protein catabolism. Arginase is the sixth and final enzyme of this cycle. Arginase catalyzes the conversion of arginine to urea and ornithine, the latter recycled to continue the cycle. Hyperargininemia due to arginase deficiency is inherited in an autosomal recessive manner and gene for arginase, designated AI, has been cloned. Unlike the other urea cycle enzymes, a second gene encoding arginase, with similar structural properties and enzyme characteristics, exists and has been named Arginase II (AII). Comprehensive histories and physical examinations confirm a strikingly uniform clinical picture and one notably different from patients with other urea cycle disorders. This condition rarely presents in the neonatal period and first symptoms typically present in children between 2 and 4 years of age. First symptoms are often neurologically based. If untreated, symptoms are progressive with a gradual loss of developmental milestones. With adherence to a dietary and drug regimen, a favorable outcome can be expected, with cessation of further neurological deterioration and in some instances, of improvement. This article summarizes the clinical course of selected patients who represent the full spectrum of presentations of arginase deficiency. In addition to the clinical characterization of this disorder; the biochemical, enzymatic, and molecular evidence of disease is summarized. Treatment and prenatal diagnosis are also discussed.", "corpus_id": 34180378, "score": 0 }, { "doc_id": "10403697", "title": "Alternative pathway therapy for urea cycle disorders: twenty years later.", "abstract": "Alternative pathway therapy is currently an accepted treatment approach for inborn errors of the urea cycle. This involves the long-term use of oral sodium phenylbutyrate, arginine supplements, or both, depending on the specific enzyme deficiency, and treatment of acute hyperammonemic crises with intravenous sodium benzoate/sodium phenylacetate plus arginine. A review of 20 years of experience with this approach illustrates the strengths and limitations of this treatment. It has clearly decreased the mortality and morbidity from these disorders, but they remain unacceptably high. The medications are generally well tolerated, but severe accidental overdosage has been reported because of the infrequent use of the medication. There is also a difference in their metabolism between newborns and older children that must be addressed in determining dosage. To avoid these complications it is recommended that drug levels in blood be monitored routinely and that very specific treatment protocols and oversight be followed to avoid overdoses. Finally, it must be acknowledged that alternative pathway therapy has limited effectiveness in preventing hyperammonemia and must be combined with effective dietary management. Therefore in children with neonatal-onset disease or in those with very poor metabolic control, liver transplantation should be considered. There should also be the continued search for innovative therapies that may offer a more permanent and complete correction, such as gene therapy.", "corpus_id": 10403697, "score": 0 }, { "doc_id": "40170004", "title": "The gene for human liver arginase (ARG1) is assigned to chromosome band 6q23.", "abstract": "The human liver arginase gene, whose deficiency is responsible for argininemia (McKusick no. 20780), has been assigned to 6q23 through a combination of somatic cell hybrid analysis and in situ hybridization using a 1,550-base pair (bp) human DNA probe for this gene.", "corpus_id": 40170004, "score": 0 }, { "doc_id": "630200", "title": "Human liver-type arginase gene: structure of the gene and analysis of the promoter region.", "abstract": "The gene for human liver-type arginase (EC 3.5.3.1), a urea cycle enzyme, was cloned and the structure was determined. This gene is 11.5 kilobases long and is split into 8 exons. The cap site was determined by nuclease S1 mapping and primer extension. A \"TATA box\"-like sequence is located 28 bases upstream from the cap site, and a sequence similar to the binding sites of the transcription factor CTF/NF1, a \"CAAT box\"-binding protein, is located 72 bases upstream. In the 5' end region, sequences resembling the glucocorticoid responsive elements, the cAMP responsive elements, and the enhancer core sequences are present. The immediately 5' flanking region of the human gene up to position -105 is 84% identical with the corresponding segment of the rat gene. In this region of the human gene, one DNase I-protected area and several hypersensitive cleavage sites were detected by footprint analysis, using nuclear extracts from the rat liver. The protected area contains the sequence similar to the binding sites of CTF/NF1 and also overlaps with the sequence resembling the glucocorticoid responsive elements.", "corpus_id": 630200, "score": 0 }, { "doc_id": "21177570", "title": "Cloning of rat liver arginase cDNA and elucidation of regulation of arginase gene expression in H4 rat hepatoma cells", "abstract": "In order to study the regulation of expression of the two arginase genes in mammalian tissues, we undertook to clone cDNA specific for rat liver arginase. mRNA was isolated from rat liver poly somes enriched for the arginase message by immunopurification and was used to produce an 800-member cDNA library carried in pBR322. Four arginase clones were identified by hybrid selection, and one was used to find two others following colony hybridization. Clonal identity was verified by its enrichment in the cDNA made from immunopurified mRNA; by hybrid selection, immunoprecipitation, and competition by purified arginase; hybridization on Northern analysis with liver-derived RNA (high in arginase) and its absence with mRNA from tissues low in arginase; and independent identification by hybrid selection and colony hybridization. Northern analysis of mRNA from H4-II-E-C3 (H4) rat hepatoma cells in which arginase activity was induced by hydrocortisone demonstrated equal, eightfold augmentation of both arginase activity and arginase mRNA levels. Southern blot analysis of DNA from these cells indicated that no change in arrangement or copy number accompanied induction. Southern analysis also suggested that the gene for rat liver arginase is present in a single copy, without pseudogenes, and that a high degree of homology exists between it and its mouse counterpart.", "corpus_id": 21177570, "score": 0 }, { "doc_id": "1297976", "title": "Molecular cloning and nucleotide sequence of cDNA for human liver arginase.", "abstract": "Arginase (EC 3.5.3.1) catalyzes the last step of the urea cycle in the liver of ureotelic animals. Inherited deficiency of the enzyme results in argininemia, an autosomal recessive disorder characterized by hyperammonemia. To facilitate investigation of the enzyme and gene structures and to elucidate the nature of the mutation in argininemia, we isolated cDNA clones for human liver arginase. Oligo(dT)-primed and random primer human liver cDNA libraries in lambda gt11 were screened using isolated rat arginase cDNA as a probe. Two of the positive clones, designated lambda hARG6 and lambda hARG109, contained an overlapping cDNA sequence with an open reading frame encoding a polypeptide of 322 amino acid residues (predicted Mr, 34,732), a 5'-untranslated sequence of 56 base pairs, a 3'-untranslated sequence of 423 base pairs, and a poly(A) segment. Arginase activity was detected in Escherichia coli cells transformed with the plasmid carrying lambda hARG6 cDNA insert. RNA gel blot analysis of human liver RNA showed a single mRNA of 1.6 kilobases. The predicted amino acid sequence of human liver arginase is 87% and 41% identical with those of the rat liver and yeast enzymes, respectively. There are several highly conserved segments among the human, rat, and yeast enzymes.", "corpus_id": 1297976, "score": 0 }, { "doc_id": "16096962", "title": "Mouse Model for Human Arginase Deficiency", "abstract": "ABSTRACT Deficiency of liver arginase (AI) causes hyperargininemia (OMIM 207800), a disorder characterized by progressive mental impairment, growth retardation, and spasticity and punctuated by sometimes fatal episodes of hyperammonemia. We constructed a knockout mouse strain carrying a nonfunctional AI gene by homologous recombination. Arginase AI knockout mice completely lacked liver arginase (AI) activity, exhibited severe symptoms of hyperammonemia, and died between postnatal days 10 and 14. During hyperammonemic crisis, plasma ammonia levels of these mice increased >10-fold compared to those for normal animals. Livers of AI-deficient animals showed hepatocyte abnormalities, including cell swelling and inclusions. Plasma amino acid analysis showed the mean arginine level in knockouts to be approximately fourfold greater than that for the wild type and threefold greater than that for heterozygotes; the mean proline level was approximately one-third and the ornithine level was one-half of the proline and ornithine levels, respectively, for wild-type or heterozygote mice—understandable biochemical consequences of arginase deficiency. Glutamic acid, citrulline, and histidine levels were about 1.5-fold higher than those seen in the phenotypically normal animals. Concentrations of the branched-chain amino acids valine, isoleucine, and leucine were 0.4 to 0.5 times the concentrations seen in phenotypically normal animals. In summary, the AI-deficient mouse duplicates several pathobiological aspects of the human condition and should prove to be a useful model for further study of the disease mechanism(s) and to explore treatment options, such as pharmaceutical administration of sodium phenylbutyrate and/or ornithine and development of gene therapy protocols.", "corpus_id": 16096962, "score": 1 }, { "doc_id": "31955409", "title": "Inducible Cre mice.", "abstract": "The Cre/lox site-specific recombination system has emerged as an important tool for the generation of conditional somatic mouse mutants. This method allows one to control gene activity in space and time in almost any tissue of the mouse, thus opening new avenues for studying gene function and for establishing sophisticated animal models of human diseases. A major technical advance in terms of in vivo inducibility was the development of ligand-dependent Cre recombinases that can be activated by administration of tamoxifen to the animal. Here we describe how tamoxifen-dependent Cre recombinases, so-called CreER recombinases, work and how they can be used to generate time- and tissue-specific mouse mutants. The focus will be on the CreER(T2) recombinase, which is currently the most successful CreER version. We will give an overview of available CreER(T2) transgenic mouse lines and present protocols that detail the generation of experimental mice for inducible gene knockout studies, the induction of recombination by tamoxifen treatment, and the analysis of the quality and quantity of recombination by reporter gene and target gene studies. Most of the protocols can also be used as general guidelines for the generation and characterization of Cre/lox-mediated genome modifications in mice.", "corpus_id": 31955409, "score": 1 }, { "doc_id": "28998700", "title": "Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals.", "abstract": "Guanidino compound levels were quantitatively determined in serum, urine, liver, kidney, and brain of man and of some ureotelic animals. The guanidino compounds were separated over a cation exchange resin, using sodium citrate buffers, and detected with the fluorescence ninhydrin method. Species-specific differences in the levels of some guanidino compounds in the studied ureotelic animals are shown. alpha-Keto-delta-guanidinovaleric acid is a naturally occurring guanidino compound in ureotelic animals, and is not restricted to the pathobiochemistry of hyperargininemic patients. The fasting serum levels observed in beagles are the same as those found in hyperargininemic patients. In serum, liver, and kidney, the homoarginine, beta-guanidinopropionic acid, and gamma-guanidinobutyric acid levels are the highest in rats. The last two compounds have the highest levels of the studied guanidino compounds, with the exception of creatinine, in kidney. Specific high levels of gamma-guanidinobutyric acid and argininic acid are found in brain of rabbits.", "corpus_id": 28998700, "score": 0 }, { "doc_id": "205204882", "title": "Short-term correction of arginase deficiency in a neonatal murine model with a helper-dependent adenoviral vector.", "abstract": "Neonatal gene therapy has the potential to ameliorate abnormalities before disease onset. Our gene knockout of arginase I (AI) deficiency is characterized by increasing hyperammonemia, neurological deterioration, and early death. We constructed a helper-dependent adenoviral vector (HDV) carrying AI and examined for correction of this defect. Neonates were administered 5 x 10(9) viral particles/g and analyzed for survival, arginase activity, and ammonia and amino acids levels. The life expectancy of arg(-/-) mice increased to 27 days while controls died at 14 days with hyperammonemia and in extremis. Death correlated with a decrease in viral DNA/RNA per cell as liver mass increased. Arginase assays demonstrated that vector-injected hepatocytes had ~20% activity of heterozygotes at 2 weeks of age. Hepatic arginine and ornithine in treated mice were similar to those of saline-injected heterozygotes at 2 weeks, whereas ammonia was normal. By 26 days, arginase activity in the treated arg(-/-) livers declined to <10%, and arginine and ornithine increased. Ammonia levels began increasing by day 25, suggesting the cause of death to be similar to that of uninjected arg(-/-) mice, albeit at a later time. These studies demonstrate that the AI deficient newborn mouse can be temporarily corrected and rescued using a HDV.", "corpus_id": 205204882, "score": 0 }, { "doc_id": "19651824", "title": "Argininemia: A Treatable Genetic Cause of Progressive Spastic Diplegia Simulating Cerebral Palsy: Case Reports and Literature Review", "abstract": "Argininemia, a rare autosomal recessive urea cycle disorder, is caused by a deficiency of arginase, with resulting elevated plasma arginine and ammonia levels. Reports to date have focused little on the neurology of this disorder or the efficacy of treatments. A MEDLINE search revealed 25 previously reported cases, to which we have added two brothers who presented with late onset progressive spastic diplegia. Though their degree of enzyme deficiency was comparable, the severity of their phenotypic abnormalities differed substantially. With dietary therapy, both showed improved cognitive and motor function. Late metabolic crises occurred in both, resulting in death of the less severely affected brother. Based on analysis of our clinical database, we report on the full spectrum of neurologic abnormalities seen in argininemia with particular focus on the accompanying progressive spastic diplegia and its response to treatment; progressive decline in head growth; distinctive neuroradiologic findings; and life-threatening later complications. Current and potential future therapies and long-term outcome are summarized. (J Child Neurol 1997;12:301-309).", "corpus_id": 19651824, "score": 0 }, { "doc_id": "37142949", "title": "Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach.", "abstract": "Tamoxifen, a selective estrogen receptor modulator, is widely used in research and clinically in patients. We find that treatment of normal mice with a single ≥3 mg/20 g body weight dose of tamoxifen leads to apoptosis of >90% of all gastric parietal cells (PCs) and metaplasia of zymogenic chief cells within 3 days. Remarkably, gastric histology returns to nearly normal by 3 weeks. Tamoxifen toxicity occurs by oral and intraperitoneal administration, in both sexes, in multiple strains, and does not depend on estrogen, though acid secretion inhibition is partially protective. Thus, substantial gastric toxicity is a heretofore unappreciated tamoxifen side effect.", "corpus_id": 37142949, "score": 0 }, { "doc_id": "205781858", "title": "Regulation of nitric oxide production in health and disease", "abstract": "Purpose of reviewThe purpose of this review is to highlight recent publications examining nitric oxide production in health and disease and its association with clinical nutrition and alterations in metabolism. Recent findingsThe role of the cofactor tetrahydrobiopterin in nitric oxide production and its relation with arginine availability is indicated as an important explanation for the arginine paradox. This offers potential for nitric oxide regulation by dietary factors such as arginine or its precursors and vitamin C. Because diets with a high saturated fat content induce high plasma fatty acid levels, endothelial nitric oxide production is often impaired due to a reduction in nitric oxide synthase 3 phosphorylation. Increasing the arginine availability by arginine therapy or arginase inhibition was, therefore, proposed as a potential therapy to treat hypertension. Recent studies in septic patients and transgenic mice models found that inadequate de-novo arginine production from citrulline reduces nitric oxide production. Citrulline supplementation may, therefore, be a novel therapeutic approach in conditions of arginine deficiency. SummaryBoth lack and excess of nitric oxide production in diseases can have various important implications in which dietary factors can play a modulating role. Future research is needed to expand our understanding of the regulation and adequate measurement of nitric oxide production at the organ level and by the different nitric oxide synthase isoforms, also in relation to clinical nutrition.", "corpus_id": 205781858, "score": 0 }, { "doc_id": "21382472", "title": "Guanidino compounds in hyperargininemia.", "abstract": "Plasma and cerebrospinal fluid (CSF) concentrations and urinary excretion of guanidino compounds were investigated in a patient with hyperargininemia during the treatment with low-protein diet, oral administration of an essential amino acid mixture and sodium benzoate, or enzyme replacement therapy such as exchange transfusion or erythrocyte transfusion. In the patient, alpha-keto-delta-guanidinovaleric acid (GVA), N-alpha-acetylarginine (NAA), argininic acid (ArgA) and homoarginine concentrations in plasma were elevated as well as arginine. Urinary excretion of GVA, ArgA, NAA and gamma-guanidinobutyric acid (GBA) were also increased. CSF concentrations of ArgA, homoarginine and arginine were also elevated. On the other hand, guanidinosuccinic acid (GSA), which is usually detected in all samples, was not detected in plasma, CSF and urine of the patient. The present results suggest that in patients with hyperargininemia other factors such as arginine and its metabolites including GVA, GAA, ArgA and homoarginine may cause the neurological symptoms. Furthermore, it is suggested that in patients with hyperargininemia, arginine may be catabolized via other pathways and nitrogen may be excreted partially in urine in the form of some of guanidino compounds.", "corpus_id": 21382472, "score": 0 }, { "doc_id": "25656067", "title": "Guanidino compound levels in blood, cerebrospinal fluid, and post-mortem brain material of patients with argininemia.", "abstract": "The paucity of hyperammonemic crises together with spasticity, only seen in human arginase I deficient patients and not in patients with other urea cycle disorders, forces a search for candidates other than ammonia to associate with the pathophysiology and symptomatology. Therefore, we determined arginine together with some catabolites of arginine in blood and cerebrospinal fluid of these patients as well as in extremely rare post-mortem brain material of two patients with argininemia. The levels of alpha-keto-delta-guanidinovaleric acid, argininic acid and alpha-N-acetylarginine correlate with the arginine levels in blood and cerebrospinal fluid of patients with imposed or spontaneous protein restriction. The levels in blood are higher than the upper limit of normal in all studied patients. In addition to the highly increased levels of these same compounds in blood of a child with argininemia, the increase of guanidinoacetic acid, 24h before death, is remarkable. However, the manifest increases of these studied catabolites of arginine are not seen in post-mortem brain material of the same pediatric patient. Otherwise a clear increase of guanidinoacetic acid in post-mortem brain material of an adult patient was shown. A similar, comparable increase of homoarginine in both studied post-mortem brain materials is observed. Therefore the study of the pathobiochemistry of arginine in argininemia must be completed in the future by the determination of the end catabolites of the nitric oxide and agmatine biosynthesis pathways in the knockouts as well as in the patients to evaluate their role, together with the here studied catabolites, as candidates for association with pathophysiology and symptomatology.", "corpus_id": 25656067, "score": 0 }, { "doc_id": "9289303", "title": "Increased plasma and tissue guanidino compounds in a mouse model of hyperargininemia.", "abstract": "In humans, arginase I (AI)-deficiency results in hyperargininemia, a metabolic disorder with symptoms of progressive neurological and intellectual impairment, spasticity, persistent growth retardation, and episodic hyperammonemia. A deficiency of arginase II (AII) has never been detected and the clinical disorder, if any, associated with its deficiency has not been defined. Since the spasticity and paucity of hyperammonemic crises seen in human AI-deficient patients are not features of the other urea cycle disorders, the likelihood of ammonia as the main neuropathogenic agent becomes extremely low, and the modest elevations of arginine seen in the brains of our mouse model of hyperargininemia make it an unlikely candidate as well. Specific guanidino compounds, direct or indirect metabolites of arginine, are elevated in the blood of patients with uremia. Other guanidino compounds are also increased in plasma and cerebrospinal fluid of hyperargininemic patients making them plausible as neurotoxins in these disorders. We analyzed several guanidino compounds in our arginase single and double knockout animals and found that alpha-keto-delta-guanidinovaleric acid, alpha-N-acetylarginine, and argininic acid were increased in the brain tissue from the AI knockout and double knockout animals. Several compounds were also increased in the plasma, liver, and kidneys. This is the first time that several of the guanidino compounds have been shown to be elevated in the brain tissue of an arginase-deficient mammal, and it further supports their possible role as the neuropathogenic agents responsible for the complications seen in arginase deficiency.", "corpus_id": 9289303, "score": 0 }, { "doc_id": "25096103", "title": "Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress.", "abstract": "The potential of proline to suppress reactive oxygen species (ROS) and apoptosis in mammalian cells was tested by manipulating intracellular proline levels exogenously and endogenously by overexpression of proline metabolic enzymes. Proline was observed to protect cells against H(2)O(2), tert-butyl hydroperoxide, and a carcinogenic oxidative stress inducer but was not effective against superoxide generators such as menadione. Oxidative stress protection by proline requires the secondary amine of the pyrrolidine ring and involves preservation of the glutathione redox environment. Overexpression of proline dehydrogenase (PRODH), a mitochondrial flavoenzyme that oxidizes proline, resulted in 6-fold lower intracellular proline content and decreased cell survival relative to control cells. Cells overexpressing PRODH were rescued by pipecolate, an analog that mimics the antioxidant properties of proline, and by tetrahydro-2-furoic acid, a specific inhibitor of PRODH. In contrast, overexpression of the proline biosynthetic enzymes Delta(1)-pyrroline-5-carboxylate (P5C) synthetase (P5CS) and P5C reductase (P5CR) resulted in 2-fold higher proline content, significantly lower ROS levels, and increased cell survival relative to control cells. In different mammalian cell lines exposed to physiological H(2)O(2) levels, increased endogenous P5CS and P5CR expression was observed, indicating that upregulation of proline biosynthesis is an oxidative stress response.", "corpus_id": 25096103, "score": 0 }, { "doc_id": "34476754", "title": "Plasma concentrations of arginine and related amino acids following traumatic brain injury: Proline as a promising biomarker of brain damage severity.", "abstract": "The aim of this study was to find a plasma biomarker, in relation with nitric oxide (NO), as a sign of brain damage severity following traumatic brain injury (TBI). We first investigated the post-traumatic evolution of the plasma concentrations of NO via the level of NO end-products metabolites (nitrite plus nitrate, NO(x)), that of l-arginine (Arg) and amino acids involved in its metabolism as well as the time course of neurological score in a rat model of lateral fluid percussion brain injury. First, the level of NO(x) was increased in plasma at 24 and 48 h post-TBI with a marked increase at 72 h. In contrast, this elevation was neither accompanied by a modification of plasma concentrations of Arg, nor of amino acids involved in NO and Arg metabolism, l-ornithine (Orn), l-glutamate (Glu), and l-glutamine (Gln). Second, TBI induced a fall of plasma l-proline (Pro) concentrations. The time course of post-TBI neurological deficit showed also a decrease of neurological score at 24, 48, and 72 h. Furthermore, there is a weak negative correlation between the neurological score and the plasma level of NO(x) (r=-0.305; P<0.05), while a marked positive correlation has been found between the neurological score and the plasma level of Pro (r=0.563; P<0.001). In conclusion, the plasma concentrations of Pro could be a promising marker of post-traumatic neurological deficit.", "corpus_id": 34476754, "score": 0 }, { "doc_id": "21310475", "title": "Dietary L-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats.", "abstract": "Previous studies showed that dietary L-arginine supplementation decreased white fat mass in genetically obese rats. This study tested the effectiveness of L-arginine in diet-induced obesity. Male Sprague-Dawley rats were fed for 15 wk a high-fat (HF) (40% energy) or low-fat (LF) (10% energy) diet beginning at 4 wk of age, resulting in 18% higher body weight gains and 74% higher weights of major white fat pads (retroperitoneal, epididymal, subcutaneous, and mesenteric adipose tissues) in HF than in LF fed rats. Starting at 19 wk of age, rats in each dietary group were supplemented for 12 wk with 1.51% L-arginine-HCl or 2.55% L-alanine (isonitrogenous control) (n = 8 per treatment) in drinking water and arginine groups were individually pair-fed to alanine controls. Despite similar energy intake, absolute weights of white fat pads increased by 98% in control rats over a 12-wk period but only by 35% in arginine-supplemented rats. The arginine treatment reduced the relative weights of white fat pads by 30% and enhanced those of soleus muscle by 13%, extensor digitorum longus muscle by 11%, and brown fat by 34% compared with control rats. Serum concentrations of insulin, adiponectin, growth hormone, corticosterone, triiodothyronine, and thyroxine did not differ between control and arginine-supplemented rats. However, arginine treatment resulted in lower serum concentrations of leptin, glucose, triglycerides, urea, glutamine, and branched-chain amino acids, higher serum concentrations of nitric-oxide metabolites, and improvement in glucose tolerance. Thus, dietary arginine supplementation shifts nutrient partitioning to promote muscle over fat gain and may provide a useful treatment for improving the metabolic profile and reducing body white fat in diet-induced obese rats.", "corpus_id": 21310475, "score": 0 }, { "doc_id": "11003649", "title": "Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle", "abstract": "Hyperammonemia is considered to be the main cause of decreased levels of the branched-chain amino acids (BCAA), valine, leucine, and isoleucine, in liver cirrhosis. In this study we investigated whether the decrease in BCAA is caused by the direct effect of ammonia on BCAA metabolism and the effect of ammonia on BCAA and protein metabolism in different types of skeletal muscle. M. soleus (SOL, slow-twitch, red muscle) and m. extensor digitorum longus (EDL, fast-twitch, white muscle) of white rat were isolated and incubated in a medium with or without 500 μM ammonia. We measured the exchange of amino acids between the muscle and the medium, amino acid concentrations in the muscle, release of branched-chain keto acids (BCKA), leucine oxidation, total and myofibrillar proteolysis, and protein synthesis. Hyperammonemia inhibited the BCAA release (81% in SOL and 60% in EDL vs. controls), increased the release of BCKA (133% in SOL and 161% in EDL vs. controls) and glutamine (138% in SOL and 145% in EDL vs. controls), and increased the leucine oxidation in EDL (174% of controls). Ammonia also induced a significant increase in glutamine concentration in skeletal muscle. The effect of ammonia on intracellular BCAA concentration, protein synthesis and on total and myofibrillar proteolysis was insignificant. The data indicates that hyperammonemia directly affects the BCAA metabolism in skeletal muscle which results in decreased levels of BCAA in the extracellular fluid. The effect is associated with activated synthesis of glutamine, increased BCAA oxidation, decreased release of BCAA, and enhanced release of BCKA. These metabolic changes are not directly associated with marked changes in protein turnover. The effect of ammonia is more pronounced in muscles with high content of white fibres.", "corpus_id": 11003649, "score": 0 }, { "doc_id": "4433300", "title": "Protein intake, brain amino acid and serotonin concentrations and protein self-selection.", "abstract": "Analysis of evidence of associations among dietary protein content, brain amino acid and serotonin concentrations, and protein self-selection by rats suggests that 1) protein intake is not regulated precisely, although rats will select between low and high protein diets to obtain an adequate, but not excessive, amount of protein; 2) associations between brain serotonin concentration and protein intake are weak, although consumption of single meals of protein-deficient diets will elevate brain serotonin concentration; 3) the nature of signals that drive rats to avoid diets containing inadequate or excessive amounts of protein remains obscure; (4) whole brain amino acid and serotonin concentrations are quite stable over the usual range of protein intakes, owing to competition among amino acids for uptake across the blood-brain barrier and effective metabolic regulation of blood amino acid concentrations; 5) protein intake and preference are not in themselves regulated, but what appears to be regulation of intake and preference is a reflection of the responses of systems for control of plasma amino acid concentrations; and (6) the relative stability of the average protein intake of groups of self-selecting rats (which gives the appearance of regulation) results from averaging the variable behavioral responses--learned aversions and preferences--of rats to the variety of sensory cues arising from diets that differ in protein content.", "corpus_id": 4433300, "score": 0 }, { "doc_id": "16267305", "title": "Multiple neural systems controlling food intake and body weight", "abstract": "Discovery of the leptin receptor and its downstream peptidergic pathways has reconfirmed the crucial role of the hypothalamus in the regulation of food intake and energy balance. Strategically located in the midst of the mammalian neuraxis, the hypothalamus receives at least three distinct types of relevant information via direct or indirect neural connections as well as hormone receptors and substrate sensors bestowed on hypothalamic neurons. First, the medial and to a lesser extent the lateral hypothalamus receive a rich mix of information pertaining to the internal state of relative energy repletion/depletion. Second, specific hypothalamic nuclei receive information about the behavioral state, such as diurnal clock, physical activity-level, reproductive cycle, developmental stage, as well as imminent (e.g. fight and flight) and chronic (e.g. infection) stressors, that can potentially impact on short-term availability of fuels and long-term energy balance. Third, the hypothalamus, particularly its lateral aspects, receives information from areas in the forebrain involved in the acquisition, storage, and retrieval of sensory representations of the external food space and internal food experience, as well as from the executive forebrain involved in behavior selection and initiation. In addition, rich intrahypothalamic connections facilitate further distribution of incoming information to various hypothalamic nuclei. On the other hand, the hypothalamus has widespread neural projections to the same cortical areas it receives inputs, and many hypothalamic neurons are one synapse away from most endocrine systems and from both sympathetic and parasympathetic effector organs involved in the flux, storage, mobilization, and utilization of fuels. It is argued that processing within cortico-limbic areas and communication with hypothalamic areas are particularly important in human food intake control that is more and more guided by cognitive rather than metabolic aspects in the obesigenic environment of affluent societies. A distributed neural network for the control of food intake and energy balance consisting of a central processor and several parallel processing loops is hypothesized. Detailed neurochemical, anatomical, and functional analysis of reciprocal connections of the numerous peptidergic neuron populations in the hypothalamus with extrahypothalamic brain areas will be necessary to better understand what hypothalamus, forebrain, and brainstem tell each other and who is in charge under specific conditions of internal and external nutrient availability.", "corpus_id": 16267305, "score": 0 }, { "doc_id": "32041794", "title": "Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse.", "abstract": "Human arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia, which lead to neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation; uncommonly, patients suffer early death from this disorder. In a murine targeted knockout model, onset of the phenotypic abnormality is heralded by weight loss at around day 15, and death occurs typically by postnatal day 17 with hyperargininemia and markedly elevated ammonia. This discrepancy between the more attenuated juvenile-onset human disease and the lethal neonatal murine model has remained suboptimal for studying and developing therapy for the more common presentation of arginase deficiency. These investigations aimed to address this issue by creating an adult conditional knockout mouse to determine whether later onset of arginase deficiency also resulted in lethality. Animal survival and ammonia levels, body weight, circulating amino acids, and tissue arginase levels were examined as outcome parameters after widespread Cre-recombinase activation in a conditional knockout model of arginase 1 deficiency. One hundred percent of adult female and 70% of adult male mice died an average of 21.0 and 21.6 days, respectively, after the initiation of tamoxifen administration. Animals demonstrated elevated circulating ammonia and arginine at the onset of phenotypic abnormalities. In addition, brain and liver amino acids demonstrated abnormalities. These studies demonstrate that (a) the absence of arginase in adult animals results in a disease profile (leading to death) similar to that of the targeted knockout and (b) the phenotypic abnormalities seen in the juvenile-onset model are not exclusive to the age of the animal but instead to the biochemistry of the disorder. This adult model will be useful for developing gene- and cell-based therapies for this disorder that will not be limited by the small animal size of neonatal therapy and for developing a better understanding of the characteristics of hyperargininemia.", "corpus_id": 32041794, "score": 1 }, { "doc_id": "25740498", "title": "Clinical biochemistry parameters in C57BL/6J mice after blood collection from the submandibular vein and retroorbital plexus.", "abstract": "Collection of blood from the submandibular vein allows simple and rapid processing of many animals without anesthesia and facilitates rapid recovery with no signs of pain and discomfort in the mice. Here we compared the submandibular vein and retroorbital plexus blood collection methods, to determine the potential effect of the sampling technique on several clinical biochemistry parameters in C57BL/6J mice. We found statistically significant differences for 8 of the 9 biochemical parameters studied between the 2 blood sampling techniques. Compared with samples collected from the retroorbital plexus, blood obtained from the submandibular vein had higher levels of AST, ALT, protein, albumin, triglycerides, total cholesterol, and creatinine. Glucose values of retroorbital blood were higher than those from the submandibular vein. Urea levels were similar for both sampling techniques. Our results demonstrate that the technique used to obtain blood samples affects parameters commonly used to assess animal health. We recommend caution when comparing results of biochemical analysis of blood obtained from the submandibular vein in mice with reference values obtained by other blood sampling techniques.", "corpus_id": 25740498, "score": 0 }, { "doc_id": "205206414", "title": "Long-term survival of the juvenile lethal arginase-deficient mouse with AAV gene therapy.", "abstract": "Arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia. Human patients suffer from neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation. In a murine model, onset of the phenotypic abnormality is heralded by weight loss beginning around day 15 with death occurring typically by postnatal day 17 with hyperargininemia and markedly elevated ammonia. The goal of this study was to address the development of a gene therapy approach for arginase deficiency beginning in the neonatal period. Lifespan extension, body weight, circulating amino acids and ammonia levels were examined as outcome parameters after gene therapy with an adeno-associated viral vector expressing arginase was administered to mice on the second day of life (DOL). One-hundred percent of untreated arginase-deficient mice died by DOL 24, whereas 89% of the adeno-associated virus (AAV)-treated arginase deficient mice have survived for >8 months. While animals at 8 months demonstrate elevated glutamine levels, ammonia is less than three times that of controls and arginine levels are normal. These studies are the first to demonstrate that AAV-based therapy for arginase deficiency is effective and supports the development of gene therapy for this and the other urea cycle disorders.", "corpus_id": 205206414, "score": 0 }, { "doc_id": "13103634", "title": "AAV-based Gene Therapy Prevents Neuropathology and Results in Normal Cognitive Development in the Hyperargininemic Mouse", "abstract": "Complete arginase I deficiency is the least severe urea cycle disorder, characterized by hyperargininemia and infrequent episodes of hyperammonemia. Patients suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation and seizures, and is associated with intellectual disability. In mice, onset is heralded by weight loss beginning around day 15; gait instability follows progressing to inability to stand and development of tail tremor with seizure-like activity and death. Here we report that hyperargininemic mice treated neonatally with an adeno-associated virus (AAV)-expressing arginase and followed long-term lack any presentation consistent with brain dysfunction. Behavioral and histopathological evaluation demonstrated that treated mice are indistinguishable from littermates, and that putative compounds associated with neurotoxicity are diminished. In addition, treatment results in near complete resolution of metabolic abnormalities early in life; however, there is the development of some derangement later with decline in transgene expression. Ammonium challenging revealed that treated mice are affected by exogenous loading much greater than littermates. These results demonstrate that AAV-based therapy for hyperargininemia is effective and prevents development of neurological abnormalities and cognitive dysfunction in a mouse model of hyperargininemia; however, nitrogen challenging reveals that these mice remain impaired in the handling of waste nitrogen.", "corpus_id": 13103634, "score": 0 } ]

{ "doc_id": "38281247", "title": "Regulation of Antisense Transcription by NuA4 Histone Acetyltransferase and Other Chromatin Regulatory Factors", "abstract": "ABSTRACT NuA4 histone lysine (K) acetyltransferase (KAT) promotes transcriptional initiation of TATA-binding protein (TBP)-associated factor (TAF)-dependent ribosomal protein genes. TAFs have also been recently found to enhance antisense transcription from the 3′ end of the GAL10 coding sequence. However, it remains unknown whether, like sense transcription of the ribosomal protein genes, TAF-dependent antisense transcription of GAL10 also requires NuA4 KAT. Here, we show that NuA4 KAT associates with the GAL10 antisense transcription initiation site at the 3′ end of the coding sequence. Such association of NuA4 KAT depends on the Reb1p-binding site that recruits Reb1p activator to the GAL10 antisense transcription initiation site. Targeted recruitment of NuA4 KAT to the GAL10 antisense transcription initiation site promotes GAL10 antisense transcription. Like NuA4 KAT, histone H3 K4/36 methyltransferases and histone H2B ubiquitin conjugase facilitate GAL10 antisense transcription, while the Swi/Snf and SAGA chromatin remodeling/modification factors are dispensable for antisense, but not sense, transcription of GAL10. Taken together, our results demonstrate for the first time the roles of NuA4 KAT and other chromatin regulatory factors in controlling antisense transcription, thus illuminating chromatin regulation of antisense transcription.", "corpus_id": 38281247 }

[ { "doc_id": "30741842", "title": "Genome‐wide natural antisense transcription: coupling its regulation to its different regulatory mechanisms", "abstract": "Many genomic loci contain transcription units on both strands, therefore two oppositely oriented transcripts can overlap. Often, one strand codes for a protein, whereas the transcript from the other strand is non‐encoding. Such natural antisense transcripts (NATs) can negatively regulate the conjugated sense transcript. NATs are highly prevalent in a wide range of species—for example, around 15% of human protein‐encoding genes have an associated NAT. The regulatory mechanisms by which NATs act are diverse, as are the means to control their expression. Here, we review the current understanding of NAT function and its mechanistic basis, which has been gathered from both individual gene cases and genome‐wide studies. In parallel, we survey findings about the regulation of NAT transcription. Finally, we hypothesize that the regulation of antisense transcription might be tailored to its mode of action. According to this model, the observed relationship between the expression patterns of NATs and their targets might indicate the regulatory mechanism that is in action.", "corpus_id": 30741842, "score": 0 }, { "doc_id": "25871572", "title": "In search of antisense.", "abstract": "In recent years, natural antisense transcripts (NATs) have been implicated in many aspects of eukaryotic gene expression including genomic imprinting, RNA interference, translational regulation, alternative splicing, X-inactivation and RNA editing. Moreover, there is growing evidence to suggest that antisense transcription might have a key role in a range of human diseases. Consequently, there have been several recent attempts to identify novel NATs. To date, approximately 2500 mammalian NATs have been found, indicating that antisense transcription might be a common mechanism of regulating gene expression in human cells. There are increasingly diverse ways in which antisense transcription can regulate gene expression and evidence for the involvement of NATs in human disease is emerging. A range of bioinformatic resources could be used to assist future antisense research.", "corpus_id": 25871572, "score": 0 }, { "doc_id": "25028187", "title": "Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome.", "abstract": "Transcriptome studies are revealing that the eukaryotic genome actively transcribes a diverse repertoire of large noncoding RNAs (ncRNAs), many of which are unannotated and distinct from the small RNAs that have garnered much attention in recent years. Why are they so pervasive, and do they have a function? X-chromosome inactivation (XCI) is a classic epigenetic phenomenon associated with many large ncRNAs. Here, I provide a perspective on how XCI is achieved in mice and suggest how this knowledge can be applied to the rest of the genome. Emerging data indicate that long ncRNAs can function as guides and tethers, and may be the molecules of choice for epigenetic regulation: First, unlike proteins and small RNAs, large ncRNAs remain tethered to the site of transcription, and can therefore uniquely direct allelic regulation. Second, ncRNAs command a much larger sequence space than proteins, and can therefore achieve very precise spatiotemporal control of development. These properties imply that long noncoding transcripts may ultimately rival small RNAs and proteins in their versatility as epigenetic regulators, particularly for locus- and allele-specific control.", "corpus_id": 25028187, "score": 0 }, { "doc_id": "7226446", "title": "Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease", "abstract": "Nearly all human genetic disorders result from a limited repertoire of mutations in an associated gene or its regulatory elements. We recently described an individual with an inherited form of anemia (α-thalassemia) who has a deletion that results in a truncated, widely expressed gene (LUC7L) becoming juxtaposed to a structurally normal α-globin gene (HBA2). Although it retains all of its local and remote cis-regulatory elements, expression of HBA2 is silenced and its CpG island becomes completely methylated early during development. Here we show that in the affected individual, in a transgenic model and in differentiating embryonic stem cells, transcription of antisense RNA mediates silencing and methylation of the associated CpG island. These findings identify a new mechanism underlying human genetic disease.", "corpus_id": 7226446, "score": 0 }, { "doc_id": "11220635", "title": "Crucial role of antisense transcription across the Xist promoter in Tsix-mediated Xist chromatin modification", "abstract": "Expression of Xist, which triggers X inactivation, is negatively regulated in cis by an antisense gene, Tsix, transcribed along the entire Xist gene. We recently demonstrated that Tsix silences Xist through modification of the chromatin structure in the Xist promoter region. This finding prompted us to investigate the role of antisense transcription across the Xist promoter in Tsix-mediated silencing. Here, we prematurely terminated Tsix transcription before the Xist promoter and addressed its effect on Xist silencing in mouse embryos. We found that although 93% of the region encoding Tsix was transcribed, truncation of Tsix abolished the antisense regulation of Xist. This resulted in a failure to establish the repressive chromatin configuration at the Xist promoter on the mutated X, including DNA methylation and repressive histone modifications, especially in extraembryonic tissues. These results suggest a crucial role for antisense transcription across the Xist promoter in Xist silencing.", "corpus_id": 11220635, "score": 0 }, { "doc_id": "44499829", "title": "Pervasive transcription - Lessons from yeast.", "abstract": "Pervasive transcription is now accepted to be a general feature of eukaryotic genomes, generating short and long non-coding RNAs (ncRNAs). Growing number of examples have shown that regulatory ncRNAs can control gene expression and chromatin domain formation. In this review, we discuss recent reports that show that Saccharomyces cerevisiae's genome also supports pervasive transcription, which is strongly controlled by RNA decay pathways and nucleosome positioning. We therefore propose that S. cerevisiae is an excellent model for studying large ncRNAs, which has already provided important examples of antisense-mediated transcriptional silencing.", "corpus_id": 44499829, "score": 0 }, { "doc_id": "34559885", "title": "Antisense Transcription in the Mammalian Transcriptome", "abstract": "Antisense transcription (transcription from the opposite strand to a protein-coding or sense strand) has been ascribed roles in gene regulation involving degradation of the corresponding sense transcripts (RNA interference), as well as gene silencing at the chromatin level. Global transcriptome analysis provides evidence that a large proportion of the genome can produce transcripts from both strands, and that antisense transcripts commonly link neighboring “genes” in complex loci into chains of linked transcriptional units. Expression profiling reveals frequent concordant regulation of sense/antisense pairs. We present experimental evidence that perturbation of an antisense RNA can alter the expression of sense messenger RNAs, suggesting that antisense transcription contributes to control of transcriptional outputs in mammals.", "corpus_id": 34559885, "score": 0 }, { "doc_id": "5902688", "title": "The Antisense Transcriptomes of Human Cells", "abstract": "Transcription in mammalian cells can be assessed at a genome-wide level, but it has been difficult to reliably determine whether individual transcripts are derived from the plus or minus strands of chromosomes. This distinction can be critical for understanding the relationship between known transcripts (sense) and the complementary antisense transcripts that may regulate them. Here, we describe a technique that can be used to (i) identify the DNA strand of origin for any particular RNA transcript, and (ii) quantify the number of sense and antisense transcripts from expressed genes at a global level. We examined five different human cell types and in each case found evidence for antisense transcripts in 2900 to 6400 human genes. The distribution of antisense transcripts was distinct from that of sense transcripts, was nonrandom across the genome, and differed among cell types. Antisense transcripts thus appear to be a pervasive feature of human cells, which suggests that they are a fundamental component of gene regulation.", "corpus_id": 5902688, "score": 0 }, { "doc_id": "29326539", "title": "Oligonucleotides: a multi-targeted approach for the treatment of respiratory diseases.", "abstract": "Reversing inflammatory lung disease remains the foremost challenge in treating respiratory diseases such as asthma and chronic obstructive pulmonary disease. Reducing (or modifying) the underlying inflammatory process with mono-target drugs has proven challenging. The era of designing 'one target for one disease' has evolved such that a growing body of evidence suggests a single drug that is capable of specifically targeting multiple targets and pathways would be better at arresting progression of these respiratory diseases and be an important advancement in current therapy. Oligonucleotide-based drugs represent an emerging class of drug candidates. Their properties, a broader range of targets over conventional small-molecule drugs and recent clinical proof-of-concept support their development as novel multi-targeting agents for the treatment of respiratory diseases.", "corpus_id": 29326539, "score": 0 }, { "doc_id": "29635729", "title": "Antisense-Mediated Inhibition of Human Immunodeficiency Virus (HIV) Replication by Use of an HIV Type 1-Based Vector Results in Severely Attenuated Mutants Incapable of Developing Resistance", "abstract": "ABSTRACT We have constructed a human immunodeficiency virus type 1 (HIV-1)-based lentiviral vector expressing a 937-base antisense sequence against the HIV-1 envelope gene. Transduction of CD4+ T lymphocytes with this vector results in expression of the therapeutic antisense sequence and subsequent inhibition of productive HIV-1 replication. In this report, we examined the effect of antisense-mediated suppression on the potential development of virus escape mutants using a permissive T-cell line cultured under conditions that over serial passages specifically allowed for generation and amplification of mutants selected for by antisense pressure. In the resulting virus clones, we found a significant increase in the number of deletions at the envelope target region (91% compared to 27.5% in wild-type HIV). Deletions were most often greater than 1 kb in length. These data demonstrate for the first time that during antisense-mediated suppression of HIV, mutants develop as a direct result of selective pressure on the HIV genomic RNA. Interestingly, in clones where deletions were not observed, there was a high rate of A-G transitions in mutants at the antisense target region but not outside this region, which is consistent with those mutations that are predicted as a result of antisense-mediated modification of double-stranded RNA by the enzyme double-stranded RNA-specific adenosine deaminase. These clones were not found to be escape mutants, as their replicative ability was severely attenuated, and they did not replicate in the presence of vector.", "corpus_id": 29635729, "score": 0 }, { "doc_id": "16115429", "title": "Antisense Oligonucleotides: Treating Neurodegeneration at the Level of RNA", "abstract": "Adequate therapies are lacking for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. The ability to use antisense oligonucleotides (ASOs) to target disease-associated genes by means of RNA may offer a potent approach for the treatment of these, and other, neurodegenerative disorders. In modifying the basic backbone chemistry, chemical groups, and target sequence, ASOs can act through numerous mechanisms to decrease or increase total protein levels, preferentially shift splicing patterns, and inhibit microRNAs, all at the level of the RNA molecule. Here, we discuss many of the more commonly used ASO chemistries, as well as the different mechanisms of action that can result from these specific chemical modifications. When applied to multiple neurodegenerative mouse models, ASOs that specifically target the detrimental transgenes have been shown to rescue disease associated phenotypes in vivo. These supporting mouse model data have moved the ASOs from the bench to the clinic, with two neuro-focused human clinical trials now underway and several more being proposed. Although still early in development, translating ASOs into human patients for neurodegeneration appears promising.", "corpus_id": 16115429, "score": 0 }, { "doc_id": "30325214", "title": "Antisense oligonucleotides: rising stars in eliminating RNA toxicity in myotonic dystrophy.", "abstract": "Myotonic dystrophy (DM) is a dominantly inherited, multisystemic disease caused by expanded CTG (type 1, DM1) or CCTG (type 2, DM2) repeats in untranslated regions of the mutated genes. Pathogenesis results from expression of RNAs from the mutated alleles that are toxic because of the expanded CUG or CCUG repeats. Increased understanding of the repeat-containing RNA (C/CUG(exp) RNA)-induced toxicity has led to the development of multiple strategies targeting the toxic RNA. Among these approaches, antisense oligonucleotides (ASOs) have demonstrated high potency in reversing the RNA toxicity in both cultured DM1 cells and DM1 animal models, thus offering great promise for the potential treatment of DM1. ASO targeting approaches will also provide avenues for the treatment of other repeat RNA-mediated diseases.", "corpus_id": 30325214, "score": 0 }, { "doc_id": "15281802", "title": "Antisense oligonucleotides for the treatment of dyslipidaemia.", "abstract": "Antisense oligonucleotides (ASOs) are short synthetic analogues of natural nucleic acids designed to specifically bind to a target messenger RNA (mRNA) by Watson-Crick hybridization, inducing selective degradation of the mRNA or prohibiting translation of the selected mRNA into protein. Antisense technology has the ability to inhibit unique targets with high specificity and can be used to inhibit synthesis of a wide range of proteins that could influence lipoprotein levels and other targets. A number of different classes of antisense agents are under development. To date, mipomersen, a 2'-O-methoxyethyl phosphorothioate 20-mer ASO, is the most advanced ASO in clinical development. It is a second-generation ASO developed to inhibit the synthesis of apolipoprotein B (apoB)-100 in the liver. In Phase 3 clinical trials, mipomersen has been shown to significantly reduce plasma low-density lipoprotein cholesterol (LDL-c) as well as other atherogenic apoB containing lipoproteins such as lipoprotein (a) [Lp(a)] and small-dense LDL particles. Although concerns have been raised because of an increase in intrahepatic triglyceride content, preliminary data from long-term studies suggest that with continued treatment, liver fat levels tend to stabilize or decline. Further studies are needed to evaluate potential clinical relevance of these changes. Proprotein convertase subtilisin/kexin-9 (PCSK9) is another promising novel target for lowering LDL-c by ASOs. Both second-generation ASOs and ASOs using locked nucleic acid technology have been developed to inhibit PCSK9 and are under clinical development. Other targets currently being addressed include apoC-III and apo(a) or Lp(a). By directly inhibiting the synthesis of specific proteins, ASO technology offers a promising new approach to influence the metabolism of lipids and to control lipoprotein levels. Its application to a wide variety of potential targets can be expected if these agents prove to be clinically safe and effective.", "corpus_id": 15281802, "score": 0 }, { "doc_id": "31587321", "title": "Mechanisms of Antisense Transcription Initiation from the 3′ End of the GAL10 Coding Sequence In Vivo", "abstract": "ABSTRACT In spite of the important regulatory functions of antisense transcripts in gene expression, it remains unknown how antisense transcription is initiated. Recent studies implicated RNA polymerase II in initiation of antisense transcription. However, how RNA polymerase II is targeted to initiate antisense transcription has not been elucidated. Here, we have analyzed the association of RNA polymerase II with the antisense initiation site at the 3′ end of the GAL10 coding sequence in dextrose-containing growth medium that induces antisense transcription. We find that RNA polymerase II is targeted to the antisense initiation site at GAL10 by Reb1p activator as well as general transcription factors (e.g., TFIID, TFIIB, and Mediator) for antisense transcription initiation. Intriguingly, while GAL10 antisense transcription is dependent on TFIID, its sense transcription does not require TFIID. Further, the Gal4p activator that promotes GAL10 sense transcription is dispensable for antisense transcription. Moreover, the proteasome that facilitates GAL10 sense transcription does not control its antisense transcription. Taken together, our results reveal that GAL10 sense and antisense transcriptions are regulated differently and shed much light on the mechanisms of antisense transcription initiation.", "corpus_id": 31587321, "score": 1 }, { "doc_id": "148170", "title": "A ncRNA modulates histone modification and mRNA induction in the yeast GAL gene cluster.", "abstract": "The extensively studied yeast GAL1-10 gene cluster is tightly regulated by environmental sugar availability. Unexpectedly, under repressive conditions the 3' region of the GAL10 coding sequence is trimethylated by Set1 on histone H3 K4, normally characteristic of 5' regions of actively transcribed genes. This reflects transcription of a long noncoding RNA (GAL10-ncRNA) that is reciprocal to GAL1 and GAL10 mRNAs and driven by the DNA-binding protein Reb1. Point mutations in predicted Reb1-binding sites abolished Reb1 binding and ncRNA synthesis. The GAL10-ncRNA is transcribed approximately once every 50 min and targeted for degradation by the TRAMP and exosome complexes, resulting in low steady-state levels (approximately one molecule per 14 cells). GAL10-ncRNA transcription recruits the methyltransferase Set2 and histone deacetylation activities in cis, leading to stable changes in chromatin structure. These chromatin modifications act principally through the Rpd3S complex to aid glucose repression of GAL1-10 at physiologically relevant sugar concentrations.", "corpus_id": 148170, "score": 1 }, { "doc_id": "9621720", "title": "H3 lysine 4 di‐ and tri‐methylation deposited by cryptic transcription attenuates promoter activation", "abstract": "Set1‐dependent H3K4 di‐ and tri‐methylation (H3K4me2/3) have been associated with active transcription. Recent data indicate that the H3K4me2/3 also plays a poorly characterized RNA‐dependent repressive role. Here, we show that GAL1 promoter is attenuated by the H3K4me2/3 deposited by cryptic transcription. The H3K4me2/3 delay the recruitment of RNA polymerase II (RNAPII) and TBP on GAL1 promoter. Inactivation of RNA decay components revealed the existence of the RNAPII‐dependent unstable RNAs, initiating upstream of GAL1 (GAL1ucut). GAL1ucut RNAs are synthesized in glucose and require the Reb1 transcription factor. Consistent with a regulatory function of the cryptic transcription, Reb1 depletion leads to a decrease of H3K4me3 on GAL10‐GAL1 locus in glucose and to an acceleration of GAL1 induction. A candidate approach shows that the RPD3 histone deacetylase attenuates GAL1 induction and is tethered at the GAL10‐GAL1 locus by H3K4me2/3 upon repression. Strikingly, Set1‐dependent Rpd3 recruitment represses also the usage of a hidden promoter within SUC2, suggesting a general function for H3K4me2/3 in promoter fidelity. Our data support a model wherein certain promoters are embedded in a repressive chromatin controlled by cryptic transcription.", "corpus_id": 9621720, "score": 1 }, { "doc_id": "17103257", "title": "The 19S proteasome subcomplex promotes the targeting of NuA4 HAT to the promoters of ribosomal protein genes to facilitate the recruitment of TFIID for transcriptional initiation in vivo", "abstract": "Previous studies have implicated SAGA (Spt-Ada-Gcn5-acetyltransferase) and TFIID (Transcription factor-IID)-dependent mechanisms of transcriptional activation in yeast. SAGA-dependent transcriptional activation is further regulated by the 19S proteasome subcomplex. However, the role of the 19S proteasome subcomplex in transcriptional activation of the TFIID-dependent genes has not been elucidated. Therefore, we have performed a series of chromatin immunoprecipitation, mutational and transcriptional analyses at the TFIID-dependent ribosomal protein genes such as RPS5, RPL2B and RPS11B. We find that the 19S proteasome subcomplex is recruited to the promoters of these ribosomal protein genes, and promotes the association of NuA4 (Nucleosome acetyltransferase of histone H4) co-activator, but not activator Rap1p (repressor-activator protein 1). These observations support that the 19S proteasome subcomplex enhances the targeting of co-activator at the TFIID-dependent promoter. Such an enhanced targeting of NuA4 HAT (histone acetyltransferase) promotes the recruitment of the TFIID complex for transcriptional initiation. Collectively, our data demonstrate that the 19S proteasome subcomplex enhances the targeting of NuA4 HAT to activator Rap1p at the promoters of ribosomal protein genes to facilitate the recruitment of TFIID for transcriptional stimulation, hence providing a new role of the 19S proteasome subcomplex in establishing a specific regulatory network at the TFIID-dependent promoter for productive transcriptional initiation in vivo.", "corpus_id": 17103257, "score": 1 }, { "doc_id": "22108204", "title": "Eaf1p Is Required for Recruitment of NuA4 in Targeting TFIID to the Promoters of the Ribosomal Protein Genes for Transcriptional Initiation In Vivo", "abstract": "ABSTRACT NuA4 (nucleosome acetyltransferase of H4) promotes transcriptional initiation of TFIID (a complex of TBP and TBP-associated factors [TAFs])-dependent ribosomal protein genes involved in ribosome biogenesis. However, it is not clearly understood how NuA4 regulates the transcription of ribosomal protein genes. Here, we show that NuA4 is recruited to the promoters of ribosomal protein genes, such as RPS5, RPL2B, and RPS11B, for TFIID recruitment to initiate transcription, and the recruitment of NuA4 to these promoters is impaired in the absence of its Eaf1p component. Intriguingly, impaired NuA4 recruitment in a Δeaf1 strain depletes recruitment of TFIID (a TAF-dependent form of TBP) but not the TAF-independent form of TBP to the promoters of ribosomal protein genes. However, in the absence of NuA4, SAGA (Spt-Ada-Gcn5-acetyltransferase) is involved in targeting the TAF-independent form of TBP to the promoters of ribosomal protein genes for transcriptional initiation. Thus, NuA4 plays an important role in targeting TFIID to the promoters of ribosomal protein genes for transcriptional initiation in vivo. Such a function is mediated via its targeted histone acetyltransferase activity. In the absence of NuA4, ribosomal protein genes lose TFIID dependency and become SAGA dependent for transcriptional initiation. Collectively, these results provide significant insights into the regulation of ribosomal protein gene expression and, hence, ribosome biogenesis and functions.", "corpus_id": 22108204, "score": 1 }, { "doc_id": "30850260", "title": "Coordinate regulation of yeast ribosomal protein genes is associated with targeted recruitment of Esa1 histone acetylase.", "abstract": "The Esa1-containing NuA4 histone acetylase complex can interact with activation domains in vitro and stimulate transcription on reconstituted chromatin templates. In yeast cells, Esa1 is targeted to a small subset of promoters in an activator-specific manner. Esa1 is specifically recruited to ribosomal protein (RP) promoters, and this recruitment appears to require binding by Rap1 or Abf1. Esa1 is important for RP transcription, and Esa1 recruitment to RP promoters correlates with coordinate regulation of RP genes in response to growth stimuli. However, following Esa1 depletion, H4 acetylation decreases dramatically at many loci, but transcription is not generally affected. Therefore, the transcription-associated targeted recruitment of Esa1 to RP promoters occurs in a background of more global nontargeted acetylation that is itself not required for transcription.", "corpus_id": 30850260, "score": 1 }, { "doc_id": "1516149", "title": "Additional modules for versatile and economical PCR‐based gene deletion and modification in Saccharomyces cerevisiae", "abstract": "An important recent advance in the functional analysis of Saccharomyces cerevisiae genes is the development of the one‐step PCR‐mediated technique for deletion and modification of chromosomal genes. This method allows very rapid gene manipulations without requiring plasmid clones of the gene of interest. We describe here a new set of plasmids that serve as templates for the PCR synthesis of fragments that allow a variety of gene modifications. Using as selectable marker the S. cerevisiae TRP1 gene or modules containing the heterologous Schizosaccharomyces pombe his5+ or Escherichia coli kanr gene, these plasmids allow gene deletion, gene overexpression (using the regulatable GAL1 promoter), C‐ or N‐terminal protein tagging [with GFP(S65T), GST, or the 3HA or 13Myc epitope], and partial N‐ or C‐terminal deletions (with or without concomitant protein tagging). Because of the modular nature of the plasmids, they allow efficient and economical use of a small number of PCR primers for a wide variety of gene manipulations. Thus, these plasmids should further facilitate the rapid analysis of gene function in S. cerevisiae. © 1998 John Wiley & Sons, Ltd.", "corpus_id": 1516149, "score": 0 }, { "doc_id": "9565525", "title": "A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae.", "abstract": "A series of yeast shuttle vectors and host strains has been created to allow more efficient manipulation of DNA in Saccharomyces cerevisiae. Transplacement vectors were constructed and used to derive yeast strains containing nonreverting his3, trp1, leu2 and ura3 mutations. A set of YCp and YIp vectors (pRS series) was then made based on the backbone of the multipurpose plasmid pBLUESCRIPT. These pRS vectors are all uniform in structure and differ only in the yeast selectable marker gene used (HIS3, TRP1, LEU2 and URA3). They possess all of the attributes of pBLUESCRIPT and several yeast-specific features as well. Using a pRS vector, one can perform most standard DNA manipulations in the same plasmid that is introduced into yeast.", "corpus_id": 9565525, "score": 0 }, { "doc_id": "40353372", "title": "Esa1p Is an Essential Histone Acetyltransferase Required for Cell Cycle Progression", "abstract": "ABSTRACT Histones are dynamically modified during chromatin assembly, as specific transcriptional patterns are established, and during mitosis and development. Modifications include acetylation, phosphorylation, ubiquitination, methylation, and ADP-ribosylation, but the biological significance of each of these is not well understood. For example, distinct acetylation patterns correlate with nucleosome formation and with transcriptionally activated or silenced chromatin, yet mutations in genes encoding several yeast histone acetyltransferase (HAT) activities result in either no cellular phenotype or only modest growth defects. Here we report characterization of ESA1, an essential gene that is a member of the MYST family that includes two yeast silencing genes, human genes associated with leukemia and with the human immunodeficiency virus type 1 Tat protein, and Drosophila mof, a gene essential for male dosage compensation. Esa1p acetylates histones in a pattern distinct from those of other yeast enzymes, and temperature-sensitive mutant alleles abolish enzymatic activity in vitro and result in partial loss of an acetylated isoform of histone H4 in vivo. Strains carrying these mutations are also blocked in the cell cycle such that at restrictive temperatures,esa1 mutants succeed in replicating their DNA but fail to proceed normally through mitosis and cytokinesis. Recent studies show that Esa1p enhances transcription in vitro and thus may modulate expression of genes important for cell cycle control. These observations therefore link an essential HAT activity to cell cycle progression, potentially through discrete transcriptional regulatory events.", "corpus_id": 40353372, "score": 0 }, { "doc_id": "26914788", "title": "The Swi/Snf Complex Is Important for Histone Eviction during Transcriptional Activation and RNA Polymerase II Elongation In Vivo", "abstract": "ABSTRACT The Swi/Snf nucleosome-remodeling complex is recruited by DNA-binding activator proteins, whereupon it alters chromatin structure to increase preinitiation complex formation and transcription. At the SUC2 promoter, the Swi/Snf complex is required for histone eviction in a manner that is independent of transcriptional activity. Swi/Snf travels through coding regions with elongating RNA polymerase (Pol) II, and swi2 mutants exhibit sensitivity to drugs affecting Pol elongation. In FACT-depleted cells, Swi/Snf is important for internal initiation within coding regions, suggesting that Swi/Snf is important for histone eviction that occurs during Pol II elongation. Taken together, these observations suggest that Swi/Snf is important for histone eviction at enhancers and that it also functions as a Pol II elongation factor.", "corpus_id": 26914788, "score": 1 }, { "doc_id": "18317401", "title": "Opposing roles for Set2 and yFACT in regulating TBP binding at promoters", "abstract": "Previous work links histone methylation by Set2 with transcriptional elongation. yFACT (Spt16–Pob3 and Nhp6) reorganizes nucleosomes and functions in both transcriptional initiation and elongation. We show that growth defects caused by spt16 or pob3 mutations can be suppressed by deleting SET2, suggesting that Set2 and yFACT have opposing roles. Set2 methylates K36 of histone H3, and K36 substitutions also suppress yFACT mutations. In contrast, set1 enhances yFACT mutations. Methylation at H3 K4 by Set1 is required for set2 to suppress yFACT defects. We did not detect an elongation defect at an 8 kb ORF in yFACT mutants. Instead, pob3 mutants displayed reduced binding of both pol II and TBP to the GAL1 promoter. Importantly, both GAL1 transcription and promoter binding of pol II and TBP are significantly restored in the pob3 set2 double mutant. Defects caused by an spt16 mutation are enhanced by either TBP or TFIIA mutants. These synthetic defects are suppressed by set2, demonstrating that yFACT and Set2 oppose one another during transcriptional initiation at a step involving DNA binding by TBP and TFIIA.", "corpus_id": 18317401, "score": 0 }, { "doc_id": "23006212", "title": "SPT20/ADA5 encodes a novel protein functionally related to the TATA-binding protein and important for transcription in Saccharomyces cerevisiae", "abstract": "Mutations selected as suppressors of Ty and solo delta insertion mutations is Saccharomyces cerevisiae have identified a number of genes important for transcription initiation. One of these gens, SPT15, encodes the TATA-binding protein, and three others, SPT3, SPT7, and SPT8, encode proteins functionally related to the TATA-binding protein. To identify additional related functions, we have selected for new spt mutations. This work has identified one new gene, SPT20. Null mutations in SPT20 cause poor growth and a set of severe transcriptional defects very similar to those caused by null mutations in SPT3, SPT7, and SPT8 and also very similar to those caused by certain missense mutations in SPT15. Consistent with its having an important function in transcription in vivo, SPT20 was also recently identified as ADA5 and has been shown to be important for transcriptional activation (G.A. Marcus, J. Horiuchi, N. Silverman, and L. Guarente, Mol. Cell. Biol. 16:3197-3205, 1996.", "corpus_id": 23006212, "score": 0 }, { "doc_id": "1621029", "title": "Rad6 plays a role in transcriptional activation through ubiquitylation of histone H2B.", "abstract": "Covalent modifications of the histone N tails play important roles in eukaryotic gene expression. Histone acetylation, in particular, is required for the activation of a subset of eukaryotic genes through the targeted recruitment of histone acetyltransferases. We have reported that a histone C tail modification, ubiquitylation of H2B, is required for optimal expression of several inducible yeast genes, consistent with a role in transcriptional activation. H2B was shown to be ubiquitylated and then deubiquitylated at the GAL1 core promoter following galactose induction. We now show that the Rad6 protein, which catalyzes monoubiquitylation of H2B, is transiently associated with the GAL1 promoter upon gene activation, and that the period of its association temporally overlaps with the period of H2B ubiquitylation. Rad6 promoter association depends on the Gal4 activator and the Rad6-associated E3 ligase, Bre1, but is independent of the histone acetyltransferase, Gcn5. The SAGA complex, which contains a ubiquitin protease that targets H2B for deubiquitylation, is recruited to the GAL1 promoter in the absence of H2B ubiquitylation. The data suggest that Rad6 and SAGA function independently during galactose induction, and that the staged recruitment of these two factors to the GAL1 promoter regulates the ubiquitylation and deubiquitylation of H2B. We additionally show that both Rad6 and ubiquitylated H2B are absent from two regions of transcriptionally silent chromatin but present at genes that are actively transcribed. Thus, like histone H3 lysine 4 and lysine 79 methylation, two modifications that it regulates, Rad6-directed H2B ubiquitylation defines regions of active chromatin.", "corpus_id": 1621029, "score": 0 }, { "doc_id": "25499917", "title": "Elongating RNA Polymerase II Is Disassembled through Specific Degradation of Its Largest but Not Other Subunits in Response to DNA Damage in Vivo*", "abstract": "Although previous biochemical studies have demonstrated global degradation of the largest subunit, Rpb1p, of RNA polymerase II in response to DNA damage, it is still not clear whether the initiating or elongating form of Rpb1p is targeted for degradation in vivo. Further, whether other components of RNA polymerase II are degraded in response to DNA damage remains unknown. Here, we show that the Rpb1p subunit of the elongating, but not initiating, form of RNA polymerase II is degraded at the active genes in response to 4-nitroquinoline-1-oxide-induced DNA damage in Saccharomyces cerevisiae. However, other subunits of RNA polymerase II are not degraded in response to DNA damage. Further, we show that Rpb1p is essential for RNA polymerase II assembly at the active gene, and thus, the degradation of Rpb1p following DNA damage disassembles elongating RNA polymerase II. Taken together, our data demonstrate that Rpb1p but not other subunits of elongating RNA polymerase II is specifically degraded in response to DNA damage, and such a degradation of Rpb1p is critical for the disassembly of elongating RNA polymerase II at the DNA lesion in vivo.", "corpus_id": 25499917, "score": 0 }, { "doc_id": "14603214", "title": "Rad26p, a transcription-coupled repair factor, is recruited to the site of DNA lesion in an elongating RNA polymerase II-dependent manner in vivo", "abstract": "Rad26p, a yeast homologue of human Cockayne syndrome B with an ATPase activity, plays a pivotal role in stimulating DNA repair at the coding sequences of active genes. On the other hand, DNA repair at inactive genes or silent areas of the genome is not regulated by Rad26p. However, how Rad26p recognizes DNA lesions at the actively transcribing genes to facilitate DNA repair is not clearly understood in vivo. Here, we show that Rad26p associates with the coding sequences of genes in a transcription-dependent manner, but independently of DNA lesions induced by 4-nitroquinoline-1-oxide in Saccharomyces cerevisiae. Further, histone H3 lysine 36 methylation that occurs at the active coding sequence stimulates the recruitment of Rad26p. Intriguingly, we find that Rad26p is recruited to the site of DNA lesion in an elongating RNA polymerase II-dependent manner. However, Rad26p does not recognize DNA lesions in the absence of active transcription. Together, these results provide an important insight as to how Rad26p is delivered to the damage sites at the active, but not inactive, genes to stimulate repair in vivo, shedding much light on the early steps of transcription-coupled repair in living eukaryotic cells.", "corpus_id": 14603214, "score": 0 }, { "doc_id": "23479112", "title": "Functional Analysis of Bre1p, an E3 Ligase for Histone H2B Ubiquitylation, in Regulation of RNA Polymerase II Association with Active Genes and Transcription in Vivo*", "abstract": "Background: Bre1p is required for H2B ubiquitylation that promotes RNA polymerase II association with active genes, and hence transcription. Results: The RING domain of Bre1p facilitates, but a non-RING domain represses, transcription and RNA polymerase II association with active genes. Conclusion: Bre1p has a dominant-negative role in addition to its well known stimulatory function in transcription. Significance: This study unravels a hidden role of Bre1p in transcriptional regulation. H2B ubiquitylation is carried out by Bre1p, an E3 ligase, along with an E2 conjugase, Rad6p. H2B ubiquitylation has been previously implicated in promoting the association of RNA polymerase II with the coding sequence of the active GAL1 gene, and hence transcriptional elongation. Intriguingly, we find here that the association of RNA polymerase II with the active GAL1 coding sequence is not decreased in Δbre1, although it is required for H2B ubiquitylation. In contrast, the loss of Rad6p significantly impairs the association of RNA polymerase II with GAL1. Likewise, the point mutation of lysine 123 (ubiquitylation site) to arginine of H2B (H2B-K123R) also lowers the association of RNA polymerase II with GAL1, consistent with the role of H2B ubiquitylation in promoting RNA polymerase II association. Surprisingly, unlike the Δrad6 and H2B-K123R strains, complete deletion of BRE1 does not impair the association of RNA polymerase II with GAL1. However, deletion of the RING domain of Bre1p (that is essential for H2B ubiquitylation) impairs RNA polymerase II association with GAL1. These results imply that a non-RING domain of Bre1p counteracts the stimulatory role of the RING domain in regulating the association of RNA polymerase II with GAL1, and hence RNA polymerase II occupancy is not impaired in Δbre1. Consistently, GAL1 transcription is impaired in the absence of the RING domain of Bre1p, but not in Δbre1. Similar results are also obtained at other genes. Collectively, our results implicate both the stimulatory and repressive roles of Bre1p in regulation of RNA polymerase II association with active genes (and hence transcription) in vivo.", "corpus_id": 23479112, "score": 1 }, { "doc_id": "36669768", "title": "Evidence That Proteolysis of Gal4 Cannot Explain the Transcriptional Effects of Proteasome ATPase Mutations*", "abstract": "The Gal system of Saccharomyces cerevisiae is a paradigm for eukaryotic gene regulation. Expression of genes required for growth on galactose is regulated by the transcriptional activator Gal4. The activation function of Gal4 has been localized to 34 amino acids near the C terminus of the protein. The gal4D allele of GAL4 encodes a truncated protein in which only 14 amino acids of the activation domain remain. Expression of GAL genes is dramatically reduced in gal4Dstrains and these strains are unable to grow on galactose as the sole carbon source. Overexpression of gal4D partially relieves the defect in GAL gene expression and allows growth on galactose. A search for extragenic suppressors of gal4D identified recessive mutations in the SUG1 and SUG2 genes, which encode ATPases of the 19S regulatory complex of the proteasome. The proteasome is responsible for the ATP-dependent degradation of proteins marked for destruction by the ubiquitin system. It has been commonly assumed that effects of SUG1 and SUG2mutations on transcription are explained by alterations in the proteolysis of gal4D protein. We have investigated this assumption. Surprisingly, we find that SUG1 and SUG2alleles that are unable to suppress gal4D cause a larger increase in gal4D protein levels than do suppressing alleles. In addition, mutations in genes encoding subunits of the proteolytic 20S sub-complex of the proteasome increase the levels of gal4D protein but do not rescue its transcriptional activity. Therefore, an alteration in the proteolysis of gal4D by the proteasome cannot explain the effects of mutations in SUG1 and SUG2 on expression of GAL genes. These findings suggest that the 19S regulatory complex may play a more direct role in transcription.", "corpus_id": 36669768, "score": 0 }, { "doc_id": "10499587", "title": "Ubp8p, a Histone Deubiquitinase Whose Association with SAGA Is Mediated by Sgf11p, Differentially Regulates Lysine 4 Methylation of Histone H3 In Vivo", "abstract": "ABSTRACT Despite recent advances in characterizing the regulation of histone H3 lysine 4 (H3-K4) methylation at the GAL1 gene by the H2B-K123-specific deubiquitinase activity of Saccharomyces cerevisiae SAGA (Spt-Ada-Gcn5-acetyltransferase)-associated Ubp8p, our knowledge on the general role of Ubp8p at the SAGA-dependent genes is lacking. For this study, using a formaldehyde-based in vivo cross-linking and chromatin immunoprecipitation (ChIP) assay, we have analyzed the role of Ubp8p in the regulation of H3-K4 methylation at three other SAGA-dependent yeast genes, namely, PHO84, ADH1, and CUP1. Like that at GAL1, H3-K4 methylation is increased at the PHO84 core promoter in the UBP8 deletion mutant. We also show that H3-K4 methylation remains invariant at the PHO84 open reading frame in the Δubp8 mutant, demonstrating a highly localized role of Upb8p in regulation of H3-K4 methylation at the promoter in vivo. However, unlike that at PHO84, H3-K4 methylation at the two other SAGA-dependent genes is not controlled by Ubp8p. Interestingly, Ubp8p and H3-K4 methylation are dispensable for preinitiation complex assembly at the core promoters of these genes. Our ChIP assay further demonstrates that the association of Ubp8p with SAGA is mediated by Sgf11p, consistent with recent biochemical data. Collectively, the data show that Ubp8p differentially controls H3-K4 methylation at the SAGA-dependent promoters, revealing a complex regulatory network of histone methylation in vivo.", "corpus_id": 10499587, "score": 1 }, { "doc_id": "24632167", "title": "A functional interaction between the C-terminal domain of RNA polymerase II and the negative regulator SIN1", "abstract": "The C-terminal domain (CTD) of the largest subunit of yeast RNA polymerase II contains 26-27 tandem copies of a conserved heptapeptide of unknown function. Yeast strains whose CTD contains ten heptamers are viable but defective for transcription of the INO1 gene and cold sensitive for growth. Deletion of the SIN1 gene, which codes for a DNA-binding protein that negatively regulates HO transcription, restores INO1 transcription and reduces the cold sensitivity of such strains. A SIN1 deletion suppresses the lethality of a CTD with nine heptamer repeats but not with seven repeats. These observations indicate a functional relationship between SIN1 and the CTD: the CTD might remove SIN1 from DNA, or removal of SIN1 may be a prerequisite for function of the CTD. The SWI1, SWI2, and SWI3 genes, whose products activate HO transcription by antagonizing SIN1, are also required for INO1 transcription and may assist the CTD. In addition, an intact CTD binds nonspecifically to DNA in vitro.", "corpus_id": 24632167, "score": 0 }, { "doc_id": "8617286", "title": "Homopurine and homopyrimidine strands complementary in parallel orientation form an antiparallel duplex at neutral pH with A-C, G-T, and T-C mismatched base pairs.", "abstract": "DNA sequences d-TGAGGAAAGAAGGT (a 14-mer) and d-CTCCTTTCTTCC (a 12-mer) are complementary in parallel orientation forming either Donohue (reverse Watson-Crick) base pairing at neutral pH or Hoogsteen base pairing at slightly acidic pH. The structure of the complex formed by dissolving the two strands in equimolar ratio in water has been investigated by nmr. At neutral pH, the system forms an ordered antiparallel duplex with five A : T and four G : C Watson-Crick base pairs and three mismatches, namely G-T, A-C, and T-C. The nuclear Overhauser effect cross-peak pattern suggests an overall B-DNA conformation with major structural perturbations near the mismatches. The duplex has a low melting point and dissociates directly into single strands with a broad melting profile. The hydrogen-bonding schemes in the mismatched base pairs have been investigated. It has been shown earlier that in acidic pH, the system prefers a triple-stranded structure with two pyrimidine strands and one purine strand. One of the pyrimidine strands has protonated cytosines, forms Hoogsteen base pairing, and is aligned parallel to the purine strand; the other has nonprotonated cytosines and has base-pairing scheme similar to the one discussed in this paper. The parallel duplex is therefore less stable than either the antiparallel duplex or the triplex, in spite of its perfect complementarity.", "corpus_id": 8617286, "score": 0 }, { "doc_id": "46083908", "title": "Stability of DNA duplexes containing GG, CC, AA, and TT mismatches.", "abstract": "We employed salt-dependent differential scanning calorimetric measurements to characterize the stability of six oligomeric DNA duplexes (5'-GCCGGAXTGCCGG-3'/5'-CCGGCAYTCCGGC-3') that contain in the central XY position the GC, AT, GG, CC, AA, or TT base pair. The heat-induced helix-to-coil transitions of all the duplexes are associated with positive changes in heat capacity, DeltaC(p), ranging from 0.43 to 0.53 kcal/mol. Positive values of DeltaC(p) result in strong temperature dependences of changes in enthalpy, DeltaH degrees, and entropy, DeltaS degrees , accompanying duplex melting and cause melting free energies, DeltaG degrees, to exhibit characteristically curved shapes. These observations suggest that DeltaC(p) needs to be carefully taken into account when the parameters of duplex stability are extrapolated to temperatures distant from the transition temperature, T(M). Comparison of the calorimetric and van't Hoff enthalpies revealed that none of the duplexes studied in this work exhibits two-state melting. Within the context of the central AXT/TYA triplet, the thermal and thermodynamic stabilities of the duplexes in question change in the following order: GC > AT > GG > AA approximately TT > CC. Our estimates revealed that the thermodynamic impact of the GG, AA, and TT mismatches is confined within the central triplet. In contrast, the thermodynamic impact of the CC mismatch propagates into the adjacent helix domains and may involve 7-9 bp. We discuss implications of our results for understanding the origins of initial recognition of mismatched DNA sites by enzymes of the DNA repair machinery.", "corpus_id": 46083908, "score": 0 }, { "doc_id": "18980650", "title": "A rule of seven in Watson-Crick base pairing of mismatched sequences", "abstract": "Sequence recognition through base-pairing is essential for DNA repair and gene regulation, but the basic rules governing this process remain elusive. In particular, the kinetics of annealing between two imperfectly matched strands is not well characterized, despite its potential importance in nucleic acid–based biotechnologies and gene silencing. Here we use single-molecule fluorescence to visualize the multiple annealing and melting reactions of two untethered strands inside a porous vesicle, allowing us to precisely quantify the annealing and melting rates. The data as a function of mismatch position suggest that seven contiguous base pairs are needed for rapid annealing of DNA and RNA. This phenomenological rule of seven may underlie the requirement for seven nucleotides of complementarity to seed gene silencing by small noncoding RNA and may help guide performance improvement in DNA- and RNA-based bio- and nanotechnologies, in which off-target effects can be detrimental.", "corpus_id": 18980650, "score": 0 }, { "doc_id": "41295375", "title": "Functional Dissection of the NuA4 Histone Acetyltransferase Reveals Its Role as a Genetic Hub and that Eaf1 Is Essential for Complex Integrity", "abstract": "ABSTRACT The Saccharomyces cerevisiae NuA4 histone acetyltransferase complex catalyzes the acetylation of histone H4 and the histone variant Htz1 to regulate key cellular events, including transcription, DNA repair, and faithful chromosome segregation. To further investigate the cellular processes impacted by NuA4, we exploited the nonessential subunits of the complex to build an extensive NuA4 genetic-interaction network map. The map reveals that NuA4 is a genetic hub whose function buffers a diverse range of cellular processes, many not previously linked to the complex, including Golgi complex-to-vacuole vesicle-mediated transport. Further, we probe the role that nonessential subunits play in NuA4 complex integrity. We find that most nonessential subunits have little impact on NuA4 complex integrity and display between 12 and 42 genetic interactions. In contrast, the deletion of EAF1 causes the collapse of the NuA4 complex and displays 148 genetic interactions. Our study indicates that Eaf1 plays a crucial function in NuA4 complex integrity. Further, we determine that Eaf5 and Eaf7 form a subcomplex, which reflects their similar genetic interaction profiles and phenotypes. Our integrative study demonstrates that genetic interaction maps are valuable in dissecting complex structure and provides insight into why the human NuA4 complex, Tip60, has been associated with a diverse range of pathologies.", "corpus_id": 41295375, "score": 0 }, { "doc_id": "25988545", "title": "Eaf1 Is the Platform for NuA4 Molecular Assembly That Evolutionarily Links Chromatin Acetylation to ATP-Dependent Exchange of Histone H2A Variants", "abstract": "ABSTRACT Eaf1 (for Esa1-associated factor 1) and Eaf2 have been identified as stable subunits of NuA4, a yeast histone H4/H2A acetyltransferase complex implicated in gene regulation and DNA repair. While both SWI3-ADA2-N-CoR-TF IIIB domain-containing proteins are required for normal cell cycle progression, their depletion does not affect the global Esa1-dependent acetylation of histones. In contrast to all other subunits, Eaf1 is found exclusively associated with the NuA4 complex in vivo. It serves as a platform that coordinates the assembly of functional groups of subunits into the native NuA4 complex. Eaf1 shows structural similarities with human p400/Domino, a subunit of the NuA4-related TIP60 complex. On the other hand, p400 also possesses an SWI2/SNF2 family ATPase domain that is absent from the yeast NuA4 complex. This domain is highly related to the yeast Swr1 protein, which is responsible for the incorporation of histone variant H2AZ in chromatin. Since all of the components of the TIP60 complex are homologous to SWR1 or NuA4 subunits, we proposed that the human complex corresponds to a physical merge of two yeast complexes. p400 function in TIP60 then would be accomplished in yeast by cooperation between SWR1 and NuA4. In agreement with such a model, NuA4 and SWR1 mutants show strong genetic interactions, NuA4 affects histone H2AZ incorporation/acetylation in vivo, and both preset the PHO5 promoter for activation. Interestingly, the expression of a chimeric Eaf1-Swr1 protein recreates a single human-like complex in yeast cells. Our results identified the key central subunit for the structure and functions of the NuA4 histone acetyltransferase complex and functionally linked this activity with the histone variant H2AZ from yeast to human cells.", "corpus_id": 25988545, "score": 0 }, { "doc_id": "14371822", "title": "A glycolytic burst drives glucose induction of global histone acetylation by picNuA4 and SAGA", "abstract": "Little is known about what enzyme complexes or mechanisms control global lysine acetylation in the amino-terminal tails of the histones. Here, we show that glucose induces overall acetylation of H3 K9, 18, 27 and H4 K5, 8, 12 in quiescent yeast cells mainly by stimulating two KATs, Gcn5 and Esa1. Genetic and pharmacological perturbation of carbon metabolism, combined with 1H-NMR metabolic profiling, revealed that glucose induction of KAT activity directly depends on increased glucose catabolism. Glucose-inducible Esa1 and Gcn5 activities predominantly reside in the picNuA4 and SAGA complexes, respectively, and act on chromatin by an untargeted mechanism. We conclude that direct metabolic regulation of globally acting KATs can be a potent driving force for reconfiguration of overall histone acetylation in response to a physiological cue.", "corpus_id": 14371822, "score": 0 }, { "doc_id": "16279777", "title": "The Saccharomyces cerevisiae Piccolo NuA4 Histone Acetyltransferase Complex Requires the Enhancer of Polycomb A Domain and Chromodomain To Acetylate Nucleosomes", "abstract": "ABSTRACT Chromatin modification complexes are key gene regulatory factors which posttranslationally modify the histone component of chromatin with epigenetic marks. To address what features of chromatin modification complexes are responsible for the specific recognition of nucleosomes compared to naked histones, we have performed a functional dissection of the Esa1-containing Saccharomyces cerevisiae Piccolo NuA4 histone acetyltransferase complex. Our studies define the Piccolo determinants sufficient to assemble its three subunits into a complex as well as Piccolo determinants sufficient to specifically acetylate a chromatin template. We find that the conserved Enhancer of Polycomb A (EPcA) homology region of the Epl1 component and the N-terminal 165 amino acids of the Yng2 component of Piccolo are sufficient with Esa1 to specifically act on nucleosomes. We also find that the Esa1 chromodomain plays a critical role in Piccolo's ability to distinguish between histones and nucleosomes. In particular, specific point mutations in the chromodomain putative hydrophobic cage which strongly hinder growth in yeast greatly reduce histone acetyltransferase activity on nucleosome substrates, independent of histone methylation or other modifications. However, the chromodomain is not required for Piccolo to bind to nucleosomes, suggesting a role for the chromodomain in a catalysis step after nucleosome binding.", "corpus_id": 16279777, "score": 0 }, { "doc_id": "8836960", "title": "The Tor Pathway Regulates Gene Expression by Linking Nutrient Sensing to Histone Acetylation", "abstract": "ABSTRACT The Tor pathway mediates cell growth in response to nutrient availability, in part by inducing ribosomal protein (RP) gene expression via an unknown mechanism. Expression of RP genes coincides with recruitment of the Esa1 histone acetylase to RP gene promoters. We show that inhibition of Tor with rapamycin releases Esa1 from RP gene promoters and leads to histone H4 deacetylation without affecting promoter occupancy by Rap1 and Abf1. Genetic and biochemical evidence identifies Rpd3 as the major histone deacetylase responsible for reversing histone H4 acetylation at RP gene promoters in response to Tor inhibition by rapamycin or nutrient limitation. Our results illustrate that the Tor pathway links nutrient sensing with histone acetylation to control RP gene expression and cell growth.", "corpus_id": 8836960, "score": 1 }, { "doc_id": "7741552", "title": "Evidence that Set1, a Factor Required for Methylation of Histone H3, Regulates rDNA Silencing in S. cerevisiae by a Sir2-Independent Mechanism", "abstract": "Several types of histone modifications have been shown to control transcription. Recent evidence suggests that specific combinations of these modifications determine particular transcription patterns. The histone modifications most recently shown to play critical roles in transcription are arginine-specific and lysine-specific methylation. Lysine-specific histone methyltransferases all contain a SET domain, a conserved 130 amino acid motif originally identified in polycomb- and trithorax-group proteins from Drosophila. Members of the SU(VAR)3-9 family of SET-domain proteins methylate K9 of histone H3. Methylation of H3 has also been shown to occur at K4. Several studies have suggested a correlation between K4-methylated H3 and active transcription. In this paper, we provide evidence that K4-methylated H3 is required in a negative role, rDNA silencing in Saccharomyces cerevisiae. In a screen for rDNA silencing mutants, we identified a mutation in SET1, previously shown to regulate silencing at telomeres and HML. Recent work has shown that Set1 is a member of a complex and is required for methylation of K4 of H3 at several genomic locations. In addition, we demonstrate that a K4R change in H3, which prevents K4 methylation, impairs rDNA silencing, indicating that Set1 regulates rDNA silencing, directly or indirectly, via H3 methylation. Furthermore, we present several lines of evidence that the role of Set1 in rDNA silencing is distinct from that of the histone deacetylase Sir2. Together, these results suggest that Set1-dependent H3 methylation is required for rDNA silencing in a Sir2-independent fashion.", "corpus_id": 7741552, "score": 0 }, { "doc_id": "11783020", "title": "Histone Crosstalk between H2B Monoubiquitination and H3 Methylation Mediated by COMPASS", "abstract": "COMPASS, the yeast homolog of the mammalian MLL complex, is a histone H3 lysine 4 (H3K4) methylase consisting of Set1 (KMT2) and seven other polypeptides, including Cps35, the only essential subunit. Histone H2B monoubiquitination by Rad6/Bre1 is required for both H3K4 methylation by COMPASS, and H3K79 methylation by Dot1. However, the molecular mechanism for such histone crosstalk is poorly understood. Here, we demonstrate that histone H2B monoubiquitination controls the binding of Cps35 with COMPASS complex. Cps 35 is required for COMPASS' catalytic activity in vivo, and the addition of exogenous purified Cps35 to COMPASS purified from a Deltarad6 background results in the generation of a methylation competent COMPASS. Cps35 associates with the chromatin of COMPASS-regulated genes in a H2BK123 monoubiquitination-dependent but Set1-independent manner. Cps35 is also required for proper H3K79 trimethylation. These findings offer insight into the molecular role of Cps35 in translating the H2B monoubiquitination signal into H3 methylation.", "corpus_id": 11783020, "score": 0 }, { "doc_id": "4356260", "title": "Active genes are tri-methylated at K4 of histone H3", "abstract": "Lysine methylation of histones in vivo occurs in three states: mono-, di- and tri-methyl. Histone H3 has been found to be di-methylated at lysine 4 (K4) in active euchromatic regions but not in silent heterochromatic sites. Here we show that the Saccharomyces cerevisiae Set1 protein can catalyse di- and tri-methylation of K4 and stimulate the activity of many genes. Using antibodies that discriminate between the di- and tri-methylated state of K4 we show that di-methylation occurs at both inactive and active euchromatic genes, whereas tri-methylation is present exclusively at active genes. It is therefore the presence of a tri-methylated K4 that defines an active state of gene expression. These findings establish the concept of methyl status as a determinant for gene activity and thus extend considerably the complexity of histone modifications.", "corpus_id": 4356260, "score": 0 }, { "doc_id": "205260725", "title": "H3K4 methyltransferase Set1 is involved in maintenance of ergosterol homeostasis and resistance to Brefeldin A", "abstract": "Set1 is a conserved histone H3 lysine 4 (H3K4) methyltransferase that exists as a multisubunit complex. Although H3K4 methylation is located on many actively transcribed genes, few studies have established a direct connection showing that loss of Set1 and H3K4 methylation results in a phenotype caused by disruption of gene expression. In this study, we determined that cells lacking Set1 or Set1 complex members that disrupt H3K4 methylation have a growth defect when grown in the presence of the antifungal drug Brefeldin A (BFA), indicating that H3K4 methylation is needed for BFA resistance. To determine the role of Set1 in BFA resistance, we discovered that Set1 is important for the expression of genes in the ergosterol biosynthetic pathway, including the rate-limiting enzyme HMG-CoA reductase. Consequently, deletion of SET1 leads to a reduction in HMG-CoA reductase protein and total cellular ergosterol. In addition, the lack of Set1 results in an increase in the expression of DAN1 and PDR11, two genes involved in ergosterol uptake. The increase in expression of uptake genes in set1Δ cells allows sterols such as cholesterol and ergosterol to be actively taken up under aerobic conditions. Interestingly, when grown in the presence of ergosterol set1Δ cells become resistant to BFA, indicating that proper ergosterol levels are needed for antifungal drug resistance. These data show that H3K4 methylation impacts gene expression and output of a biologically and medically relevant pathway and determines why cells lacking H3K4 methylation have antifungal drug sensitivity.", "corpus_id": 205260725, "score": 0 }, { "doc_id": "18946094", "title": "Set3 HDAC Mediates Effects of Overlapping Noncoding Transcription on Gene Induction Kinetics", "abstract": "The Set3 histone deacetylase complex (Set3C) binds histone H3 dimethylated at lysine 4 (H3K4me2) to mediate deacetylation of histones in 5'-transcribed regions. To discern how Set3C affects gene expression, genome-wide transcription was analyzed in yeast undergoing a series of carbon source shifts. Deleting SET3 primarily caused changes during transition periods, as genes were induced or repressed. Surprisingly, a majority of Set3-affected genes are overlapped by noncoding RNA (ncRNA) transcription. Many Set3-repressed genes have H3K4me2 instead of me3 over promoter regions, due to either reduced H3K4me3 or ncRNA transcription from distal or antisense promoters. Set3C also represses internal cryptic promoters, but in different regions of genes than the Set2/Rpd3S pathway. Finally, Set3C stimulates some genes by repressing an overlapping antagonistic antisense transcript. These results show that overlapping noncoding transcription can fine-tune gene expression, not via the ncRNA but by depositing H3K4me2 to recruit the Set3C deacetylase.", "corpus_id": 18946094, "score": 0 }, { "doc_id": "16129409", "title": "Cotranscriptional Set2 Methylation of Histone H3 Lysine 36 Recruits a Repressive Rpd3 Complex", "abstract": "The yeast histone deacetylase Rpd3 can be recruited to promoters to repress transcription initiation. Biochemical, genetic, and gene-expression analyses show that Rpd3 exists in two distinct complexes. The smaller complex, Rpd3C(S), shares Sin3 and Ume1 with Rpd3C(L) but contains the unique subunits Rco1 and Eaf3. Rpd3C(S) mutants exhibit phenotypes remarkably similar to those of Set2, a histone methyltransferase associated with elongating RNA polymerase II. Chromatin immunoprecipitation and biochemical experiments indicate that the chromodomain of Eaf3 recruits Rpd3C(S) to nucleosomes methylated by Set2 on histone H3 lysine 36, leading to deacetylation of transcribed regions. This pathway apparently acts to negatively regulate transcription because deleting the genes for Set2 or Rpd3C(S) bypasses the requirement for the positive elongation factor Bur1/Bur2.", "corpus_id": 16129409, "score": 0 }, { "doc_id": "9328002", "title": "Histone H3 Methylation by Set2 Directs Deacetylation of Coding Regions by Rpd3S to Suppress Spurious Intragenic Transcription", "abstract": "Yeast Rpd3 histone deacetylase plays an important role at actively transcribed genes. We characterized two distinct Rpd3 complexes, Rpd3L and Rpd3S, by MudPIT analysis. Both complexes shared a three subunit core and Rpd3L contains unique subunits consistent with being a promoter targeted corepressor. Rco1 and Eaf3 were subunits specific to Rpd3S. Mutants of RCO1 and EAF3 exhibited increased acetylation in the FLO8 and STE11 open reading frames (ORFs) and the appearance of aberrant transcripts initiating within the body of these ORFs. Mutants in the RNA polymerase II-associated SET2 histone methyltransferase also displayed these defects. Set2 functioned upstream of Rpd3S and the Eaf3 methyl-histone binding chromodomain was important for recruitment of Rpd3S and for deacetylation within the STE11 ORF. These data indicate that Pol II-associated Set2 methylates H3 providing a transcriptional memory which signals for deacetylation of ORFs by Rpd3S. This erases transcription elongation-associated acetylation to suppress intragenic transcription initiation.", "corpus_id": 9328002, "score": 0 }, { "doc_id": "16501281", "title": "Chromatin remodelers Isw1 and Chd1 maintain chromatin structure during transcription by preventing histone exchange", "abstract": "Set2-mediated methylation of histone H3 Lys36 (H3K36) is a mark associated with the coding sequences of actively transcribed genes, but it has a negative role during transcription elongation. It prevents trans-histone exchange over coding regions and signals for histone deacetylation in the wake of RNA polymerase II (RNAPII) passage. We have found that in Saccharomyces cerevisiae the Isw1b chromatin-remodeling complex is specifically recruited to open reading frames (ORFs) by H3K36 methylation through the PWWP domain of its Ioc4 subunit in vivo and in vitro. Isw1b acts in conjunction with Chd1 to regulate chromatin structure by preventing trans-histone exchange from taking place over coding regions. In this way, Isw1b and Chd1 are important in maintaining chromatin integrity during transcription elongation by RNAPII.", "corpus_id": 16501281, "score": 0 }, { "doc_id": "20404124", "title": "Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability", "abstract": "Abstract:Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore, is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation and roles in controlling gene expression and stability.", "corpus_id": 20404124, "score": 0 }, { "doc_id": "7309845", "title": "H2B-K123 ubiquitination stimulates RNAPII elongation independent of H3-K4 methylation.", "abstract": "Eukaryotic gene regulation is closely correlated with histone covalent modifications. Recently, histone H2B lysine-123 (H2B-K123) ubiquitination has been implicated in regulation of transcription as well as histone H3 lysine-4 (H3-K4) methylation which is further associated with active transcription. However, whether H2B-K123 ubiquitination controls transcription through regulation of H3-K4 methylation remains unknown under physiological conditions. Here, we show that H2B-K123 ubiquitination enhances the rate of elongating RNA polymerase II (RNAPII) recruitment to the coding sequence of an inducible yeast gene, GAL1. Consistently, GAL1 transcription is significantly impaired in absence of H2B-K123 ubiquitination. On the other hand, H3-K4 methylation does not alter the rate of elongating RNAPII recruitment at GAL1. Further, these covalent modifications do not regulate pre-initiation complex formation at GAL1. Collectively, our data demonstrate the function of H2B-K123 ubiquitination in regulation of transcriptional elongation independently of H3-K4 methylation in vivo, providing a new insight on epigenetic regulation of gene expression.", "corpus_id": 7309845, "score": 0 }, { "doc_id": "22282214", "title": "H2B ubiquitylation plays a role in nucleosome dynamics during transcription elongation.", "abstract": "The monoubiquitylation of histone H2B has been associated with transcription initiation and elongation, but its role in these processes is poorly understood. We report that H2B ubiquitylation is required for efficient reassembly of nucleosomes during RNA polymerase II (Pol II)-mediated transcription elongation in yeast. This role is carried out in cooperation with the histone chaperone Spt16, and in the absence of H2B ubiquitylation and functional Spt16, chromatin structure is not properly restored in the wake of elongating Pol II. Moreover, H2B ubiquitylation and Spt16 play a role in each other's regulation. H2B ubiquitylation is required for the stable accumulation of Spt16 at the GAL1 coding region, and Spt16 regulates the formation of ubiquitylated H2B both globally and at the GAL1 gene. These data provide a mechanism linking H2B ubiquitylation to Spt16 in the regulation of nucleosome dynamics during transcription elongation.", "corpus_id": 22282214, "score": 0 }, { "doc_id": "20626638", "title": "Activator-specific recruitment of Mediator in vivo", "abstract": "The Mediator complex associates with eukaryotic RNA polymerase (Pol) II and is recruited to transcriptional enhancers by activator proteins. It is believed that Mediator is a general component of the Pol II machinery that is crucial to connect enhancer-bound activators to basic transcription factors. However, we show that Mediator does not detectably associate with many highly active Pol II promoters in yeast cells. Furthermore, in response to stress conditions, Mediator association is not directly related to Pol II association and in some cases is not detectable at highly activated promoters. Thus, Mediator is recruited to enhancers in an activator-specific manner, and it does not seem to be a stoichiometric component of the basic Pol II machinery in vivo. Mediator is recruited by many activators involved in stress responses, but not by the major activators that function under optimal conditions.", "corpus_id": 20626638, "score": 0 }, { "doc_id": "205292328", "title": "Direct Bre1-Paf1 Complex Interactions and RING Finger-independent Bre1-Rad6 Interactions Mediate Histone H2B Ubiquitylation in Yeast*", "abstract": "Recent yeast genetic studies have implicated the ubiquitin-conjugating enzyme and ubiquitin ligase functions of yRad6 and yBre1, respectively, in H2B ubiquitylation. However, there have been no corresponding biochemical analyses demonstrating intrinsic enzyme activities of yRad6 and yBre1 or related mechanistic details. Here, we describe a robust in vitro chromatin ubiquitylation assay that involves purified H2B ubiquitylation factors and natural nucleosomes. Our results indicate that yRad6 has an in vitro ability to nonspecifically ubiquitylate all core histones in the absence of an ubiquitin ligase but that yBre1 functions, through direct interactions with yRad6, to direct the ubiquitin conjugating activity of yRad6 toward the physiological H2B ubiquitylation site. Moreover, a yRad6 domain mapping analysis shows that an intact UBC domain is required for binding to yBre1, whereas the C-terminal acidic tail domain that is not required for a stable yBre1-yRad6 interaction is necessary for full enzyme activity of yRad6. We also find that, analogous to heteromeric complex formation by BRE1 paralogues in other organisms, yBre1 forms a homo-multimeric complex. Of special significance, our detailed biochemical analyses further show that the yBre1 RING finger domain is essential for H2B ubiquitylation but, surprisingly, dispensable for interaction of yBre1 with yRad6. In further support of the genetically identified requirement of the RNA polymerase II-associated yPaf1 complex for H2B ubiquitylation, protein interaction studies reveal that a purified yPaf1 complex directly and selectively interacts with yBre1 and thus serves to link the H2B ubiquitylation and general transcription machineries. These studies provide a more detailed mechanistic basis for H2B ubiquitylation in yeast.", "corpus_id": 205292328, "score": 0 }, { "doc_id": "44757247", "title": "The Rtf1 Component of the Paf1 Transcriptional Elongation Complex Is Required for Ubiquitination of Histone H2B*", "abstract": "In yeast cells, the Rtf1 and Paf1 components of the Paf1 transcriptional elongation complex are important for recruitment of Set1, the histone H3-lysine 4 (H3-Lys4) methylase, to a highly localized domain at the 5′ portion of active mRNA coding regions. Here, we show that Rtf1 is essential for global methylation of H3-Lys4 and H3-Lys79, but not H3-Lys36. This role of Rtf1 resembles that of Rad6, which mediates ubiquitination of histone H2B at lysine 123. Indeed, Rtf1 is required for H2B ubiquitination, suggesting that its effects on H3-Lys4 and H3-Lys79 methylation are an indirect consequence of its effect on H2B ubiquitination. Rtf1 is important for telomeric silencing, with loss of H3-Lys4 and H3-Lys79 methylation synergistically reducing Sir2 association with telomeric DNA. Dot1, the H3-Lys79 methylase, associates with transcriptionally active genes, but unlike the association of Set1 and Set2 (the H3-Lys36 methylase), this association is largely independent of Rtf1. We suggest that Rtf1 affects genome-wide ubiquitination of H2B by a mechanism that is distinct from its function as a transcriptional elongation factor.", "corpus_id": 44757247, "score": 0 }, { "doc_id": "34604500", "title": "The S. cerevisiae SAGA complex functions in vivo as a coactivator for transcriptional activation by Gal4.", "abstract": "Previous studies demonstrated that the SAGA (Spt-Ada-Gcn5-Acetyltransferase) complex facilitates the binding of TATA-binding protein (TBP) during transcriptional activation of the GAL1 gene of Saccharomyces cerevisiae. TBP binding was shown to require the SAGA components Spt3 and Spt20/Ada5, but not the SAGA component Gcn5. We have now examined whether SAGA is directly required as a coactivator in vivo by using chromatin immunoprecipitation analysis. Our results demonstrate that SAGA is physically recruited in vivo to the upstream activation sequence (UAS) regions of the galactose-inducible GAL genes. This recruitment is dependent on both induction by galactose and the Gal4 activation domain. Furthermore, we demonstrate that another well-characterized activator, Gal4-VP16, also recruits SAGA in vivo. Finally, we provide evidence that a specific interaction between Spt3 and TBP in vivo is important for Gal4 transcriptional activation at a step after SAGA recruitment. These results, taken together with previous studies, demonstrate a dependent pathway for the recruitment of TBP to GAL gene promoters consisting of the recruitment of SAGA by Gal4 and the subsequent recruitment of TBP by SAGA.", "corpus_id": 34604500, "score": 1 }, { "doc_id": "30691184", "title": "SAGA is an essential in vivo target of the yeast acidic activator Gal4p.", "abstract": "Despite major advances in characterizing the eukaryotic transcriptional machinery, the function of promoter-specific transcriptional activators (activators) is still not understood. For example, in no case have the direct in vivo targets of a transcriptional activator been unambiguously identified, nor has it been resolved whether activators have a single essential target or multiple redundant targets. Here we address these issues for the prototype acidic activator yeast Gal4p. Gal4p binds to the upstream activating sequence (UAS) of GAL1 and several other GAL genes and stimulates transcription in the presence of galactose. Previous studies have shown that GAL1 transcription is dependent on the yeast SAGA (Spt/Ada/GCN5/acetyltransferase) complex. Using formaldehyde-based in vivo cross-linking, we show that the Gal4p activation domain recruits SAGA to the GAL1 UAS. If SAGA is not recruited to the UAS, the preinitiation complex (PIC) fails to assemble at the GAL1 core promoter, and transcription does not occur. SAGA, but not other transcription components, is also recruited by the Gal4p activation domain to a plasmid containing minimal Gal4p-binding sites. Recruitment of SAGA by Gal4p and stimulation of PIC assembly is dependent on several SAGA subunits but not the SAGA histone acetyl-transferase (HAT) GCN5. Based on these and other results, we conclude that SAGA is an essential target of Gal4p that, following recruitment to the UAS, facilitates PIC assembly and transcription.", "corpus_id": 30691184, "score": 1 }, { "doc_id": "7522626", "title": "Continuous and widespread roles for the Swi–Snf complex in transcription", "abstract": "Chromatin presents a significant obstacle to transcription, but two means of overcoming its repressive effects, histone acetylation and the activities of the Swi–Snf complex, have been proposed. Histone acetylation and Swi–Snf activity have been shown to be crucial for transcriptional induction and to facilitate binding of transcription factors to DNA. By regulating the activity of the Swi–Snf complex in vivo, we found that active transcription requires continuous Swi–Snf function, demonstrating a role for this complex beyond the induction of transcription. Despite the presumably generalized packaging of genes into chromatin, previous studies have indicated that the transcriptional requirements for the histone acetyltransferase, Gcn5, and the Swi–Snf complex are limited to a handful of genes. However, inactivating Swi–Snf function in cells also lacking GCN5 revealed defects in transcription of several genes previously thought to be SWI–SNF‐ and GCN5‐independent. These findings suggest that chromatin remodeling plays a widespread role in gene expression and that these two chromatin remodeling activities perform independent and overlapping functions during transcriptional activation.", "corpus_id": 7522626, "score": 0 }, { "doc_id": "1804472", "title": "Rad26p regulates the occupancy of histone H2A–H2B dimer at the active genes in vivo", "abstract": "Recently, we have demonstrated a predominant association of Rad26p with the coding sequences but not promoters of several GAL genes following transcriptional induction. Here, we show that the occupancy of histone H2A–H2B dimer at the coding sequences of these genes is not altered following transcriptional induction in the absence of Rad26p. A histone H2A–H2B dimer-enriched chromatin in Δrad26 is correlated to decreased association of RNA polymerase II with the active coding sequences (and hence transcription). However, the reduced association of RNA polymerase II with the active coding sequence in the absence of Rad26p is not due to the defect in formation of transcription complex at the promoter. Thus, Rad26p regulates the occupancy of histone H2A–H2B dimer, which is correlated to the association of elongating RNA polymerase II with active GAL genes. Similar results are also found at other inducible non-GAL genes. Collectively, our results define a new role of Rad26p in orchestrating chromatin structure and hence transcription in vivo.", "corpus_id": 1804472, "score": 0 }, { "doc_id": "25732380", "title": "The multifunctional transcription factors Abf1p, Rap1p and Reb1p are required for full transcriptional activation of the chromosomalPGK gene inSaccharomyces cerevisiae", "abstract": "We have identified two new transcription factor binding sites upstream of the previously defined UAS within the phosphoglycerate kinase (PGK) gene promoter inSaccharomyces cerevisiae. These sites are bound in vitro by the multifunctional factors Cpf1p and Reb1p. We have generated targeted deletions of Rap1p, Abf1p and Reb1p binding sites in the promoter of the chromosomal copy of thePGK gene. Northern blot analysis confirmed that mostPGK promoter activity is mediated through the Rap1p binding site. However, significant effects are also mediated through both the Reb1p and Abf1p sites. In contrast, when the promoter is present on a high-copy-number plasmid, both the Abf1p and Reb1p sites play no role in transcriptional activation. The role of Cpf1p was examined using acfp1 null strain. Cpf1p was found to have little if any, effect on activation of either the chromosomal or plasmid-bornePGK gene.", "corpus_id": 25732380, "score": 0 }, { "doc_id": "8618943", "title": "Importance of general regulatory factors Rap1p, Abf1p and Reb1p for the activation of yeast fatty acid synthase genes FAS1 and FAS2.", "abstract": "The fatty acid synthase genes FAS1 and FAS2 of the yeast Saccharomyces cerevisiae are under transcriptional control of pathway-specific regulators of phospholipid biosynthesis. However, site-directed mutagenesis of the respective cis-acting elements upstream of FAS1 and FAS2 revealed that additional sequences activating both genes must exist. A deletion analysis of the FAS1 promoter lacking the previously characterized inositol/choline-responsive-element motif defined a region (nucleotides -760 to -850) responsible for most of the remaining activation potency. Gel-retardation experiments and in-vitro DNase footprint studies proved the binding of the general regulatory factors Rap1p, Abf1p and Reb1p to this FAS1 upstream region. Mutation of the respective binding sites led to a drop of gene activation to 8% of the wild-type level. Similarly, we also demonstrated the presence of a Reb1p-binding site upstream of FAS2 and its importance for gene activation. Thus, in addition to the previously characterized FAS-binding factor 1 interacting with the inositol/choline-responsive-element motif, a second motif common to the promoter regions of both FAS genes could be identified. Transcription of yeast fatty acid synthase genes is therefore subjected to both the pathway-specific control affecting genes of phospholipid biosynthesis and to the activation by general transcription factors allowing a sufficiently high level of constitutive gene expression.", "corpus_id": 8618943, "score": 0 }, { "doc_id": "19862388", "title": "A REB1-binding site is required for GCN4-independent ILV1 basal level transcription and can be functionally replaced by an ABF1-binding site.", "abstract": "The ILV1 gene of Saccharomyces cerevisiae encodes the first committed step in isoleucine biosynthesis and is regulated by general control of amino acid biosynthesis. Deletion analysis of the ILV1 promoter revealed a GC-rich element important for the basal level expression. This cis-acting element, called ILV1BAS, is functional independently of whether GCN4 protein is present. Furthermore, unlike the situation at HIS4, the magnitude of GCN4-mediated derepression is independent of ILV1BAS. The element has homology to the consensus REB1-binding sequence CGGGTARNNR. Gel retardation assays showed that REB1 binds specifically to this element. We show that REB1-binding sites normally situated in the SIN3 promoter and in the 35S rRNA promoter can substitute for the ILV1 REB1 site. Furthermore, a SIN3 REB1 site containing a point mutation that abolishes REB1 binding does not support ILV1 basal level expression, suggesting that binding of REB1 is important for the control of ILV1 basal level expression. Interestingly, an ABF1-binding site can also functionally replace the ILV1 REB1-binding site. A mutated ABF1 site that displays a very low affinity for ABF1 does not functionally replace the ILV1 REB1 site. This suggests that ABF1 and REB1 may have related functions within the cell. Although the REB1-binding site is required for the ILV1 basal level expression, the site on its own stimulates transcription only slightly when combined with the CYC1 downstream promoter elements, indicating that another ILV1 promoter element functions in combination with the REB1 site to control high basal level expression.", "corpus_id": 19862388, "score": 0 }, { "doc_id": "4421200", "title": "Transcriptional regulatory code of a eukaryotic genome", "abstract": "DNA-binding transcriptional regulators interpret the genome's regulatory code by binding to specific sequences to induce or repress gene expression. Comparative genomics has recently been used to identify potential cis-regulatory sequences within the yeast genome on the basis of phylogenetic conservation, but this information alone does not reveal if or when transcriptional regulators occupy these binding sites. We have constructed an initial map of yeast's transcriptional regulatory code by identifying the sequence elements that are bound by regulators under various conditions and that are conserved among Saccharomyces species. The organization of regulatory elements in promoters and the environment-dependent use of these elements by regulators are discussed. We find that environment-specific use of regulatory elements predicts mechanistic models for the function of a large population of yeast's transcriptional regulators.", "corpus_id": 4421200, "score": 0 }, { "doc_id": "205300068", "title": "Regulation of Chromatin Assembly/Disassembly by Rtt109p, a Histone H3 Lys56-specific Acetyltransferase, in Vivo*", "abstract": "Rtt109p, a histone acetyltransferase, associates with active genes and acetylates lysine 56 on histone H3 in Saccharomyces cerevisiae. However, the functional role of Rtt109p or H3 Lys56 acetylation in chromatin assembly/disassembly (and hence gene expression) immediately switching transcription on or off has not been clearly elucidated in vivo. Here, we show that Rtt109p promotes the eviction of histone H3 from a fast inducible yeast gene, GAL1, following transcriptional initiation via histone H3 Lys56 acetylation. Conversely, the deposition of histone H3 to GAL1 is significantly decreased in the presence of Rtt109p following transcriptional termination. Intriguingly, we also find that the deposition of histone H2B on preexisting non-acetylated histone H3 Lys56 at GAL1 in Δrtt109 is significantly increased independently of histone H3 deposition immediately following transcriptional termination subsequent to a short induction. Consistently, histone H2B is not efficiently evicted from GAL1 in the absence of Rtt109p immediately following transcriptional induction. Furthermore, we show that the stimulated eviction or reduced deposition of histones by Rtt109p promotes the association of RNA polymerase II with GAL1 and hence the synthesis of GAL1 mRNA. These results, taken together, support the fact that Rtt109p regulates the deposition/eviction of histone H2B in addition to its role in stimulating histone H3 eviction, thus providing insight into chromatin assembly/disassembly and hence gene expression in vivo.", "corpus_id": 205300068, "score": 0 } ]

{ "doc_id": "12420527", "title": "Host allometry influences the evolution of parasite host-generalism: theory and meta-analysis", "abstract": "Parasites vary widely in the diversity of hosts they infect: some parasite species are specialists—infecting just a single host species, while others are generalists, capable of infecting many. Understanding the factors that drive parasite host-generalism is of basic biological interest, but also directly relevant to predicting disease emergence in new host species, identifying parasites that are likely to have unidentified additional hosts, and assessing transmission risk. Here, we use mathematical models to investigate how variation in host body size and environmental temperature affect the evolution of parasite host-generalism. We predict that parasites are more likely to evolve a generalist strategy when hosts are large-bodied, when variation in host body size is large, and in cooler environments. We then explore these predictions using a newly updated database of over 20 000 fish–macroparasite associations. Within the database we see some evidence supporting these predictions, but also highlight mismatches between theory and data. By combining these two approaches, we establish a theoretical basis for interpreting empirical data on parasites' host specificity and identify key areas for future work that will help untangle the drivers of parasite host-generalism. This article is part of the themed issue ‘Opening the black box: re-examining the ecology and evolution of parasite transmission’.", "corpus_id": 12420527 }

[ { "doc_id": "16467124", "title": "Differential sources of host species heterogeneity influence the transmission and control of multihost parasites", "abstract": "Controlling parasites that infect multiple host species often requires targeting single species that dominate transmission. Yet, it is rarely recognised that such ‘key hosts’ can arise through disparate mechanisms, potentially requiring different approaches for control. We identify three distinct, but not mutually exclusive, processes that underlie host species heterogeneity: infection prevalence, population abundance and infectiousness. We construct a theoretical framework to isolate the role of each process from ecological data and to explore the outcome of different control approaches. Applying this framework to data on 11 gastrointestinal parasites in small mammal communities across the eastern United States reveals variation not only in the magnitude of transmission asymmetries among host species but also in the processes driving heterogeneity. These differences influence the efficiency by which different control strategies reduce transmission. Identifying and tailoring interventions to a specific type of key host may therefore enable more effective management of multihost parasites.", "corpus_id": 16467124, "score": 0 }, { "doc_id": "8136362", "title": "Assembling evidence for identifying reservoirs of infection", "abstract": "\n \n Many pathogens persist in multihost systems, making the identification of infection reservoirs crucial for devising effective interventions. Here, we present a conceptual framework for classifying patterns of incidence and prevalence, and review recent scientific advances that allow us to study and manage reservoirs simultaneously. We argue that interventions can have a crucial role in enriching our mechanistic understanding of how reservoirs function and should be embedded as quasi-experimental studies in adaptive management frameworks. Single approaches to the study of reservoirs are unlikely to generate conclusive insights whereas the formal integration of data and methodologies, involving interventions, pathogen genetics, and contemporary surveillance techniques, promises to open up new opportunities to advance understanding of complex multihost systems.\n \n", "corpus_id": 8136362, "score": 0 }, { "doc_id": "24756071", "title": "Generalism and the evolution of parasite virulence.", "abstract": "The evolution of parasite-imposed host harm (virulence) will be affected by numerous factors, not least the range of hosts that parasites can infect. Here, we consider four ways that parasite host range (generalism) might directly affect observed levels of parasite virulence: costs of generalism, multiplicity of infection, maladaptive virulence, and host availability. Integrating parasite infectivity range with life-history evolution will generate novel general hypotheses for the evolutionary ecology of virulence, as well as explicit predictions about the virulence of emerging diseases resulting from host shifts.", "corpus_id": 24756071, "score": 0 }, { "doc_id": "25604480", "title": "Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence.", "abstract": "Pathogens that can be transmitted between different host species are of fundamental interest and importance from public health, conservation and economic perspectives, yet systematic quantification of these pathogens is lacking. Here, pathogen characteristics, host range and risk factors determining disease emergence were analysed by constructing a database of disease-causing pathogens of humans and domestic mammals. The database consisted of 1415 pathogens causing disease in humans, 616 in livestock and 374 in domestic carnivores. Multihost pathogens were very prevalent among human pathogens (61.6%) and even more so among domestic mammal pathogens (livestock 77.3%, carnivores 90.0%). Pathogens able to infect human, domestic and wildlife hosts contained a similar proportion of disease-causing pathogens for all three host groups. One hundred and ninety-six pathogens were associated with emerging diseases, 175 in humans, 29 in livestock and 12 in domestic carnivores. Across all these groups, helminths and fungi were relatively unlikely to emerge whereas viruses, particularly RNA viruses, were highly likely to emerge. The ability of a pathogen to infect multiple hosts, particularly hosts in other taxonomic orders or wildlife, were also risk factors for emergence in human and livestock pathogens. There is clearly a need to understand the dynamics of infectious diseases in complex multihost communities in order to mitigate disease threats to public health, livestock economies and wildlife.", "corpus_id": 25604480, "score": 1 }, { "doc_id": "40290820", "title": "Population Biology of Multihost Pathogens", "abstract": "The majority of pathogens, including many of medical and veterinary importance, can infect more than one species of host. Population biology has yet to explain why perceived evolutionary advantages of pathogen specialization are, in practice, outweighed by those of generalization. Factors that predispose pathogens to generalism include high levels of genetic diversity and abundant opportunities for cross-species transmission, and the taxonomic distributions of generalists and specialists appear to reflect these factors. Generalism also has consequences for the evolution of virulence and for pathogen epidemiology, making both much less predictable. The evolutionary advantages and disadvantages of generalism are so finely balanced that even closely related pathogens can have very different host range sizes.", "corpus_id": 40290820, "score": 0 }, { "doc_id": "86202028", "title": "The Evolution of Ecological Specialization", "abstract": "The evolution of \"niche breadth,\" or \"niche width,\" was a more popular topic in the evolutionary ecological literature of the 1960s and 1970s than it has been recently (109, 118, 120, 134, 155, 156). This review summarizes current hypotheses on the evolution of specialization and generalization and suggests areas in which future research might be rewarding. The topic is so broad that every area of biology bears on it. We cannot hope to offer an exhaustive review of evidence and in particular have slighted much of the ecological literature to emphasize genetic and evolutionary perspectives. We limit our discussion almost entirely to animals. We adopt Hutchinson's (86) representation of a population's ecological niche as an n-dimensional hypervolume, the axes of which are environmental variables or resources. Along each of these, the population displays a wide or narrow tolerance or pattern of utilization, relative to other populations or species. Specialization and generalization must be defined with reference to particular axes (e.g. temperature, range of food particle sizes). Brown (9) suggests that niche breadth along different axes is positively correlated and that this explains positive correlations across species between local abundance and breadth of geographic range. Multidimensional specialization might be expected if species arise in localized regions that differ in several ecological respects from those occupied by parent species. Cody (20), however, suggested that the breadth of habitat is negatively correlated with diet breadth among certain bird species. In practice, quantitative measurement of niche breadth can be difficult (22,", "corpus_id": 86202028, "score": 0 }, { "doc_id": "85807027", "title": "Large‐scale patterns of host use by parasites of freshwater fishes", "abstract": "Organisms that are abundant locally in a habitat patch are commonly observed to be frequent regionally, or among patches. In parasites, species present in high numbers in host individuals are also present in many individuals in the host population. On a larger scale, however, when host species are considered as patches, we may expect the opposite pattern because of the cost of producing mechanisms to evade the immune responses of several host species. Thus parasite species exploiting many host species may achieve lower average abundance in their hosts than parasite species exploiting fewer host species. This prediction was tested with data from 188 species of metazoan parasites of freshwater fish, using a comparative approach that controlled for study effort and phylogenetic influences. A negative correlation was found between the number of host species used by parasites and their average abundance in hosts, measured as either prevalence or intensity of infection. There was no evidence that parasite species fall into distinct categories based on abundance patterns, but rather that they fall along a continuum ranging from a generally low abundance in many host species, to a generally high abundance in few host species. These results applied to both ecto- and endoparasites. The pattern observed suggests the existence of a trade-off between how many host species a parasite can exploit and how well it does on average in those hosts.", "corpus_id": 85807027, "score": 0 }, { "doc_id": "22794597", "title": "The evolution of virulence and host specialization in malaria parasites of primates.", "abstract": "Parasite virulence, i.e. the damage done to the host, may be a by-product of the parasite's effort to maximize its fitness. Accordingly, several life-history trade-offs may explain interspecific differences in virulence, but such constraints remain little tested in an evolutionary context. In this phylogenetic study of primate malarias, I investigated the relationship between virulence and other parasite life-history traits. I used peak parasitaemia as a proxy for virulence, because it reflected parasite reproductive success and parasite-induced mortality. Peak parasitaemia was higher in specialist than in generalist species, even when confounding life-history traits were controlled. While there was a significant phylogenetic relationship between the number of competitors per host and host specialization, peak parasitaemia was unrelated to within-host competition. Therefore, the key evolutionary factor that favours virulence is host specialization, and the evolutionary success of virulent parasites, such as Plasmodium falciparum, may be better understood when the trade-off in virulence between different hosts is considered. Such phylogenetic results may help us design better protection programmes against malaria.", "corpus_id": 22794597, "score": 0 }, { "doc_id": "144775582", "title": "Evolutionary Ecology of Parasites", "abstract": "parallels to selection for group behavior in natural populations. It could be argued that all scientific inquiry is based on the assertion that gathering information increases our understanding of the natural world, and that we should use this information to further improve countless diverse, human agendas. A great amount of information is gathered and disseminated in this second volume of t e Desig and Nature series-and it amounts to a sometimes overwhelming and always stimulating array of biological and engineering questions. The high cost of the book will limit its audience to academic and corporate buyers, but it is this same group who has the most to gain from integrating scientific disciplines to a level beyond simple metaphor. That com lexity is an inherent and u avoidable outcome of natural systems is a major theme of this book and I have little doubt that such", "corpus_id": 144775582, "score": 1 }, { "doc_id": "19042241", "title": "Is specialization an evolutionary dead end? Testing for differences in speciation, extinction and trait transition rates across diverse phylogenies of specialists and generalists", "abstract": "Specialization has often been claimed to be an evolutionary dead end, with specialist lineages having a reduced capacity to persist or diversify. In a phylogenetic comparative framework, an evolutionary dead end may be detectable from the phylogenetic distribution of specialists, if specialists rarely give rise to large, diverse clades. Previous phylogenetic studies of the influence of specialization on macroevolutionary processes have demonstrated a range of patterns, including examples where specialists have both higher and lower diversification rates than generalists, as well as examples where the rates of evolutionary transitions from generalists to specialists are higher, lower or equal to transitions from specialists to generalists. Here, we wish to ask whether these varied answers are due to the differences in macroevolutionary processes in different clades, or partly due to differences in methodology. We analysed ten phylogenies containing multiple independent origins of specialization and quantified the phylogenetic distribution of specialists by applying a common set of metrics to all datasets. We compared the tip branch lengths of specialists to generalists, the size of specialist clades arising from each evolutionary origin of a specialized trait and whether specialists tend to be clustered or scattered on phylogenies. For each of these measures, we compared the observed values to expectations under null models of trait evolution and expected outcomes under alternative macroevolutionary scenarios. We found that specialization is sometimes an evolutionary dead end: in two of the ten case studies (pollinator‐specific plants and host‐specific flies), specialization is associated with a reduced rate of diversification or trait persistence. However, in the majority of studies, we could not distinguish the observed phylogenetic distribution of specialists from null models in which specialization has no effect on diversification or trait persistence.", "corpus_id": 19042241, "score": 0 }, { "doc_id": "15070400", "title": "How specialists can be generalists: resolving the “parasite paradox” and implications for emerging infectious disease", "abstract": "The parasite paradox arises from the dual observations that parasites (broadly construed, including phy- tophagous insects) are resource specialists with restricted host ranges, and yet shifts onto relatively unrelated hosts are common in the phylogenetic diversification of parasite lineages and directly observable in ecological time. We synthe- size the emerging solution to this paradox: phenotypic flexibility and phylogenetic conservatism in traits related to resource use, grouped under the term ecological fitting, provide substantial opportunities for rapid host switching in changing environments, in the absence of the evolution of novel host-utilization capabilities. We discuss mechanisms behind ecological fitting, its implications for defining specialists and generalists, and briefly review empirical examples of host shifts in the context of ecological fitting. We conclude that host shifts via ecological fitting provide the fuel for the expansion phase of the recently proposed oscillation hypothesis of host range and speciation, and, more generally, the generation of novel combinations of interacting species within the geographic mosaic theory of coevolution. Finally, we conclude that taxon pulses, driven by climate change and large-scale ecological perturbation are drivers of biotic mixing and resultant ecological fitting, which leads to increased rates of rapid host switching, including the agents of Emerging Infectious Disease.", "corpus_id": 15070400, "score": 0 }, { "doc_id": "6021900", "title": "Competition promotes the evolution of host generalists in obligate parasites", "abstract": "Ecological theory traditionally predicts that interspecific competition selects for an increase in ecological specialization. Specialization, in turn, is often thought to be an evolutionary ‘dead end,’ with specialist lineages unlikely to evolve into generalist lineages. In host–parasite systems, this specialization can take the form of host specificity, with more specialized parasites using fewer hosts. We tested the hypothesis that specialists are evolutionarily more derived, and whether competition favours specialization, using the ectoparasitic feather lice of doves. Phylogenetic analyses revealed that complete host specificity is actually the ancestral condition, with generalists repeatedly evolving from specialist ancestors. These multiple origins of generalists are correlated with the presence of potentially competing species of the same genus. A competition experiment with captive doves and lice confirmed that congeneric species of lice do, in fact, have the potential to compete in ecological time. Taken together, these results suggest that interspecific competition can favour the evolution of host generalists, not specialists, over macroevolutionary time.", "corpus_id": 6021900, "score": 0 }, { "doc_id": "7925856", "title": "Evolution of host specificity in monogeneans parasitizing African cichlid fish", "abstract": "BackgroundThe patterns and processes linked to the host specificity of parasites represent one of the central themes in the study of host-parasite interactions. We investigated the evolution and determinants of host specificity in gill monogeneans of Cichlidogyrus and Scutogyrus species parasitizing African freshwater fish of Cichlidae.MethodsWe analyzed (1) the link between host specificity and parasite phylogeny, (2) potential morphometric correlates of host specificity (i.e. parasite body size and the morphometrics of the attachment apparatus), and (3) potential determinants of host specificity following the hypothesis of ecological specialization and the hypothesis of specialization on predictable resources (i.e. host body size and longevity were considered as measures of host predictability), and (4) the role of brooding behavior of cichlids in Cichlidogyrus and Scutogyrus diversification.ResultsNo significant relationships were found between host specificity and phylogeny of Cichlidogyrus and Scutogyrus species. The mapping of host specificity onto the parasite phylogenetic tree revealed that an intermediate specialist parasitizing congeneric cichlid hosts represents the ancestral state for the Cichlidogyrus/Scutogyrus group. Only a weak relationship was found between the morphometry of the parasites’ attachment apparatus and host specificity. Our study did not support the specialization on predictable resources or ecological specialization hypotheses. Nevertheless, host specificity was significantly related to fish phylogeny and form of parental care.ConclusionsOur results confirm that host specificity is not a derived condition for Cichlidogyrus/Scutogyrus parasites and may reflect other than historical constraints. Attachment apparatus morphometry reflects only partially (if at all) parasite adaptation to the host species, probably because of the morphological similarity of rapidly evolved cichlids (analyzed in our study). However, we showed that parental care behavior of cichlids may play an important role linked to host specificity of Cichlidogyrus/Scutogyrus parasites.", "corpus_id": 7925856, "score": 0 }, { "doc_id": "83974920", "title": "Specificity and host predictability: a comparative analysis among monogenean parasites of fish", "abstract": "1. This article compares generalist (parasite species found on two or more host species) and specialist (found on only one host species) monogenean parasite species of fish. The reduction of the host range – that is an increase in host specificity – may correspond with a better adaptation of the parasite to a more predictable host environment. A more predictable environment may allow the parasite species to develop specific adaptations. \n \n \n \n2. We assume that the more predictable host environment can be evaluated by host body size, since numerous life-traits, such as longevity, are positively correlated with size. \n \n \n \n3. We found that specialist parasites parasitize larger hosts species than generalist parasites. We also found a good relationship between host body size and parasite body size for specialist parasite species. \n \n \n \n4. An adaptation to the mechanical problems encountered in the host's gill chamber may lead to an increase in parasite body size. The infection of a larger part of the host population in order to decrease the chances of local extinction due to fluctuations of host abundance may be another adaptive mechanism. \n \n \n \n5. We found a negative correlation between parasite body size and prevalence for generalist parasite species. This relationship disappeared when using the comparative method controlling for phylogeny, which proved that it was a phylogenetic effect.", "corpus_id": 83974920, "score": 0 }, { "doc_id": "39926864", "title": "Resource predictability and host specificity in fleas: the effect of host body mass", "abstract": "Ecological specialization is hypothesized to result from the exploitation of predictable resource bases. For parasitic organisms, one prediction is that parasites of large-bodied host species, which tend to be long-lived, should specialize on these hosts, whereas parasites of small host species, which represent more ephemeral and less predictable resources, should become generalists. We tested this prediction by quantifying the association between the level of host specificity of fleas and the mean body mass of their mammalian hosts, using published data from 2 large, distinct geographical regions (South Africa and northern North America). In general, we found supporting evidence that flea host specificity, measured either as the number of host species exploited or their taxonomic distinctness, became more pronounced with increasing host body mass. There were, however, some discrepancies among the results depending on the different measures of host specificity, the geographical region studied, or whether we used the raw values or phylogenetically independent contrasts. These are discussed with respect to other forces acting on the evolution of host specificity in parasites, as well as in the context of the regions' contrasting evolutionary histories. Overall, though, our findings indicate that the exploitation of large-bodied, and therefore long-lived, host species has promoted specialization in fleas, most likely because these hosts represent predictable resources.", "corpus_id": 39926864, "score": 1 }, { "doc_id": "4693534", "title": "Effects of Body Size and Temperature on Population Growth", "abstract": "For at least 200 years, since the time of Malthus, population growth has been recognized as providing a critical link between the performance of individual organisms and the ecology and evolution of species. We present a theory that shows how the intrinsic rate of exponential population growth, \n\\documentclass{aastex}\n\\usepackage{amsbsy}\n\\usepackage{amsfonts}\n\\usepackage{amssymb}\n\\usepackage{bm}\n\\usepackage{mathrsfs}\n\\usepackage{pifont}\n\\usepackage{stmaryrd}\n\\usepackage{textcomp}\n\\usepackage{portland,xspace}\n\\usepackage{amsmath,amsxtra}\n\\usepackage[OT2,OT1]{fontenc}\n\\newcommand\\cyr{\n\\renewcommand\\rmdefault{wncyr}\n\\renewcommand\\sfdefault{wncyss}\n\\renewcommand\\encodingdefault{OT2}\n\\normalfont\n\\selectfont}\n\\DeclareTextFontCommand{\\textcyr}{\\cyr}\n\\pagestyle{empty}\n\\DeclareMathSizes{10}{9}{7}{6}\n\\begin{document}\n\\landscape\n$$r_{\\mathrm{max}\\,}$$\n\\end{document} , and the carrying capacity, K, depend on individual metabolic rate and resource supply rate. To do this, we construct equations for the metabolic rates of entire populations by summing over individuals, and then we combine these population‐level equations with Malthusian growth. Thus, the theory makes explicit the relationship between rates of resource supply in the environment and rates of production of new biomass and individuals. These individual‐level and population‐level processes are inextricably linked because metabolism sets both the demand for environmental resources and the resource allocation to survival, growth, and reproduction. We use the theory to make explicit how and why \n\\documentclass{aastex}\n\\usepackage{amsbsy}\n\\usepackage{amsfonts}\n\\usepackage{amssymb}\n\\usepackage{bm}\n\\usepackage{mathrsfs}\n\\usepackage{pifont}\n\\usepackage{stmaryrd}\n\\usepackage{textcomp}\n\\usepackage{portland,xspace}\n\\usepackage{amsmath,amsxtra}\n\\usepackage[OT2,OT1]{fontenc}\n\\newcommand\\cyr{\n\\renewcommand\\rmdefault{wncyr}\n\\renewcommand\\sfdefault{wncyss}\n\\renewcommand\\encodingdefault{OT2}\n\\normalfont\n\\selectfont}\n\\DeclareTextFontCommand{\\textcyr}{\\cyr}\n\\pagestyle{empty}\n\\DeclareMathSizes{10}{9}{7}{6}\n\\begin{document}\n\\landscape\n$$r_{\\mathrm{max}\\,}$$\n\\end{document} exhibits its characteristic dependence on body size and temperature. Data for aerobic eukaryotes, including algae, protists, insects, zooplankton, fishes, and mammals, support these predicted scalings for \n\\documentclass{aastex}\n\\usepackage{amsbsy}\n\\usepackage{amsfonts}\n\\usepackage{amssymb}\n\\usepackage{bm}\n\\usepackage{mathrsfs}\n\\usepackage{pifont}\n\\usepackage{stmaryrd}\n\\usepackage{textcomp}\n\\usepackage{portland,xspace}\n\\usepackage{amsmath,amsxtra}\n\\usepackage[OT2,OT1]{fontenc}\n\\newcommand\\cyr{\n\\renewcommand\\rmdefault{wncyr}\n\\renewcommand\\sfdefault{wncyss}\n\\renewcommand\\encodingdefault{OT2}\n\\normalfont\n\\selectfont}\n\\DeclareTextFontCommand{\\textcyr}{\\cyr}\n\\pagestyle{empty}\n\\DeclareMathSizes{10}{9}{7}{6}\n\\begin{document}\n\\landscape\n$$r_{\\mathrm{max}\\,}$$\n\\end{document} . The metabolic flux of energy and materials also dictates that the carrying capacity or equilibrium density of populations should decrease with increasing body size and increasing temperature. Finally, we argue that body mass and body temperature, through their effects on metabolic rate, can explain most of the variation in fecundity and mortality rates. Data for marine fishes in the field support these predictions for instantaneous rates of mortality. This theory links the rates of metabolism and resource use of individuals to life‐history attributes and population dynamics for a broad assortment of organisms, from unicellular organisms to mammals.", "corpus_id": 4693534, "score": 1 }, { "doc_id": "84361674", "title": "Ecology of marine parasites : an introduction to marine parasitology", "abstract": "The nature of parasitism the types of marine parasites the variety of hosts of marine parasites parasites of parasites general adaptations of parasitic animals host-parasite interactions the ecological niches of parasites the structure of parasite communities characteristics of parasite faunas of different seas economic and hygienic importance of marine parasites future research.", "corpus_id": 84361674, "score": 1 }, { "doc_id": "131587862", "title": "Global Biodiversity, Biochemical Kinetics, and the Energetic-Equivalence Rule", "abstract": "The latitudinal gradient of increasing biodiversity from poles to equator is one of the most prominent but least understood features of life on Earth. Here we show that species diversity can be predicted from the biochemical kinetics of metabolism. We first demonstrate that the average energy flux of populations is temperature invariant. We then derive a model that quantitatively predicts how species diversity increases with environmental temperature. Predictions are supported by data for terrestrial, freshwater, and marine taxa along latitudinal and elevational gradients. These results establish a thermodynamic basis for the regulation of species diversity and the organization of ecological communities.", "corpus_id": 131587862, "score": 0 }, { "doc_id": "28219945", "title": "Free-living endohelminth stages: at the mercy of environmental conditions.", "abstract": "During their free-living phases, endohelminths are directly exposed to environmental conditions in their respective macrohabitats. Both natural environmental factors and pollutants released into the environment through anthropogenic activities can influence the success of the free-living stages. This overview examines the effects of natural variables and pollutants on two specific properties (survival and infectivity) of free-living stages of endohelminths, mainly trematodes, while fully recognizing that other parasitic life history stages in addition to the hosts can also be affected. As most parasite pollution studies have been carried out in aquatic habitats, this paper focuses on parasites of aquatic or amphibious hosts.", "corpus_id": 28219945, "score": 0 }, { "doc_id": "22622263", "title": "Immune responses of teleost fish.", "abstract": "In fish all the pre-requisites to mount a specific immune response are present, but the main differences from the mammalian system are that the secondary response is relatively minor and IgG is not present. In teleosts mainly IgM is present, and IgD has been recently described but its function is, as yet, unknown. However, different forms of fish IgM and its observed flexibility of structure may compensate for a lack of Ig class diversity. The innate immune response of teleosts is highly developed. Multiple forms of key constitutive and inducible components, such as lysozyme, C3, alpha2-macroglobulin and C-reactive protein, are present, and may enhance immune recognition. Low ambient temperature appears to have an impact on all aspects of the immune response, particularly the T-dependent specific immune response due to the non-adaptive lipid composition of T-cell membranes. Temperature effects on the nonspecific immune system are less well characterised, but there is evidence that low temperatures are also suppressive. Knowledge of immune system function becomes essential for disease prevention strategies such as the development of vaccines, selection for increased disease resistance and identification of genes suitable for trangenesis.", "corpus_id": 22622263, "score": 0 }, { "doc_id": "9645795", "title": "Evolutionarily singular strategies and the adaptive growth and branching of the evolutionary tree", "abstract": "We present a general framework for modelling adaptive trait dynamics in which we integrate various concepts and techniques from modern ESS-theory. The concept of evolutionarily singular strategies is introduced as a generalization of the ESS-concept. We give a full classification of the singular strategies in terms of ESS-stability, convergence stability, the ability of the singular strategy to invade other populations if initially rare itself, and the possibility of protected dimorphisms occurring within the singular strategy's neighbourhood. Of particular interest is a type of singular strategy that is an evolutionary attractor from a great distance, but once in its neighbourhood a population becomes dimorphic and undergoes disruptive selection leading to evolutionary branching. Modelling the adaptive growth and branching of the evolutionary tree can thus be considered as a major application of the framework. A haploid version of Levene's ‘soft selection’ model is developed as a specific example to demonstrate evolutionary dynamics and branching in monomorphic and polymorphic populations.", "corpus_id": 9645795, "score": 0 }, { "doc_id": "3940436", "title": "Host specificity in phylogenetic and geographic space.", "abstract": "The measurement of host specificity goes well beyond counting how many host species can successfully be used by a parasite. In particular, specificity can be assessed with respect to how closely related the host species are, or whether a parasite exploits the same or different hosts across its entire geographic range. Recent developments in the measurement of biodiversity offer a new set of analytical tools that can be used to quantify the many aspects of host specificity. We describe here the multifaceted nature of host specificity, summarize the indices available to measure its different facets one at a time or in combination, and discuss their implications for parasite evolution and disease epidemiology.", "corpus_id": 3940436, "score": 1 }, { "doc_id": "86284290", "title": "Host range, host ecology, and distribution of more than 11 800 fish parasite species", "abstract": "Our data set includes 38 008 fish parasite records (for Acanthocephala, Cestoda, Monogenea, Nematoda, Trematoda) compiled from the scientific literature, Internet databases, and museum collections paired to the corresponding host ecological, biogeographical, and phylogenetic traits (maximum length, growth rate, life span, age at maturity, trophic level, habitat preference, geographical range size, taxonomy). The data focus on host features, because specific parasite traits are not consistently available across records. For this reason, the data set is intended as a flexible resource able to extend the principles of ecological niche modeling to the host–parasite system, providing researchers with the data to model parasite niches based on their distribution in host species and the associated host features. In this sense, the database offers a framework for testing general ecological, biogeographical, and phylogenetic hypotheses based on the identification of hosts as parasite habitat. Potential applications of the data set are, for example, the investigation of species–area relationships or the taxonomic distribution of host-specificity. The provided host–parasite list is that currently used by Fish Parasite Ecology Software Tool (FishPEST, http://purl.oclc.org/fishpest), which is a website that allows researchers to model several aspects of the relationships between fish parasites and their hosts. The database is intended for researchers who wish to have more freedom to analyze the database than currently possible with FishPEST. However, for readers who have not seen FishPEST, we recommend using this as a starting point for interacting with the database.", "corpus_id": 86284290, "score": 0 }, { "doc_id": "8341721", "title": "Co-infection and super-infection models in evolutionary epidemiology", "abstract": "Multiple infections are intensively studied because of their consequences for the health of the host but also because they can radically alter the selective pressures acting on parasites. I discuss how multiple infections have been modelled in evolutionary epidemiology. First, I briefly mention within-host models, which are at the root of these epidemiological models. Then, I present the super-infection framework, with an original focus on how the definition of the super-infection function can lead to evolutionary branching. There are several co-infection models and, for each of them, I briefly go through the underlying mathematics (especially the invasion fitness of a mutant strain) and I discuss the biological assumptions they make and the questions they consequently may ask. In particular, I show that a widely used co-infection model should not be invoked for invasion analyses because it confers a frequency-dependent advantage to rare neutral mutants. Finally, I present more recent frameworks, such as the Price equation framework in epidemiology, that can account for increased parasite diversity. To conclude, I discuss some perspectives for the study of multiple infections in evolutionary epidemiology.", "corpus_id": 8341721, "score": 0 }, { "doc_id": "9234104", "title": "Ecology and biogeography of marine parasites.", "abstract": "A review is given of (mainly recent) work on the biodiversity, ecology, biogeography and practical importance of marine parasites. Problems in estimating species numbers have been thoroughly discussed for free-living species, and the main points of these discussions are reviewed here. Even rough estimates of the richness of most parasite groups in the oceans are premature for the following reasons: species numbers of host groups, in particular in the deep sea and the meiofauna, are not known; most host groups have been examined only insufficiently for parasites or not at all; even in some of the best known groups, latitudinal, longitudinal and depth gradients in species richness are only poorly understood or not known at all; effects of hosts on parasite morphology and geographical variation have been studied only in a few cases; there are few studies using techniques of molecular biology to distinguish sibling species. Estimates of species richness in the best known groups, trematodes, monogeneans and copepods of marine fishes, are given. Parasites are found in almost all taxa of eukaryotes, but most parasitic species are concentrated in a few taxa. Important aspects of the ecology of marine parasites are discussed. It is emphasized that host specificity and host ranges should be distinguished, and an index that permits calculation of host specificity is discussed. The same index can be applied to measure site specificity. Central problems in ecology are the importance of interspecific competition and whether equilibrium or non-equilibrium conditions prevail. Marine parasites are among the few groups of organisms that have been extensively examined in this regard. A holistic approach, i.e. application of many methods, has unambiguously shown that metazoan ecto- (and probably endo-) parasites of marine fish live in largely non-saturated niche space under non-equilibrium conditions, i.e. they live in assemblages rather than in communities structured by competition. Nestedness occurs in such assemblages, but it can be explained by characteristics of the species themselves. There is little agreement on which other factors are involved in \"structuring\" parasite assemblages. Few studies on metapopulations of marine parasites have been made. A new approach, that of fuzzy chaos modelling, is discussed. It is likely that marine parasites are commonly found in metapopulations consisting of many subpopulations, and they are ideally suited to test the predictions of fuzzy chaos. Some recent studies on functional ecology and morphology--especially with regard to host, site and mate finding--are discussed, and attention is drawn to the amazing variety of sensory receptors in some marine parasites. Effects of parasites on hosts, and some studies on the evolution and speciation of marine parasites are discussed as well. A detailed overview of biogeographical studies is given, with respect to latitudinal gradients in species diversity, reproductive strategies and host ranges/specificity. Studies of marine parasites have contributed significantly to giving a non-equilibrium explanation for latitudinal diversity gradients. Recent studies on longitudinal and depth gradients are discussed, as well as parasites in brackish water, parasites as indicators of zoogeographical regions and barriers, and parasites as biological tags. The practical importance of marine parasites in mariculture, as monitors of pollution, agents of human disease, the use of parasites for controlling introduced marine pests, and some related aspects, are also discussed.", "corpus_id": 9234104, "score": 0 }, { "doc_id": "6646939", "title": "Next-generation tools for evolutionary invasion analyses", "abstract": "Evolutionary invasion analysis is a powerful technique for modelling in evolutionary biology. The general approach is to derive an expression for the growth rate of a mutant allele encoding some novel phenotype, and then to use this expression to predict long-term evolutionary outcomes. Mathematically, such ‘invasion fitness’ expressions are most often derived using standard linear stability analyses from dynamical systems theory. Interestingly, there is a mathematically equivalent approach to such stability analyses that is often employed in mathematical epidemiology, and that is based on so-called ‘next-generation’ matrices. Although this next-generation matrix approach has sometimes also been used in evolutionary invasion analyses, it is not yet common in this area despite the fact that it can sometimes greatly simplify calculations. The aim of this article is to bring the approach to a wider evolutionary audience in two ways. First, we review the next-generation matrix approach and provide a novel, and easily intuited, interpretation of how this approach relates to more standard techniques. Second, we illustrate next-generation methods in evolutionary invasion analysis through a series of informative examples. Although focusing primarily on evolutionary invasion analysis, we provide several insights that apply to biological modelling in general.", "corpus_id": 6646939, "score": 0 }, { "doc_id": "85748044", "title": "Conservation evaluation and phylogenetic diversity", "abstract": "Protecting biological diversity with limited resources may require placing conservation priorities on different taxa. A system of priorities that reflects the value of taxonomic diversity can be achieved by setting priorities such that the subset of taxa that is protected has maximum underlying feature diversity. Such feature diversity of taxon subsets is difficult to estimate directly, but can be predicted by the cladistic/phylogenetic relationships among the taxa. In this study, a simple measure of phylogenetic diversity is defined based on cladistic information. The measure of phylogenetic diversity, PD, is contrasted with a measure of taxic diversity recently developed by Vane-Wright et al. (Biol. Conserv., 55, 1991). In re-examining reserve-selection scenarios based on a phylogeny of bumble bees (Apidae), PD produces quite different priorities for species conservation, relative to taxic diversity. The potential application of PD at levels below that of the species is then illustrated using a mtDNA phylogeny for populations of crested newts Triturus cristatus. Calculation of PD for different population subsets shows that protection of populations at either of two extremes of the geographic range of the group can significantly increase the phylogenetic diversity that is protected.", "corpus_id": 85748044, "score": 0 }, { "doc_id": "6469345", "title": "Host traits and parasite species richness in even and odd-toed hoofed mammals, Artiodactyla and Perissodactyla", "abstract": "Host social, ecological and life history traits are predicted to influence both parasite establishment within host species and the distribution of parasites among host species. Yet only a few studies have investigated the role multiple host traits play in determining patterns of infection across diverse parasite groups. To explore the association between host traits and parasite species richness (PSR), we assembled a comprehensive database encompassing 601 parasites (including viruses, bacteria, protozoa, helminths and arthropods) reported to infect 96 species from two well-studied and diverse host clades: even- and odd-toed hoofed mammals (Artiodactyla and Perissodactyla). Comparative analyses were used to examine associations between three sets of host variables (life history and body mass, social and mating behavior, and ecological traits) and PSR for all parasites combined and for distinct parasite sub-groups. Results from a combination of phylogenetic and non-phylogenetic tests showed that PSR increased with host body size across all parasites groups. Counter to expectations, measures of parasite diversity decreased with host longevity and social group size, and associations between group size and PSR further depended on the underlying mating system of the host species. Our results suggest that body mass, longevity, and social organization influence the diversity and types of parasites reported to infect wild populations of hoofed mammals, and that multiple host and parasite traits can combine in unexpected ways to shape observed patterns.", "corpus_id": 6469345, "score": 0 }, { "doc_id": "18452657", "title": "Can host body size explain the parasite species richness in tropical freshwater fishes?", "abstract": "SummaryThe variability of monogenean gill ectoparasite species richness in 19 West African cyprinid species was analyzed using the following seven predictor variables: host size, number of drainage basins, number of sympatric cyprinid species, host diversity, association with mainland forest, host ecology, and monogenean biological labelling. The size of the host species accounted for 77% of the variation in the number of parasite species per host, and host ecology an additional 8%. Together the effects of host size and host ecology accounted for 85% of the variation in monogenean species richness. This study shows that the deciding factors for explaining monogenean species richness in West African cyprinid fishes are host species size and host ecology. These results were compared with main factors responsible for parasite species richness in fish communities. Other possible explanations of monogenean community structure in west African cyprinids are discussed.", "corpus_id": 18452657, "score": 0 }, { "doc_id": "41249400", "title": "Determinants of host-specificity in parasites of freshwater fishes.", "abstract": "Factors responsible for interspecific variability in host-specificity were investigated within 15 genera (including 176 species) of metazoan parasites found in Canadian freshwater fish. For each species in a genus, the parasite's number of known hosts was determined from published host-parasite records. The effects of the total number and mean size of potential hosts (i.e. all fish species belonging to the family or families that include a parasite's known hosts) on number of hosts of congeneric species were evaluated using multiple regressions. Since parasite species that have been recorded often tend to have greater numbers of known hosts than do seldom-recorded parasites, it was necessary to control for the confounding effect of study intensity. In all parasite genera, whether from highly specific taxa such as monogeneans or from less host-specific ones, there was a positive relationship between the number of potential hosts and the number of known hosts. However, no consistent relationships were observed between the mean size of potential hosts and number of known hosts. These results suggest that the availability of suitable host species may have been a key factor limiting the colonization of new hosts by fish parasites.", "corpus_id": 41249400, "score": 0 }, { "doc_id": "85351416", "title": "Assessing Functional Explanations of Host-Specificity", "abstract": "Many species of aphids, cyst-nematodes, and other parasites show considerable host-specificity. A number of factors have been invoked to explain this specificity: nutritional quality and host-plants' secondary chemicals (Ehrlich and Raven 1964; Feeny 1976), natural enemies (Lawton 1978; Bernays and Graham 1988), and the need to find mates by first seeking a host (Rohde 1979). What these explanations share is the implicit assumption that host-selection behavior is adaptive, that the observed host range is, or is close to, an evolutionarily stable strategy. In other words, the restricted host range observed is near-optimal because natural enemies or chemical defenses would reduce the fitness of any parasites that extended it. Although evidence is often presented that nonhosts, or nonpreferred hosts, are indeed less suitable than preferred hosts, it is difficult o determine whether the factors invoked can provide a sufficient explanation of the observed specificity. To do this we need to know how unsuitable a host must be for an optimally foraging parasite to reject it. Quantitative criteria are required for assessing the sufficiency of such implicitly game-theoretic explanations. The literature contains a number of models for the evolution of host range or habitat specificity (e.g., Levins and MacArthur 1969; Doyle 1975; Jaenike 1978; Ward 1987a), but these are difficult o apply since they include terms such as \"rate of encounter\" or \"instantaneous mortality,\" which cannot easily be measured in the field. In this note I show how such models can be used to check whether proposed selection pressures are strong enough to account for hostspecificity, without the need for detailed measurements of behavior or mortality in the field. I first derive equations that express the conditions for specificity in terms of the proportion of dispersing parasites that find hosts; I then simplify these conditions, assuming that the parasite population is at equilibrium. Finally, I show how these conditions can be used to assess explanations of host-specificity.", "corpus_id": 85351416, "score": 0 }, { "doc_id": "22220024", "title": "Transmission rates and adaptive evolution of pathogens in sympatric heterogeneous plant populations", "abstract": "Diversification in agricultural cropping patterns is widely practised to delay the build–up of virulent races that can overcome host resistance in pathogen populations. This can lead to balanced polymorphism, but the long–term consequences of this strategy for the evolution of crop pathogen populations are still unclear. The widespread occurrence of sibling species and reproductively isolated sub–species among fungal and oomycete plant pathogens suggests that evolutionary divergence is common. This paper develops a mathematical model of host–pathogen interactions using a simple framework of two hosts to analyse the influences of sympatric host heterogeneity on the long–term evolutionary behaviour of plant pathogens. Using adaptive dynamics, which assumes that sequential mutations induce small changes in pathogen fitness, we show that evolutionary outcomes strongly depend on the shape of the trade–off curve between pathogen transmission on sympatric hosts. In particular, we determine the conditions under which the evolutionary branching of a monomorphic into a dimorphic population occurs, as well as the conditions that lead to the evolution of specialist (single host range) or generalist (multiple host range) pathogen populations.", "corpus_id": 22220024, "score": 0 }, { "doc_id": "37892400", "title": "Experimental evolution of parasites.", "abstract": "Serial passage experiments are a form of experimental evolution that is frequently used in applied sciences; for example, in vaccine development. During these experiments, molecular and phenotypic evolution can be monitored in real time, providing insights into the causes and consequences of parasite evolution. Within-host competition generally drives an increase in a parasite's virulence in a new host, whereas the parasite becomes avirulent to its former host, indicating a trade-off between parasite fitnesses on different hosts. Understanding why parasite virulence seldom escalates similarly in natural populations could help us to manage virulence and deal with emerging diseases.", "corpus_id": 37892400, "score": 0 }, { "doc_id": "87850232", "title": "Life-history traits in parasitic nematodes : a comparative approach for the search of invariants", "abstract": "1. This study investigates the evolution of life-history traits in parasitic and free-living nematodes. A database on 35 species was assembled for values on: body size of female nematodes; egg production; life expectancies of both adult and free-stages; the length of maturation time for free-living nematodes and prepatent period for parasites (time needed for an infective stage to reach maturity in its definitive host). Comparative methods were used to account for the effects of phylogeny. 2. The well-known allometries of life-history traits with body size were found, such as the allometry between size and total fecundity. Daily fecundity and prepatent period of parasitic nematodes are both correlated with body size, suggesting that delaying maturity increases fecundity. 3. Phylogeny affects relationships between investigated life-history traits, i.e. daily reproductive output (b) and female life expectancy (1/M). 4. Prepatent period (a) in parasitic nematodes is equivalent to maturation time (a) of free-living nematodes. 5. A search was carried out for life-history invariants (Charnov 1993). There was no correlation between prepatent period (a) and daily reproductive output (b) and hence no invariant ab. This could be explained by constrained life styles of reproduction among Nematoda. Indeed, invariant aM (or aM, where M is the mortality rate of adult stage) were found for both parasites of vertebrate ((aM) = 0.23) and free-living, plant and insect nematodes ((aM) = 0.50). 6. A causal chain of evolution of life-history traits of parasite nematodes is proposed and discussed. It is suggested that adult mortality is the main factor driving the evolution of life-history traits.", "corpus_id": 87850232, "score": 0 }, { "doc_id": "40683788", "title": "Helminth fecundity: density dependence or statistical illusion?", "abstract": "Density-dependent constraints on fecundity or survival are critical for the regulation and stability o f all populations. Helminth parasites are no exception to this rule. In medical helminthology, it has been widely assumed that the most effective density-dependent constraints act upon parasite fecundity and are the result of intra-specific parasite competition or acquired immunity to infection. In this article, Anne Keymer and Andrew Slater advocate a more detailed examination of the evidence on which this assumption rests.", "corpus_id": 40683788, "score": 0 }, { "doc_id": "33833318", "title": "Home Range and Parasite Diversity in Mammals", "abstract": "Parasite diversity among and within host species is not solely the result of random processes; rather, it depends on a suite of physiological or ecological host traits as well as environmental factors. Because most macroparasites exhibit life cycles that include infective stages off the definitive host and that rely on host movements for dissemination, parasite acquisition by a host depends largely on hosts being present in a given area where and when infective stages are present. Consequently, host ranging pattern may have a major influence on parasite diversity. Larger home range size is hypothesized to be associated with higher parasite species richness because hosts living in large home ranges should encounter a greater diversity of habitats and other host individuals, which in turn may favor infection by a great diversity of parasite species. By focusing on helminths in wild mammals, we show that an increase in home range area does not lead to an increase in parasite diversity in ungulates and, moreover, that it is associated with a decrease in parasite species richness in carnivores and in glires (rodents and lagomorphs). We also show that home range size is negatively correlated with host density in mammals after correcting both variables for host body mass. We discuss these results from an epidemiological perspective.", "corpus_id": 33833318, "score": 0 } ]

{ "doc_id": "55748128", "title": "Sustainable infrastructure delivery in Nigeria: implementation of the analytic network process for contractor selection", "abstract": "Purpose: This paper presents research findings that involve the use of analytic network process (ANP) to select contractors for build–operate–transfer (BOT) infrastructure in Nigeria. To deliver sustainable infrastructure (SI), a responsive methodology is required for contractors' selection process, which combines judgement and data for an effective outcomes prediction. Design/methodology/approach: Theoretically grounded on a system theory, sustainable infrastructure delivery (SID) model has been developed in this study. At the deductive phase of the model is the integration of the ANP (a multicriteria decision-making technique) for data synthesis. To obtain decision criteria, 55 sustainability indicators for contractor selection were identified from the literature review. The criteria were first developed to a web-based questionnaire where respondents were requested to rank the importance of the criteria towards selecting contractors that deliver SI, using Likert scale of 1–5 (where “5” is very important and “1” is not important). The results were analysed using factor analysis. Data were further reduced to 16 variables after multicollinearity issues in the data set had been resolved. To weigh the relative importance of the 16 criteria among contractors, ANP methodology was adopted for the second-round questionnaire. The seven-man decision panel that completed the pairwise comparison survey was selected through a purposeful sampling technique. The final survey results were synthesised by Super Decisions (computer package that implements ANP) trial version to rank contractors' options and predict outcomes. Findings/results: Sensitivity analysis of the research findings reveals that the 16 criteria have differential comparative advantages, which requires critical judgement during contractor's pre-evaluation process. Although the overall priorities rank multinational construction corporations (MCC) higher than local construction companies (LCC), MCC are not absolute to deliver SI. LCC are sensitive to some key criteria that are critical to the actualisation SI agenda. Originality/value: This study fills the gap in the knowledge of SID in Nigeria. The study theoretically suggests a framework to harmonise sustainability indicators in contractor selection. The findings further provide feedbacks that can be incorporated to Government's Ministries, Department and Agencies (MDAs) procurement policy to promote SID.", "corpus_id": 55748128 }

[ { "doc_id": "111309103", "title": "A strategic framework for sustainable construction in developing countries", "abstract": "There is no doubt that large-scale development in the built environment and its physical infrastructure is needed in the so-called 'developing countries'. However, these problems need to be addressed in a way that is socially and ecologically responsible. There is great urgency to make sustainable interventions now, while these built environments are being created, rather than try and change things after the fact. However, there are a number of challenges to the introduction of sustainable construction technologies and practices, and certain enablers need to be developed to help these countries adopt a more sustainable path. The Agenda 21 for Sustainable Construction in Developing Countries suggested a strategy for addressing some of these challenges by developing a Research and Development Agenda, based on a matrix of immediate, medium-term and long-term technological, institutional and value enablers. This Agenda is supported by a Stakeholder Plan for Action. The challenge now is to find the means to implement these suggestions at a local level by developing regional and national action plans.", "corpus_id": 111309103, "score": 1 }, { "doc_id": "108685046", "title": "A framework for the strategic development of the construction industry in developing countries", "abstract": "The authors explore construction industry problems in developing countries and the approaches that have been successful in Newly Industrialized Countries (NICs) and develop a framework for strategic development.", "corpus_id": 108685046, "score": 0 }, { "doc_id": "154665604", "title": "Combating Poverty for Sustainable Human Development in Nigeria: The Continuing Struggle", "abstract": "ABSTRACT Poverty is by all standards a condition of deprivation that impedes human development. Given Nigeria's vast resource base, she ordinarily should have no business with poverty. In fact, she should rank among the richest countries of the world. Ironically, the reverse has so far been the case. This article critically engages the perennial problem of poverty in Nigeria with emphasis on its impacts on human development. The article argues that the pervasiveness and persistence of poverty in the country is a massive betrayal of her rich resource base. The failure of antipoverty initiatives, with its attendant negative implications, may not be unconnected with the pervasiveness of perverse incentive structures that engender and nourish opportunism at the expense of a fairly even distribution of income and wealth. If the new initiatives must yield dividends, the article contends that the democratization process must be energized, the role of the state in the developmental process revisited, community self-help projects encouraged, and socioeconomic growth accelerated. Then human development can be attained and sustained.", "corpus_id": 154665604, "score": 1 }, { "doc_id": "153885970", "title": "Poverty and Globalization in Africa", "abstract": "Poverty in Africa is not an indigenous problem.’ It is intertwined with Africa’s relations with the rest of the world. Scholars generally agree that Africa’s poverty is embedded within the global capitalist system and associated with the global socio-political structures that maintain it (Ake, 1987; Wallerstein, 1993; Edoho, 1997; Thomas, 1999); and that Africa has been part of this global economy for centuries (Berlin, 1998; Mshoma, 2000). A contemporary interpretation of this global economy is The concept refers to a continual process of integrating local economies into the world capitalist system as well as their transformation. Globalization is seen to entail changes in all dimensions of society, states and markets. It is said to be driven by the quest for higher returns on financial capital. Globalization is justified by the promise of a trickle down of the financial benefits to all people in society (Pasha, 1995). However, benefits have so far accrued developed countries. In particular, the African continent has failed to benefit.", "corpus_id": 153885970, "score": 1 }, { "doc_id": "110682122", "title": "Indicators for measuring construction industry development in developing countries", "abstract": "The problems of construction industries in developing countries are well researched. For over three decades, proposals have been made for action to address these difficulties. Developing countries have implemented these recommendations, and other initiatives. However, results have been disappointing and the problems have persisted. A possible reason for the lack of progress is the absence of measurable targets in construction industry development programmes to guide and assess, at intervals, the success of their implementation. This paper critically discusses the formulation of a set of indicators for measuring and monitoring progress in the effort to improve the construction industry in a developing country. Previous proposals of indicators and those used in Singapore are examined. A set of indicators is suggested and their merits and possible problems are considered. Recommendations are made on how the indicators can be most effectively implemented. Les problèmes liés à l'industrie du bâtiment dans les pays en voie de développement sont clairement définis. Pendant plus de trois décennies, des propositions ont été formulées en vue de mener des actions visant à surmonter ces difficultés. Les pays en voie de développement ont suivi ces recommandations et pris d'autres initiatives. Néanmoins, les résultats ont été décevants et les problèmes ont persisté. L'une des raisons possibles du manque d'avancée est l'absence d'objectifs mesurables dans les programmes de développement de l'industrie du bâtiment, qui permettraient de guider et d'évaluer, par intervalles, la réussite de leur mise en oeuvre. Le présent document aborde de façon critique la formulation d'un groupe d'indicateurs destinés à mesurer et à surveiller la progression des efforts destinés à améliorer l'industrie du bâtiment dans un pays en voie de développement. Il examine également les propositions antérieures relatives à des indicateurs, ainsi que celles utilisées à Singapore. Il suggère enfin un groupe d'indicateurs et examine leurs avantages et leurs inconvénients éventuels. Des recommendations visant à optimiser l'utilisation de ces indicateurs sont également formulées.", "corpus_id": 110682122, "score": 1 }, { "doc_id": "153416036", "title": "Challenges of Youth Unemployment in Nigeria: Effective Career Guidance as a Panacea", "abstract": "Unemployment has become a major problem bedeviling the lives of Nigerian youth, causing increased militancy, violent crimes, kidnappings, restiveness and socially delinquent behaviour. Youth unemployment is devastating to both the individual and the society as a whole both psychologically and economically. The paper examines the issue of youth unemployment and looks at potential interventions such as effective career guidance, technical and vocational education as well entrepreneurship education. A number of recommendations were made which include that youths should be trained to possess skills which are congruent with real labour market demand, developing a special focus on career guidance and counselling support in schools and introduction of entrepreneurship education into the school curriculum. Key words: Youth unemployment, career guidance, panacea, entrepreneurship, technical and vocational education.", "corpus_id": 153416036, "score": 1 }, { "doc_id": "167427619", "title": "Benchmarking parties’ obligations in the execution of concession-based PPP projects in Nigeria", "abstract": "Purpose – Demand–supply matrices with adverse consequences has occasioned government response to concession initiatives in infrastructure in Nigeria. However, concession-based projects have been trailed by administrative and legal controversies. While this scenario has negatively impacted the acceptability of a concession contract, there is, nevertheless, a paucity of research effort aimed at developing a sustainable framework. The purpose of this paper is to develop a conceptual framework for the evaluation and allocation of obligations of parties, thereby enhancing the synergy and cooperation between the public and private sector organization. Design/methodology/approach – Data were obtained through a questionnaire administered to professionals in concession-based contracts in southwestern Nigeria, which included architects, estate surveyors, quantity surveyors, engineers and builders, accountants/bankers/economists and lawyers. The respondents were selected using random and respondent driven sampling a...", "corpus_id": 167427619, "score": 1 }, { "doc_id": "111093676", "title": "From demand driven contractor selection towards value driven contractor selection", "abstract": "The procurement of a construction contractor should consider more aspects than only cost or price. Taking value and price into account to select the ‘best value for money’ bid results in adopting a structured multi‐criteria approach. An alternative contractor selection method is presented, which identifies the contractor with the best potential to deliver the highest value for money. An investigation of the client needs and product performances for contractor selection has been conducted for a building type, and the relative weight of each product performance is analysed through a questionnaire. The relative weights of the product performances are identified by allocating a fictional budget to the client needs and translating these values into the relative weight of the product performances by using the quality function deployment method. In the contractor selection method, the relative importance of the product performances are combined with the scores of the bids, resulting in the best bid and contractor in a specific building project.", "corpus_id": 111093676, "score": 1 }, { "doc_id": "154663986", "title": "China's relations with Nigeria", "abstract": "Abstract Nigeria has become one of China's most important trading partners. China is investing heavily in Nigeria in both commercial and political terms. This article analyses the relationship between China and Nigeria and suggests ways it might develop in the future.", "corpus_id": 154663986, "score": 1 }, { "doc_id": "159030329", "title": "The need for economic performance measures for life cycle costing of sustainable commercial office buildings", "abstract": "Purpose \n \n \n \n \nThe purpose of this paper is to investigate the current level of awareness, usage and advocated benefits of economic performance measures of life cycle costing (LCC) in sustainable commercial office buildings. \n \n \n \n \nDesign/methodology/approach \n \n \n \n \nQuestionnaire survey to 120 construction professionals was used to gauge the current level of awareness, usage and advocated benefits of economic performance measures in LCC. \n \n \n \n \nFindings \n \n \n \n \nThe key findings of the statistical analysis indicated that there is a low awareness and usage of economic performance measures, and revealing the entire value of capital outflow alternatives was the most advocated benefit of its application. \n \n \n \n \nResearch limitations/implications \n \n \n \n \nAlthough the data used in this paper were from professionally qualified members of either the Royal Institution of Chartered Surveyors (RICS), the Chartered Institute of Building (CIOB) and the British Institute for Facilities Management (BIFM), the research is limited in some ways in that it does not cover all the professionals in the construction industry. Nevertheless, all the professionals who responded to the questionnaire have up-to-date level of awareness of economic performance measures in LCC. \n \n \n \n \nPractical implications \n \n \n \n \nThe use of economic performance measures helps to make available the information required for building performance. Therefore, economic performance methods in LCC are useful devices for users to appraise and distribute recognisable values from initial costs, operating and maintenance costs to clients in the life cycle of an asset. \n \n \n \n \nSocial implications \n \n \n \n \nValue for money for construction products and its facilities should not be viewed only in terms of costs to design and construction. Rather, it is vital for corporate occupants and society in general to consider other key variables such as operations, maintenance, renovation, replacement and end-of-life costs. \n \n \n \n \nOriginality/value \n \n \n \n \nThis study fills the gap in the existing knowledge by addressing concerns over performance measurement to improve the confidence in LCC for sustainable commercial office buildings.", "corpus_id": 159030329, "score": 0 }, { "doc_id": "109462686", "title": "Understanding barriers affecting the selection of sustainable materials in building projects", "abstract": "Abstract The selection of sustainable building materials has been identified as an important strategy in the design of a building. Although the sustainability imperative is gaining in importance, there are still major barriers preventing this’‘new style’ architectural practice becoming the norm. This paper examines the major barriers encountered in the selection of sustainable building materials among building construction professionals in Nigeria. A questionnaire survey was developed to capture the perception of construction professionals regarding the significance of the identified barriers as it affects the selection and use of sustainable building materials. Case studies of three completed building projects were conducted with design team to validate the result of the survey. Research results show that perception of extra cost being incurred and lack of sustainable material information are identified as the top barriers to sustainable materials selection. The paper concludes with suggestions and actions that can help overcome these existing barriers.", "corpus_id": 109462686, "score": 0 }, { "doc_id": "110218333", "title": "Time‐cost model for building projects in Nigeria", "abstract": "The concept of project duration is important in assessing the success or viability of a construction project. A time‐cost relationship for construction projects in Nigeria has been developed based on Bromilow's time‐cost model. Cost data on 87 completed building projects executed within the period 1991–2000 were obtained. The data were subjected to regression analyses using double log and later the piecewise model with breakpoint. For the Nigerian situation, the Bromilow's time‐cost model was found to be T = 63C0.262 with poor predictive abilities (R = 0.453, R2 = 0.205). An improved model using piecewise model with good predictive abilities (R = 0.875, R2 = 0.765) was found to be T = 118.563−0.401C (C ⩽ 408) or 603.427 + 0.610C (C>408). The model is shown to be useful in predicting construction project durations.", "corpus_id": 110218333, "score": 0 }, { "doc_id": "110283047", "title": "Influence of quality performance on clients’ patronage of indigenous and expatriate construction contractors in Nigeria", "abstract": "Abstract Contractors operating in Nigeria are classified as either indigenous or expatriates. The latter is often giving preference over the former in the award of contracts and stakeholders consider this practice unhealthy for growth and development. This study evaluates the influence of the quality performance of the two categories of contractors on their patronage. The objectives are to determine the level and difference in the patronage and quality performance of indigenous and expatriate contractors and the correlation between clients’ assessment of the quality performance and patronage of indigenous and expatriate contractors in the Nigerian construction industry. To achieve these objectives, a field survey involving a sample of 43 clients selected from the population of organised clients in Nigeria was conducted. Structured questionnaires were used to collect data. The data collected were analysed to determine the ranking and test of difference in clients’ patronage and clients’ assessment of quali...", "corpus_id": 110283047, "score": 1 }, { "doc_id": "152391186", "title": "Nigeria's Economic Reforms: Progress and Challenges", "abstract": "Following years of economic stagnation, Nigeria embarked on a comprehensive reform program during the second term of the Obasanjo administration. The program was based on the National Economic Empowerment and Development Strategy (NEEDS) and focused on four main areas: improving the macroeconomic environment, pursuing structural reforms, strengthening public expenditure management, and implementing institutional and governance reforms. This paper reviews Nigeria's recent experience with economic reforms and outlines major policy measures that have been implemented. Although there have been notable achievements under the program, significant challenges exist, particularly in translating the benefits of reforms into welfare improvements for citizens, in improving the domestic business environment, and in extending reform policies to states and local governments. Consequently, we argue that the recent reform program must be viewed as the initial steps of a much longer journey of economic recovery and sustained growth. This paper concludes by outlining a number of outstanding issues that future Nigerian administrations must address.", "corpus_id": 152391186, "score": 1 }, { "doc_id": "91182167", "title": "Risk management framework for build, operate and transfer (BOT) projects in Kuwait", "abstract": "AbstractSuccessful implementation of build-operate-transfer (BOT), infrastructure projects is dependent on a full and thorough analysis of factors that include social, economic and political, amongst others. Alongside the financially focused evaluations, qualitative factors will also have a strong impact on the project and so require specific techniques for the analysis. This paper presents a new evaluation framework, based on the analytical hierarchy process technique, for use in assessing the most common and significant decision factors relating to risks in BOT projects. Consultations with an expert group identified a series of risk decision factors. The results produced twenty-eight critical Risk Factors, which have a particular impact on the risks of BOT projects. The project risk framework was constructed by classifying the factors into five categories. The framework was successfully validated using a BOT project case study. This research seeks to make a valuable contribution to the field by having d...", "corpus_id": 91182167, "score": 0 }, { "doc_id": "152925523", "title": "Infrastructure development through PPPs in India: criteria for sustainability assessment", "abstract": "Public private partnerships (PPPs) allow the Indian Government to leverage private capital for meeting the widening demand-supply gap in the provision of infrastructure services. The private sector, however, prefers to limit the participation to financially attractive projects only, thereby resulting in patterns of infrastructure creation impeding the progress towards sustainable development. In order to promote sustainable development, the PPP procurement process should focus on incentivising the private sector for sustainable infrastructure development rather than concentrating on ensuring financial sustainability only. This paper discusses the principles-based PPP-specific framework that has been developed to facilitate assessment of PPP projects' progress towards sustainable development. The framework development was based on a holistic approach to sustainability assessment and subsequently validated through questionnaire survey with key stakeholders in the Indian PPP programme. This framework will provide the decision makers with appropriate decision aid for integration of sustainable development principles in the PPP procurement process.", "corpus_id": 152925523, "score": 0 }, { "doc_id": "31313317", "title": "Construction costs and value management: study of multinational practices in Nigeria", "abstract": "The practice of multinational construction corporations (MCC) in Nigeria construction industry has been viewed as a value for money approach through construction cost management. Assessment of the opportunity cost of the initiatives is equally important in order to gauge the progress of millennium development goals (MDGs), set up by the United Nations in 2000 on human development in developing countries. The study is aimed at the evaluation of current infrastructure procurement framework, introducing novel sustainable infrastructure delivery (SID) model as a holistic value management methodology and a decision making technique. Key components of the model are Checkland’s soft system methodology (SSM) and analytic network process (ANP) by Saaty. SID input data is collected from the pilot questionnaire with the professionals in Nigeria’s construction industry, reinforced by a thorough literature review. Questions sought paired comparison judgements on key aspects of project management and implications on sustainable infrastructure procurement. The concept is discussed in the methodology section. Preliminary findings reveal that current practice lacks a holistic decision making technique, reflected in divergent value interests among stakeholders on infrastructure procurement through different views on the constitution of values. Though there is practical evidence regarding the growth in the construction sector, quantification of the implications on local economy and human development are less visible and require further investigations.", "corpus_id": 31313317, "score": 0 }, { "doc_id": "110306809", "title": "Contractors’ Selection Criteria: Opinions of Palestinian Construction Professionals", "abstract": "Abstract Bid awarding practice in Palestine suffers from a myriad of problems. The aggressive competition, as well as the selection of the lowest bidder, may be considered as the major causes of such problems. The aim of this paper is to investigate the opinions of Palestinian construction professionals concerning contractors’ evaluation and selection criteria. A questionnaire survey was adopted for this study, incorporating 38 factors that are believed to be related to contractors’ selection. These factors were identified through a rigorous literature review, and grouped into 10 classes. The results show that the financial evaluation of the bid is considered as the most important class, being ranked in the first position, with a weight equal to 40.10%. The remaining nine classes are all related to technical criteria, with a total weight of 59.90%. The respondents placed a very low emphasis on the health and safety criteria, indicating a substantial lack of awareness of the importance of health and safety. There needs to be a paradigm shift in selecting contractors based upon lowest price to multi-criteria selection. Such a process can be implemented by establishing alternative methods to select the contractors, based on technical and financial criteria. Local official authorities need to make legislative changes on related statutes/law, so that the awarding committees can lawfully consider the only cost, as well as technical factors that are useful to predict the quality of the construction. The findings offer local clients some assistance with reviewing their process when assessing bids received from contractors. Further, the findings also help contractors to improve their bid preparation so that their bid more closely aligns with factors considered important by the clients.", "corpus_id": 110306809, "score": 0 }, { "doc_id": "108972232", "title": "Contractor selection using the analytic network process", "abstract": "Contractor selection is one of the main activities of clients. Without a proper and accurate method for selecting the most appropriate contractor, the performance of the project will be affected. The multi‐criteria decision‐making (MCDM) is suggested to be a viable method for contractor selection. The analytic hierarchy process (AHP) has been used as a tool for MCDM. However, AHP can only be employed in hierarchical decision models. For complicated decision problems, the analytic network process (ANP) is highly recommended since ANP allows interdependent influences specified in the model. An example is demonstrated to illustrate how this method is conducted, including the formation of supermatrix and the limit matrix.", "corpus_id": 108972232, "score": 1 }, { "doc_id": "110433485", "title": "Targeting optimum value in public sector projects through “best value”‐focused contractor selection", "abstract": "Procuring best value should be one of the key objectives in public sector construction projects. Best value depends upon sound “selection” strategies which ensure that the outlined project procurement objectives, including client/user demands are met. Examples of “best value” procurement are presented to demonstrate their usefulness and acceptance in principle. Further conceptualizations of various aspects of best value and the “dominance vectors” influencing the ultimate value definitions are developed, in accordance with basic public sector procurement principles. Presents a structured best value based contractor selection framework to optimize realizable value in public sector construction projects.", "corpus_id": 110433485, "score": 1 }, { "doc_id": "111255611", "title": "Benchmarking contractor selection practices in public‐sector construction—a proposed model", "abstract": "Benchmarking of best practices has proved useful in the business and manufacturing sectors. However, benchmarking is not established in the construction industry in general and in government organizations in particular. A study of the contractor selection methodologies used by various clients confirms the multiplicity of approaches in practice. This paper aims at identifying some relevant ‘best’ practices and highlighting ‘innovative’ contractor selection approaches that have been used by large public clients. A ‘co‐operative’ and ‘non‐competitive’ conceptual benchmarking model is formulated and presented with a view to encouraging continuous improvement in contractor selection for construction projects.", "corpus_id": 111255611, "score": 0 }, { "doc_id": "110812145", "title": "Lowest price or value? Investigation of UK construction clients' tender selection process", "abstract": "There is a growing urge for a shift from ‘lowest-price wins’ to ‘multi-criteria selection’ practices in the contractor selection process. The rationale is to achieve best value (for money) for the client. Earlier investigations have found that the tender price (i.e. capital cost) still dominates the final selection decision despite increased emphases on the need for contractor selection based on ‘value’. This paper provides insights into the evaluation of contractors' attributes, particularly for project-specific criteria (PSC), that is, criteria against which tendering contractors may be considered. The importance attached by clients to the ‘lowestprice wins’ philosophy is also reported. The perceived importance of PSC (i.e. their influence on final selection choice) is determined through a structured questionnaire survey of UK construction clients. The results show an increasing use of PSC. It is also found that ‘lowest-price’ is not now necessarily the client's principal selection criterion, but rather, the realization that cost has to be tempered with evaluation of PSC in any attempt to identify value for money.", "corpus_id": 110812145, "score": 1 }, { "doc_id": "23736198", "title": "An Analytic Network Process approach for siting a municipal solid waste plant in the Metropolitan Area of Valencia (Spain).", "abstract": "In this paper the Analytic Network Process (ANP) is applied to select the best location for the construction of a municipal solid waste (MSW) plant in the Metropolitan area of Valencia (Spain). Selection of the appropriate MSW facility location can be viewed as a complex multicriteria decision-making problem that requires an extensive evaluation process of the potential MSW plant locations and other factors as diverse as economic, technical, legal, social or environmental issues. The decision-making process includes the identification of six candidate MSW plant sites and 21 criteria grouped into clusters for the construction of a network. Two technicians of the Metropolitan Waste Disposal Agency acted as decision makers (DMs). The influences between the elements of the network were identified and analyzed using the ANP multicriteria decision method. Two different ANP models were used: one hierarchy model (that considers AHP as a particular case of ANP) and another network-based model. The results obtained in each model were compared and analyzed. The strengths and weaknesses of ANP as a multicriteria decision analysis tool are also described in the paper. The main findings of this research have proved that ANP is a useful tool to help technicians to make their decision process traceable and reliable. Moreover, this approach helps DMs undertake a sound reflection of the siting problem.", "corpus_id": 23736198, "score": 0 }, { "doc_id": "9570761", "title": "DECISION MAKING WITH THE ANALYTIC HIERARCHY PROCESS", "abstract": "Decisions involve many intangibles that need to be traded off. To do that, they have to be measured along side tangibles whose measurements must also be evaluated as to, how well, they serve the objectives of the decision maker. The Analytic Hierarchy Process (AHP) is a theory of measurement through pairwise comparisons and relies on the judgements of experts to derive priority scales. It is these scales that measure intangibles in relative terms. The comparisons are made using a scale of absolute judgements that represents, how much more, one element dominates another with respect to a given attribute. The judgements may be inconsistent, and how to measure inconsistency and improve the judgements, when possible to obtain better consistency is a concern of the AHP. The derived priority scales are synthesised by multiplying them by the priority of their parent nodes and adding for all such nodes. An illustration is included.", "corpus_id": 9570761, "score": 0 }, { "doc_id": "108640941", "title": "Practical approaches for engaging stakeholders: findings from the UK", "abstract": "Principles for managing stakeholders are discussed in the context of UK construction practice. The number of stakeholders in a modern construction project can be large, presenting numerous interfaces that have to be managed. Meanwhile, each organization has its own characteristic disposition. Therefore, the interactions between diverse organizations in a project pose a high potential for conflicting stakes. Against this background, stakeholder management assumes high priority. Qualitative research was used to investigate the practice of stakeholder management with 12 UK companies in the construction sector. Interviews were held with these companies and content analysis was used to identify themes that demonstrate effective stakeholder management practice. Construct validity and a workshop underpinned the verification of underlying and frontline approaches for managing stakeholders. The underlying approaches include maintaining existing relationships, providing top‐level support and being proactive while the frontline approaches include the use of negotiations, trade‐offs, incentives and concessions.", "corpus_id": 108640941, "score": 0 }, { "doc_id": "57402259", "title": "Multiple criteria decision-making techniques and their applications – a review of the literature from 2000 to 2014", "abstract": "Multiple criteria decision-making (MCDM) is considered as a complex decision-making (DM) tool involving both quantitative and qualitative factors. In recent years, several MCDM techniques and approaches have been suggested to choosing the optimal probable options. The purpose of this article is to systematically review the applications and methodologies of the MCDM techniques and approaches. This study reviewed a total of 393 articles published from 2000 to 2014 in more than 120 peer reviewed journals (extracted from Web of Science). According to experts’ opinion, these articles were grouped into 15 fields. Furthermore, these articles were categorised based on authors, publication date, name of journals, methods, tools, and type of research (MCDM utilising research, MCDM developing research, and MCDM proposing research). The results of this study indicated that in 2013 scholars have published articles more than in other years. In addition, the analytic hierarchy process (AHP) method in the individual tools and hybrid MCDM in the integrated methods were ranked as the first and second methods in use. Additionally, the European Journal of Operational Research as the first journal with 70 publications was the significant journal in this study. Finally, energy, environment and sustainability were ranked as the first areas that have applied MCDM techniques and approaches.", "corpus_id": 57402259, "score": 0 }, { "doc_id": "154791432", "title": "Sustainable procurement in the public sector: an international comparative study", "abstract": "Purpose – Public bodies are being encouraged to procure sustainably, to reduce their social and environmental footprint and in order to stimulate sustainability in the private sector. However, little is known about how public sector organisations internationally are responding to this encouragement or of the conditions that are most conducive to sustainable procurement (SP). The purpose of this paper is to address these gaps in our knowledge so as to inform policy development at the government and organisational levels. \n \nDesign/methodology/approach – The authors report the findings of a survey of SP practices within a sample of over 280 public procurement practitioners from 20 countries and with collective responsibility for expenditure totalling $45bn p.a. \n \nFindings – The authors' analysis shows that some SP practices are evident in public sector procurement practice and that the extent and nature of SP practices varies significantly across regions. In addition, the authors highlight the main facilitators of, and barriers to, engagement with SP and investigate their importance for engagement with particular dimensions of SP. \n \nResearch limitations/implications – Survey respondents are volunteers and may to some degree be more interested in, or engaged with, SP than other public sector organisations. The analysis is cross-sectional and therefore provides only a snapshot of SP practice in the public sector organisations studied. \n \nPractical implications – The paper identifies how policy and practice in SP vary across regions, providing practical insights into whether and how government policies are being implemented around the world. \n \nOriginality/value – The paper provides the first systematic and comprehensive insight into how public bodies are implementing SP internationally and of the major situational factors that are shaping engagement with SP. The authors evaluate the current effectiveness of policy initiatives regarding SP and highlight the organisational catalysts and inhibitors of greater involvement in SP. \n \nDesign/methodology/approach – The authors report the findings of a survey of SP practices within a sample of over 280 public procurement practitioners from 20 countries and with collective responsibility for expenditure totalling $45bn p.a. \n \nFindings – The authors' analysis shows that some SP practices are evident in public sector procurement practice and that the extent and nature of SP practices varies significantly across regions. In addition, the authors highlight the main facilitators of, and barriers to, engagement with SP and investigate their importance for engagement with particular dimensions of SP. \n \nResearch limitations/implications – Survey respondents are volunteers and may to some degree be more interested in, or engaged with, SP than other public sector organisations. The analysis is cross-sectional and therefore provides only a snapshot of SP practice in the public sector organisations studied. \n \nPractical implications – The paper identifies how policy and practice in SP vary across regions, providing practical insights into whether and how government policies are being implemented around the world. \n \nOriginality/value – The paper provides the first systematic and comprehensive insight into how public bodies are implementing SP internationally and of the major situational factors that are shaping engagement with SP. The authors evaluate the current effectiveness of policy initiatives regarding SP and highlight the organisational catalysts and inhibitors of greater involvement in SP.", "corpus_id": 154791432, "score": 0 }, { "doc_id": "110784677", "title": "Clients’ assessment of architects’ performance in building delivery process: Evidence from Nigeria", "abstract": "Abstract The overall intent of this research is to provide architects with information that can be used to improve their performance so as to optimally satisfy the client's requirements and achieve high-quality overall project performance in Nigerian construction industry. Architect performance criteria were identified based on literature within the domain of architect responsibilities. The assessment of architects’ performance was carried out through a questionnaire survey of clients of recently completed building projects in Nigeria. Analysis of data includes comparison of criteria using importance–performance index analysis. Factor analysis was carried out on criteria where architects are falling below average, to group and explore the latent structure of the criteria in the data. The results showed that the architect needs to focus on management skills and ability, buildability, design quality, project communication, project integration and client focus. These results would encourage architects to perform better within their full responsibilities in the building delivery process and deliver high-quality projects within Nigerian construction industry.", "corpus_id": 110784677, "score": 0 } ]

{ "doc_id": "18948963", "title": "ar X iv : c s . PL / 0 10 30 09 v 2 2 3 N ov 2 00 1 Toward an architecture for quantum programming", "abstract": "It is becoming increasingly clear that, if a useful device for quantum computation will ever be built, it will be embodied by a classical computing machine with control over a truly quantum subsystem, this apparatus performing a mixture of classical and quantum computation. This paper investigates a possible approach to the problem of programming such machines: a template high level quantum language is presented which complements a generic general purpose classical language with a set of quantum primitives. The underlying scheme involves a run-time environment which calculates the byte-code for the quantum operations and pipes it to a quantum device controller or to a simulator. This language can compactly express existing quantum algorithms and reduce them to sequences of elementary operations; it also easily lends itself to automatic, hardware independent , circuit simplification. A publicly available preliminary implementation of the proposed ideas has been realized using the C++ language. In the last decade the field of quantum computing has raised large interest among physicists, mathematicians and computer scientists due to the possibility of solving at least some \" hard \" problems exponentially faster than with the familiar classical computers [1]. Relevant efforts have been concentrated in two directions: on one hand a (still not so large) set of quantum algorithms exploiting features inherent to the basic postulates of quantum mechanics has been developed [2]; on the other hand a number of experimental schemes have been proposed which could support the execution of these algorithms, moving quantum computation from the realm of speculation to reality (see a review of basic requirements in DiVincenzo [3]). The link between these two areas is a framework for describing feasible quantum algorithms , namely a computational model, which appears to have settled down to the quantum circuit model 1 , due to Deutsch [4], Bernstein and Vazirani [5] and Yao [6]. Though this is satisfactory from the point of view of computational complexity theory, it is not enough for a practical use (programming) of quantum computers, once they will become available. 1 Different computational models, involving physical systems with continuous-variable quantum systems used as computational spaces, are far less developed and will not be considered in this paper. It should be noted however that any such quantum device will most likely require very different interface abstractions from quantum circuits.", "corpus_id": 18948963 }

[ { "doc_id": "16128238", "title": "Quantum algorithms revisited", "abstract": "Quantum computers use the quantum interference of different computational paths to enhance correct outcomes and suppress erroneous outcomes of computations. A common pattern underpinning quantum algorithms can be identified when quantum computation is viewed as multiparticle interference. We use this approach to review (and improve) some of the existing quantum algorithms and to show how they are related to different instances of quantum phase estimation. We provide an explicit algorithm for generating any prescribed interference pattern with an arbitrary precision.", "corpus_id": 16128238, "score": 1 }, { "doc_id": "15439711", "title": "The Physical Implementation of Quantum Computation", "abstract": "After a brief introduction to the principles and promise of quantum information processing, the requirements for the physical implementation of quantum computation are discussed. These five requirements, plus two relating to the communication of quantum information, are extensively ex- plored and related to the many schemes in atomic physics, quantum optics, nuclear and electron magnetic resonance spectroscopy, superconducting electronics, and quantum-dot physics, for achiev- ing quantum computing. I. INTRODUCTION � The advent of quantum information processing, as an abstract concept, has given birth to a great deal of new thinking, of a very concrete form, about how to create physical computing devices that operate in the hitherto unexplored quantum mechanical regime. The efforts now underway to produce working laboratory devices that perform this profoundly new form of information pro- cessing are the subject of this book. In this chapter I provide an overview of the common objectives of the investigations reported in the remain- der of this special issue. The scope of the approaches, proposed and underway, to the implementation of quan- tum hardware is remarkable, emerging from specialties in atomic physics (1), in quantum optics (2), in nuclear (3) and electron (4) magnetic resonance spectroscopy, in su- perconducting device physics (5), in electron physics (6), and in mesoscopic and quantum dot research (7). This amazing variety of approaches has arisen because, as we will see, the principles of quantum computing are posed using the most fundamental ideas of quantum mechanics, ones whose embodiment can be contemplated in virtually every branch of quantum physics. The interdisciplinary spirit which has been fostered as a result is one of the most pleasant and remarkable fea- tures of this field. The excitement and freshness that has been produced bodes well for the prospect for discovery, invention, and innovation in this endeavor.", "corpus_id": 15439711, "score": 1 }, { "doc_id": "123073680", "title": "Quantum computational networks", "abstract": "The theory of quantum computational networks is the quantum generalization of the theory of logic circuits used in classical computing machines. Quantum gates are the generalization of classical logic gates. A single type of gate, the universal quantum gate, together with quantum ‘unit wires’, is adequate for constructing networks with any possible quantum computational property.", "corpus_id": 123073680, "score": 0 }, { "doc_id": "676378", "title": "Quantum complexity theory", "abstract": "In this dissertation we study quantum computation from a complexity theoretic viewpoint. Our first result is the existence of an efficient universal quantum Turing Machine in Deutsch's model of a quantum Turing Machine. This construction is substantially more complicated than the corresponding construction for classical Turing Machines--in fact, even simple primitives such as looping, branching and composition are not straightforward in the context of quantum Turing Machines. We establish how these familiar primitives can be implemented, and also introduce some new, purely quantum mechanical primitives, such as changing the computational basis, and carrying out an arbitrary unitary transformation of polynomially bounded dimension. \nWe also consider the precision to which the transition amplitudes of a quantum Turing Machine need to be specified. We prove that O(log T) bits of precision suffice to support a T step computation. This justifies the claim that the quantum Turing Machine model should be regarded as a discrete model of computation and not an analog one. \nWe give the first evidence indicating that quantum Turing Machines are more powerful than classical probabilistic Turing Machines. We show the existence of a problem, relative to an oracle, that can be solved in polynomial time on a quantum Turing Machine, but requires super-polynomial time on a bounded-error probabilistic Turing Machine; and thus not in the class BPP. In fact, we show that this problem cannot be solved in MA relative to the same oracle, thus showing that even non-determinism together with randomness is not sufficient to solve the problem in poly-nomial time. The class BQP, of languages that are efficiently decidable (with small error-probability) on a quantum Turing Machine, satisfies: BPP $\\subseteq$ BQP $\\subseteq$ P$\\sp{\\sharp P}$. Therefore there is no possibility of giving a mathematical proof that quantum Turing Machines are more powerful than classical probabilistic Turing Machines (in the unrelativized setting) unless there is a major breakthrough in complexity theory. \nWe also give evidence suggesting that quantum Turing Machines cannot efficiently solve all of NP. Specifically, we prove that relative to an oracle chosen uniformly at random, with probability 1, the class NP cannot be solved on a quantum Turing machine in time $o(2\\sp{n/2}).$", "corpus_id": 676378, "score": 1 }, { "doc_id": "195866146", "title": "Quantum circuit complexity", "abstract": "We propose a complexity model of quantum circuits analogous to the standard (acyclic) Boolean circuit model. It is shown that any function computable in polynomial time by a quantum Turing machine has a polynomial-size quantum circuit. This result also enables us to construct a universal quantum computer which can simulate, with a polynomial factor slowdown, a broader class of quantum machines than that considered by E. Bernstein and U. Vazirani (1993), thus answering an open question raised by them. We also develop a theory of quantum communication complexity, and use it as a tool to prove that the majority function does not have a linear-size quantum formula.<<ETX>>", "corpus_id": 195866146, "score": 1 }, { "doc_id": "61063980", "title": "Conventions for quantum pseudocode", "abstract": "A few conventions for thinking about and writing quantum pseudocode are proposed. The conventions can be used for presenting any quantum algorithm down to the lowest level and are consistent with a quantum random access machine (QRAM) model for quantum computing. In principle a formal version of quantum pseudocode could be used in a future extension of a conventional language.", "corpus_id": 61063980, "score": 1 }, { "doc_id": "119447939", "title": "Programmable Quantum Gate Arrays", "abstract": "We show how to construct quantum gate arrays that can be programmed to perform different unitary operations on a data register, depending on the input to some program register. It is shown that a universal quantum gate array\\char22{}a gate array which can be programmed to perform any unitary operation\\char22{}exists only if one allows the gate array to operate in a probabilistic fashion. Thus it is not possible to build a fixed, general purpose quantum computer which can be programmed to perform an arbitrary quantum computation.", "corpus_id": 119447939, "score": 0 }, { "doc_id": "118328193", "title": "Theory of quantum computation", "abstract": "Short review article on quantum computation accepted for Supplement III, Encyclopaedia of Mathematics (publication expected Summer 2001). See also this http URL", "corpus_id": 118328193, "score": 0 }, { "doc_id": "17450629", "title": "An approximate Fourier transform useful in quantum factoring\", IBM Research Report RC19642 ,; R. Cle", "abstract": "We define an approximate version of the Fourier transform on $2^L$ elements, which is computationally attractive in a certain setting, and which may find application to the problem of factoring integers with a quantum computer as is currently under investigation by Peter Shor. (1994 IBM Internal Report)", "corpus_id": 17450629, "score": 0 }, { "doc_id": "5591827", "title": "C++ Programming Language", "abstract": "From the Publisher: \nWritten by Bjarne Stroustrup, the creator of C, this is the world's most trusted and widely read book on C. \n \nFor this special hardcover edition, two new appendixes on locales and standard library exception safety have been added. The result is complete, authoritative coverage of the C language, its standard library, and key design techniques. Based on the ANSI/ISO C standard, The C Programming Language provides current and comprehensive coverage of all C language features and standard library components. \n \nFor example: \nabstract classes as interfaces class hierarchies for object-oriented programming templates as the basis for type-safe generic software exceptions for regular error handling namespaces for modularity in large-scale software run-time type identification for loosely coupled systems the C subset of C for C compatibility and system-level work standard containers and algorithms standard strings, I/O streams, and numerics C compatibility, internationalization, and exception safety \nBjarne Stroustrup makes C even more accessible to those new to the language, while adding advanced information and techniques that even expert C programmers will find invaluable.", "corpus_id": 5591827, "score": 0 }, { "doc_id": "118458753", "title": "Addition on a Quantum Computer", "abstract": "A new method for computing sums on a quantum computer is introduced. This technique uses the quantum Fourier transform and reduces the number of qubits necessary for addition by removing the need for temporary carry bits. This approach also allows the addition of a classical number to a quantum superposition without encoding the classical number in the quantum register. This method also allows for massive parallelization in its execution.", "corpus_id": 118458753, "score": 0 }, { "doc_id": "14641793", "title": "Logical reversibility of computation", "abstract": "The usual general-purpose computing automaton (e.g.. a Turing machine) is logically irreversible- its transition function lacks a single-valued inverse. Here it is shown that such machines may he made logically reversible at every step, while retainillg their simplicity and their ability to do general computations. This result is of great physical interest because it makes plausible the existence of thermodynamically reversible computers which could perform useful computations at useful speed while dissipating considerably less than kT of energy per logical step. In the first stage of its computation the logically reversible automaton parallels the corresponding irreversible automaton, except that it saves all intermediate results, there by avoiding the irreversible operation of erasure. The second stage consists of printing out the desired output. The third stage then reversibly disposes of all the undesired intermediate results by retracing the steps of the first stage in backward order (a process which is only possible because the first stage has been carried out reversibly), there by restoring the machine (except for the now-written output tape) to its original condition. The final machine configuration thus contains the desired output and a reconstructed copy of the input, but no other undesired data. The foregoing results are demonstrated explicitly using a type of three-tape Turing machine. The biosynthesis of messenger RNA is discussed as a physical example of reversible computation.", "corpus_id": 14641793, "score": 0 }, { "doc_id": "8764584", "title": "Elementary gates for quantum computation.", "abstract": "We show that a set of gates that consists of all one-bit quantum gates (U(2)) and the two-bit exclusive-or gate (that maps Boolean values (x,y) to (x,x ⊕y)) is universal in the sense that all unitary operations on arbitrarily many bits n (U(2 n )) can be expressed as compositions of these gates. We investigate the number of the above gates required to implement other gates, such as generalized Deutsch-Toffoli gates, that apply a specific U(2) transformation to one input bit if and only if the logical AND of all remaining input bits is satisfied. These gates play a central role in many proposed constructions of quantum computational networks. We derive upper and lower bounds on the exact number of elementary gates required to build up a variety of two- and three-bit quantum gates, the asymptotic number required for n-bit Deutsch-Toffoli gates, and make some observations about the number required for arbitrary n-bit unitary operations.", "corpus_id": 8764584, "score": 0 }, { "doc_id": "207198067", "title": "A fast quantum mechanical algorithm for database search", "abstract": "were proposed in the early 1980’s [Benioff80] and shown to be at least as powerful as classical computers an important but not surprising result, since classical computers, at the deepest level, ultimately follow the laws of quantum mechanics. The description of quantum mechanical computers was formalized in the late 80’s and early 90’s [Deutsch85][BB92] [BV93] [Yao93] and they were shown to be more powerful than classical computers on various specialized problems. In early 1994, [Shor94] demonstrated that a quantum mechanical computer could efficiently solve a well-known problem for which there was no known efficient algorithm using classical computers. This is the problem of integer factorization, i.e. testing whether or not a given integer, N, is prime, in a time which is a finite power of o (logN) . ----------------------------------------------", "corpus_id": 207198067, "score": 0 } ]

{ "doc_id": "162183568", "title": "Hippo Signaling in Cancer: Lessons From Drosophila Models", "abstract": "Hippo pathway was initially identified through genetic screens for genes regulating organ size in fruitflies. Recent studies have highlighted the role of Hippo signaling as a key regulator of homeostasis, and in tumorigenesis. Hippo pathway is comprised of genes that act as tumor suppressor genes like hippo (hpo) and warts (wts), and oncogenes like yorkie (yki). YAP and TAZ are two related mammalian homologs of Drosophila Yki that act as effectors of the Hippo pathway. Hippo signaling deficiency can cause YAP- or TAZ-dependent oncogene addiction for cancer cells. YAP and TAZ are often activated in human malignant cancers. These transcriptional regulators may initiate tumorigenic changes in solid tumors by inducing cancer stem cells and proliferation, culminating in metastasis and chemo-resistance. Given the complex mechanisms (e.g., of the cancer microenvironment, and the extrinsic and intrinsic cues) that overpower YAP/TAZ inhibition, the molecular roles of the Hippo pathway in tumor growth and progression remain poorly defined. Here we review recent findings from studies in whole animal model organism like Drosophila on the role of Hippo signaling regarding its connection to inflammation, tumor microenvironment, and other oncogenic signaling in cancer growth and progression.", "corpus_id": 162183568 }

[ { "doc_id": "4414674", "title": "Cancer: Dangerous liaisons", "abstract": "The cells of multicellular organisms are highly communicative and so can strongly influence one another's behaviour. One line of communication is particularly important in keeping cell growth in check.", "corpus_id": 4414674, "score": 0 }, { "doc_id": "26195195", "title": "Understanding resistance to targeted cancer drugs through loss of function genetic screens.", "abstract": "Comprehensive analysis of cancer genomes has provided important insights in the critical alterations that confer proliferation and survival advantage to the tumor, so-called driver mutations. Tumors harboring these genetic changes frequently exhibit striking sensitivities to inhibition of these oncogenic driver pathways, a principle referred to as oncogene addiction. Substantial progress has been made in the development of drugs that specifically target components of the pathways that are associated with these driver mutations. This has enabled the first steps in a shift from the use of cytotoxic drugs to highly selective targeted therapeutic agents for the treatment of cancer. Unfortunately, despite the expanding development of targeted anti-cancer strategies, treatment failure due to primary or acquired resistance is still an almost inevitable outcome in most advanced human cancers. Understanding drug resistance mechanisms will help design more efficient combination treatment strategies that help block resistance mechanisms before they become clinically manifest. In this review, we discuss how RNA interference functional genetic screens can be used to identify clinically relevant mechanisms of drug resistance and how this technology can be used to develop effective combination therapies.", "corpus_id": 26195195, "score": 0 }, { "doc_id": "205287125", "title": "The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal", "abstract": "Precise control of organ size is crucial during animal development and regeneration. In Drosophila and mammals, studies over the past decade have uncovered a critical role for the Hippo tumour-suppressor pathway in the regulation of organ size. Dysregulation of this pathway leads to massive overgrowth of tissue. The Hippo signalling pathway is highly conserved and limits organ size by phosphorylating and inhibiting the transcription co-activators YAP and TAZ in mammals and Yki in Drosophila, key regulators of proliferation and apoptosis. The Hippo pathway also has a critical role in the self-renewal and expansion of stem cells and tissue-specific progenitor cells, and has important functions in tissue regeneration. Emerging evidence shows that the Hippo pathway is regulated by cell polarity, cell adhesion and cell junction proteins. In this review we summarize current understanding of the composition and regulation of the Hippo pathway, and discuss how cell polarity and cell adhesion proteins inform the role of this pathway in organ size control and regeneration.", "corpus_id": 205287125, "score": 0 }, { "doc_id": "42828488", "title": "Dissecting tumour heterogeneity in flies: genetic basis of interclonal oncogenic cooperation.", "abstract": "Cancers develop through sequential acquisition of oncogenic mutations, indicating a crucial role of genetic alterations in tumour progression. However, accumulating evidence suggests that cancers also progress towards malignancy through cell-cell interactions within heterogeneous tumour tissue. Recent studies have indicated that tumour heterogeneity not only contributes to drug resistance and tumour recurrence but also plays an active role in promoting tumour progression. Especially, genetic studies in Drosophila have discovered novel types of tumour progression through cell-cell interactions and have dissected the underlying mechanisms. This review focuses on describing recent findings obtained from Drosophila genetics that provide genetic basis of interclonal oncogenic cooperation in heterogeneous tumour tissue.", "corpus_id": 42828488, "score": 0 }, { "doc_id": "5594281", "title": "The Hippo-YAP pathway: new connections between regulation of organ size and cancer.", "abstract": "The control of organ size is a basic biological question. In the past several years, the Hippo signaling pathway has been delineated and shown to be crucial in control of organ size in both Drosophila and mammals. Acting downstream of the Hippo pathway is the Yki/YAP/TAZ transcription co-activators. In mammalian cells, the Hippo pathway kinase cascade inhibits YAP and its paralog TAZ by phosphorylation and promotion of their cytoplasmic localization. The TEAD family transcription factors have recently been identified as evolutionarily conserved key mediators of YAP biological functions. yap is a candidate oncogene, and several other components of the Hippo pathway are tumor suppressors. Dysregulation of the Hippo pathway contributes to the loss of contact inhibition observed in cancer cells. Therefore, the Hippo-YAP pathway connects the regulation of organ size and tumorigenesis.", "corpus_id": 5594281, "score": 0 }, { "doc_id": "4598107", "title": "Upstream paths for Hippo signaling in Drosophila organ development", "abstract": "Organ growth is fundamental to animal development. One of major mechanisms for growth control is mediated by the conserved Hippo signaling pathway initially identified in Drosophila. The core of this pathway in Drosophila consists of a cascade of protein kinases Hippo and Warts that negatively regulate transcriptional coactivator Yorkie (Yki). Activation of Yki promotes cell survival and proliferation to induce organ growth. A key issue in Hippo signaling is to understand how core kinase cascade is activated. Activation of Hippo kinase cascade is regulated in the upstream by at least two transmembrane proteins Crumbs and Fat that act in parallel. These membrane proteins interact with additional factors such as FERM-domain proteins Expanded and Merlin to modulate subcellular localization and function of the Hippo kinase cascade. Hippo signaling is also influenced by cytoskeletal networks and cell tension in epithelia of developing organs. These upstream events in the regulation of Hippo signaling are only partially understood. This review focuses on our current understanding of some upstream processes involved in Hippo signaling in developing Drosophila organs.", "corpus_id": 4598107, "score": 0 }, { "doc_id": "4576676", "title": "The history and regulatory mechanism of the Hippo pathway", "abstract": "How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long-standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer. By regulating the downstream transcriptional coactivators YAP and TAZ, the Hippo pathway coordinates cell proliferation and apoptosis in response to a variety of signals including cell contact inhibition, polarity, mechanical sensation and soluble factors. Since the core components and their functions of the Hippo pathway are evolutionarily conserved, this pathway serves as a global regulator of organ size control. Therefore, further investigation of the regulatory mechanisms will provide physiological insights to better understand tissue homeostasis. In this review, the historical developments and current understandings of the regulatory mechanism of Hippo signaling pathway are discussed.", "corpus_id": 4576676, "score": 0 }, { "doc_id": "343677", "title": "Signal Transduction by the JNK Group of MAP Kinases", "abstract": "MAP kinases are evolutionarily conserved proteins that are activated by a protein kinase cascade, including a MAP kinase kinase kinase, which phosphorylates a MAP kinase kinase, which in turn activates the MAP kinase by phosphorylation on Thr and Tyr residues. The primary sequence surrounding these phosphorylation sites serves to distinguish three major groups of mammalian MAP kinases. These include the Ras-activated ERK MAP kinases, which are characterized by the sequence TEY and the two stress-activated MAP kinases: p38 with the sequence TGY, and the c-Jun NH2-terminal kinases (JNK) with the sequence TPY. This review will focus on the JNK group of MAP kinases.", "corpus_id": 343677, "score": 0 }, { "doc_id": "12112142", "title": "Initiator caspases in apoptosis signaling pathways", "abstract": "Death receptor- or mitochondrion-dependent apoptosis is initiated by the recruitment and activation of apical caspases in the apoptosis signaling pathways. In death receptor-mediated apoptosis, engagement of death receptors leads to the formation of the death-inducing signaling complex (DISC) containing the death receptors, adaptor proteins, caspase-8 and caspase-10. In mitochondrion-dependent apoptosis, release of cytochrome C into the cytosol results in the formation of apoptosome containing cytochrome C, Apaf-1 and caspase-9. Caspase-8, caspase-10 and caspase-9 are believed to be the initiator caspases at the top of the caspase signaling cascade. Recruitment of caspases to DISC and apoptosome leads to their activation by dimer formation. Recent biochemical and structural analyses of components in the DISC and apoptosome shed new lights on their roles in inducing the onset of apoptosis signaling.", "corpus_id": 12112142, "score": 0 }, { "doc_id": "1399698", "title": "Hippo signaling: growth control and beyond", "abstract": "The Hippo pathway has emerged as a conserved signaling pathway that is essential for the proper regulation of organ growth in Drosophila and vertebrates. Although the mechanisms of signal transduction of the core kinases Hippo/Mst and Warts/Lats are relatively well understood, less is known about the upstream inputs of the pathway and about the downstream cellular and developmental outputs. Here, we review recently discovered mechanisms that contribute to the dynamic regulation of Hippo signaling during Drosophila and vertebrate development. We also discuss the expanding diversity of Hippo signaling functions during development, discoveries that shed light on a complex regulatory system and provide exciting new insights into the elusive mechanisms that regulate organ growth and regeneration.", "corpus_id": 1399698, "score": 0 }, { "doc_id": "10402099", "title": "Wingless/Wnt signaling in Drosophila: The pattern and the pathway", "abstract": "Wnt signaling generates pattern in all animal embryos, from flies and worms to humans, and promotes the undifferentiated, proliferative state critical for stem cells in adult tissues. Inappropriate Wnt pathway activation is the major cause of colorectal cancers, a leading cause of cancer death in humans. Although this pathway has been studied extensively for years, large gaps remain in our understanding of how it switches on and off, and how its activation changes cellular behaviors. Much of what is known about the pathway comes from genetic studies in Drosophila, where a single Wnt molecule, encoded by wingless (wg), directs an array of cell‐fate decisions similar to those made by the combined activities of all 19 Wnt family members in vertebrates. Although Wg specifies fate in many tissues, including the brain, limbs, and major organs, the fly embryonic epidermis has proven to be a very powerful system for dissecting pathway activity. It is a simple, accessible tissue, with a pattern that is highly sensitive to small changes in Wg pathway activity. This review discusses what we have learned about Wnt signaling from studying mutations that disrupt epidermal pattern in the fly embryo, highlights recent advances and controversies in the field, and sets these issues in the context of questions that remain about how this essential signaling pathway functions. Mol. Reprod. Dev. 80: 882–894, 2013. © 2013 Wiley Periodicals, Inc.", "corpus_id": 10402099, "score": 0 }, { "doc_id": "46428157", "title": "The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation.", "abstract": "Homozygous loss of the warts (wts) gene of Drosophila, caused by mitotic recombination in somatic cells, leads to the formation of cell clones that are fragmented, rounded, and greatly overgrown compared with normal controls. Therefore, the gene is required for the control of the amount and direction of cell proliferation as well as for normal morphogenesis. The absence of wts function also results in apical hypertrophy of imaginal disc epithelial cells. Secretion of cuticle over and between the domed apical surfaces of these cells leads to a honeycomb-like structure and gives the superficial wart-like phenotype of mitotic clones on the adult. One wts allele allows survival of homozygotes to the late larval stage, and these larvae show extensive imaginal disc overgrowth. Because of the excess growth and abnormalities of differentiation that follow homozygous loss, we consider wts to be a tumor suppressor gene. The wts gene is defined by the breakpoints of overlapping deficiencies in the right telomeric region of chromosome 3, region 100A, and by lethal P-element insertions and excisions. It encodes a protein kinase that is most similar to human myotonic dystrophy kinase, the Neurospora cot-1 protein kinase, two cell-cycle regulated kinases of yeast, and several putative kinases from plants. These proteins define a new subfamily of protein kinases that are closely related to but distinct from the cyclic AMP-dependent kinases. Although myotonic dystrophy is defined by a neuromuscular disorder, it is sometimes associated with multiple pilomatrixomas, which are otherwise rare epithelial tumors, and with other tumors including neurofibromas and parathyroid adenomas. Our results raise the possibility that homozygous loss of the myotonic dystrophy kinase may contribute to the development of these tumors.", "corpus_id": 46428157, "score": 0 }, { "doc_id": "22838749", "title": "Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase.", "abstract": "We have identified recessive overproliferation mutations by screening and examining clones of mutant cells in genetic mosaics of the fruitfly Drosophila melanogaster. This type of screen provides a powerful approach for identifying and studying potential tumor suppressors. One of the identified genes, lats, has been cloned and encodes a putative protein kinase that shares high levels of sequence similarity with three proteins in budding yeast and Neurospora that are involved in regulation of the cell cycle and growth. Mutations in lats cause dramatic overproliferation phenotypes and various developmental defects in both mosaic animals and homozygous mutants.", "corpus_id": 22838749, "score": 0 }, { "doc_id": "6662824", "title": "Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila", "abstract": "During animal development, organ size is determined primarily by the amount of cell proliferation, which must be tightly regulated to ensure the generation of properly proportioned organs. However, little is known about the molecular pathways that direct cells to stop proliferating when an organ has attained its proper size. We have identified mutations in a novel gene, shar-pei, that is required for proper termination of cell proliferation during Drosophila imaginal disc development. Clones of shar-pei mutant cells in imaginal discs produce enlarged tissues containing more cells of normal size. We show that this phenotype is the result of both increased cell proliferation and reduced apoptosis. Hence, shar-pei restricts cell proliferation and promotes apoptosis. By contrast, shar-pei is not required for cell differentiation and pattern formation of adult tissue. Shar-pei is also not required for cell cycle exit during terminal differentiation, indicating that the mechanisms directing cell proliferation arrest during organ growth are distinct from those directing cell cycle exit during terminal differentiation. shar-pei encodes a WW-domain-containing protein that has homologs in worms, mice and humans, suggesting that mechanisms of organ growth control are evolutionarily conserved.", "corpus_id": 6662824, "score": 0 }, { "doc_id": "18204088", "title": "salvador Promotes Both Cell Cycle Exit and Apoptosis in Drosophila and Is Mutated in Human Cancer Cell Lines", "abstract": "The number of cells in an organism is determined by regulating both cell proliferation and cell death. Relatively few mechanisms have been identified that can modulate both of these processes. In a screen for Drosophila mutations that result in tissue overgrowth, we identified salvador (sav), a gene that promotes both cell cycle exit and cell death. Elevated Cyclin E and DIAP1 levels are found in mutant cells, resulting in delayed cell cycle exit and impaired apoptosis. Salvador contains two WW domains and binds to the Warts (or LATS) protein kinase. The human ortholog of salvador (hWW45) is mutated in three cancer cell lines. Thus, salvador restricts cell numbers in vivo by functioning as a dual regulator of cell proliferation and apoptosis.", "corpus_id": 18204088, "score": 0 }, { "doc_id": "17894660", "title": "The Drosophila Mst Ortholog, hippo, Restricts Growth and Cell Proliferation and Promotes Apoptosis", "abstract": "Establishing and maintaining homeostasis is critical to the well-being of an organism and is determined by the balance of cell proliferation and death. Two genes that function together to regulate growth, proliferation, and apoptosis in Drosophila are warts (wts), encoding a serine/threonine kinase, and salvador (sav), encoding a WW domain containing Wts-interacting protein. However, the mechanisms by which sav and wts regulate growth and apoptosis are not well understood. Here, we describe mutations in hippo (hpo), which encodes a protein kinase most related to mammalian Mst1 and Mst2. Like wts and sav, hpo mutations result in increased tissue growth and impaired apoptosis characterized by elevated levels of the cell cycle regulator cyclin E and apoptosis inhibitor DIAP1. Hpo, Sav, and Wts interact physically and functionally, and regulate DIAP1 levels, likely by Hpo-mediated phosphorylation and subsequent degradation. Thus, Hpo links Sav and Wts to a key regulator of apoptosis.", "corpus_id": 17894660, "score": 0 }, { "doc_id": "41707139", "title": "The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis.", "abstract": "In a genetic screen for mutations that restrict cell growth and organ size, we identified a new tumor suppressor gene, dMST, which encodes the Drosophila homolog of the mammalian Ste20 kinase family members MST1 and MST2. Loss-of-function mutations in dMST result in overgrown tissues containing more cells of normal size. dMST mutant cells exhibit elevated levels of Cyclin E and DIAP1, increased cell growth and proliferation, and impaired apoptosis. dMST forms a complex with Sav and Wts, two tumor suppressors also implicated in regulating both cell proliferation and apoptosis, suggesting that they act in common pathways.", "corpus_id": 41707139, "score": 0 }, { "doc_id": "9642598", "title": "The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila", "abstract": "Tissue growth during animal development is tightly controlled so that the organism can develop harmoniously. The salvador (sav) gene, which encodes a scaffold protein, has been shown to restrict cell number by coordinating cell-cycle exit and apoptosis during Drosophila development. Here we identify Hippo (Hpo), the Drosophila orthologue of the mammalian MST1 and MST2 serine/threonine kinases, as a partner of Sav. Loss of hpo function leads to sav-like phenotypes, whereas gain of hpo function results in the opposite phenotype. Whereas Sav and Hpo normally restrict cellular quantities of the Drosophila inhibitor of apoptosis protein DIAP1, overexpression of Hpo destabilizes DIAP1 in cell culture. We show that DIAP1 is phosphorylated in a Hpo-dependent manner in S2 cells and that Hpo can phosphorylate DIAP1 in vitro. Thus, Hpo may promote apoptosis by reducing cellular amounts of DIAP1. In addition, we show that Sav is an unstable protein that is stabilized by Hpo. We propose that Hpo and Sav function together to restrict tissue growth in vivo.", "corpus_id": 9642598, "score": 0 }, { "doc_id": "1527051", "title": "Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway", "abstract": "Proliferation and apoptosis must be precisely regulated to form organs with appropriate cell numbers and to avoid tumour growth. Here we show that Hippo (Hpo), the Drosophila homologue of the mammalian Ste20-like kinases, MST1/2, promotes proper termination of cell proliferation and stimulates apoptosis during development. hpo mutant tissues are larger than normal because mutant cells continue to proliferate beyond normal tissue size and are resistant to apoptotic stimuli that usually eliminate extra cells. Hpo negatively regulates expression of Cyclin E to restrict cell proliferation, downregulates the Drosophila inhibitor of apoptosis protein DIAP1, and induces the proapoptotic gene head involution defective (hid) to promote apoptosis. The mutant phenotypes of hpo are similar to those of warts (wts), which encodes a serine/threonine kinase of the myotonic dystrophy protein kinase family, and salvador (sav), which encodes a WW domain protein that binds to Wts. We find that Sav binds to a regulatory domain of Hpo that is essential for its function, indicating that Hpo acts together with Sav and Wts in a signalling module that coordinately regulates cell proliferation and apoptosis.", "corpus_id": 1527051, "score": 0 }, { "doc_id": "9532050", "title": "hippo Encodes a Ste-20 Family Protein Kinase that Restricts Cell Proliferation and Promotes Apoptosis in Conjunction with salvador and warts", "abstract": "The coordination between cell proliferation and cell death is essential to maintain homeostasis within multicellular organisms. The mechanisms underlying this regulation are yet to be completely understood. Here, we report the identification of hippo (hpo) as a gene that regulates both cell proliferation and cell death in Drosophila. hpo encodes a Ste-20 family protein kinase that binds to and phosphorylates the tumor suppressor protein Salvador (Sav), which is known to interact with the Warts (Wts) protein kinase. Loss of hpo results in elevated transcription of the cell cycle regulator cyclin E and the cell-death inhibitor diap1, leading to increased proliferation and reduced apoptosis. Further, we show that hpo, sav, and wts define a pathway that regulates diap1 at the transcriptional level. A human homolog of hpo completely rescues the overgrowth phenotype of Drosophila hpo mutants, suggesting that hpo might play a conserved role for growth control in mammals.", "corpus_id": 9532050, "score": 1 }, { "doc_id": "21287642", "title": "Cloning and Characterization of a Human Protein Kinase with Homology to Ste20 (*)", "abstract": "A human protein kinase (termed MST1) has been cloned and characterized. The MST1 catalytic domain is most homologous to Ste20 and other Ste20-like kinases (62-65% similar). MST1 is expressed ubiquitously, and the MST1 protein is present in all human cell lines examined. Biochemical characterization of MST1 catalytic activity demonstrates that it is a serine/threonine kinase, and that it can phosphorylate an exogenous substrate as well as itself in an in vitro kinase assay. Further characterization of the protein indicates MST1 activity increases approximately 3-4-fold upon treatment with PP2A, suggesting that MST1 is negatively regulated by phosphorylation. MST1 activity decreases approximately 2-fold upon treatment with epidermal growth factor; however, overexpression of MST1 does not affect extracellular signal-regulated kinase-1 and −2 activation. MST1 is unaffected by heat shock or high osmolarity, indicating that it is not involved in the stress-activated or high osmolarity glycerol signal transduction pathways. Thus MST1, although homologous to a member of a yeast MAPK cascade, is not involved in the regulation of a known mammalian MAPK pathway and potentially regulates a novel signaling cascade.", "corpus_id": 21287642, "score": 0 }, { "doc_id": "32220148", "title": "The Ste20 group kinases as regulators of MAP kinase cascades.", "abstract": "Ste20p (sterile 20 protein) is a putative yeast mitogen-activated protein kinase kinase kinase kinase (MAP4K) involved in the mating pathway. Its homologs in mammals, Drosophila, Caenorhabditis elegans and other organisms make up a large emerging group of protein kinases including 28 members in human. The Ste20 group kinases are further divided into the p21-activated kinase (PAK) and germinal center kinase (GCK) families. They are characterized by the presence of a conserved kinase domain and a noncatalytic region of great structural diversity that enables the kinases to interact with various signaling molecules and regulatory proteins of the cytoskeleton. This review describes the phylogenetic relationships of the Ste20 group kinases based on discussions with many researchers in this field. With the newly established phylogenetic relationships, crucial arguments can be advanced regarding the functions of these kinases as upstream activators of the MAPK pathways and possible activity as MAP4Ks. Their involvement in apoptosis, morphogenesis and cytoskeletal rearrangements is also discussed.", "corpus_id": 32220148, "score": 0 }, { "doc_id": "7431763", "title": "From Cell Structure to Transcription: Hippo Forges a New Path", "abstract": "The control of cell number during animal development is a longstanding puzzle. Recent studies in the fruit fly Drosophila melanogaster have defined a new signaling pathway that restricts cell proliferation in differentiating epithelia. The cytoskeletal proteins Merlin and Expanded, which play a role in cell adhesion and structure, control the activation of the Hippo/Salvador kinase complex, which in turn activates the Warts/Mats kinase complex. Warts/Mats kinase phosphorylates and inhibits Yorkie, a transcriptional coactivator that positively regulates cell growth, survival, and proliferation. This conserved signaling pathway contains several tumor-suppressor genes and regulates the contact inhibition of proliferation in cultured cells.", "corpus_id": 7431763, "score": 0 }, { "doc_id": "14139806", "title": "The Hippo Signaling Pathway Coordinately Regulates Cell Proliferation and Apoptosis by Inactivating Yorkie, the Drosophila Homolog of YAP", "abstract": "Coordination between cell proliferation and cell death is essential to maintain homeostasis in multicellular organisms. In Drosophila, these two processes are regulated by a pathway involving the Ste20-like kinase Hippo (Hpo) and the NDR family kinase Warts (Wts; also called Lats). Hpo phosphorylates and activates Wts, which in turn, through unknown mechanisms, negatively regulates the transcription of cell-cycle and cell-death regulators such as cycE and diap1. Here we identify Yorkie (Yki), the Drosophila ortholog of the mammalian transcriptional coactivator yes-associated protein (YAP), as a missing link between Wts and transcriptional regulation. Yki is required for normal tissue growth and diap1 transcription and is phosphorylated and inactivated by Wts. Overexpression of yki phenocopies loss-of-function mutations of hpo or wts, including elevated transcription of cycE and diap1, increased proliferation, defective apoptosis, and tissue overgrowth. Thus, Yki is a critical target of the Wts/Lats protein kinase and a potential oncogene.", "corpus_id": 14139806, "score": 0 }, { "doc_id": "13196779", "title": "Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product.", "abstract": "Yes belongs to the Src family of protein-tyrosine kinases. In order to understand molecular aspects of its signaling, we decided to isolate proteins that bind to the modulatory region of the Yes molecule. By generating anti-idiotypic antibodies against the aminoterminal domain of the Yes protein, we have identified, characterized and cloned a cDNA for a novel protein that binds to the Src homology domain 3 (SH3) of the Yes proto-oncogene product. The protein is of 65 kiloDalton (kDa) molecular mass, it is phosphorylated in vivo on serine and is particularly rich in proline. We named it YAP65 for Yes-Associated Protein of 65 kDa. Within the YAP65 sequence, we identified a motif, PVKQPPPLAP, similar to that found in proteins that bind to the SH3 domain of the Abl kinase. Competition assays with synthetic peptides showed the involvement of the predicted proline-rich sequence in binding between YAP65 and the Yes kinase. The YAP65 protein was also shown to bind to other signaling molecules that contain SH3 domains including Nck, Crk and Src. At lower stoichiometry, YAP65 was also shown to bind to the SH3 domains of Abl and guanosine triphosphatase activating protein (GAP). Further characterization of YAP65 should illuminate Yes signaling pathways and could also identify a novel link between protein-tyrosine and serine kinases.", "corpus_id": 13196779, "score": 0 }, { "doc_id": "10566416", "title": "TAZ: a novel transcriptional co‐activator regulated by interactions with 14‐3‐3 and PDZ domain proteins", "abstract": "The highly conserved and ubiquitously expressed 14‐3‐3 proteins regulate differentiation, cell cycle progression and apoptosis by binding intracellular phosphoproteins involved in signal transduction. By screening in vitro translated cDNA pools for the ability to bind 14‐3‐3, we identified a novel transcriptional co‐activator, TAZ (transcriptional co‐activator with PDZ‐binding motif) as a 14‐3‐3‐binding molecule. TAZ shares homology with Yes‐associated protein (YAP), contains a WW domain and functions as a transcriptional co‐activator by binding to the PPXY motif present on transcription factors. 14‐3‐3 binding requires TAZ phosphorylation on a single serine residue, resulting in the inhibition of TAZ transcriptional co‐activation through 14‐3‐3‐mediated nuclear export. The C‐terminus of TAZ contains a highly conserved PDZ‐binding motif that localizes TAZ into discrete nuclear foci and is essential for TAZ‐stimulated gene transcription. TAZ uses this same motif to bind the PDZ domain‐containing protein NHERF‐2, a molecule that tethers plasma membrane ion channels and receptors to cytoskeletal actin. TAZ may link events at the plasma membrane and cytoskeleton to nuclear transcription in a manner that can be regulated by 14‐3‐3.", "corpus_id": 10566416, "score": 0 }, { "doc_id": "20946111", "title": "Identification of Novel Human WW Domain-containing Proteins by Cloning of Ligand Targets*", "abstract": "A recently described protein module consisting of 35–40 semiconserved residues, termed the WW domain, has been identified in a number of diverse proteins including dystrophin and Yes-associated protein (YAP). Two putative ligands of YAP, termed WBP-1 and WBP-2, have been found previously to contain several short peptide regions consisting of PPPPY residues (PY motif) that mediate binding to the WW domain of YAP. Although the function(s) of the WW domain remain to be elucidated, these observations strongly support a role for the WW domain in protein-protein interactions. Here we report the isolation of three novel human cDNAs encoding a total of nine WW domains, using a newly developed approach termed COLT (cloningof ligand targets), in which the rapid cloning of modular protein domains is accomplished by screening cDNA expression libraries with specific peptide ligands. Two of the new genes identified appear to be members of a family of proteins, including Rsp5 and Nedd-4, which have ubiquitin-protein ligase activity. In addition, we demonstrate that peptides corresponding to PY and PY-like motifs present in several known signaling or regulatory proteins, including RasGAP, AP-2, p53BP-2 (p53-bindingprotein-2), interleukin-6 receptor-α, chloride channel CLCN5, and epithelial sodium channel ENaC, can selectively bind to certain of these novel WW domains.", "corpus_id": 20946111, "score": 0 }, { "doc_id": "1271839", "title": "YAP, TAZ, and Yorkie: a conserved family of signal-responsive transcriptional coregulators in animal development and human disease.", "abstract": "How extracellular cues are transduced to the nucleus is a fundamental issue in biology. The paralogous WW-domain proteins YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif; also known as WWTR1, for WW-domain containing transcription regulator 1) constitute a pair of transducers linking cytoplasmic signaling events to transcriptional regulation in the nucleus. A cascade composed of mammalian Ste20-like (MST) and large tumor suppressor (LATS) kinases directs multisite phosphorylation, promotes 14-3-3 binding, and hinders nuclear import of YAP and TAZ, thereby inhibiting their transcriptional coactivator and growth-promoting activities. A similar cascade regulates the trafficking and function of Yorkie, the fly orthologue of YAP. Mammalian YAP and TAZ are expressed in various tissues and serve as coregulators for transcriptional enhancer factors (TEFs; also referred to as TEADs, for TEA-domain proteins), runt-domain transcription factors (Runxs), peroxisome proliferator-activated receptor gamma (PPARgamma), T-box transcription factor 5 (Tbx5), and several others. YAP and TAZ play distinct roles during mouse development. Both, and their upstream regulators, are intimately linked to tumorigenesis and other pathogenic processes. Here, we review studies on this family of signal-responsive transcriptional coregulators and emphasize how relative sequence conservation predicates their function and regulation, to provide a conceptual framework for organizing available information and seeking new knowledge about these signal transducers.", "corpus_id": 1271839, "score": 0 }, { "doc_id": "22883769", "title": "Newcomers to the WW Domain-Mediated Network of the Hippo Tumor Suppressor Pathway.", "abstract": "The Hippo tumor suppressor pathway regulates the size of organs by controlling 2 opposing processes: proliferation and apoptosis. The pathway was originally defined in Drosophila, but it is well conserved in mammals. One of the unique features of Hippo signaling is the unusually wide occurrence of WW domains and its cognate PPxY ligand motifs within components of this pathway. Recently, it was proposed that the prevalence of WW domain-mediated complexes in the Hippo signaling pathway should facilitate its molecular analysis and help in the identification of new components of the Hippo-centered network. Indeed, several new members of the Hippo pathway, which form functional complexes with WW domains of YAP and TAZ effectors, were recently described. We focus here on 2 families of such proteins, angiomotins and SMADs, plus 1 regulatory factor, WBP-2, which together shed new light on the rapidly expanding Hippo network. Since the Hippo pathway acts as a tumor suppressor pathway, the complexes described here, which assemble on WW domains of YAP and TAZ, represent potential targets of cancer therapy.", "corpus_id": 22883769, "score": 0 }, { "doc_id": "84331659", "title": "Physical Interaction with Yes-associated Protein Enhances p73 Transcriptional Activity*", "abstract": "Specific protein-protein interactions are involved in a large number of cellular processes and are mainly mediated by structurally and functionally defined domains. Here we report that the nuclear phosphoprotein p73 can engage in a physical association with the Yes-associated protein (YAP). This association occurs under physiological conditions as shown by reciprocal co-immunoprecipitation of complexes from lysates of P19 cells. The WW domain of YAP and the PPPPY motif of p73 are directly involved in the association. Furthermore, as required for ligands to group I WW domains, the terminal tyrosine (Y) of the PPPPYmotif of p73 was shown to be essential for the association with YAP. Unlike p73α, p73β, and p63α, which bind to YAP, the endogenous as well as exogenously expressed wild-type p53 (wt-p53) and the p73γ isoform do not interact with YAP. Indeed, we documented that YAP interacts only with those members of the p53 family that have a well conserved PPXY motif, a target sequence for WW domains. Overexpression of YAP causes an increase of p73α transcriptional activity. Differential interaction of YAP with members of the p53 family may provide a molecular explanation for their functional divergence in signaling.", "corpus_id": 84331659, "score": 0 }, { "doc_id": "38660087", "title": "The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway.", "abstract": "The Hippo signaling pathway was initially defined by genetic studies in Drosophila to regulate tissue growth and organ size [1,2]. This pathway is highly conserved in mammals and dysregulation of the Hippo pathway has been implicated in human cancer. Although the exact extracellular signal that controls the Hippo pathway is currently unknown, compelling evidence supports a critical role of the Hippo pathway in cell contact inhibition, which is a property commonly lost in cancer cells. Many molecules, such as the merlin tumor suppressor protein, have been identified as regulating the activity of the core Hippo pathway components [1,2]. Acting downstream are two key transcription co-activators, YAP and TAZ, which mediate the major gene regulation and biological functions of the Hippo pathway. This article will focus on the physiological function and molecular regulation of YAP/TAZ and its Drosophila homolog Yki.", "corpus_id": 38660087, "score": 0 }, { "doc_id": "52158482", "title": "The Hippo Signaling Network and Its Biological Functions.", "abstract": "Hippo signaling is an evolutionarily conserved network that has a central role in regulating cell proliferation and cell fate to control organ growth and regeneration. It promotes activation of the LATS kinases, which control gene expression by inhibiting the activity of the transcriptional coactivator proteins YAP and TAZ in mammals and Yorkie in Drosophila. Diverse upstream inputs, including both biochemical cues and biomechanical cues, regulate Hippo signaling and enable it to have a key role as a sensor of cells' physical environment and an integrator of growth control signals. Several components of this pathway localize to cell-cell junctions and contribute to regulation of Hippo signaling by cell polarity, cell contacts, and the cytoskeleton. Downregulation of Hippo signaling promotes uncontrolled cell proliferation, impairs differentiation, and is associated with cancer. We review the current understanding of Hippo signaling and highlight progress in the elucidation of its regulatory mechanisms and biological functions.", "corpus_id": 52158482, "score": 0 }, { "doc_id": "14967252", "title": "Elucidation of a Universal Size-Control Mechanism in Drosophila and Mammals", "abstract": "Coordination of cell proliferation and cell death is essential to attain proper organ size during development and for maintaining tissue homeostasis throughout postnatal life. In Drosophila, these two processes are orchestrated by the Hippo kinase cascade, a growth-suppressive pathway that ultimately antagonizes the transcriptional coactivator Yorkie (Yki). Here we demonstrate that a single phosphorylation site in Yki mediates the growth-suppressive output of the Hippo pathway. Hippo-mediated phosphorylation inactivates Yki by excluding it from the nucleus, whereas loss of Hippo signaling leads to nuclear accumulation and therefore increased Yki activity. We further delineate a mammalian Hippo signaling pathway that culminates in the phosphorylation of YAP, the mammalian homolog of Yki. Using a conditional YAP transgenic mouse model, we demonstrate that the mammalian Hippo pathway is a potent regulator of organ size, and that its dysregulation leads to tumorigenesis. These results uncover a universal size-control mechanism in metazoan.", "corpus_id": 14967252, "score": 1 }, { "doc_id": "12737132", "title": "TEAD mediates YAP-dependent gene induction and growth control.", "abstract": "The YAP transcription coactivator has been implicated as an oncogene and is amplified in human cancers. Recent studies have established that YAP is phosphorylated and inhibited by the Hippo tumor suppressor pathway. Here we demonstrate that the TEAD family transcription factors are essential in mediating YAP-dependent gene expression. TEAD is also required for YAP-induced cell growth, oncogenic transformation, and epithelial-mesenchymal transition. CTGF is identified as a direct YAP target gene important for cell growth. Moreover, the functional relationship between YAP and TEAD is conserved in Drosophila Yki (the YAP homolog) and Scalloped (the TEAD homolog). Our study reveals TEAD as a new component in the Hippo pathway playing essential roles in mediating biological functions of YAP.", "corpus_id": 12737132, "score": 1 }, { "doc_id": "2161109", "title": "WW domain-mediated interaction with Wbp2 is important for the oncogenic property of TAZ", "abstract": "The transcriptional co-activators YAP and TAZ are downstream targets inhibited by the Hippo tumor suppressor pathway. YAP and TAZ both possess WW domains, which are important protein–protein interaction modules that mediate interaction with proline-rich motifs, most commonly PPXY. The WW domains of YAP have complex regulatory roles as exemplified by recent reports showing that they can positively or negatively influence YAP activity in a cell and context-specific manner. In this study, we show that the WW domain of TAZ is important for it to transform both MCF10A and NIH3T3 cells and to activate transcription of ITGB2 but not CTGF, as introducing point mutations into the WW domain of TAZ (WWm) abolished its transforming and transcription-promoting ability. Using a proteomic approach, we discovered potential regulatory proteins that interact with TAZ WW domain and identified Wbp2. The interaction of Wbp2 with TAZ is dependent on the WW domain of TAZ and the PPXY-containing C-terminal region of Wbp2. Knockdown of endogenous Wbp2 suppresses, whereas overexpression of Wbp2 enhances, TAZ-driven transformation. Forced interaction of WWm with Wbp2 by direct C-terminal fusion of full-length Wbp2 or its TAZ-interacting C-terminal domain restored the transforming and transcription-promoting ability of TAZ. These results suggest that the WW domain-mediated interaction with Wbp2 promotes the transforming ability of TAZ.", "corpus_id": 2161109, "score": 0 }, { "doc_id": "15745156", "title": "WW domain interactions regulate the Hippo tumor suppressor pathway", "abstract": "The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis in Drosophila and mammalians. Although the signaling of the core kinases is relatively well understood, less is known about the upstream inputs, downstream outputs and regulation of the whole cascade. Enrichment of the Hippo pathway components with WW domains and their cognate proline-rich interacting motifs provides a versatile platform for further understanding the mechanisms that regulate organ growth and tumorigenesis. Here, we review recently discovered mechanisms of WW domain-mediated interactions that contribute to the regulation of the Hippo signaling pathway in tumorigenesis. We further discuss new insights and future directions on the emerging role of such regulation.", "corpus_id": 15745156, "score": 1 }, { "doc_id": "7240370", "title": "Mechanisms of Hippo pathway regulation.", "abstract": "The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell-cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.", "corpus_id": 7240370, "score": 0 }, { "doc_id": "13785447", "title": "Control of Cell Proliferation and Apoptosis by Mob as Tumor Suppressor, Mats", "abstract": "Appropriate cell number and organ size in a multicellular organism are determined by coordinated cell growth, proliferation, and apoptosis. Disruption of these processes can cause cancer. Recent studies have identified the Large tumor suppressor (Lats)/Warts (Wts) protein kinase as a key component of a pathway that controls the coordination between cell proliferation and apoptosis. Here we describe growth inhibitory functions for a Mob superfamily protein, termed Mats (Mob as tumor suppressor), in Drosophila. Loss of Mats function results in increased cell proliferation, defective apoptosis, and induction of tissue overgrowth. We show that mats and wts function in a common pathway. Mats physically associates with Wts to stimulate the catalytic activity of the Wts kinase. A human Mats ortholog (Mats1) can rescue the lethality associated with loss of Mats function in Drosophila. As Mats1 is mutated in human tumors, Mats-mediated growth inhibition and tumor suppression is likely conserved in humans.", "corpus_id": 13785447, "score": 0 }, { "doc_id": "18910653", "title": "Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila", "abstract": "Tissue growth and organ size are determined by coordinated cell proliferation and apoptosis in development. Recent studies have demonstrated that Hippo (Hpo) signaling plays a crucial role in coordinating these processes by restricting cell proliferation and promoting apoptosis. Here we provide evidence that the Mob as tumor suppressor protein, Mats, functions as a key component of the Hpo signaling pathway. We found that Mats associates with Hpo in a protein complex and is a target of the Hpo serine/threonine protein kinase. Mats phosphorylation by Hpo increases its affinity with Warts (Wts)/large tumor suppressor (Lats) serine/threonine protein kinase and ability to upregulate Wts catalytic activity to target downstream molecules such as Yorkie (Yki). Consistently, our epistatic analysis suggests that mats acts downstream of hpo. Coexpression analysis indicated that Mats can indeed potentiate Hpo‐mediated growth inhibition in vivo. Our results support a model in which Mats is activated by Hpo through phosphorylation for growth inhibition, and this regulatory mechanism is conserved from flies to mammals.", "corpus_id": 18910653, "score": 0 }, { "doc_id": "11091575", "title": "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.", "abstract": "The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.", "corpus_id": 11091575, "score": 1 }, { "doc_id": "205374283", "title": "Mst2 and Lats Kinases Regulate Apoptotic Function of Yes Kinase-associated Protein (YAP)*", "abstract": "The Hippo pathway in Drosophila controls the size and shape of organs. In the fly, activation of this pathway conveys growth-inhibitory signals and promotes apoptosis in epithelial cells. We “reconstituted” the Hippo pathway in a human epithelial cell line and showed that, in contrast to flies, the activation of this pathway results in anti-apoptotic signals. We have shown that in human embryonic kidney (HEK) 293 cells, the complex formation between transcriptional co-activators YAPs (Yes kinase-associated proteins) and Lats kinases requires the intact WW domains of YAPs, as well as intact Pro-Pro-AA-Tyr (where AA is any amino acid) motifs in Lats kinases. These kinases cooperate with the upstream Mst2 kinase to phosphorylate YAPs at Ser-127. Overexpression of YAP2 in HEK293 cells promoted apoptosis, whereas the Mst2/Lats1-induced phosphorylation of YAP partially rescued the cells from apoptotic death. Apoptotic signaling of YAP2 was mediated via stabilization of p73, which formed a complex with YAP2. All components of the Hippo pathway that we studied were localized in the cytoplasm, with the exception of YAP, which also localized in the nucleus. The localization of YAP2 in the nucleus was negatively controlled by the Lats1 kinase. Our apoptotic “readout” of the Hippo pathway in embryonic kidney cells represents a useful experimental system for the identification of the putative upstream receptor, membrane protein, or extracellular factor that initiates an entire signaling cascade and ultimately controls the size of organs.", "corpus_id": 205374283, "score": 0 }, { "doc_id": "41080913", "title": "Protein kinases of the Hippo pathway: regulation and substrates.", "abstract": "The \"Hippo\" signaling pathway has emerged as a major regulator of cell proliferation and survival in metazoans. The pathway, as delineated by genetic and biochemical studies in Drosophila, consists of a kinase cascade regulated by cell-cell contact and cell polarity that inhibits the transcriptional coactivator Yorkie and its proliferative, anti-differentiation, antiapoptotic transcriptional program. The core pathway components are the GC kinase Hippo, which phosphorylates the noncatalytic polypeptide Mats/Mob1 and, with the assistance of the scaffold protein Salvador, phosphorylates the ndr-family kinase Lats. In turn phospho-Lats, after binding to phospho-Mats, autoactivates and phosphorylates Yorkie, resulting in its nuclear exit. Hippo also uses the scaffold protein Furry and a different Mob protein to control another ndr-like kinase, the morphogenetic regulator Tricornered. Architecturally homologous kinase cascades consisting of a GC kinase, a Mob protein, a scaffolding polypeptide and an ndr-like kinase are well described in yeast; in Saccharomyces cerevisiae, e.g., the MEN pathway promotes mitotic exit whereas the RAM network, using a different GC kinase, Mob protein, scaffold and ndr-like kinase, regulates cell polarity and morphogenesis. In mammals, the Hippo orthologs Mst1 and Mst2 utilize the Salvador ortholog WW45/Sav1 and other scaffolds to regulate the kinases Lats1/Lats2 and ndr1/ndr2. As in Drosophila, murine Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in the epithelial cells of the liver and gut; loss of both Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be largely negated by reduction or elimination of YAP. Despite this conservation, considerable diversification in pathway composition and regulation is already evident; in skin, e.g., YAP phosphorylation is independent of Mst1Mst2 and Lats1Lats2. Moreover, in lymphoid cells, Mst1/Mst2, under the control of the Rap1 GTPase and independent of YAP, promotes integrin clustering, actin remodeling and motility while restraining the proliferation of naïve T cells. This review will summarize current knowledge of the structure and regulation of the kinases Hippo/Mst1&2, their noncatalytic binding partners, Salvador and the Rassf polypeptides, and their major substrates Warts/Lats1&2, Trc/ndr1&2, Mats/Mob1 and FOXO.", "corpus_id": 41080913, "score": 0 }, { "doc_id": "13901512", "title": "MOBKL1A/MOBKL1B Phosphorylation by MST1 and MST2 Inhibits Cell Proliferation", "abstract": "BACKGROUND\nMST1 and MST2 are the mammalian Ste20-related protein kinases most closely related to Drosophila Hippo, a major regulator of cell proliferation and survival during development. Overexpression of MST1 or MST2 in mammalian cells is proapototic; however, little is known concerning the physiologic regulation of the endogenous MST1/MST2 kinases, their role in mammalian cell proliferation, or the identity of the MST1/MST2 substrates critical to proliferative regulation.\n\n\nRESULTS\nWe show that MST1 and MST2 activity increases during mitosis, especially in nocodazole-arrested mitotic cells, where these kinases exhibit both an increase in both abundance and activation. MST1 and MST2 also can be activated nonphysiologically by okadaic acid or H2O2. The MOBKL1A and MOBKL1B polypeptides, homologs of the Drosophila MATS polypeptide, are identified as preferred MST1/MST2 substrates in vitro and are phosphorylated in cells in an MST1/MST2-dependent manner in mitosis and in response to okadaic acid or H2O2. MST1/MST2-catalyzed MOBKL1A/MOBKL1B phosphorylation alters the ability of MOBKL1A/MOBKL1B to bind and regulate downstream targets such as the NDR-family protein kinases. Thus, MOBKL1A/MOBKL1B phosphorylation in cells promotes MOBKL1A/MOBKL1B binding to the LATS1 kinase and enables H2O2-stimulated LATS1 activation loop phosphorylation. Most importantly, replacement of endogenous MOBKL1A/MOBKL1B by a nonphosphorylatable mutant is sufficient to accelerate cell proliferation substantially by speeding progression through G1/S as well as mitotic exit.\n\n\nCONCLUSIONS\nThese results establish that MST1 and MST2 are activated in mitosis and catalyze the mitotic phosphorylation of MOBKL1A/MOBKL1B. MOBKL1A/MOBKL1B phosphorylation, in turn, is sufficient to inhibit proliferation through actions at several points in the cell cycle.", "corpus_id": 13901512, "score": 0 }, { "doc_id": "24114735", "title": "Tumor Suppressor LATS1 Is a Negative Regulator of Oncogene YAP*", "abstract": "LATS (large tumor suppressor) or warts is a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of AGC (protein kinase A/PKG/PKC) kinases. It is a tumor suppressor gene originally isolated from Drosophila and recently isolated from mice and humans. Drosophila or mice mutant for LATS develop tumors in various tissues. Recent studies in Drosophila demonstrate that LATS is a central player of an emerging tumor suppressor pathway called the Hippo-LATS/Warts pathway that suppresses tumor growth by regulating cell proliferation, cell growth, and cell death. Although tremendous progress has been made toward understanding the roles of LATS in tumorigenesis, the kinase substrates of LATS or downstream target proteins mediating LATS function remain largely unknown. In this study, we have provided convincing evidence that the LATS1 tumor suppressor can bind to and phosphorylate transcription regulator and oncogene YAP in vitro and in vivo. We have also identified HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence for LATS/Ndr kinase substrates. Significantly, we have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP. Finally, by using microarray analysis, we have also identified many oncogenes or tumor suppressor genes up-regulated or down-regulated by YAP. These research findings will have profound impacts on our understanding of the molecular mechanism of the LATS tumor suppressor and the emerging Hippo-LATS/Warts pathway.", "corpus_id": 24114735, "score": 0 }, { "doc_id": "18023185", "title": "In vivo regulation of Yorkie phosphorylation and localization", "abstract": "Yorkie (Yki), a transcription factor of the Fat and Hippo signaling pathways, is negatively regulated by the Warts kinase. Here, we use Phos-tag gels to characterize Warts-dependent phosphorylation of Yki in vivo, and show that Warts promotes phosphorylation of Yki at multiple sites. We also show that Warts inhibits Yki nuclear localization in vivo, and can promote binding of Yki to 14-3-3 proteins in cultured cells. In vivo assessment of the influence of individual upstream regulators of Warts reveals that some mutants (e.g. fat) have only partial effects on Yki phosphorylation, and weak effects on Yki localization, whereas other genotypes (e.g. ex fat double mutants) have stronger effects on both Yki phosphorylation and localization. We also identify serine 168 as a critical site through which negative regulation of Yki by Warts-mediated phosphorylation occurs, but find that this site is not sufficient to explain effects of Hippo signaling on Yki in vivo. These results identify modulation of subcellular localization as a mechanism of Yki regulation, and establish that this regulation occurs in vivo through multiple sites of Warts-dependent phosphorylation on Yki.", "corpus_id": 18023185, "score": 0 }, { "doc_id": "22226461", "title": "Hippo signaling regulates Yorkie nuclear localization and activity through 14-3-3 dependent and independent mechanisms.", "abstract": "The Hippo (Hpo) signaling pathway controls cell growth, proliferation and apoptosis in both Drosophila and vertebrates. In Drosophila, Hpo signaling regulates gene expression by inhibiting a transcription complex consisting of the transcriptional coactivator Yorkie (Yki) and the TEAD/TEF family of transcription factor Scalloped (Sd). Here we provide genetic evidence that both isoforms of 14-3-3, 14-3-3varepsilon and 14-3-3zeta, regulate Yki activity through modulating its subcellular localization. Inactivation of 14-3-3 by RNAi or genetic mutations enhanced whereas overexpression of 14-3-3 suppressed tissue overgrowth induced by Yki overexpression. Loss of 14-3-3 resulted in the accumulation of Yki in the nucleus. We found that regulation of Yki by 14-3-3 was mediated by phosphorylation of Yki at S168. In addition, we found that Hpo signaling also inhibited Yki nuclear localization and activity by phosphorylating Yki at S111 and S250, and this inhibition appears to be independent of 14-3-3. Finally, we provided evidence that Hpo signaling restricted Yki nuclear localization depending on CRM1-mediated nuclear export.", "corpus_id": 22226461, "score": 0 }, { "doc_id": "14790584", "title": "Dmp53 Activates the Hippo Pathway to Promote Cell Death in Response to DNA Damage", "abstract": "Developmental and environmental signals control a precise program of growth, proliferation, and cell death. This program ensures that animals reach, but do not exceed, their typical size . Understanding how cells sense the limits of tissue size and respond accordingly by exiting the cell cycle or undergoing apoptosis has important implications for both developmental and cancer biology. The Hippo (Hpo) pathway comprises the kinases Hpo and Warts/Lats (Wts), the adaptors Salvador (Sav) and Mob1 as a tumor suppressor (Mats), the cytoskeletal proteins Expanded and Merlin, and the transcriptional cofactor Yorkie (Yki) . This pathway has been shown to restrict cell division and promote apoptosis. The caspase repressor DIAP1 appears to be a primary target of the Hpo pathway in cell-death control. Firstly, Hpo promotes DIAP1 phosphorylation, likely decreasing its stability. Secondly, Wts phosphorylates and inactivates Yki, decreasing DIAP1 transcription. Although we understand some of the events downstream of the Hpo kinase, its mode of activation remains mysterious. Here, we show that Hpo can be activated by Ionizing Radiations (IR) in a Dmp53 (Drosophila melanogaster p53)-dependent manner and that Hpo is required (though not absolutely) for the cell death response elicited by IR or Dmp53 ectopic expression.", "corpus_id": 14790584, "score": 0 }, { "doc_id": "13897523", "title": "The Drosophila RASSF Homolog Antagonizes the Hippo Pathway", "abstract": "Summary Correct organ size is determined by the balance between cell death and proliferation. Perturbation of this delicate balance leads to cancer formation [1]. Hippo (Hpo), the Drosophila ortholog of MST1 and MST2 (Mammalian Sterile 20-like 1 and 2) is a key regulator of a signaling pathway that controls both cell death and proliferation 2, 3. This pathway is so far composed of two Band 4.1 proteins, Expanded (Ex) and Merlin (Mer), two serine/threonine kinases, Hpo and Warts (Wts), the scaffold proteins Salvador (Sav) and Mats, and the transcriptional coactivator Yorkie (Yki). It has been proposed that Ex and Mer act upstream of Hpo, which in turn phosphorylates and activates Wts. Wts phosphorylates Yki and thus inhibits its activity and reduces expression of Yki target genes such as the caspase inhibitor DIAP1 and the micro RNA bantam4, 5, 6. However, the mechanisms leading to Hpo activation are still poorly understood. In mammalian cells, members of the Ras association family (RASSF) of tumor suppressors have been shown to bind to MST1 and modulate its activity [7]. In this study, we show that the Drosophila RASSF ortholog (dRASSF) restricts Hpo activity by competing with Sav for binding to Hpo. In addition, we observe that dRASSF also possesses a tumor-suppressor function.", "corpus_id": 13897523, "score": 0 }, { "doc_id": "23332716", "title": "Salvador Protein Is a Tumor Suppressor Effector of RASSF1A with Hippo Pathway-independent Functions*", "abstract": "The RASSF1A tumor suppressor binds and activates proapoptotic MST kinases. The Salvador adaptor protein couples MST kinases to the LATS kinases to form the hippo pathway. Upon activation by RASSF1A, LATS1 phosphorylates the transcriptional regulator YAP, which binds to p73 and activates its proapoptotic effects. However, although serving as an adaptor for MST and LATS, Salvador can also bind RASSF1A. The functional role of the RASSF1A/Salvador interaction is unclear. Although Salvador is a novel tumor suppressor in Drosophila and mice, its role in human systems remains largely unknown. Here we show that Salvador promotes apoptosis in human cells and that Salvador inactivation deregulates the cell cycle and enhances the transformed phenotype. Moreover, we show that although the salvador gene is seldom mutated or epigenetically inactivated in human cancers, it is frequently down-regulated posttranscriptionally. Surprisingly, we also find that although RASSF1A requires the presence of Salvador for full apoptotic activity and to activate p73, this effect does not require a direct interaction of RASSF1A with MST kinases or the activation of the hippo pathway. Thus, we confirm a role for Salvador as a human tumor suppressor and RASSF1A effector and show that Salvador allows RASSF1A to modulate p73 independently of the hippo pathway.", "corpus_id": 23332716, "score": 0 }, { "doc_id": "17082665", "title": "Ajuba LIM Proteins Are Negative Regulators of the Hippo Signaling Pathway", "abstract": "The mammalian Ajuba LIM proteins (Ajuba, LIMD1, and WTIP) are adaptor proteins that exhibit the potential to communicate cell adhesive events with nuclear responses to remodel epithelia. Determining their role in vivo, however, has been challenging due to overlapping tissue expression and functional redundancy. Thus, we turned to Drosophila, where a single gene, CG11063 or djub, exists. Drosophila lacking the djub gene or depleted of dJub by RNA interference identify djub as an essential gene for development and a novel regulator of epithelial organ size as a component of the conserved Hippo (Hpo) pathway, which has been implicated in both tissue size control and cancer development. djub-deficient tissues were small and had decreased cell numbers as a result of increased apoptosis and decreased proliferation, due to downregulation of DIAP1 and cyclin E. This phenocopies tissues deficient for Yorkie (Yki), the downstream target of the Hippo pathway. djub genetically interacts with the Hippo pathway, and epistasis suggests that djub lies downstream of hpo. In mammalian and Drosophila cells, Ajuba LIM proteins/dJub interact with LATS/Warts (Wts) and WW45/Sav to inhibit phosphorylation of YAP/Yki. This work describes a novel role for the Ajuba LIM proteins as negative regulators of the Hippo signaling pathway.", "corpus_id": 17082665, "score": 0 }, { "doc_id": "13495744", "title": "Zyxin Links Fat Signaling to the Hippo Pathway", "abstract": "Using genetic and molecular analyses, the authors identify Zyx as a positive regulator of Hippo signaling and characterize its role within the pathway.", "corpus_id": 13495744, "score": 0 }, { "doc_id": "32461518", "title": "JNK signaling is converted from anti- to pro-tumor pathway by Ras-mediated switch of Warts activity.", "abstract": "The c-Jun N-terminal kinase (JNK) pathway is a dual-functional oncogenic signaling that exerts both anti- and pro-tumor activities. However, the mechanism by which JNK switches its oncogenic roles depending on different cellular contexts has been elusive. Here, using the Drosophila genetics, we show that hyperactive Ras acts as a signaling switch that converts JNK's role from anti- to pro-tumor signaling through the regulation of Hippo signaling activity. In the normal epithelium, JNK signaling antagonizes the Hippo pathway effector Yorkie (Yki) through elevation of Warts activity, thereby suppressing tissue growth. In contrast, in the presence of hyperactive Ras, JNK signaling enhances Yki activation by accumulating F-actin through the activity of the LIM domain protein Ajuba, thereby promoting tissue growth. We also find that the epidermal growth factor receptor (EGFR) signaling uses this Ras-mediated conversion of JNK signaling to promote tissue growth. Our observations suggest that Ras-mediated switch of the JNK pathway from anti- to pro-tumor signaling could play crucial roles in tumorigenesis as well as in normal development.", "corpus_id": 32461518, "score": 0 }, { "doc_id": "4907529", "title": "Zyxin Antagonizes the FERM Protein Expanded to Couple F-Actin and Yorkie-Dependent Organ Growth", "abstract": "BACKGROUND\nCoordinated multicellular growth during development is achieved by the sensing of spatial and nutritional boundaries. The conserved Hippo (Hpo) signaling pathway has been proposed to restrict tissue growth by perceiving mechanical constraints through actin cytoskeleton networks. The actin-associated LIM proteins Zyxin (Zyx) and Ajuba (Jub) have been linked to the control of tissue growth via regulation of Hpo signaling, but the study of Zyx has been hampered by a lack of genetic tools.\n\n\nRESULTS\nWe generated a zyx mutant in Drosophila using TALEN endonucleases and used this to show that Zyx antagonizes the FERM-domain protein Expanded (Ex) to control tissue growth, eye differentiation, and F-actin accumulation. Zyx membrane targeting promotes the interaction between the transcriptional co-activator Yorkie (Yki) and the transcription factor Scalloped (Sd), leading to activation of Yki target gene expression and promoting tissue growth. Finally, we show that Zyx's growth-promoting function is dependent on its interaction with the actin-associated protein Enabled (Ena) via a conserved LPPPP motif and is antagonized by Capping Protein (CP).\n\n\nCONCLUSIONS\nOur results show that Zyx is a functional antagonist of Ex in growth control and establish a link between actin filament polymerization and Yki activity.", "corpus_id": 4907529, "score": 0 }, { "doc_id": "42535525", "title": "Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway.", "abstract": "Recent studies have shown that the Hippo-Salvador-Warts (HSW) pathway restrains tissue growth by phosphorylating and inactivating the oncoprotein Yorkie. How growth-suppressive signals are transduced upstream of Hippo remains unclear. We show that the Sterile 20 family kinase, Tao-1, directly phosphorylates T195 in the Hippo activation loop and that, like other HSW pathway genes, Tao-1 functions to restrict cell proliferation in developing imaginal epithelia. This relationship appears to be evolutionarily conserved, because mammalian Tao-1 similarly affects MST kinases. In S2 cells, Tao-1 mediates the effects of the upstream HSW components Merlin and Expanded, consistent with the idea that Tao-1 functions in tissues to regulate Hippo phosphorylation. These results demonstrate that one family of Ste20 kinases can activate another and identify Tao-1 as a component of the regulatory network controlling HSW pathway signaling, and therefore tissue growth, during development.", "corpus_id": 42535525, "score": 0 }, { "doc_id": "45214933", "title": "The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway.", "abstract": "The Salvador-Warts-Hippo (SWH) pathway is a complex signaling network that controls both developmental and regenerative tissue growth. Using a genetic screen in Drosophila melanogaster, we identified the sterile 20-like kinase, Tao-1, as an SWH pathway member. Tao-1 controls various biological phenomena, including microtubule dynamics, animal behavior, and brain development. Here we describe a role for Tao-1 as a regulator of epithelial tissue growth that modulates activity of the core SWH pathway kinase cassette. Tao-1 functions together with Hippo to activate Warts-mediated repression of Yorkie. Tao-1's ability to control SWH pathway activity is evolutionarily conserved because human TAO1 can suppress activity of the Yorkie ortholog, YAP. Human TAO1 controls SWH pathway activity by phosphorylating, and activating, the Hippo ortholog, MST2. Given that SWH pathway activity is subverted in many human cancers, our findings identify human TAO kinases as potential tumor suppressor genes.", "corpus_id": 45214933, "score": 0 }, { "doc_id": "22027310", "title": "Regulators of mammalian Hippo pathway in cancer.", "abstract": "Hippo pathway, originally discovered in Drosophila, is responsible for organ size control. The pathway is conserved in mammals and has a significant role in restraining cancer development. Regulating the Hippo pathway thus represents a potential therapeutic approach to treat cancer, which however requires deep understanding of the targeted pathway. Despite our limited knowledge on the pathway, there are increasing discoveries of new molecules that regulate and modulate the Hippo downstream signaling particularly in various solid malignancies, from extracellular stimuli or via pathway crosstalk. Herein, we discuss the roles of newly identified and key regulators that connect with core components (MST1/2, LATS1/2, SAV1, and MOB1) and downstream effector (YAP) in the Hippo pathway having an important role in cancer development and progression. Understanding of the mammalian Hippo pathway regulation may shed new insights to allow us selecting the right oncogenic targets and designing effective drugs for cancer treatments.", "corpus_id": 22027310, "score": 0 }, { "doc_id": "44083812", "title": "The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell", "abstract": "The Hippo pathway plays an important role in regulating tissue homeostasis, and its effectors, the transcriptional co-activators Yes-associated protein (YAP) and WW domain–containing transcription regulator 1 (WWTR1 or TAZ), are responsible for mediating the vast majority of its physiological functions. Although YAP and TAZ are thought to be largely redundant and similarly regulated by Hippo signaling, they have developmental, structural, and physiological differences that suggest they may differ in their regulation and downstream functions. To better understand the functions of YAP and TAZ in the Hippo pathway, using CRISPR/Cas9, we generated YAP KO, TAZ KO, and YAP/TAZ KO cell lines in HEK293A cells. We evaluated them in response to many environmental conditions and stimuli and used RNA-Seq to compare their transcriptional profiles. We found that YAP inactivation has a greater effect on cellular physiology (namely, cell spreading, volume, granularity, glucose uptake, proliferation, and migration) than TAZ inactivation. However, functional redundancy between YAP and TAZ was also observed. In summary, our findings confirm that the Hippo pathway effectors YAP and TAZ are master regulators for multiple cellular processes but also reveal that YAP has a stronger influence than TAZ.", "corpus_id": 44083812, "score": 0 }, { "doc_id": "6188547", "title": "The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost", "abstract": "Membrane-associated guanylate kinase (Maguk) proteins are scaffold proteins that contain PSD-95–Discs Large–zona occludens-1 (PDZ), Src homology 3, and guanylate kinase domains. A subset of Maguk proteins, such as mLin-2 and protein associated with Lin-7 (Pals)1, also contain two L27 domains: an L27C domain that binds mLin-7 and an L27N domain of unknown function. Here, we demonstrate that the L27N domain targets Pals1 to tight junctions by binding to a PDZ domain protein, Pals1-associated tight junction (PATJ) protein, via a unique Maguk recruitment domain. PATJ is a homologue of Drosophila Discs Lost, a protein that is crucial for epithelial polarity and that exists in a complex with the apical polarity determinant, Crumbs. PATJ and a human Crumbs homologue, CRB1, colocalize with Pals1 to tight junctions, and CRB1 interacts with PATJ albeit indirectly via binding the Pals1 PDZ domain. In agreement, we find that a Drosophila homologue of Pals1 participates in identical interactions with Drosophila Crumbs and Discs Lost. This Drosophila Pals1 homologue has been demonstrated recently to represent Stardust, a crucial polarity gene in Drosophila. Thus, our data identifies a new multiprotein complex that appears to be evolutionarily conserved and likely plays an important role in protein targeting and cell polarity.", "corpus_id": 6188547, "score": 0 }, { "doc_id": "15329212", "title": "Scribble protein domain mapping reveals a multistep localization mechanism and domains necessary for establishing cortical polarity", "abstract": "The Drosophila tumor suppressor protein Scribble is required for epithelial polarity, neuroblast polarity, neuroblast spindle asymmetry and limiting cell proliferation. It is a member of the newly described LAP protein family, containing 16 leucine rich repeats (LRRs), four PDZ domains and an extensive carboxyl-terminal (CT) domain. LRR and PDZ domains mediate protein-protein interactions, but little is know about their function within LAP family proteins. We have determined the role of the LRR, PDZ and CT domains for Scribble localization in neuroblasts and epithelia, and for Scribble function in neuroblasts. We found that the LRR and PDZ domains are both required for proper targeting of Scribble to septate junctions in epithelia; that the LRR domain is necessary and sufficient for cortical localization in mitotic neuroblasts, and that the PDZ2 domain is required for efficient cortical and apical localization of Scribble in neuroblasts. In addition, we show that the LRR domain is sufficient to target Miranda protein to the neuroblast cortex, but that LRR+PDZ will exclude Miranda from the cortex. Our results highlight the importance of both LRR and PDZ domains for the proper localization and function of Scribble in neuroblasts.", "corpus_id": 15329212, "score": 0 }, { "doc_id": "22230615", "title": "Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras.", "abstract": "MST1 (mammalian Sterile20-like 1) and MST2 are closely related Class II GC (protein Ser/Thr) kinases that initiate apoptosis when transiently overexpressed in mammalian cells. In the present study, we show that recombinant MST1/2 undergo a robust autoactivation in vitro, mediated by an intramolecular autophosphorylation of a single site [MST1(Thr183)/MST2(Thr180)] on the activation loop of an MST dimer. Endogenous full-length MST1 is activated by a variety of stressful stimuli, accompanied by the secondary appearance of a 36 kDa Thr183-phosphorylated, caspase-cleaved catalytic fragment. Recombinant MST1 exhibits only 2-5% activation during transient expression; endogenous MST1 in the cycling HeLa or KB cells has a similar low fractional activation, but 2 h incubation with okadaic acid (1 mM) results in 100% activation. Endogenous MST1 immunoprecipitated from KB cells is specifically associated with substoichiometric amounts of the growth inhibitory polypeptides RASSF1A and NORE1A (novel Ras effector 1A; a Ras-GTP-binding protein). Co-expression of RASSF1A, RASSF1C, NORE1A and NORE1B with MST1 markedly suppresses MST1(Thr183) phosphorylation in vivo and abolishes the ability of MST1 to undergo Mg-ATP-mediated autoactivation in vitro; direct addition of purified NORE1A in vitro also inhibits MST1 activation. In contrast, co-transfection of MST1 with NORE1A modified by the addition of a C-terminal CAAX motif results in a substantial increase in MST1(Thr183) phosphorylation, as does fusion of a myristoylation motif directly on to the MST1 N-terminus. Moreover, MST1 polypeptides, bound via wild-type NORE1A to Ras(G12V) (where G12V stands for Gly12Val), exhibit higher Thr183 phosphorylation compared with MST1 bound to NORE1A alone. Nevertheless, serum stimulation of KB cells does not detectably increase the activation state of endogenous MST1 or MST2 despite promoting the recruitment of the endogenous NORE1-MST1 complex to endogenous Ras. We propose that the NORE1/RASSF1 polypeptides, in addition to their role in maintaining the low activity of MST1 in vivo, direct MST1 to sites of activation and perhaps co-localization with endogenous substrates.", "corpus_id": 22230615, "score": 0 }, { "doc_id": "35303042", "title": "Tight Junction Protein Par6 Interacts with an Evolutionarily Conserved Region in the Amino Terminus of PALS1/Stardust*", "abstract": "Tight junctions are the structures in mammalian epithelial cells that separate the apical and basolateral membranes and may also be important in the establishment of cell polarity. Two evolutionarily conserved multiprotein complexes, Crumbs-PALS1 (Stardust)-PATJ and Cdc42-Par6-Par3-atypical protein kinase C, have been implicated in the assembly of tight junctions and in polarization of Drosophila melanogaster epithelia. These two complexes have been linked physically and functionally by an interaction between PALS1 and Par6. Here we identify an evolutionarily conserved region in the amino terminus of PALS1 as the Par6 binding site and identify valine and aspartic acid residues in this region as essential for interacting with the PDZ domain of Par6. We have also characterized, in more detail, the amino terminus of Drosophila Stardust and demonstrate that the interaction mechanism between Stardust and Drosophila Par6 is evolutionarily conserved. Par6 interferes with PATJ in binding PALS1, and these two interactions do not appear to function synergistically. Taken together, these results define the molecular mechanisms linking two conserved polarity complexes.", "corpus_id": 35303042, "score": 0 }, { "doc_id": "8261982", "title": "Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C‐terminal coiled‐coil domains, leads to its stabilization and phosphorylation", "abstract": "Genetic screens in Drosophila have revealed that the serine/threonine kinase Hippo (Hpo) and the scaffold protein Salvador participate in a pathway that controls cell proliferation and apoptosis. Hpo most closely resembles the pro‐apoptotic mammalian sterile20 kinases 1 and 2 (Mst1 and 2), and Salvador (Sav) has a human orthologue hSav (also called hWW45). Here we show that Mst and hSav heterodimerize in an interaction requiring the conserved C‐terminal coiled‐coil domains of both proteins. hSav was also able to homodimerize, but this did not require its coiled‐coil domain. Coexpression of Mst and hSav led to phosphorylation of hSav and also increased its abundance. In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N‐terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C‐terminal coiled‐coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav, whereas catalytically inactive Mst mutants that retained the ability to bind to hSav were still able to increase its abundance, although they were no longer able to phosphorylate hSav. Together these results show that hSav can bind to, and be phosphorylated by, Mst, and that the stabilizing effect of Mst on hSav requires its interaction with hSav but is probably not due to phosphorylation of hSav by Mst.", "corpus_id": 8261982, "score": 0 }, { "doc_id": "41654457", "title": "The conserved c2 domain protein lethal (2) giant discs regulates protein trafficking in Drosophila.", "abstract": "Drosophila sensory organ precursor (SOP) cells undergo several rounds of asymmetric cell division to generate the four different cell types that make up external sensory organs. Establishment of different fates among daughter cells of the SOP relies on differential regulation of the Notch pathway. Here, we identify the protein Lethal (2) giant discs (Lgd) as a critical regulator of Notch signaling in the SOP lineage. We show that lgd encodes a conserved C2 domain protein that binds to phospholipids present on early endosomes. When Lgd function is compromised, Notch and other transmembrane proteins accumulate in enlarged early endosomal compartments. These enlarged endosomes are positive for Rab5 and Hrs, a protein involved in trafficking into the degradative pathway. Our experiments suggest that Lgd is a critical regulator of endocytosis that is not present in yeast and acts in the degradative pathway after Hrs.", "corpus_id": 41654457, "score": 0 }, { "doc_id": "1354498", "title": "The Fat Cadherin Acts through the Hippo Tumor-Suppressor Pathway to Regulate Tissue Size", "abstract": "BACKGROUND\nThe Hippo tumor-suppressor pathway has emerged as a key signaling pathway that controls tissue size in Drosophila. Merlin, the Drosophila homolog of the human Neurofibromatosis type-2 (NF2) tumor-suppressor gene, and the related protein Expanded are the most upstream components of the Hippo pathway identified so far. However, components acting upstream of Expanded and Merlin, such as transmembrane receptors, have not yet been identified.\n\n\nRESULTS\nHere, we report that the protocadherin Fat acts as an upstream component in the Hippo pathway. Fat is a known tumor-suppressor gene in Drosophila, and fat mutants have severely overgrown imaginal discs. We found that the overgrowth phenotypes of fat mutants are similar to those of mutants in Hippo pathway components: fat mutant cells continued to proliferate after wild-type cells stopped proliferating, and fat mutant cells deregulated Hippo target genes such as cyclin E and diap1. Fat acts genetically and biochemically upstream of other Hippo pathway components such as Expanded, the Hippo and Warts kinases, and the transcriptional coactivator Yorkie. Fat is required for the stability of Expanded and its localization to the plasma membrane. In contrast, Fat is not required for Merlin localization, and Fat and Merlin act in parallel in growth regulation.\n\n\nCONCLUSIONS\nTaken together, our data identify a cell-surface molecule that may act as a receptor of the Hippo signaling pathway.", "corpus_id": 1354498, "score": 0 }, { "doc_id": "16481924", "title": "Drosophila lowfat, a novel modulator of Fat signaling", "abstract": "The Fat-Hippo-Warts signaling network regulates both transcription and planar cell polarity. Despite its crucial importance to the normal control of growth and planar polarity, we have only a limited understanding of the mechanisms that regulate Fat. We report here the identification of a conserved cytoplasmic protein, Lowfat (Lft), as a modulator of Fat signaling. Drosophila Lft, and its human homologs LIX1 and LIX1-like, bind to the cytoplasmic domains of the Fat ligand Dachsous, the receptor protein Fat, and its human homolog FAT4. Lft protein can localize to the sub-apical membrane in disc cells, and this membrane localization is influenced by Fat and Dachsous. Lft expression is normally upregulated along the dorsoventral boundary of the developing wing, and is responsible for elevated levels of Fat protein there. Levels of Fat and Dachsous protein are reduced in lft mutant cells, and can be increased by overexpression of Lft. lft mutant animals exhibit a wing phenotype similar to that of animals with weak alleles of fat, and lft interacts genetically with both fat and dachsous. These studies identify Lft as a novel component of the Fat signaling pathway, and the Lft-mediated elevation of Fat levels as a mechanism for modulating Fat signaling.", "corpus_id": 16481924, "score": 0 }, { "doc_id": "36475596", "title": "The RASSF proteins in cancer; from epigenetic silencing to functional characterization.", "abstract": "The Ras-Association Domain Family (RASSF) comprises ten members, termed RASSF1 to RASSF10. RASSF1 to RASSF6 harbor a C-terminal Ras-association (RA) domain and RASSF7 to RASSF10 contain an N-terminal RA domain. Interestingly, it was observed that in various tumor types distinct RASSFs transcripts (e.g. RASSF1A and RASSF2A) are missing due to hypermethylation of their CpG island promoter. Since methylation of the RASSF1A promoter is described as an early and frequent event in tumorigenesis, RASSF1A could serve as a useful diagnostic marker in cancer screens. RASSFs are implicated in various cellular mechanisms including apoptosis, cell cycle control and microtubule stabilization, though little is known about the underlying mechanisms. Tumor suppressing functions were reported for several members. Here we review the current literature on RASSF members focusing on structural, functional and epigenetic aspects. Characterizing the cellular mechanisms that regulate the signaling pathways RASSFs are involved in, could lead to a deeper understanding of tumor development and, furthermore, to new strategies in cancer treatment.", "corpus_id": 36475596, "score": 0 }, { "doc_id": "83876239", "title": "An autoinhibitory effect of the homothorax domain of Meis2", "abstract": "Myeloid ecotropic insertion site (Meis)2 is a homeodomain protein containing a conserved homothorax (Hth) domain that is present in all Meis and Prep family proteins and in the Drosophila Hth protein. The Hth domain mediates interaction with Pbx homeodomain proteins, allowing for efficient DNA binding. Here we show that, like Meis1, Meis2 has a strong C‐terminal transcriptional activation domain, which is required for full activation of transcription by homeodomain protein complexes composed of Meis2 and Pbx1. We also show that the activity of the activation domain is inhibited by the Hth domain, and that this autoinhibition can be partially relieved by the interaction of Pbx1 with the Hth domain of Meis2. Targeting of the Hth domain to DNA suggests that it is not a portable trans‐acting repression domain. However, the Hth domain can inhibit a linked activation domain, and this inhibition is not limited to the Meis2 activation domain. Database searching reveals that the Meis3.2 splice variant, which is found in several vertebrate species, disrupts the Hth domain by removing 17 codons from the 5′‐end of exon 6. We show that the equivalent deletion in Meis2 derepresses the C‐terminal activation domain and weakens interaction with Pbx1. This work suggests that the transcriptional activity of all members of the Meis/Prep Hth protein family is subject to autoinhibition by their Hth domains, and that the Meis3.2 splice variant encodes a protein that bypasses this autoinhibitory effect.", "corpus_id": 83876239, "score": 0 }, { "doc_id": "22213499", "title": "Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded.", "abstract": "The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. Central to this pathway is a kinase cascade wherein Hippo (Hpo), in complex with Salvador (Sav), phosphorylates and activates Warts (Wts), which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein, known as the YAP coactivator in mammalian cells. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are upstream components that regulate Hpo activity through unknown mechanisms. Here we identify Kibra as another upstream component of the Hippo signaling pathway. We show that Kibra functions together with Mer and Ex in a protein complex localized to the apical domain of epithelial cells, and that this protein complex regulates the Hippo kinase cascade via direct binding to Hpo and Sav. These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis.", "corpus_id": 22213499, "score": 0 }, { "doc_id": "29349834", "title": "MOB control: reviewing a conserved family of kinase regulators.", "abstract": "The family of Mps One binder (MOB) co-activator proteins is highly conserved from yeast to man. At least two different MOB proteins have been identified in every eukaryote analysed to date. Initially, yeast genetics revealed essential roles for Mob1p and Mob2p in the regulation of mitotic exit and cell morphogenesis. Studies in flies then showed that dMOB1/MATS is a core component of Hippo signalling. Loss of dMOB1 resulted in increased cell proliferation and decreased cell death, suggesting that MOB1 acts as tumour suppressor protein. Recent work focused primarily on mammalian cells has shown how hMOB1 can regulate NDR/LATS kinases, a function that can to be counteracted by hMOB2. Here we summarise and discuss our current knowledge of this emerging protein family, with emphasis on subcellular localisation, protein-protein interactions and biological functions in apoptosis, mitosis, morphogenesis, cell proliferation and centrosome duplication.", "corpus_id": 29349834, "score": 0 }, { "doc_id": "22085813", "title": "A novel partner of Scalloped regulates Hippo signaling via antagonizing Scalloped-Yorkie activity", "abstract": "The Hippo (Hpo) pathway controls tissue growth and organ size by regulating the activity of transcriptional co-activator Yorkie (Yki), which associates with transcription factor Scalloped (Sd) in the nucleus to promote downstream target gene expression. Here we identify a novel protein Sd-Binding-Protein (SdBP)/Tgi, which directly competes with Yki for binding to Sd through its TDU domains and inhibits the Sd-Yki transcriptional activity. We also find that SdBP retains Yki in the nucleus through the association with Yki WW domains via its PPXY motifs. Collectively, we identify SdBP as a novel component of the Hpo pathway, negatively regulating the transcriptional activity of Sd-Yki to restrict tissue growth.", "corpus_id": 22085813, "score": 0 }, { "doc_id": "5842858", "title": "Biochemical Large-Scale Interaction Analysis of Murine Olfactory Receptors and Associated Signaling Proteins with Post-Synaptic Density 95, Drosophila Discs Large, Zona-Occludens 1 (PDZ) Domains*", "abstract": "G protein-coupled receptors (GPCRs) constitute the largest family among mammalian membrane proteins and are capable of initiating numerous essential signaling cascades. Various GPCR-mediated pathways are organized into protein microdomains that can be orchestrated and regulated through scaffolding proteins, such as PSD-95/discs-large/ZO1 (PDZ) domain proteins. However, detailed binding characteristics of PDZ–GPCR interactions remain elusive because these interactions seem to be more complex than previously thought. To address this issue, we analyzed binding modalities using our established model system. This system includes the 13 individual PDZ domains of the multiple PDZ domain protein 1 (MUPP1; the largest PDZ protein), a broad range of murine olfactory receptors (a multifaceted gene cluster within the family of GPCRs), and associated olfactory signaling proteins. These proteins were analyzed in a large-scale peptide microarray approach and continuative interaction studies. As a result, we demonstrate that canonical binding motifs were not overrepresented among the interaction partners of MUPP1. Furthermore, C-terminal phosphorylation and distinct amino acid replacements abolished PDZ binding promiscuity. In addition to the described in vitro experiments, we identified new interaction partners within the murine olfactory epithelium using pull-down-based interactomics and could verify the partners through co-immunoprecipitation. In summary, the present study provides important insight into the complexity of the binding characteristics of PDZ–GPCR interactions based on olfactory signaling proteins, which could identify novel clinical targets for GPCR-associated diseases in the future.", "corpus_id": 5842858, "score": 0 }, { "doc_id": "25742614", "title": "Localization and Function of Pals1-associated Tight Junction Protein in Drosophila Is Regulated by Two Distinct Apical Complexes*", "abstract": "Background: Pals1-associated tight junction protein (PATJ) is an important regulator of Myosin-driven morphogenetic processes. Results: PATJ associates with two different apical complexes and accomplishes its function by a redundancy of its protein interaction domains. Conclusion: The correct targeting of PATJ to distinct apical domains is important for its function in Drosophila development. Significance: Learning how adaptor proteins can be regulated by protein targeting to distinct cellular compartments. The transmembrane protein Crumbs (Crb) and its intracellular adaptor protein Pals1 (Stardust, Sdt in Drosophila) play a crucial role in the establishment and maintenance of apical-basal polarity in epithelial cells in various organisms. In contrast, the multiple PDZ domain-containing protein Pals1-associated tight junction protein (PATJ), which has been described to form a complex with Crb/Sdt, is not essential for apical basal polarity or for the stability of the Crb/Sdt complex in the Drosophila epidermis. Here we show that, in the embryonic epidermis, Sdt is essential for the correct subcellular localization of PATJ in differentiated epithelial cells but not during cellularization. Consistently, the L27 domain of PATJ is crucial for the correct localization and function of the protein. Our data further indicate that the four PDZ domains of PATJ function, to a large extent, in redundancy, regulating the function of the protein. Interestingly, the PATJ-Sdt heterodimer is not only recruited to the apical cell-cell contacts by binding to Crb but depends on functional Bazooka (Baz). However, biochemical experiments show that PATJ associates with both complexes, the Baz-Sdt and the Crb-Sdt complex, in the mature epithelium of the embryonic epidermis, suggesting a role of these two complexes for the function of PATJ during the development of Drosophila.", "corpus_id": 25742614, "score": 0 }, { "doc_id": "14102423", "title": "AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol", "abstract": "ABSTRACT The Hippo pathway controls organ growth and is implicated in cancer development. Whether and how Hippo pathway activity is limited to sustain or initiate cell growth when needed is not understood. The members of the AJUBA family of LIM proteins are negative regulators of the Hippo pathway. In mammalian epithelial cells, we found that AJUBA LIM proteins limit Hippo regulation of YAP, in proliferating cells only, by sequestering a cytosolic Hippo kinase complex in which LATS kinase is inhibited. At the plasma membranes of growth-arrested cells, AJUBA LIM proteins do not inhibit or associate with the Hippo kinase complex. The ability of AJUBA LIM proteins to inhibit YAP regulation by Hippo and to associate with the kinase complex directly correlate with their capacity to limit Hippo signaling during Drosophila wing development. AJUBA LIM proteins did not influence YAP activity in response to cell-extrinsic or cell-intrinsic mechanical signals. Thus, AJUBA LIM proteins limit Hippo pathway activity in contexts where cell proliferation is needed.", "corpus_id": 14102423, "score": 0 }, { "doc_id": "2159184", "title": "Domain-specific functions of Stardust in Drosophila embryonic development", "abstract": "In Drosophila, the adaptor protein Stardust is essential for the stabilization of the polarity determinant Crumbs in various epithelial tissues, including the embryonic epidermis, the follicular epithelium and photoreceptor cells of the compound eye. In turn, Stardust recruits another adaptor protein, PATJ, to the subapical region to support adherens junction formation and morphogenetic events. Moreover, Stardust binds to Lin-7, which is dispensable in epithelial cells but functions in postsynaptic vesicle fusion. Finally, Stardust has been reported to bind directly to PAR-6, thereby linking the Crumbs–Stardust–PATJ complex to the PAR-6/aPKC complex. PAR-6 and aPKC are also capable of directly binding Bazooka (the Drosophila homologue of PAR-3) to form the PAR/aPKC complex, which is essential for apical–basal polarity and cell–cell contact formation in most epithelia. However, little is known about the physiological relevance of these interactions in the embryonic epidermis of Drosophila in vivo. Thus, we performed a structure–function analysis of the annotated domains with GFP-tagged Stardust and evaluated the localization and function of the mutant proteins in epithelial cells of the embryonic epidermis. The data presented here confirm a crucial role of the PDZ domain in binding Crumbs and recruiting the protein to the subapical region. However, the isolated PDZ domain is not capable of being recruited to the cortex, and the SH3 domain is essential to support the binding to Crumbs. Notably, the conserved N-terminal regions (ECR1 and ECR2) are not crucial for epithelial polarity. Finally, the GUK domain plays an important role for the protein's function, which is not directly linked to Crumbs stabilization, and the L27N domain is essential for epithelial polarization independently of recruiting PATJ.", "corpus_id": 2159184, "score": 0 }, { "doc_id": "3594387", "title": "Structures of the L27 Domain of Disc Large Homologue 1 Protein Illustrate a Self-Assembly Module.", "abstract": "Disc large 1 (Dlg1) proteins, members of the MAGUK protein family, are linked to cell polarity via their participation in multiprotein assemblies. At their N-termini, Dlg1 proteins contain a L27 domain. Typically, the L27 domains participate in the formation of obligate hetero-oligomers with the L27 domains from their cognate partners. Among the MAGUKs, Dlg1 proteins exist as homo-oligomers, and the oligomerization is solely dependent on the L27 domain. Here we provide biochemical and structural evidence of homodimerization via the L27 domain of Dlg1 from Drosophila melanogaster. The structure reveals that the core of the dimer is formed by a distinctive six-helix assembly, involving all three conserved helices from each subunit (monomer). The homodimer interface is extended by the C-terminal tail of the L27 domain of Dlg1, which forms a two-stranded antiparallel β-sheet. The structure reconciles and provides a structural context for a large body of available mutational data. From our analyses, we conclude that the observed L27 homodimerization is most likely a feature unique to the Dlg1 orthologs within the MAGUK family.", "corpus_id": 3594387, "score": 0 }, { "doc_id": "11531577", "title": "A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP).", "abstract": "The Yes-associated protein (YAP) transcription coactivator is a key regulator of organ size and a candidate human oncogene. YAP is inhibited by the Hippo pathway kinase cascade, at least in part via phosphorylation of Ser 127, which results in YAP 14-3-3 binding and cytoplasmic retention. Here we report that YAP is phosphorylated by Lats on all of the five consensus HXRXXS motifs. Phosphorylation of Ser 381 in one of them primes YAP for subsequent phosphorylation by CK1delta/epsilon in a phosphodegron. The phosphorylated phosphodegron then recruits the SCF(beta-TRCP) E3 ubiquitin ligase, which catalyzes YAP ubiquitination, ultimately leading to YAP degradation. The phosphodegron-mediated degradation and the Ser 127 phosphorylation-dependent translocation coordinately suppress YAP oncogenic activity. Our study identified CK1delta/epsilon as new regulators of YAP and uncovered an intricate mechanism of YAP regulation by the Hippo pathway via both S127 phosphorylation-mediated spatial regulation (nuclear-cytoplasmic shuttling) and the phosphodegron-mediated temporal regulation (degradation).", "corpus_id": 11531577, "score": 0 }, { "doc_id": "24559468", "title": "Processing and phosphorylation of the Fat receptor", "abstract": "The Drosophila tumor suppressors fat and discs overgrown (dco) function within an intercellular signaling pathway that controls growth and polarity. fat encodes a transmembrane receptor, but post-translational regulation of Fat has not been described. We show here that Fat is subject to a constitutive proteolytic processing, such that most or all cell surface Fat comprises a heterodimer of stably associated N- and C-terminal fragments. The cytoplasmic domain of Fat is phosphorylated, and this phosphorylation is promoted by the Fat ligand Dachsous. dco encodes a kinase that influences Fat signaling, and Dco is able to promote the phosphorylation of the Fat intracellular domain in cultured cells and in vivo. Evaluation of dco mutants indicates that they affect Fat's influence on growth and gene expression but not its influence on planar cell polarity. Our observations identify processing and phosphorylation as post-translational modifications of Fat, correlate the phosphorylation of Fat with its activation by Dachsous in the Fat-Warts pathway, and enhance our understanding of the requirement for Dco in Fat signaling.", "corpus_id": 24559468, "score": 0 }, { "doc_id": "18320402", "title": "Phosphorylation of the Tumor Suppressor Fat Is Regulated by Its Ligand Dachsous and the Kinase Discs Overgrown", "abstract": "The Drosophila tumor suppressor gene fat encodes a large cadherin that regulates growth and a form of tissue organization known as planar cell polarity (PCP). Fat regulates growth via the Hippo kinase pathway, which controls expression of genes promoting cell proliferation and inhibiting apoptosis (reviewed in). The Hippo pathway is highly conserved and is implicated in the regulation of mammalian growth and cancer development. Genetic studies suggest that Fat activity is regulated by binding to another large cadherin, Dachsous (Ds). The tumor suppressor discs overgrown (dco)/Casein Kinase I delta/epsilon also regulates Hippo activity and PCP. The biochemical nature of how Fat, Ds, and Dco interact to regulate these pathways is poorly understood. Here we demonstrate that Fat is cleaved to generate 450 kDa and 110 kDa fragments (Fat(450) and Fat(110)). Fat(110) contains the cytoplasmic and transmembrane domain. The cytoplasmic domain of Fat binds Dco and is phosphorylated by Dco at multiple sites. Importantly, we show Fat forms cis-dimers and that Fat phosphorylation is regulated by Dachsous and Dco in vivo. We propose that Ds regulates Dco-dependent phosphorylation of Fat and Fat-associated proteins to control Fat signaling in growth and PCP.", "corpus_id": 18320402, "score": 0 }, { "doc_id": "13824988", "title": "Regulation of Yki/Yap subcellular localization and Hpo signaling by a nuclear kinase PRP4K", "abstract": "Hippo (Hpo) signaling pathway controls tissue growth by regulating the subcellular localization of Yorkie (Yki)/Yap via a cytoplasmic kinase cassette containing an upstream kinase Hpo/MST1/2 and a downstream kinase Warts (Wts)/Lats1/2. Here we show that PRP4K, a kinase involved in mRNA splicing, phosphorylates Yki/Yap in the nucleus to prevent its nuclear accumulation and restrict Hpo pathway target gene expression. PRP4K inactivation accelerates whereas excessive PRP4K inhibits Yki-driven tissue overgrowth. PRP4K phosphorylates a subset of Wts/Lats1/2 sites on Yki/Yap to inhibit the binding of Yki/Yap to the Scalloped (Sd)/TEAD transcription factor and exclude Yki/Yap nuclear localization depending on nuclear export. Furthermore, PRP4K inhibits proliferation and invasiveness of cultured breast cancer cells and its high expression correlates with good prognosis in breast cancer patients. Our study unravels an unanticipated layer of Hpo pathway regulation and suggests that PRP4K-mediated Yki/Yap phosphorylation in the nucleus provides a fail-safe mechanism to restrict aberrant pathway activation.The Hippo signaling pathway controls tissue growth by regulating the subcellular localization of Yorkie /Yap. Here the authors show that PRP4K, a kinase involved in mRNA splicing, phosphorylates Yki/Yap in the nucleus, which prevents its nuclear accumulation and inhibits Hippo signaling.", "corpus_id": 13824988, "score": 0 }, { "doc_id": "21663770", "title": "Dynamic Fluctuations in Subcellular Localization of the Hippo Pathway Effector Yorkie In Vivo", "abstract": "The Hippo pathway is an evolutionarily conserved signaling network that integrates diverse cues to control organ size and cell fate. The central downstream pathway protein in Drosophila is the transcriptional co-activator Yorkie (YAP and TAZ in humans), which regulates gene expression with the Scalloped/TEA domain family member (TEAD) transcription factors [1-8]. A central regulatory step in the Hippo pathway is phosphorylation of Yorkie by the NDR family kinase Warts, which promotes Yorkie cytoplasmic localization by stimulating association with 14-3-3 proteins [9-12]. Numerous reports have purported a static model of Hippo signaling whereby, upon Hippo activation, Yorkie/YAP/TAZ become cytoplasmic and therefore inactive, and upon Hippo repression, Yorkie/YAP/TAZ transit to the nucleus and are active. However, we have little appreciation for the dynamics of Yorkie/YAP/TAZ subcellular localization because most studies have been performed in fixed cells and tissues. To address this, we used live multiphoton microscopy to investigate the dynamics of an endogenously tagged Yorkie-Venus protein in growing epithelial organs. We found that the majority of Yorkie rapidly traffics between the cytoplasm and nucleus, rather than being statically localized in either compartment. In addition, discrete cell populations within the same organ display different rates of Yorkie nucleo-cytoplasmic shuttling. By assessing Yorkie dynamics in warts mutant tissue, we found that the Hippo pathway regulates Yorkie subcellular distribution by regulating its rate of nuclear import. Furthermore, Yorkie's localization fluctuates dramatically throughout the cell cycle, being predominantly cytoplasmic during interphase and, unexpectedly, chromatin enriched during mitosis. Yorkie's association with mitotic chromatin is Scalloped dependent, suggesting a potential role in mitotic bookmarking.", "corpus_id": 21663770, "score": 0 }, { "doc_id": "4384959", "title": "The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage", "abstract": "Cancer chemotherapeutic agents such as cisplatin exert their cytotoxic effect by inducing DNA damage and activating programmed cell death (apoptosis). The tumour-suppressor protein p53 is an important activator of apoptosis. Although p53-deficient cancer cells are less responsive to chemotherapy, their resistance is not complete, which suggests that other apoptotic pathways may exist. A p53 -related gene, p73, which encodes several proteins as a result of alternative splicing,, can also induce apoptosis. Here we show that the amount of p73 protein in the cell is increased by cisplatin. This induction of p73 is not seen in cells unable to carry out mismatch repair and in which the nuclear enzyme c-Abl tyrosine kinase is not activated by cisplatin. The half-life of p73 is prolonged by cisplatin and by co-expression with c-Abl tyrosine kinase; the apoptosis-inducing function of p73 is also enhanced by the c-Abl kinase. Mouse embryo fibroblasts deficient in mismatch repair or in c-Abl do not upregulate p73 and are more resistant to killing by cisplatin. Our results indicate that c-Abl and p73 are components of a mismatch-repair-dependent apoptosis pathway which contributes to cisplatin-induced cytotoxicity.", "corpus_id": 4384959, "score": 0 }, { "doc_id": "205373911", "title": "A Regulatory Circuit Controlling Itch-mediated p73 Degradation by Runx*", "abstract": "The members of the tumor suppressor p53 family are under tight regulation by distinct ubiquitin-protein isopeptide (E3) ligases. The level of p73 is regulated by the E3 ligase Itch. Itch levels are sharply reduced in response to DNA damage with concomitant p73 accumulation and activation. The mechanism of controlling Itch level is not known. We show that the Itch promoter is a target of the transcription activator Runx. Yes-associated protein (Yap1) is a shared transcription co-activator of Runx and p73. Under normal conditions, the Runx-Yap1 complex binds the Itch promoter and supports its transcription and p73 degradation. In response to DNA damage, Yap1 is phosphorylated by c-Abl at the position Tyr-357. The modified Yap1 does not co-activate Runx in supporting Itch transcription. The subsequent reduction in the Itch level gives rise to p73 accumulation. These results demonstrate how Yap1 supports degradation of p73 via Runx and how it plays an opposite role in response to DNA damage.", "corpus_id": 205373911, "score": 0 }, { "doc_id": "18427346", "title": "c-Abl forces YAP to switch sides", "abstract": "Cancer research has been significantly accelerated by viewing cancer as a functional collision between 2 dichotomous sets of genes: oncogenes and tumor suppressors. Signaling pathways turn oncogenes and tumor suppressors on and off to dictate cell fate decisions. We contend that signaling also dictates opposing behaviors of a given effector.", "corpus_id": 18427346, "score": 0 }, { "doc_id": "26476008", "title": "Modularity in the Hippo signaling pathway.", "abstract": "Metazoans have evolved several pathways to regulate the size of organs and ultimately that of organisms. One such pathway is known as Salvador-Warts-Hippo, or simply Hippo. Research on the Hippo pathway has grown exponentially during the past 8 years, revealing a complex signaling network. Intriguingly, within this complexity, there are levels of modularity. One level of modularity is represented by the unusually wide occurrence of the WW module in the Hippo core kinase cassette, the upstream regulatory components and the downstream nuclear proteins. We suggest that the prevalence of WW domain-mediated complexes in the Hippo pathway should facilitate its molecular analysis and aid prediction of new pathway components.", "corpus_id": 26476008, "score": 0 }, { "doc_id": "44986558", "title": "The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage.", "abstract": "The transcriptional coactivator Yes-associated protein (YAP) has been shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show that YAP requires the promyelocytic leukemia gene (PML) and nuclear body localization to coactivate p73. YAP imparts selectivity to p73 by promoting the activation of a subset of p53 and/or p73 target promoters. Endogenous p73, YAP, and p300 proteins are concomitantly recruited onto the regulatory regions of the apoptotic target gene p53AIP1 only when cells are exposed to apoptotic conditions. Silencing of YAP by specific siRNA impairs p300 recruitment and reduces histone acetylation on the p53AIP1 target gene, resulting in delayed or reduced apoptosis mediated by p73. We also found that YAP contributes to the DNA damage-induced accumulation of p73 and potentiates the p300-mediated acetylation of p73. Altogether, our findings identify YAP as a key determinant of p73 gene targeting in response to DNA damage.", "corpus_id": 44986558, "score": 0 }, { "doc_id": "33578343", "title": "Apical junctions and growth control in Drosophila.", "abstract": "Recent studies have revealed unexpected links between cell polarity and proliferation, suggesting that the polarized organization of cells is necessary to regulate growth. Drosophila melanogaster is a genetically simple model that is especially suited for the study of polarity and growth control, as polarized tissues undergo a well-defined pattern of proliferation and differentiation during the development. In addition, genetic studies have identified a number of tumor suppressor genes, which later studies have shown to be associated with junctions, or in the regulation of junctional proteins. We will explore in this review the links between growth and apical junction proteins in the regulation of growth control in Drosophila.", "corpus_id": 33578343, "score": 0 }, { "doc_id": "23887800", "title": "Wbp2 cooperates with Yorkie to drive tissue growth downstream of the Salvador–Warts–Hippo pathway", "abstract": "The Salvador–Warts–Hippo (SWH) pathway is a key controller of tissue growth in both flies and mammals, and deregulation of pathway activity contributes to tumour formation. The SWH pathway regulates cell growth, proliferation and apoptosis by restricting activity of the Yorkie transcriptional co-activator protein. The proteins that function together with Yorkie to drive transcription and tissue growth are beginning to be revealed and include the Scalloped (Sd), Teashirt (Tsh) and Homothorax (Hth) transcription factors. In this study, we define Wbp2 as a promoter of Yorkie-dependent growth of Drosophila melanogaster tissues. Mammalian WBP2 was previously identified as a protein that interacts with the mammalian Yorkie homologue, Yes-associated protein. WBP2 has been shown to enhance steroid hormone-dependent transcription in cultured cells but its in vivo function has remained obscure. We show that D. melanogaster Wbp2 interacts with Yorkie in a WW domain- and PY motif-dependent manner and that Wbp2 can enhance Yorkie's transcriptional co-activator properties. In vivo, Wbp2 is required for growth of the D. melanogaster wing, and reduction of Wbp2 expression suppresses overgrowth of tissues that lack the warts growth-suppressive gene. Collectively, these studies define an important role for Wbp2 as a downstream component of the SWH tissue growth-control pathway.", "corpus_id": 23887800, "score": 0 }, { "doc_id": "16369642", "title": "SCALLOPED Interacts with YORKIE, the Nuclear Effector of the Hippo Tumor-Suppressor Pathway in Drosophila", "abstract": "In Drosophila, SCALLOPED (SD) belongs to a family of evolutionarily conserved proteins characterized by the presence of a TEA/ATTS DNA-binding domain [1, 2]. SD physically interacts with the product of the vestigial (vg) gene, where the dimer functions as a master gene controlling wing formation [3, 4]. The VG-SD dimer activates the transcription of several specific wing genes, including sd and vg themselves [5, 6]. The dimer drives cell-cycle progression by inducing expression of the dE2F1 transcription factor [7], which regulates genes involved in DNA replication and cell-cycle progression. Recently, YORKIE (YKI) was identified as a transcriptional coactivator that is the downstream effector of the Hippo signaling pathway, which controls cell proliferation and apoptosis in Drosophila[8]. We identified SD as a partner for YKI. We show that interaction between YKI and SD increases SD transcriptional activity both ex vivo in Drosophila S2 cells and in vivo in Drosophila wing discs and promotes YKI nuclear localization. We also show that YKI overexpression induces vg and dE2F1 expression and that proliferation induced by YKI or by a dominant-negative form of FAT in wing disc is significantly reduced in a sd hypomorphic mutant context. Contrary to YKI, SD is not required in all imaginal tissues. This indicates that YKI-SD interaction acts in a tissue-specific fashion and that other YKI partners must exist.", "corpus_id": 16369642, "score": 0 }, { "doc_id": "207098159", "title": "The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway.", "abstract": "The Hippo (Hpo) kinase cascade restricts tissue growth by inactivating the transcriptional coactivator Yorkie (Yki), which regulates the expression of target genes such as the cell death inhibitor diap1 by unknown mechanisms. Here we identify the TEAD/TEF family protein Scalloped (Sd) as a DNA-binding transcription factor that partners with Yki to mediate the transcriptional output of the Hpo growth-regulatory pathway. The diap1 (th) locus harbors a minimal Sd-binding Hpo Responsive Element (HRE) that mediates transcriptional regulation by the Hpo pathway. Sd binds directly to Yki, and a Yki missense mutation that abrogates Sd-Yki binding also inactivates Yki function in vivo. We further demonstrate that sd is required for yki-induced tissue overgrowth and target gene expression, and that sd activity is conserved in its mammalian homolog. Our results uncover a heretofore missing link in the Hpo signaling pathway and provide a glimpse of the molecular events on a Hpo-responsive enhancer element.", "corpus_id": 207098159, "score": 0 }, { "doc_id": "12432045", "title": "The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control.", "abstract": "The Hippo (Hpo) signaling pathway governs cell growth, proliferation, and apoptosis by controlling key regulatory genes that execute these processes; however, the transcription factor of the pathway has remained elusive. Here we provide evidence that the TEAD/TEF family transcription factor Scalloped (Sd) acts together with the coactivator Yorkie (Yki) to regulate Hpo pathway-responsive genes. Sd and Yki form a transcriptional complex whose activity is inhibited by Hpo signaling. Sd overexpression enhances, whereas its inactivation suppresses, tissue overgrowth caused by Yki overexpression or tumor suppressor mutations in the Hpo pathway. Inactivation of Sd diminishes Hpo target gene expression and reduces organ size, whereas a constitutively active Sd promotes tissue overgrowth. Sd promotes Yki nuclear localization, whereas Hpo signaling retains Yki in the cytoplasm by phosphorylating Yki at S168. Finally, Sd recruits Yki to the enhancer of the pathway-responsive gene diap1, suggesting that diap1 is a direct transcriptional target of the Hpo pathway.", "corpus_id": 12432045, "score": 0 }, { "doc_id": "14815358", "title": "Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways", "abstract": "TGF-beta and BMP receptor kinases activate Smad transcription factors by C-terminal phosphorylation. We have identified a subsequent agonist-induced phosphorylation that plays a central dual role in Smad transcriptional activation and turnover. As receptor-activated Smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by CDK8 and CDK9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote Smad transcriptional action, which in the case of Smad1 is mediated by the recruitment of YAP to the phosphorylated linker sites. An effector of the highly conserved Hippo organ size control pathway, YAP supports Smad1-dependent transcription and is required for BMP suppression of neural differentiation of mouse embryonic stem cells. The phosphorylated linker is ultimately recognized by specific ubiquitin ligases, leading to proteasome-mediated turnover of activated Smad proteins. Thus, nuclear CDK8/9 drive a cycle of Smad utilization and disposal that is an integral part of canonical BMP and TGF-beta pathways.", "corpus_id": 14815358, "score": 0 }, { "doc_id": "26007663", "title": "Transcription factor choice in the Hippo signaling pathway: homothorax and yorkie regulation of the microRNA bantam in the progenitor domain of the Drosophila eye imaginal disc.", "abstract": "The accurate control of cell proliferation and survival is critical for animal development. The Hippo tumor suppressor pathway regulates both of these parameters by controlling the nuclear availability of the transcriptional coactivator Yorkie (Yki), which regulates downstream target genes together with Scalloped (Sd), a DNA-binding protein. Here we provide evidence that Yki can also regulate target genes in conjunction with Homothorax (Hth) and Teashirt (Tsh), two DNA-binding transcription factors expressed in the uncommitted progenitor cells of the Drosophila eye imaginal disc. Clonal analyses demonstrate that Hth and Tsh promote cell proliferation and protect eye progenitor cells from apoptosis. Genetic epistasis experiments suggest that Hth and Tsh execute these functions with Yki, in part by up-regulating the microRNA bantam. A physical interaction between Hth and Yki can be detected in cell culture, and we show that Hth and Yki are bound to a DNA sequence approximately 14 kb upstream of the bantam hairpin in eye imaginal disc cells, arguing that this regulation is direct. These data suggest that the Hippo pathway uses different DNA-binding transcription factors depending on the cellular context. In the eye disc, Hth and Tsh provide spatial information to this pathway, promoting cell proliferation and survival in the progenitor domain.", "corpus_id": 26007663, "score": 0 }, { "doc_id": "46024907", "title": "Cooperative regulation of growth by Yorkie and Mad through bantam.", "abstract": "The Dpp and Fat-Hippo signaling pathways both regulate growth in Drosophila. Dpp is a BMP family ligand and acts via a Smad family DNA-binding transcription factor, Mad. Fat-Hippo signaling acts via a non-DNA-binding transcriptional coactivator protein, Yorkie. Here, we show that these pathways are directly interlinked. They act synergistically to promote growth, in part via regulation of the microRNA gene bantam, and their ability to promote growth is mutually dependent. Yorkie and Mad physically bind each other, and we identify a 410 bp minimal enhancer of bantam that responds to Yorkie:Mad in vivo and in cultured cells, and show that both Yorkie and Mad associate with this enhancer in vivo. Our results indicate that in promoting the growth of Drosophila tissues, Fat-Hippo and Dpp signaling contribute distinct subunits of a shared transcriptional activation complex, Yorkie:Mad.", "corpus_id": 46024907, "score": 0 }, { "doc_id": "22697121", "title": "TGF-beta signaling, Smads, and tumor suppressors.", "abstract": "The transforming growth factor-beta (TGF-beta) superfamily is used throughout animal development for regulating the growth and patterning of many tissue types. During the past few years, rapid progress has been made in deciphering how TGF-beta signals are transduced from outside the cell to the nucleus. This progress is based on biochemical studies in vertebrate systems and a combination of genetic studies in Drosophila and Caenorhabditis elegans. These studies have identified a novel family of signaling proteins, the Smad family. Smads can act positively and be phosphorylated by TGF-beta-like receptors or can act negatively and prevent activation of the positively acting group. The positively acting Smads translocate to the nucleus, bind DNA, and act as transcriptional activators. Thus, genetic and biochemical studies suggest a very simple signaling pathway, in which Smads are the primary downstream participant.", "corpus_id": 22697121, "score": 0 }, { "doc_id": "210152411", "title": "Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling", "abstract": "HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Olivier Ferrigno, François Lallemand, Franck Verrecchia, Sébastien l’Hoste, Jacques Camonis, Azeddine Atfi, Alain Mauviel", "corpus_id": 210152411, "score": 0 }, { "doc_id": "11737044", "title": "TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal", "abstract": "Transforming growth fazctor-β (TGFβ) family members regulate many developmental and pathological events through Smad transcriptional modulators. How nuclear accumulation of Smad is coupled to the transcriptional machinery is poorly understood. Here we demonstrate that in response to TGFβ stimulation the transcriptional regulator TAZ binds heteromeric Smad2/3–4 complexes and is recruited to TGFβ response elements. In human embryonic stem cells TAZ is required to maintain self-renewal markers and loss of TAZ leads to inhibition of TGFβ signalling and differentiation into a neuroectoderm lineage. In the absence of TAZ, Smad2/3–4 complexes fail to accumulate in the nucleus and activate transcription. Furthermore, TAZ, which itself engages in shuttling, dominantly controls Smad nucleocytoplasmic localization and can be retained in the nucleus by transcriptional co-factors such as ARC105, a component of the Mediator complex. TAZ thus defines a hierarchical system regulating Smad nuclear accumulation and coupling to the transcriptional machinery.", "corpus_id": 11737044, "score": 0 }, { "doc_id": "4821432", "title": "Validating upstream regulators of Yorkie activity in Hippo signaling through scalloped-based genetic epistasis", "abstract": "ABSTRACT Genetic studies in Drosophila have been instrumental in characterizing the Hippo pathway, which converges on the co-activator Yorkie to regulate target gene transcription. A routinely used strategy to interrogate upstream regulators of Yorkie involves the examination of selected Hippo target genes upon loss or gain of function of a suspected pathway regulator. A caveat with this strategy is that aberrant expression of a given Hippo target per se does not distinguish whether it is caused by changes in Yorkie or Yorkie-independent inputs converging on the same target gene. Building on previous findings that the DNA-binding transcription factor Scalloped mediates both Yorkie overexpression and loss-of-function phenotypes yet is itself dispensable for normal eye development, we describe a simple strategy to distinguish these possibilities by analyzing double-mutant clones of scalloped and a suspected Yorkie regulator. We provide proof of principle that this strategy can be used effectively to validate canonical Yorkie regulators and to exclude proteins that impact target expression independent of Yorkie. The described methodology and reagents should facilitate efforts to assess the expanding repertoire of proteins implicated in regulation of Yorkie activity. Summary: Analysis of double-mutant clones of sd and putative Yki regulators provides a simple and efficient strategy to validate upstream regulators of Yki activity in Hippo signaling.", "corpus_id": 4821432, "score": 0 }, { "doc_id": "3819436", "title": "Mechanical strain regulates the Hippo pathway in Drosophila", "abstract": "ABSTRACT Animal cells are thought to sense mechanical forces via the transcriptional co-activators YAP (or YAP1) and TAZ (or WWTR1), the sole Drosophila homolog of which is named Yorkie (Yki). In mammalian cells in culture, artificial mechanical forces induce nuclear translocation of YAP and TAZ. Here, we show that physiological mechanical strain can also drive nuclear localisation of Yki and activation of Yki target genes in the Drosophila follicular epithelium. Mechanical strain activates Yki by stretching the apical domain, reducing the concentration of apical Crumbs, Expanded, Kibra and Merlin, and reducing apical Hippo kinase dimerisation. Overexpressing Hippo kinase to induce ectopic activation in the cytoplasm is sufficient to prevent Yki nuclear localisation even in flattened follicle cells. Conversely, blocking Hippo signalling in warts clones causes Yki nuclear localisation even in columnar follicle cells. We find no evidence for involvement of other pathways, such as Src42A kinase, in regulation of Yki. Finally, our results in follicle cells appear generally applicable to other tissues, as nuclear translocation of Yki is also readily detectable in other flattened epithelial cells such as the peripodial epithelium of the wing imaginal disc, where it promotes cell flattening. Highlighted Article: Drosophila Yorkie can sense physiological mechanical strain forces via the canonical Hippo pathway in different epithelial tissues.", "corpus_id": 3819436, "score": 0 }, { "doc_id": "58656458", "title": "Recruitment of Jub by α-catenin promotes Yki activity and Drosophila wing growth", "abstract": "ABSTRACT The Hippo signaling network controls organ growth through YAP family transcription factors, including the Drosophila Yorkie protein. YAP activity is responsive to both biochemical and biomechanical cues, with one key input being tension within the F-actin cytoskeleton. Several potential mechanisms for the biomechanical regulation of YAP proteins have been described, including tension-dependent recruitment of Ajuba family proteins, which inhibit kinases that inactivate YAP proteins, to adherens junctions. Here, we investigate the mechanism by which the Drosophila Ajuba family protein Jub is recruited to adherens junctions, and the contribution of this recruitment to the regulation of Yorkie. We identify α-catenin as the mechanotransducer responsible for tension-dependent recruitment of Jub by identifying a region of α-catenin that associates with Jub, and by identifying a region, which when deleted, allows constitutive, tension-independent recruitment of Jub. We also show that increased Jub recruitment to α-catenin is associated with increased Yorkie activity and wing growth, even in the absence of increased cytoskeletal tension. Our observations establish α-catenin as a multi-functional mechanotransducer and confirm Jub recruitment to α-catenin as a key contributor to biomechanical regulation of Hippo signaling. Highlighted Article: Identification of α-catenin as the mechanotransducer that recruits Jub to junctions under tension; this recruitment of Jub is sufficient to increase Yorkie activity.", "corpus_id": 58656458, "score": 0 }, { "doc_id": "51707644", "title": "Yorkie Functions at the Cell Cortex to Promote Myosin Activation in a Non-transcriptional Manner.", "abstract": "The Hippo signaling pathway is an evolutionarily conserved mechanism that controls organ size in animals. Yorkie is well known as a transcriptional co-activator that functions downstream of the Hippo pathway to positively regulate transcription of genes that promote tissue growth. Recent studies have shown that increased myosin activity activates both Yorkie and its vertebrate orthologue YAP, resulting in increased nuclear localization and tissue growth. Here we show that Yorkie also can accumulate at the cell cortex in the apical junctional region. Moreover, Yorkie functions at the cortex to promote activation of myosin through a myosin regulatory light chain kinase, Stretchin-Mlck. This Yorkie function is not dependent on its transcriptional activity and is required for larval and adult tissues to achieve appropriate size. Based on these results, we suggest that Yorkie functions in a feedforward \"amplifier\" loop that promotes myosin activation, and thereby greater Yorkie activity, in response to tension.", "corpus_id": 51707644, "score": 0 }, { "doc_id": "1900181", "title": "The Hippo tumor-suppressor pathway regulates apical-domain size in parallel to tissue growth", "abstract": "The Hippo tumor-suppressor pathway controls tissue growth in Drosophila and mammals by regulating cell proliferation and apoptosis. The Hippo pathway includes the Fat cadherin, a transmembrane protein, which acts upstream of several other components that form a kinase cascade that culminates in the regulation of gene expression through the transcriptional coactivator Yorkie (Yki). Our previous work in Drosophila indicated that Merlin (Mer) and Expanded (Ex) are members of the Hippo pathway and act upstream of the Hippo kinase. In contrast to this model, it was suggested that Mer and Ex primarily regulate membrane dynamics and receptor trafficking, thereby affecting Hippo pathway activity only indirectly. Here, we examined the effects of Mer, Ex and the Hippo pathway on the size of the apical membrane and on apical-basal polarity complexes. We found that mer;ex double mutant imaginal disc cells have significantly increased levels of apical membrane determinants, such as Crb, aPKC and Patj. These phenotypes were shared with mutations in other Hippo pathway components and required Yki, indicating that Mer and Ex signal through the Hippo pathway. Interestingly, however, whereas Crb was required for the accumulation of other apical proteins and for the expansion of the apical domain observed in Hippo pathway mutants, its elimination did not significantly reverse the overgrowth phenotype of warts mutant cells. Therefore, Hippo signaling regulates cell polarity complexes in addition to and independently of its growth control function in imaginal disc cells.", "corpus_id": 1900181, "score": 0 }, { "doc_id": "22162100", "title": "The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila", "abstract": "Defects in apical-basal cell polarity and abnormal expression of cell polarity determinants are often associated with cancer in vertebrates. In Drosophila, abnormal expression of apical-basal determinants can cause neoplastic phenotypes, including loss of cell polarity and overproliferation. However, the pathways through which apical-basal polarity determinants affect growth are poorly understood. Here, we investigated the mechanism by which the apical determinant Crumbs (Crb) affects growth in Drosophila imaginal discs. Overexpression of Crb causes severe overproliferation, and we found that loss of Crb similarly results in overgrowth of imaginal discs. Crb gain and loss of function caused defects in Hippo signaling, a key signaling pathway that controls tissue growth in Drosophila and mammals. Manipulation of Crb levels caused the up-regulation of Hippo target genes, genetically interacted with known Hippo pathway components, and required Yorkie, a transcriptional coactivator that acts downstream in the Hippo pathway, for target gene induction and overgrowth. Interestingly, Crb regulates growth and cell polarity through different motifs in its intracellular domain. A juxtamembrane FERM domain-binding motif is responsible for growth regulation and induction of Hippo target gene expression, whereas Crb uses a PDZ-binding motif to form a complex with other polarity factors. The Hippo pathway component Expanded, an apically localized adaptor protein, is mislocalized in both crb mutant cells and Crb overexpressing tissues, whereas the other Hippo pathway components, Fat and Merlin, are unaffected. Taken together, our data show that Crb regulates growth through Hippo signaling, and thus identify Crb as a previously undescribed upstream input into the Hippo pathway.", "corpus_id": 22162100, "score": 0 }, { "doc_id": "21093156", "title": "Transcriptional output of the Salvador/warts/hippo pathway is controlled in distinct fashions in Drosophila melanogaster and mammalian cell lines.", "abstract": "The Salvador/Warts/Hippo (SWH) pathway is an important modulator of organ size, and deregulation of pathway activity can lead to cancer. Several SWH pathway components are mutated or expressed at altered levels in different human tumors including NF2, LATS1, LATS2, SAV1, and YAP. The SWH pathway regulates tissue growth by restricting the activity of the transcriptional coactivator protein known as Yorkie (Yki) in Drosophila melanogaster and Yes-associated protein (YAP) in mammals. Yki/YAP drives tissue growth in partnership with the Scalloped (Sd)/TEAD1-4 transcription factors. Yki/YAP also possesses two WW domains, which contact several proteins that have been suggested to either promote or inhibit the ability of Yki to induce transcription. To investigate the regulatory role of the Yki/YAP WW domains, we analyzed the functional consequence of mutating these domains. WW domain mutant YAP promoted transformation and migration of breast epithelial cells with increased potency, suggesting that WW domains mediate the inhibitory regulation of YAP in these cells. By contrast, the WW domains were required for YAP to promote NIH-3T3 cell transformation and for the ability of Yki to drive tissue growth in D. melanogaster and optimally activate Sd. This shows that Yki/YAP WW domains have distinct regulatory roles in different cell types and implies the existence of proteins that promote tissue growth in collaboration with Yki and Sd.", "corpus_id": 21093156, "score": 0 }, { "doc_id": "41815041", "title": "The WW domain protein Kibra acts upstream of Hippo in Drosophila.", "abstract": "The conserved Hippo kinase pathway plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. Whereas the function of the core kinase cascade, consisting of the serine/threonine kinases Hippo and Warts, in phosphorylating and thereby inactivating the transcriptional coactivator Yorkie is well established, much less is known about the upstream events that regulate Hippo signaling activity. The FERM domain proteins Expanded and Merlin appear to represent two different signaling branches that feed into the Hippo pathway. Signaling by the atypical cadherin Fat may act via Expanded, but how Merlin is regulated has remained elusive. Here, we show that the WW domain protein Kibra is a Hippo signaling component upstream of Hippo and Merlin. Kibra acts synergistically with Expanded, and it physically interacts with Merlin. Thus, Kibra predominantly acts in the Merlin branch upstream of the core kinase cascade to regulate Hippo signaling.", "corpus_id": 41815041, "score": 0 }, { "doc_id": "25838419", "title": "Kibra Is a Regulator of the Salvador/Warts/Hippo Signaling Network", "abstract": "Summary The Salvador (Sav)/Warts (Wts)/Hippo (Hpo) (SWH) network controls tissue growth by inhibiting cell proliferation and promoting apoptosis. The core of the pathway consists of a MST and LATS family kinase cascade that ultimately phosphorylates and inactivates the YAP/Yorkie (Yki) transcription coactivator. The FERM domain proteins Merlin (Mer) and Expanded (Ex) represent one mode of upstream regulation controlling pathway activity. Here, we identify Kibra as a member of the SWH network. Kibra, which colocalizes and associates with Mer and Ex, also promotes the Mer/Ex association. Furthermore, the Kibra/Mer association is conserved in human cells. Finally, Kibra complexes with Wts and kibra depletion in tissue culture cells induces a marked reduction in Yki phosphorylation without affecting the Yki/Wts interaction. We suggest that Kibra is part of an apical scaffold that promotes SWH pathway activity.", "corpus_id": 25838419, "score": 0 }, { "doc_id": "14151723", "title": "Lgl, aPKC, and Crumbs Regulate the Salvador/Warts/Hippo Pathway through Two Distinct Mechanisms", "abstract": "BACKGROUND\nThe Drosophila neoplastic tumor suppressor Lethal (2) giant larvae (Lgl) controls apicobasal cell polarity and proliferation. We have previously shown that lgl(-) clones in the developing eye exhibit ectopic proliferation and suppress apoptosis without affecting apicobasal cell polarity. Ectopic expression of the apical polarity regulators atypical protein kinase C (aPKC) and Crumbs also leads to increased cell proliferation and/or survival. Here we investigate how these cell polarity regulators control proliferation and survival.\n\n\nRESULTS\nWe report that depletion of lgl in eye epithelial tissue, where polarity is maintained, results in upregulation of targets of the Salvador/Warts/Hippo (SWH) tumor suppressor pathway. Consistent with this, the SWH pathway transcriptional coactivator Yorkie is hyperactivated in Lgl-deficient tissue and is rate limiting for lgl(-) phenotypes. Overexpression of the apical polarity regulators Crumbs or aPKC also leads to ectopic expression of SWH pathway targets without affecting polarity. We show that Lgl depletion or aPKC overexpression results in comislocalization of Hippo and Ras-associated domain family protein (RASSF), consistent with RASSF's ability to block Hippo activation by Salvador. In contrast, Crumbs overexpression leads to mislocalization of Expanded away from the apical cortex, which is predicted to deregulate the pathway.\n\n\nCONCLUSIONS\nCollectively, our data reveal that the cell polarity regulators Lgl, aPKC, and Crumbs regulate the SWH pathway by two distinct pathways: Lgl acts antagonistically to aPKC to regulate Hippo and RASSF localization, whereas Crumbs regulates Expanded localization. Thus, our study implicates Lgl, aPKC, and Crumbs as regulators of tissue growth via the SWH pathway.", "corpus_id": 14151723, "score": 0 }, { "doc_id": "11855902", "title": "The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded", "abstract": "The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. At the core of the Hippo pathway is a kinase cascade extending from the Hippo (Hpo) tumor suppressor to the Yorkie (Yki) oncoprotein. The Hippo kinase cascade, in turn, is regulated by apical membrane-associated proteins such as the FERM domain proteins Merlin and Expanded (Ex), and the WW- and C2-domain protein Kibra. How these apical proteins are themselves regulated remains poorly understood. Here, we identify the transmembrane protein Crumbs (Crb), a determinant of epithelial apical-basal polarity in Drosophila embryos, as an upstream component of the Hippo pathway in imaginal disk growth control. Loss of Crb leads to tissue overgrowth and target gene expression characteristic of defective Hippo signaling. Crb directly binds to Ex through its juxtamembrane FERM-binding motif (FBM). Loss of Crb or mutation of its FBM leads to mislocalization of Ex to basolateral domain of imaginal disk epithelial cells. These results shed light on the mechanism of Ex regulation and provide a molecular link between apical-basal polarity and tissue growth. Furthermore, our studies implicate Crb as a putative cell surface receptor for Hippo signaling by uncovering a transmembrane protein that directly binds to an apical component of the Hippo pathway.", "corpus_id": 11855902, "score": 0 }, { "doc_id": "654767", "title": "Crumbs Regulates Salvador/Warts/Hippo Signaling in Drosophila via the FERM-Domain Protein Expanded", "abstract": "BACKGROUND\nAltered expression of apicobasal polarity factors is associated with cancer in vertebrates and tissue overgrowth in invertebrates, yet the mechanisms by which these factors affect growth-regulatory pathways are not well defined. We have tested the basis of an overgrowth phenotype driven by the Drosophila protein Crumbs (Crb), which nucleates an apical membrane complex that functionally interacts with the Par6/Par3/aPKC and Scrib/Dlg/Lgl apicobasal polarity complexes.\n\n\nRESULTS\nWe find that Crb-driven growth is dependent upon the Salvador/Warts/Hippo (SWH) pathway and its transcriptional effector Yorkie (Yki). Expression of the Crb intracellular domain elevates Yki activity, and this correlates in tissues and cultured cells with loss of Expanded (Ex), an apically localized SWH component that inhibits Yki. Reciprocally, loss of crb elevates Ex levels, although this excess Ex does not concentrate to its normal location at apical junctions. The Ex-regulatory domain of Crb maps to the juxtamembrane FERM-binding motif (JM), a cytoskeletal interaction domain distinct from the PDZ-binding motif (PBM) through which Crb binds polarity factors. Expression of Crb-JM drives Yki activity and organ growth with little effect on tissue architecture, while Crb-PBM reciprocally produces tissue architectural defects without significant effect on Yki activity.\n\n\nCONCLUSIONS\nThese studies identify Crb as a novel SWH regulator via JM-dependent effects on Ex levels and localization and suggest that discrete domains within Crb may allow it to integrate junctional polarity signals with a conserved growth pathway.", "corpus_id": 654767, "score": 0 }, { "doc_id": "43100100", "title": "The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway.", "abstract": "The Hippo pathway senses cell density information to control tissue growth by regulating the localization of the transcriptional regulators TAZ and YAP (TAZ/YAP). TAZ/YAP also regulate TGF-β-SMAD signaling, but whether this role is linked to cell density sensing is unknown. Here we demonstrate that TAZ/YAP dictate the localization of active SMAD complexes in response to cell density-mediated formation of polarity complexes. In high-density cell cultures, the Hippo pathway drives cytoplasmic localization of TAZ/YAP, which sequesters SMAD complexes, thereby suppressing TGF-β signaling. We show that during mouse embryogenesis, this is reflected by differences in TAZ/YAP localization, which define regions of active SMAD2/3 complexes. Interfering with TAZ/YAP phosphorylation drives nuclear accumulation of TAZ/YAP and SMAD2/3. Furthermore, we demonstrate that the Crumbs polarity complex interacts with TAZ/YAP, which relays cell density information by promoting TAZ/YAP phosphorylation, cytoplasmic retention, and suppressed TGF-β signaling. Accordingly, disruption of the Crumbs complex enhances TGF-β signaling and predisposes cells to TGF-β-mediated epithelial-to-mesenchymal transitions.", "corpus_id": 43100100, "score": 0 }, { "doc_id": "16621313", "title": "Fat Cadherin Modulates Organ Size in Drosophila via the Salvador/Warts/Hippo Signaling Pathway", "abstract": "BACKGROUND\nThe atypical Fat cadherin has long been known to control cell proliferation and organ size in Drosophila, but the mechanism by which Fat controls these processes has remained elusive. A newly emerging signaling pathway that controls organ size during development is the Salvador/Warts/Hippo pathway.\n\n\nRESULTS\nHere we demonstrate that Fat limits organ size by modulating activity of the Salvador/Warts/Hippo pathway. ft interacts genetically with positive and negative regulators of this pathway, and tissue lacking fat closely phenocopies tissue deficient for genes that normally promote Salvador/Warts/Hippo pathway activity. Cells lacking fat grow and proliferate more quickly than their wild-type counterparts and exhibit delayed cell-cycle exit as a result of elevated expression of Cyclin E. fat mutant cells display partial insensitivity to normal developmental apoptosis cues and express increased levels of the anti-apoptotic DIAP1 protein. Collectively, these defects lead to increased organ size and organism lethality in fat mutant animals. Fat modulates Salvador/Warts/Hippo pathway activity by promoting abundance and localization of Expanded protein at the apical membrane of epithelial tissues.\n\n\nCONCLUSIONS\nFat restricts organ size during Drosophila development via the Salvador/Warts/Hippo pathway. These studies aid our understanding of developmental organ size control and have implications for human hyperproliferative disorders, such as cancers.", "corpus_id": 16621313, "score": 0 }, { "doc_id": "25818643", "title": "Delineation of a Fat tumor suppressor pathway", "abstract": "Recent studies in Drosophila melanogaster of the protocadherins Dachsous and Fat suggest that they act as ligand and receptor, respectively, for an intercellular signaling pathway that influences tissue polarity, growth and gene expression, but the basis for signaling downstream of Fat has remained unclear. Here, we characterize functional relationships among D. melanogaster tumor suppressors and identify the kinases Discs overgrown and Warts as components of a Fat signaling pathway. fat, discs overgrown and warts regulate a common set of downstream genes in multiple tissues. Genetic experiments position the action of discs overgrown upstream of the Fat pathway component dachs, whereas warts acts downstream of dachs. Warts protein coprecipitates with Dachs, and Warts protein levels are influenced by fat, dachs and discs overgrown in vivo, consistent with its placement as a downstream component of the pathway. The tumor suppressors Merlin, expanded, hippo, salvador and mob as tumor suppressor also share multiple Fat pathway phenotypes but regulate Warts activity independently. Our results functionally link what had been four disparate groups of D. melanogaster tumor suppressors, establish a basic framework for Fat signaling from receptor to transcription factor and implicate Warts as an integrator of multiple growth control signals.", "corpus_id": 25818643, "score": 0 }, { "doc_id": "14706030", "title": "The Tumor-Suppressor Gene fat Controls Tissue Growth Upstream of Expanded in the Hippo Signaling Pathway", "abstract": "BACKGROUND\nThe tight control of cell proliferation and cell death is essential to normal tissue development, and the loss of this control is a hallmark of cancers. Cell growth and cell death are coordinately regulated during development by the Hippo signaling pathway. The Hippo pathway consists of the Ste20 family kinase Hippo, the WW adaptor protein Salvador, and the NDR kinase Warts. Loss of Hippo signaling in Drosophila leads to enhanced cell proliferation and decreased apoptosis, resulting in massive tissue overgrowth through increased expression of targets such as Cyclin E and Diap1. The cytoskeletal proteins Merlin and Expanded colocalize at apical junctions and function redundantly upstream of Hippo. It is not clear how they regulate growth or how they are localized to apical junctions.\n\n\nRESULTS\nWe find that another Drosophila tumor-suppressor gene, the atypical cadherin fat, regulates both cell proliferation and cell death in developing imaginal discs. Loss of fat leads to increased Cyclin E and Diap1 expression, phenocopying loss of Hippo signaling. Ft can regulate Hippo phosphorylation, a measure of its activation, in tissue culture. Importantly, fat is needed for normal localization of Expanded at apical junctions in vivo. Genetic-epistasis experiments place fat with expanded in the Hippo pathway.\n\n\nCONCLUSIONS\nTogether, these data suggest that Fat functions as a cell-surface receptor for the Expanded branch of the conserved Hippo growth control pathway.", "corpus_id": 14706030, "score": 0 }, { "doc_id": "7756330", "title": "Hippo signalling controls Dronc activity to regulate organ size in Drosophila", "abstract": "The Hippo pathway controls organ size by multiple mechanisms that ultimately regulate the transcriptional co-activator Yorkie (Yki). Downregulation of Hippo signalling leads to tissue overgrowths due to Yki-mediated activation of target genes, whereas overexpression of the pathway triggers apoptosis in developing tissues. However, the mechanism underlying cell death induced by Hippo (Hpo)-activation is not understood. We found that overexpression of Hpo leads to induction of Dronc (Drosophila Caspase-9 homologue) expression and downregulation of dronc can suppress/block Hpo-mediated apoptosis. Furthermore, upregulation of Dronc activity strongly suppressed the overgrowth caused by Yki overexpression thereby suggesting that Hippo signalling restricts Dronc activity. Hippo-mediated cell death requires the activity of the initiator caspase Dronc. Loss-of-function of dronc in genetic mosaics leads to cell survival and increased cell proliferation in imaginal discs. dronc is transcriptionally suppressed in Yki overexpressing cells or cells mutant for other Hippo pathway components like warts (wts). We propose that Dronc is a transcriptional target of the Hippo signalling pathway. The Hippo–Dronc connection has implications in control of overall organ size and other growth regulatory mechanisms like compensatory proliferation and cell competition.", "corpus_id": 7756330, "score": 1 }, { "doc_id": "205739434", "title": "Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors.", "abstract": "When cells undergo apoptosis, they can stimulate the proliferation of nearby cells, a process referred to as compensatory cell proliferation. The stimulation of proliferation in response to tissue damage or removal is also central to epimorphic regeneration. The Hippo signaling pathway has emerged as an important regulator of growth during normal development and oncogenesis from Drosophila to humans. Here we show that induction of apoptosis in the Drosophila wing imaginal disc stimulates activation of the Hippo pathway transcription factor Yorkie in surviving and nearby cells, and that Yorkie is required for the ability of the wing to regenerate after genetic ablation of the wing primordia. Induction of apoptosis activates Yorkie through the Jun kinase pathway, and direct activation of Jun kinase signaling also promotes Yorkie activation in the wing disc. We also show that depletion of neoplastic tumor suppressor genes, including lethal giant larvae and discs large, or activation of aPKC, activates Yorkie through Jun kinase signaling, and that Jun kinase activation is necessary, but not sufficient, for the disruption of apical-basal polarity associated with loss of lethal giant larvae. Our observations identify Jnk signaling as a modulator of Hippo pathway activity in wing imaginal discs, and implicate Yorkie activation in compensatory cell proliferation and disc regeneration.", "corpus_id": 205739434, "score": 0 }, { "doc_id": "18306408", "title": "Warts and Yorkie Mediate Intestinal Regeneration by Influencing Stem Cell Proliferation", "abstract": "Homeostasis in the Drosophila midgut is maintained by stem cells [1, 2]. The intestinal epithelium contains two types of differentiated cells that are lost and replenished: enteroendocrine (EE) cells and enterocytes (ECs). Intestinal stem cells (ISCs) are the only cells in the adult midgut that proliferate [3, 4], and ISC divisions give rise to an ISC and an enteroblast (EB), which differentiates into an EC or an EE cell [3-5]. If the midgut epithelium is damaged, then ISC proliferation increases [6-12]. Damaged ECs express secreted ligands (Unpaired proteins) that activate Jak-Stat signaling in ISCs and EBs to promote their proliferation and differentiation [7, 9, 13, 14]. We show that the Hippo pathway components Warts and Yorkie mediate a transition from low- to high-level ISC proliferation to facilitate regeneration. The Hippo pathway regulates growth in diverse organisms and has been linked to cancer [15, 16]. Yorkie is activated in ECs in response to tissue damage or activation of the damage-sensing Jnk pathway. Activation of Yorkie promotes expression of unpaired genes and triggers a nonautonomous increase in ISC proliferation. Our observations uncover a role for Hippo pathway components in regulating stem cell proliferation and intestinal regeneration.", "corpus_id": 18306408, "score": 0 }, { "doc_id": "14111232", "title": "scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs", "abstract": "BackgroundMetastatic neoplasias are characterized by excessive cell proliferation and disruptions to apico-basal cell polarity and tissue architecture. Understanding how alterations in cell polarity can impact upon tumour development is, therefore, a central issue in cancer biology. The Drosophila gene scribble (scrib) encodes a PDZ-domain scaffolding protein that regulates cell polarity and acts as a tumour suppressor in flies. Increasing evidence also implicates the loss of human Scrib in cancer. In this report, we investigate how loss of Scrib promotes epithelial tumourigenesis in Drosophila, both alone and in cooperation with oncogenic mutations.ResultsWe find that genetically distinct atypical protein kinase C (aPKC)-dependent and Jun N-terminal kinase (JNK)-dependent alterations in scrib mutants drive epithelial tumourigenesis. First, we show that over-expression of the apical cell polarity determinants Crumbs (Crb) or aPKC induces similar cell morphology defects and over-proliferation phenotypes as scrib loss-of-function. However, the morphological and proliferative defects in scrib mutants are independent of Crb function, and instead can be rescued by a dominant negative (kinase dead) aPKC transgene. Secondly, we demonstrate that loss of Scrib promotes oncogene-mediated transformation through both aPKC and JNK-dependent pathways. JNK normally promotes apoptosis of scrib mutant cells. However, in cooperation with oncogenic activated Ras or Notch signalling, JNK becomes an essential driver of tumour overgrowth and invasion. aPKC-dependent signalling in scrib mutants cooperates with JNK to significantly enhance oncogene-mediated tumour overgrowth.ConclusionThese results demonstrate distinct aPKC and JNK-dependent pathways through which loss of Scrib promotes tumourigenesis in Drosophila. This is likely to have a direct relevance to the way in which human Scrib can similarly restrain an oncogene-mediated transformation and, more generally, on how the outcome of oncogenic signalling can be profoundly perturbed by defects in apico-basal epithelial cell polarity.", "corpus_id": 14111232, "score": 0 }, { "doc_id": "35018156", "title": "Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development", "abstract": "Spatial organization of cells and their appendages is controlled by the planar cell polarity pathway, a signaling cascade initiated by the protocadherin Fat in Drosophila. Vertebrates express 4 Fat molecules, Fat1–4. We found that depletion of Fat1 caused cyst formation in the zebrafish pronephros. Knockdown of the PDZ domain containing the adaptor protein Scribble intensified the cyst-promoting phenotype of Fat1 depletion, suggesting that Fat1 and Scribble act in overlapping signaling cascades during zebrafish pronephros development. Supporting the genetic interaction with Fat1, Scribble recognized the PDZ-binding site of Fat1. Depletion of Yes-associated protein 1 (YAP1), a transcriptional co-activator inhibited by Hippo signaling, ameliorated the cyst formation in Fat1-deficient zebrafish, whereas Scribble inhibited the YAP1-induced cyst formation. Thus, reduced Hippo signaling and subsequent YAP1 disinhibition seem to play a role in the development of pronephric cysts after depletion of Fat1 or Scribble. We hypothesize that Hippo signaling is required for normal pronephros development in zebrafish and that Scribble is a candidate link between Fat and the Hippo signaling cascade in vertebrates.", "corpus_id": 35018156, "score": 0 }, { "doc_id": "4982829", "title": "Loss of Cell Adhesion Increases Tumorigenic Potential of Polarity Deficient Scribble Mutant Cells", "abstract": "Epithelial polarity genes are important for maintaining tissue architecture, and regulating growth. The Drosophila neoplastic tumor suppressor gene scribble (scrib) belongs to the basolateral polarity complex. Loss of scrib results in disruption of its growth regulatory functions, and downregulation or mislocalization of Scrib is correlated to tumor growth. Somatic scribble mutant cells (scrib-) surrounded by wild-type cells undergo apoptosis, which can be prevented by introduction of secondary mutations that provide a growth advantage. Using genetic tools in Drosophila, we analyzed the phenotypic effects of loss of scrib in different growth promoting backgrounds. We investigated if a central mechanism that regulates cell adhesion governs the growth and invasive potential of scrib mutant cells. Here we show that increased proliferation, and survival abilities of scrib- cells in different genetic backgrounds affect their differentiation, and intercellular adhesion. Further, loss of scrib is sufficient to cause reduced cell survival, activation of the JNK pathway and a mild reduction of cell adhesion. Our data show that for scrib cells to induce aggressive tumor growth characterized by loss of differentiation, cell adhesion, increased proliferation and invasion, cooperative interactions that derail signaling pathways play an essential role in the mechanisms leading to tumorigenesis. Thus, our study provides new insights on the effects of loss of scrib and the modification of these effects via cooperative interactions that enhance the overall tumorigenic potential of scrib deficient cells.", "corpus_id": 4982829, "score": 0 }, { "doc_id": "7115106", "title": "Scribble Acts in the Drosophila Fat-Hippo Pathway to Regulate Warts Activity", "abstract": "Epithelial cells are the major cell-type for all organs in multicellular organisms. In order to achieve correct organ size, epithelial tissues need mechanisms that limit their proliferation, and protect tissues from damage caused by defective epithelial cells. Recently, the Hippo signaling pathway has emerged as a major mechanism that orchestrates epithelial development. Hippo signaling is required for cells to stop proliferation as in the absence of Hippo signaling tissues continue to proliferate and produce overgrown organs or tumors. Studies in Drosophila have led the way in providing a framework for how Hippo alters the pattern of gene transcription in target cells, leading to changes in cell proliferation, survival, and other behaviors. Scribble (Scrib) belongs to a class of neoplastic tumor suppressor genes that are required to establish apical-basal cell polarity. The disruption of apical-basal polarity leads to uncontrolled cell proliferation of epithelial cells. The interaction of apical basal polarity genes with the Hippo pathway has been an area of intense investigation. Loss of scrib has been known to affect Hippo pathway targets, however, its functions in the Hippo pathway still remain largely unknown. We investigated the interactions of Scrib with the Hippo pathway. We present data suggesting that Drosophila scrib acts downstream of the Fat (Ft) receptor, and requires Hippo signaling for its growth regulatory functions. We show that Ft requires Scrib to interact with Expanded (Ex) and Dachs (D), and for regulating Warts (Wts) levels and stability, thus placing Scrib in the Hippo pathway network.", "corpus_id": 7115106, "score": 0 }, { "doc_id": "29293238", "title": "A dp53/JNK-dependant feedback amplification loop is essential for the apoptotic response to stress in Drosophila", "abstract": "Programmed cell death (apoptosis) is a conserved process aimed to eliminate unwanted cells. The key molecules are a group of proteases called caspases that cleave vital proteins, which leads to the death of cells. In Drosophila, the apoptotic pathway is usually represented as a cascade of events in which an initial stimulus activates one or more of the proapoptotic genes (hid, rpr, grim), which in turn activate caspases. In stress-induced apoptosis, the dp53 (Drosophila p53) gene and the Jun N-terminal kinase (JNK) pathway function upstream in the activation of the proapoptotic genes. Here we demonstrate that dp53 and JNK also function downstream of proapoptotic genes and the initiator caspase Dronc (Drosophila NEDD2-like caspase) and that they establish a feedback loop that amplifies the initial apoptotic stimulus. This loop plays a critical role in the apoptotic response because in its absence there is a dramatic decrease in the amount of cell death after a pulse of the proapoptotic proteins Hid and Rpr. Thus, our results indicate that stress-induced apoptosis in Drosophila is dependant on an amplification loop mediated by dp53 and JNK. Furthermore, they also demonstrate a mechanism of mutual activation of proapoptotic genes.", "corpus_id": 29293238, "score": 0 }, { "doc_id": "5705095", "title": "The Hippo pathway acts via p53 and microRNAs to control proliferation and proapoptotic gene expression during tissue growth", "abstract": "Summary The Hippo pathway has a central role in coordinating tissue growth and apoptosis. Mutations that compromise Hippo pathway activity cause tissue overgrowth and have been causally linked to cancer. In Drosophila, the transcriptional coactivator Yorkie mediates Hippo pathway activity to control the expression of cyclin E and Myc to promote cell proliferation, as well as the expression of bantam miRNA and DIAP1 to inhibit cell death. Here we present evidence that the Hippo pathway acts via Yorkie and p53 to control the expression of the proapoptotic gene reaper. Yorkie further mediates reaper levels post-transcriptionally through regulation of members of the miR-2 microRNA family to prevent apoptosis. These findings provide evidence that the Hippo pathway acts via several distinct routes to limit proliferation-induced apoptosis.", "corpus_id": 5705095, "score": 0 }, { "doc_id": "4300045", "title": "Drosophila miR2 induces pseudo-polysomes and inhibits translation initiation", "abstract": "MicroRNAs (miRs) inhibit protein synthesis by mechanisms that are as yet unresolved. We developed a cell-free system from Drosophila melanogaster embryos that faithfully recapitulates miR2-mediated translational control by means of the 3′ untranslated region of the D. melanogaster reaper messenger RNA. Here we show that miR2 inhibits translation initiation without affecting mRNA stability. Surprisingly, miR2 induces the formation of dense (heavier than 80S) miRNPs (‘pseudo-polysomes’) even when polyribosome formation and 60S ribosomal subunit joining are blocked. An mRNA bearing an ApppG instead of an m7GpppG cap structure escapes the miR2-mediated translational block. These results directly show the inhibition of m7GpppG cap-mediated translation initiation as the mechanism of miR2 function, and uncover pseudo-polysomal messenger ribonucleoprotein assemblies that may help to explain earlier findings.", "corpus_id": 4300045, "score": 0 }, { "doc_id": "17585984", "title": "bantam Encodes a Developmentally Regulated microRNA that Controls Cell Proliferation and Regulates the Proapoptotic Gene hid in Drosophila", "abstract": "Cell proliferation, cell death, and pattern formation are coordinated in animal development. Although many proteins that control cell proliferation and apoptosis have been identified, the means by which these effectors are linked to the patterning machinery remain poorly understood. Here, we report that the bantam gene of Drosophila encodes a 21 nucleotide microRNA that promotes tissue growth. bantam expression is temporally and spatially regulated in response to patterning cues. bantam microRNA simultaneously stimulates cell proliferation and prevents apoptosis. We identify the pro-apoptotic gene hid as a target for regulation by bantam miRNA, providing an explanation for bantam's anti-apoptotic activity.", "corpus_id": 17585984, "score": 0 }, { "doc_id": "15742844", "title": "The bantam MicroRNA Is a Target of the Hippo Tumor-Suppressor Pathway", "abstract": "BACKGROUND\nThe Hippo tumor-suppressor pathway has emerged as a key signaling pathway that controls tissue size in Drosophila. Hippo signaling restricts tissue size by promoting apoptosis and cell-cycle arrest, and animals carrying clones of cells mutant for hippo develop severely overgrown adult structures. The Hippo pathway is thought to exert its effects by modulating gene expression through the phosphorylation of the transcriptional coactivator Yorkie. However, how Yorkie regulates growth, and thus the identities of downstream target genes that mediate the effects of Hippo signaling, are largely unknown.\n\n\nRESULTS\nHere, we report that the bantam microRNA is a downstream target of the Hippo signaling pathway. In common with Hippo signaling, the bantam microRNA controls tissue size by regulating cell proliferation and apoptosis. We found that hippo mutant cells had elevated levels of bantam activity and that bantam was required for Yorkie-driven overgrowth. Additionally, overexpression of bantam was sufficient to rescue growth defects of yorkie mutant cells and to suppress the cell death induced by Hippo hyperactivation. Hippo regulates bantam independently of cyclin E and diap1, two other Hippo targets, and overexpression of bantam mimics overgrowth phenotypes of hippo mutant cells.\n\n\nCONCLUSIONS\nOur data indicate that bantam is an essential target of the Hippo signaling pathway to regulate cell proliferation, cell death, and thus tissue size.", "corpus_id": 15742844, "score": 0 }, { "doc_id": "15264514", "title": "The Hippo Pathway Regulates the bantam microRNA to Control Cell Proliferation and Apoptosis in Drosophila", "abstract": "The Hippo signaling pathway acts upon the Yorkie transcriptional activator to control tissue growth in Drosophila. Activated Yorkie drives growth by stimulating cell proliferation and inhibiting apoptosis, but how it achieves this is not understood. Yorkie is known to activate Cyclin E (CycE) and the apoptosis inhibitor DIAP1. However, overexpression of these targets is not sufficient to cause tissue overgrowth. Here we show that Yorkie also activates expression of the bantam microRNA, a known regulator of both proliferation and apoptosis. bantam overexpression mimics Yorkie activation while loss of bantam function slows the rate of cell proliferation. bantam is necessary for Yorkie-induced overproliferation and bantam overexpression is sufficient to rescue survival and proliferation of yorkie mutant cells. Finally, we show that bantam levels are regulated during both developmentally programmed proliferation arrest and apoptosis. In summary, the results show that the Hippo pathway regulates expression of bantam to control tissue growth in Drosophila.", "corpus_id": 15264514, "score": 0 }, { "doc_id": "11865942", "title": "Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis.", "abstract": "Cell attachment to the extracellular matrix (ECM) is crucial to cell physiology such as polarity, motility, and proliferation. In normal cells, loss of attachment to the ECM induces a specific type of apoptosis, termed anoikis. Resistance to anoikis in cancer cells promotes their survival in circulation and dispersion to distant anatomic sites, leading to tumor metastasis. The Yes-associated protein (YAP) transcription coactivator is a human oncogene and a key regulator of organ size. The Hippo tumor suppressor pathway phosphorylates and inhibits YAP. However, little is known about the signals that regulate the Hippo pathway. Here we report that through cytoskeleton reorganization, cell detachment activates the Hippo pathway kinases Lats1/2 and leads to YAP phosphorylation and inhibition. The detachment-induced YAP inactivation is required for anoikis in nontransformed cells, whereas in cancer cells with deregulation of the Hippo pathway, knockdown of YAP and TAZ restores anoikis. Furthermore, we provided evidence that Lats1/2 expression level is indeed significantly down-regulated in metastatic prostate cancer. Our findings provide a novel connection between cell attachment and anoikis through the Hippo pathway and have important implications in cancer therapeutics.", "corpus_id": 11865942, "score": 0 }, { "doc_id": "27207283", "title": "Giant and duplicated imaginal discs in a new lethal mutant of Drosophila melanogaster.", "abstract": "Abstract An account is given of a new mutant,lethal (2) giant discs (l(2)gd; 2–42.7 ± 0.5) ofDrosophila melanogaster, in which the imaginal discs grow to far beyond their normal size during an extended larval period (Figs. 2–6). The extent of the delay in puparium formation in this strain can be modified by changing the culture conditions (Fig. 1). When the larvae are crowded, puparium formation is delayed for up to 9 days, and during this time the imaginal discs grow extensively and acquire an abnormal morphology. Under noncrowded conditions, the delay in puparium formation is usually less than 1 day, and the imaginal discs are correspondingly less abnormal. The time of death (effective lethal phase) is also dependent on culture conditions. Alll(2)gd homozygotes form puparia and pupal cuticle, but there are various defects in eversion of the discs. When the larvae are grown under crowded conditions, death follows shortly after disc eversion; hence no adult cuticle is secreted. In noncrowded cultures, however, about half of the mutant animals are able to produce some adult structures (Figs. 7 and 8). There are characteristic defects in the adult structures produced in these animals, which are also produced byl(2)gd imaginal discs transplanted into wild-type host larvae for metamorphosis (Figs. 9–12). The cuticular hair patterns are normal, but the number of bristles is reduced to about 20% of the number in wild type, and the number of bracts and of sensilla is reduced even more. Those bristles which are produced are usually normal in appearance. Normal aristae are produced, but the ungius is usually missing from the claw organ. Tarsi produced by the leg disc have only two segments instead of five, and appear to have excessive amounts of intersegmental membrane (Fig. 8). In certain imaginal discs, the extensive growth during the lengthened larval period seems to occur preferentially in particular regions. This is reflected in the size of the corresponding structures produced after metamorphosis in wild-type hosts (Fig. 11). In the second and third leg discs, the region of maximal growth is in the thoracic anlage, and this growth is followed by the appearance of a secondary involution and folding in this region (Fig. 4). Leg discs which contain such secondary folds give rise to duplicated legs after metamorphosis in a wild-type host (Figs. 13 and 14), hence the new involution and folding corresponds with a real duplication of anlagen in the disc. The details of the duplication process are discussed; it is suggested that the production of these secondary anlagen resembles the normal development of the leg disc more than it resembles other examples of pattern duplication in imaginal discs. There appears to be a population of cells in the leg disc ofl(2)gd which have special regulative properties. l(2)gd tissue has the capacity for transdetermination, although the frequency is lower than in wild-type tissue.", "corpus_id": 27207283, "score": 0 }, { "doc_id": "37308491", "title": "Malignant neoplasms of genetic origin in Drosophila melanogaster.", "abstract": "Malignant neoplasms that develop in 12 recessive-lethal, larval mutants of Drosophila melanogaster are discussed. These mutations affect the adult optic neuroblasts and ganglion-mother cells in the larval brain, the imaginal discs, and the hematopoietic organs. The malignant neoplasms exhibit fast, autonomous growth, loss of the capacity for differentiation, increased mobility and invasiveness, lethality in situ and after transplantation, and histological, fine structural, and karyotypic abnormalities. Intermediate neoplasms are also found. These combine both benign and malignant qualities. They grow in a noninvasive, compact fashion, typical of benign tumors, yet they also exhibit malignant qualities such as fast, autonomous, and lethal growth, loss of differentiation capacity, changes in cellular morphology, and lethal growth after transplantation into wild-type hosts. Thus Drosophila and vertebrate neoplasms show striking similarities.", "corpus_id": 37308491, "score": 0 }, { "doc_id": "6205281", "title": "Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development", "abstract": "We have modified an FLP/FRT-based genetic mosaic system to label either neurons derived from a common progenitor or isolated single neurons, in the Drosophila CNS. These uniquely labeled neurons can also be made homozygous for a mutation of interest within an otherwise phenotypically wild-type brain. Using this new mosaic system, not only can normal brain development be described with unprecedented single cell resolution, but also the underlying molecular mechanisms can be investigated by identifying genes that are required for these developmental processes.", "corpus_id": 6205281, "score": 0 }, { "doc_id": "43040142", "title": "scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila", "abstract": "Cancer is a multistep process involving cooperation between oncogenic or tumor suppressor mutations and interactions between the tumor and surrounding normal tissue. Here we present the first description of cooperative tumorigenesis in Drosophila, by using a system that mimics the development of tumors in mammals. We have used the MARCM system to generate mutant clones of the apical–basal cell polarity tumor suppressor gene, scribble, in the context of normal tissue. We show that scribble mutant clones in the eye disc exhibit ectopic expression of cyclin E and ectopic cell cycles, but do not overgrow due to increased cell death mediated by the JNK pathway and the surrounding wild‐type tissue. In contrast, when oncogenic Ras or Notch is expressed within the scribble mutant clones, cell death is prevented and neoplastic tumors develop. This demonstrates, for the first time in Drosophila, that activated alleles of Ras and Notch can act as cooperating oncogenes in the development of epithelial tumors, and highlights the importance of epithelial polarity regulators in restraining oncogenes and preventing tumor formation.", "corpus_id": 43040142, "score": 0 }, { "doc_id": "41410051", "title": "A Genetic Screen in Drosophila for Metastatic Behavior", "abstract": "A genetic screen was designed in Drosophila to interrogate its genome for mutations sufficient to cause noninvasive tumors of the eye disc to invade neighboring or distant tissues. We found that cooperation between oncogenic RasV12 expression and inactivation of any one of a number of genes affecting cell polarity leads to metastatic behavior, including basement membrane degradation, loss of E-cadherin expression, migration, invasion, and secondary tumor formation. Inactivation of these cell polarity genes cannot drive metastatic behavior alone or in combination with other tumor-initiating alterations. These findings suggest that the oncogenic background of tissues makes a distinct contribution toward metastatic development.", "corpus_id": 41410051, "score": 0 }, { "doc_id": "2840504", "title": "A Feed-Forward Circuit Linking Wingless, Fat-Dachsous Signaling, and the Warts-Hippo Pathway to Drosophila Wing Growth", "abstract": "The secreted morphogen Wingless promotes Drosophila wing growth by fueling a wave front of Fat-Dachsous signaling that recruits new cells into the wing primordium.", "corpus_id": 2840504, "score": 0 }, { "doc_id": "20859037", "title": "Ajuba Family Proteins Link JNK to Hippo Signaling", "abstract": "An evolutionarily conserved family of proteins links pathways to promote cell proliferation in response to cell death or injury. Shutting Down Hippo The Hippo pathway exerts tumor-suppressive effects by inhibiting the transcriptional coactivator Yorkie (Yki) in Drosophila or YAP in mammals. c-Jun N-terminal kinase (JNK) can promote proliferation in response to injury and has been linked to activation of Yki and YAP. Sun and Irvine found that the Ajuba family of proteins enabled JNK to stimulate the activity of Yki and YAP. In Drosophila, the growth of tumors dependent on JNK and Yki activation was reduced by ablation of Jub (also known as Ajuba LIM protein). In mammalian cells, JNK activation decreased the activity of LATS1, a kinase that phosphorylates and inhibits YAP, and enhanced the association of LATS1 with various Ajuba family proteins in a manner dependent on phosphorylation of the Ajuba proteins. These results suggest a model in which JNK-mediated phosphorylation of Ajuba proteins inhibits the Hippo pathway and thus stimulates the transcriptional activation of genes that promote proliferation. Wounding, apoptosis, or infection can trigger a proliferative response in neighboring cells to replace damaged tissue. Studies in Drosophila have implicated c-Jun amino-terminal kinase (JNK)–dependent activation of Yorkie (Yki) as essential to regeneration-associated growth, as well as growth associated with neoplastic tumors. Yki is a transcriptional coactivator that is inhibited by Hippo signaling, a conserved pathway that regulates growth. We identified a conserved mechanism by which JNK regulated Hippo signaling. Genetic studies in Drosophila identified Jub (also known as Ajuba LIM protein) as required for JNK-mediated activation of Yki and showed that Jub contributed to wing regeneration after wounding and to tumor growth. Biochemical studies revealed that JNK promoted the phosphorylation of Ajuba family proteins in both Drosophila and mammalian cells. Binding studies in mammalian cells indicated that JNK increased binding between the Ajuba family proteins LIMD1 or WTIP and LATS1, a kinase within the Hippo pathway that inhibits the Yki homolog YAP. Moreover, JNK promoted binding of LIMD1 and LATS1 through direct phosphorylation of LIMD1. These results identify Ajuba family proteins as a conserved link between JNK and Hippo signaling, and imply that JNK increases Yki and YAP activity by promoting the binding of Ajuba family proteins to Warts and LATS.", "corpus_id": 20859037, "score": 0 }, { "doc_id": "207163458", "title": "Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy", "abstract": "ABSTRACT Cancer initiation and maintenance of the transformed cell state depend on altered cellular signaling and aberrant activities of transcription factors (TFs) that drive pathological gene expression in response to cooperating genetic lesions. Deciphering the roles of interacting TFs is therefore central to understanding carcinogenesis and for designing cancer therapies. Here, we use an unbiased genomic approach to define a TF network that triggers an abnormal gene expression program promoting malignancy of clonal tumors, generated in Drosophila imaginal disc epithelium by gain of oncogenic Ras (RasV12) and loss of the tumor suppressor Scribble (scrib1). We show that malignant transformation of the rasV12scrib1 tumors requires TFs of distinct families, namely the bZIP protein Fos, the ETS-domain factor Ets21c and the nuclear receptor Ftz-F1, all acting downstream of Jun-N-terminal kinase (JNK). Depleting any of the three TFs improves viability of tumor-bearing larvae, and this positive effect can be enhanced further by their combined removal. Although both Fos and Ftz-F1 synergistically contribute to rasV12scrib1 tumor invasiveness, only Fos is required for JNK-induced differentiation defects and Matrix metalloprotease (MMP1) upregulation. In contrast, the Fos-dimerizing partner Jun is dispensable for JNK to exert its effects in rasV12scrib1 tumors. Interestingly, Ets21c and Ftz-F1 are transcriptionally induced in these tumors in a JNK- and Fos-dependent manner, thereby demonstrating a hierarchy within the tripartite TF network, with Fos acting as the most upstream JNK effector. Of the three TFs, only Ets21c can efficiently substitute for loss of polarity and cooperate with RasV12 in inducing malignant clones that, like rasV12scrib1 tumors, invade other tissues and overexpress MMP1 and the Drosophila insulin-like peptide 8 (Dilp8). While rasV12ets21c tumors require JNK for invasiveness, the JNK activity is dispensable for their growth. In conclusion, our study delineates both unique and overlapping functions of distinct TFs that cooperatively promote aberrant expression of target genes, leading to malignant tumor phenotypes. Summary: This study provides genetic evidence that malignancy driven by oncogenic Ras and loss of polarity requires transcription factors of three distinct protein families, acting in synergy downstream of JNK signaling.", "corpus_id": 207163458, "score": 0 }, { "doc_id": "3968494", "title": "An Ectopic Network of Transcription Factors Regulated by Hippo Signaling Drives Growth and Invasion of a Malignant Tumor Model", "abstract": "Cancer cells have abnormal gene expression profiles; however, to what degree these are chaotic or driven by structured gene regulatory networks is often not known. Here we studied a model of Ras-driven invasive tumorigenesis in Drosophila epithelial tissues and combined in vivo genetics with next-generation sequencing and computational modeling to decipher the regulatory logic of tumor cells. Surprisingly, we discovered that the bulk of the tumor-specific gene expression is controlled by an ectopic network of a few transcription factors that are overexpressed and/or hyperactivated in tumor cells. These factors are Stat, AP-1, the bHLH proteins Myc and AP-4, the nuclear hormone receptor Ftz-f1, the nuclear receptor coactivator Taiman/SRC3, and Mef2. Notably, many of these transcription factors also are hyperactivated in human tumors. Bioinformatic analysis predicted that these factors directly regulate the majority of the tumor-specific gene expression, that they are interconnected by extensive cross-regulation, and that they show a high degree of co-regulation of target genes. Indeed, the factors of this network were required in multiple epithelia for tumor growth and invasiveness, and knockdown of several factors caused a reversion of the tumor-specific expression profile but had no observable effect on normal tissues. We further found that the Hippo pathway effector Yorkie was strongly activated in tumor cells and initiated cellular reprogramming by activating several transcription factors of this network. Thus, modeling regulatory networks identified an ectopic and ordered network of master regulators that control a large part of tumor cell-specific gene expression.", "corpus_id": 3968494, "score": 0 }, { "doc_id": "6410584", "title": "Non-cell-autonomous induction of tissue overgrowth by JNK/Ras cooperation in a Drosophila tumor model.", "abstract": "The role of c-Jun N-terminal kinase (JNK) signaling in cancer is enigmatic, and both tumor-promoting and tumor-suppressing functions have been ascribed to JNK pathway components. We have used the Drosophila eye to investigate the function of the JNK pathway in three different tumor models of increasing malignancy. Benign lesions caused by loss of the neoplastic tumor suppressor gene scribble can efficiently be eliminated by JNK-induced apoptosis. In such a scenario, the eye reverts to a wild-type phenotype, indicating that the JNK pathway prevents tumor formation. The situation changes in the case of aggressive tissue overgrowth, which can be induced by oncogenic activation of the Ras/Raf pathway in the eye, or in malignant invasive tumors resulting when Raf activation is combined with loss of scribble. The growth of these more aggressive tumor types is significantly, yet incompletely, suppressed by JNK-mediated apoptosis. Remarkably, oncogenic Raf and JNK cooperate in these tumors, to induce massive hyperplasia in adjacent wild-type tissue. Thus, depending on the genetic context, JNK signaling can eradicate tumors by removing premalignant cells, or promote aberrant overgrowth in tissues surrounding primary lesions.", "corpus_id": 6410584, "score": 0 }, { "doc_id": "716869", "title": "Cell Competition Drives the Growth of Intestinal Adenomas in Drosophila", "abstract": "Summary Tumor-host interactions play an increasingly recognized role in modulating tumor growth. Thus, understanding the nature and impact of this complex bidirectional communication is key to identifying successful anti-cancer strategies. It has been proposed that tumor cells compete with and kill neighboring host tissue to clear space that they can expand into; however, this has not been demonstrated experimentally. Here we use the adult fly intestine to investigate the existence and characterize the role of competitive tumor-host interactions. We show that APC−/−-driven intestinal adenomas compete with and kill surrounding cells, causing host tissue attrition. Importantly, we demonstrate that preventing cell competition, by expressing apoptosis inhibitors, restores host tissue growth and contains adenoma expansion, indicating that cell competition is essential for tumor growth. We further show that JNK signaling is activated inside the tumor and in nearby tissue and is required for both tumor growth and cell competition. Lastly, we find that APC−/− cells display higher Yorkie (YAP) activity than host cells and that this promotes tumor growth, in part via cell competition. Crucially, we find that relative, rather than absolute, Hippo activity determines adenoma growth. Overall, our data indicate that the intrinsic over-proliferative capacity of APC−/− cells is not uncontrolled and can be constrained by host tissues if cell competition is inhibited, suggesting novel possible therapeutic approaches.", "corpus_id": 716869, "score": 0 }, { "doc_id": "207613871", "title": "Hippo pathway effector Yap is an ovarian cancer oncogene.", "abstract": "The Hippo pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo pathway is of prognostic significance to cancer patients. Here we show that the key targets of Hippo signaling, transcriptional coactivators Yki and Yap, play a conserved role in promoting ovarian cancer in flies and humans, respectively. Whereas studies linking Yap to cancer in other tissues have focused on overall Yap levels, we show for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap (nYap), or low levels of cytoplasmic phosphorylated Yap (cpYap), associated with poor survival from ovarian cancer. Patients with both high nYap and low cpYap had ∼50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. We find that Yap2 is the predominantly expressed Yap isoform in both the ovarian surface epithelium (OSE) and epithelial ovarian cancers. Overexpression of Yap2 and phosphorylation-defective Yap2-5SA in immortalized OSE cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage-independent growth, whereas Yap knockdown resulted in increased sensitivity to cisplatin-induced apoptosis. Findings argue that the Hippo signaling pathway defines an important pathway in progression of ovarian cancer.", "corpus_id": 207613871, "score": 0 }, { "doc_id": "7710622", "title": "Niche Appropriation by Drosophila Intestinal Stem Cell Tumors", "abstract": "Mutations that inhibit differentiation in stem cell lineages are a common early step in cancer development, but precisely how a loss of differentiation initiates tumorigenesis is unclear. We investigated Drosophila intestinal stem cell (ISC) tumours generated by suppressing Notch (N) signalling, which blocks differentiation. Notch-defective ISCs require stress-induced divisions for tumour initiation and an autocrine EGFR ligand, Spitz, during early tumour growth. On achieving a critical mass these tumours displace surrounding enterocytes, competing with them for basement membrane space and causing their detachment, extrusion and apoptosis. This loss of epithelial integrity induces JNK and Yki/YAP activity in enterocytes and, consequently, their expression of stress-dependent cytokines (Upd2, Upd3). These paracrine signals, normally used within the stem cell niche to trigger regeneration, propel tumour growth without the need for secondary mutations in growth signalling pathways. The appropriation of niche signalling by differentiation-defective stem cells may be a common mechanism of early tumorigenesis.", "corpus_id": 7710622, "score": 0 }, { "doc_id": "6459451", "title": "A Genetic Screen Reveals an Unexpected Role for Yorkie Signaling in JAK/STAT-Dependent Hematopoietic Malignancies in Drosophila melanogaster", "abstract": "A gain-of-function mutation in the tyrosine kinase JAK2 (JAK2V617F) causes human myeloproliferative neoplasms (MPNs). These patients present with high numbers of myeloid lineage cells and have numerous complications. Since current MPN therapies are not curative, there is a need to find new regulators and targets of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling that may represent additional clinical interventions . Drosophila melanogaster offers a low complexity model to study MPNs as JAK/STAT signaling is simplified with only one JAK [Hopscotch (Hop)] and one STAT (Stat92E). hopTumorous-lethal (Tum-l) is a gain-of-function mutation that causes dramatic expansion of myeloid cells, which then form lethal melanotic tumors. Through an F1 deficiency (Df) screen, we identified 11 suppressors and 35 enhancers of melanotic tumors in hopTum-l animals. Dfs that uncover the Hippo (Hpo) pathway genes expanded (ex) and warts (wts) strongly enhanced the hopTum-l tumor burden, as did mutations in ex, wts, and other Hpo pathway genes. Target genes of the Hpo pathway effector Yorkie (Yki) were significantly upregulated in hopTum-l blood cells, indicating that Yki signaling was increased. Ectopic hematopoietic activation of Yki in otherwise wild-type animals increased hemocyte proliferation but did not induce melanotic tumors. However, hematopoietic depletion of Yki significantly reduced the hopTum-l tumor burden, demonstrating that Yki is required for melanotic tumors in this background. These results support a model in which elevated Yki signaling increases the number of hemocytes, which become melanotic tumors as a result of elevated JAK/STAT signaling.", "corpus_id": 6459451, "score": 0 }, { "doc_id": "49430164", "title": "Oncogenic cooperation between Yorkie and the conserved microRNA miR-8 in the wing disc of Drosophila", "abstract": "ABSTRACT Tissue growth has to be carefully controlled to generate well-functioning organs. MicroRNAs are small non-coding RNAs that modulate the activity of target genes and play a pivotal role in animal development. Understanding the functions of microRNAs in development requires the identification of their target genes. Here, we find that miR-8, a conserved microRNA in the miR-200 family, controls tissue growth and homeostasis in the Drosophila wing imaginal disc. Upregulation of miR-8 causes the repression of Yorkie, the effector of the Hippo pathway in Drosophila, and reduces tissue size. Remarkably, co-expression of Yorkie and miR-8 causes the formation of neoplastic tumors. We show that upregulation of miR-8 represses the growth inhibitor brinker, and depletion of brinker cooperates with Yorkie in the formation of neoplastic tumors. Hence, miR-8 modulates a positive growth regulator, Yorkie, and a negative growth regulator, brinker. Deregulation of this network can result in the loss of tissue homeostasis and the formation of tumors. Summary: miR-8 controls growth and tumorigenesis in the Drosophila wing epithelium.", "corpus_id": 49430164, "score": 0 }, { "doc_id": "17916182", "title": "Transformed Drosophila Cells Evade Diet-Mediated Insulin Resistance through Wingless Signaling", "abstract": "The risk of specific cancers increases in patients with metabolic dysfunction, including obesity and diabetes. Here, we use Drosophila as a model to explore the effects of diet on tumor progression. Feeding Drosophila a diet high in carbohydrates was previously demonstrated to direct metabolic dysfunction, including hyperglycemia, hyperinsulinemia, and insulin resistance. We demonstrate that high dietary sugar also converts Ras/Src-transformed tissue from localized growths to aggressive tumors with emergent metastases. Whereas most tissues displayed insulin resistance, Ras/Src tumors retained insulin pathway sensitivity, increased the ability to import glucose, and resisted apoptosis. High dietary sugar increased canonical Wingless/Wnt pathway activity, which upregulated insulin receptor gene expression to promote insulin sensitivity. The result is a feed-forward circuit that amplified diet-mediated malignant phenotypes within Ras/Src-transformed tumors. By targeting multiple steps in this circuit with rationally applied drug combinations, we demonstrate the potential of combinatorial drug intervention to treat diet-enhanced malignant tumors.", "corpus_id": 17916182, "score": 0 }, { "doc_id": "589874", "title": "Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila", "abstract": "Cancer cells demand excessive nutrients to support their proliferation but how cancer cells sense and promote growth in the nutrient favorable conditions remain incompletely understood. Epidemiological studies have indicated that obesity is a risk factor for various types of cancers. Feeding Drosophila a high dietary sugar was previously demonstrated to not only direct metabolic defects including obesity and organismal insulin resistance, but also transform Ras/Src-activated cells into aggressive tumors. Here we demonstrate that Ras/Src-activated cells are sensitive to perturbations in the Hippo signaling pathway. We provide evidence that nutritional cues activate Salt-inducible kinase, leading to Hippo pathway downregulation in Ras/Src-activated cells. The result is Yorkie-dependent increase in Wingless signaling, a key mediator that promotes diet-enhanced Ras/Src-tumorigenesis in an otherwise insulin-resistant environment. Through this mechanism, Ras/Src-activated cells are positioned to efficiently respond to nutritional signals and ensure tumor growth upon nutrient rich condition including obesity. DOI: http://dx.doi.org/10.7554/eLife.08501.001", "corpus_id": 589874, "score": 0 }, { "doc_id": "3550189", "title": "ARRDC3 suppresses colorectal cancer progression through destabilizing the oncoprotein YAP", "abstract": "Although colorectal cancer (CRC) is a prevalent malignancy of the digestive system, the underlying mechanisms of CRC tumorigenesis are still elusive. Arrestin‐related domain‐containing protein‐3 (ARRDC3) has been reported to promote lysosome‐mediated protein degradation. In the present study, we find that the expression of ARRDC3 is downregulated in CRC specimens. Mechanistically, we reveal that ARRDC3 binds and decreases expression of the oncoprotein YAP, the cotranscription factor of the Hippo pathway. The regulation of the Hippo pathway by ARRDC3 is conserved from Drosophila to mammals. Furthermore, we demonstrate that ARRDC3 plays an anti‐oncogenic role in CRC progression by promoting YAP degradation. Finally, we show that ARRDC3 increases the sensitivity of CRC cells toward chemotherapeutic drugs. Taken together, our findings point to ARRDC3 as a potential target for CRC treatment.", "corpus_id": 3550189, "score": 0 }, { "doc_id": "53109148", "title": "Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis", "abstract": "Significance Nonalcoholic fatty liver disease (NAFLD) is the fastest rising cause of hepatocellular carcinoma (HCC) in Western countries; however, the molecular mechanisms driving NAFLD-HCC remain elusive. Using Sleeping Beauty transposon mutagenesis in two mouse models of NAFLD-HCC, we identified hundreds of NAFLD-HCC candidate cancer genes that were enriched in pathways often associated with NAFLD and HCC. We also showed that Sav1, which functions in the Hippo signaling pathway and was the most frequently mutated gene identified by SB in both screens, prevents progression of steatohepatitis and subsequent HCC development in coordination with PI3K signaling via suppression of Yap, a downstream effector of the Hippo pathway. Our forward genetic screens have thus identified pathways and genes driving the development of NAFLD-HCC. Nonalcoholic fatty liver disease (NAFLD) is the fastest rising cause of hepatocellular carcinoma (HCC) in Western countries; however, the molecular mechanisms that cause NAFLD-HCC remain elusive. To identify molecular drivers of NAFLD-HCC, we performed Sleeping Beauty (SB) transposon mutagenesis screens in liver-specific Pten knockout and in high-fat diet-fed mice, which are murine models of NAFLD-HCC. SB mutagenesis accelerated liver tumor formation in both models and identified 588 and 376 candidate cancer genes (CCGs), respectively; 257 CCGs were common to both screens and were enriched in signaling pathways known to be important for human HCC. Comparison of these CCGs with those identified in a previous SB screen of hepatitis B virus-induced HCC identified a core set of 141 CCGs that were mutated in all screens. Forty-one CCGs appeared specific for NAFLD-HCC, including Sav1, a component of the Hippo signaling pathway and the most frequently mutated gene identified in both NAFLD-HCC screens. Liver-specific deletion of Sav1 was found to promote hepatic lipid accumulation, apoptosis, and fibrogenesis, leading to the acceleration of hepatocarcinogenesis in liver-specific Pten mutant mice. Sav1/Pten double-mutant livers also showed a striking up-regulation of markers of liver progenitor cells (LPCs), along with synergistic activation of Yap, which is a major downstream effector of Hippo signaling. Lastly, Yap activation, in combination with Pten inactivation, was found to accelerate cell growth and sphere formation of LPCs in vitro and induce their malignant transformation in allografts. Our forward genetic screens in mice have thus identified pathways and genes driving the development of NAFLD-HCC.", "corpus_id": 53109148, "score": 0 }, { "doc_id": "9392669", "title": "Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration", "abstract": "The mammalian liver has a remarkable capacity for repair following injury. Removal of up to two-third of liver mass results in a series of events that include extracellular matrix remodeling, coordinated hepatic cell cycle re-entry, restoration of liver mass and tissue remodeling to return the damaged liver to its normal state. Although there has been considerable advancement of our knowledge concerning the regenerative capacity of the mammalian liver, many outstanding questions remaining, such as: how does the regenerating liver stop proliferating when appropriate mass is restored and how do these mechanisms relate to normal regulation of organ size during development? Hippo pathway has been proposed to be central in mediating both events: organ size control during development and following regeneration. In this report, we examined the role of Yap and Taz, key components of the Hippo pathway in liver organ size regulation, both in the context of development and homeostasis. Our studies reveal that contrary to the current paradigms that Yap/Taz are not required for developmental regulation of liver size but are required for proper liver regeneration. In livers depleted of Yap and Taz, liver mass is elevated in neonates and adults. However, Yap/Taz-depleted livers exhibit profound defects in liver regeneration, including an inability to restore liver mass and to properly coordinate cell cycle entry. Taken together, our results highlight requirements for the Hippo pathway during liver regeneration and indicate that there are additional pathways that cooperate with Hippo signaling to control liver size during development and in the adult.", "corpus_id": 9392669, "score": 0 }, { "doc_id": "951100", "title": "The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma.", "abstract": "Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression and aberrant osteoblastic and chondrocytic differentiation in a TEAD-dependent fashion. Using chromatin immunoprecipitation (ChIP), we show that TAZ is directly recruited to a majority of MES gene promoters in a complex with TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with platelet-derived growth factor-B (PDGF-B) resulted in high-grade tumors with MES features in a murine model of glioma. Our studies uncover a direct role for TAZ and TEAD in driving the MES differentiation of malignant glioma.", "corpus_id": 951100, "score": 0 }, { "doc_id": "5015274", "title": "Intercellular Cooperation and Competition in Brain Cancers: Lessons From Drosophila and Human Studies", "abstract": "Glioblastoma (GBM) is a primary brain cancer with an extremely poor prognosis. GBM tumors contain heterogeneous cellular components, including a small subpopulation of tumor cells termed glioma stem cells (GSCs). GSCs are characterized as chemotherapy‐ and radiotherapy‐resistant cells with prominent tumorigenic ability. Studies in Drosophila cancer models demonstrated that interclonal cooperation and signaling from apoptotic clones provokes aggressive growth of neighboring tumorigenic clones, via compensatory proliferation or apoptosis induced proliferation. Mechanistically, these aggressive tumors depend on activation of Jun‐N‐terminal kinase (upstream of c‐JUN), and Drosophila Wnt (Wg) in the apoptotic clones. Consistent with these nonmammalian studies, data from several mammalian studies have shown that c‐JUN and Wnt are hyperactivated in aggressive tumors (including GBM). However, it remains elusive whether compensatory proliferation is an evolutionarily conserved mechanism in cancers. In the present report, we summarize recent studies in Drosophila models and mammalian models (e.g., xenografts of human cancer cells into small animals) to elucidate the intercellular interactions between the apoptosis‐prone cancer cells (e.g., non‐GSCs) and the hyperproliferative cancer cells (e.g., GSCs). These evolving investigations will yield insights about molecular signaling interactions in the context of post‐therapeutic phenotypic changes in human cancers. Furthermore, these studies are likely to revise our understanding of the genetic changes and post‐therapeutic cell‐cell interactions, which is a vital area of cancer biology with wide applications to many cancer types in humans.", "corpus_id": 5015274, "score": 0 }, { "doc_id": "73422184", "title": "Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation", "abstract": "SUMMARY Unresectable glioblastoma (GBM) cells in the invading tumor edge can act as seeds for recurrence. The molecular and phenotypic properties of these cells remain elusive. Here, we report that the invading edge and tumor core have two distinct types of glioma stem-like cells (GSCs) that resemble proneural (PN) and mesenchymal (MES) subtypes, respectively. Upon exposure to ionizing radiation (IR), GSCs, initially enriched for a CD133+ PN signature, transition to a CD109+ MES subtype in a C/EBP-β-dependent manner. Our gene expression analysis of paired cohorts of patients with primary and recurrent GBMs identified a CD133-to-CD109 shift in tumors with an MES recurrence. Patient-derived CD133−/CD109+ cells are highly enriched with clonogenic, tumor-initiating, and radiation-resistant properties, and silencing CD109 significantly inhibits these phenotypes. We also report a conserved regulation of YAP/TAZ pathways by CD109 that could be a therapeutic target in GBM.", "corpus_id": 73422184, "score": 0 }, { "doc_id": "1763627", "title": "Loss of the Drosophila cell polarity regulator Scribbled promotes epithelial tissue overgrowth and cooperation with oncogenic Ras-Raf through impaired Hippo pathway signaling", "abstract": "BackgroundEpithelial neoplasias are associated with alterations in cell polarity and excessive cell proliferation, yet how these neoplastic properties are related to one another is still poorly understood. The study of Drosophila genes that function as neoplastic tumor suppressors by regulating both of these properties has significant potential to clarify this relationship.ResultsHere we show in Drosophila that loss of Scribbled (Scrib), a cell polarity regulator and neoplastic tumor suppressor, results in impaired Hippo pathway signaling in the epithelial tissues of both the eye and wing imaginal disc. scrib mutant tissue overgrowth, but not the loss of cell polarity, is dependent upon defective Hippo signaling and can be rescued by knockdown of either the TEAD/TEF family transcription factor Scalloped or the transcriptional coactivator Yorkie in the eye disc, or reducing levels of Yorkie in the wing disc. Furthermore, loss of Scrib sensitizes tissue to transformation by oncogenic Ras-Raf signaling, and Yorkie-Scalloped activity is required to promote this cooperative tumor overgrowth. The inhibition of Hippo signaling in scrib mutant eye disc clones is not dependent upon JNK activity, but can be significantly rescued by reducing aPKC kinase activity, and ectopic aPKC activity is sufficient to impair Hippo signaling in the eye disc, even when JNK signaling is blocked. In contrast, warts mutant overgrowth does not require aPKC activity. Moreover, reducing endogenous levels of aPKC or increasing Scrib or Lethal giant larvae levels does not promote increased Hippo signaling, suggesting that aPKC activity is not normally rate limiting for Hippo pathway activity. Epistasis experiments suggest that Hippo pathway inhibition in scrib mutants occurs, at least in part, downstream or in parallel to both the Expanded and Fat arms of Hippo pathway regulation.ConclusionsLoss of Scrib promotes Yorkie/Scalloped-dependent epithelial tissue overgrowth, and this is also important for driving cooperative tumor overgrowth with oncogenic Ras-Raf signaling. Whether this is also the case in human cancers now warrants investigation since the cell polarity function of Scrib and its capacity to restrain oncogene-mediated transformation, as well as the tissue growth control function of the Hippo pathway, are conserved in mammals.", "corpus_id": 1763627, "score": 0 }, { "doc_id": "4606265", "title": "Oncogenic Signaling Pathways in The Cancer Genome Atlas", "abstract": "Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.", "corpus_id": 4606265, "score": 0 }, { "doc_id": "58599793", "title": "K‐ras Mutation Subtypes in NSCLC and Associated Co‐occuring Mutations in Other Oncogenic Pathways", "abstract": "Introduction: Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS‐mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer‐related co‐mutations and their correlation with different KRAS mutation subtypes. Methods: Diagnostic samples from 4507 patients with NSCLC were analyzed by next‐generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next‐generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole‐exome sequencing was performed in two patients. Results: We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co‐occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb‐b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co‐occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole‐exome sequencing of two patients with co‐occurring phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. Conclusion: KRAS‐mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co‐occurring mutations in cancer‐associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS‐mutated NSCLC and for future trial design.", "corpus_id": 58599793, "score": 0 }, { "doc_id": "6105238", "title": "Hippo Reprograms the Transcriptional Response to Ras Signaling.", "abstract": "Hyperactivating mutations in Ras signaling are hallmarks of carcinomas. Ras signaling mediates cell fate decisions as well as proliferation during development. It is not known what dictates whether Ras signaling drives differentiation versus proliferation. Here we show that the Hippo pathway is critical for this decision. Loss of Hippo switches Ras activation from promoting cellular differentiation to aggressive cellular proliferation. Transcriptome analysis combined with genetic tests show that this excessive proliferation depends on the synergistic induction of Ras target genes. Using ChIP-nexus, we find that Hippo signaling keeps Ras targets in check by directly regulating the expression of two key downstream transcription factors of Ras signaling: the ETS-domain transcription factor Pointed and the repressor Capicua. Our results highlight how independent signaling pathways can impinge on each other at the level of transcription factors, thereby providing a safety mechanism to keep proliferation in check under normal developmental conditions.", "corpus_id": 6105238, "score": 0 }, { "doc_id": "44147970", "title": "The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation.", "abstract": "Oligodendrogliomas are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with oligodendrogliomas; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster ortholog of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here, we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell-cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in oligodendrogliomas prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth.Significance: Inactivation of CIC inhibits its direct repression of MAPK pathway genes, leading to their increased expression and mitogen-independent growth.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4114/F1.large.jpg Cancer Res; 78(15); 4114-25. ©2018 AACR.", "corpus_id": 44147970, "score": 0 }, { "doc_id": "827852", "title": "Loss of Cell Polarity Drives Tumor Growth and Invasion through JNK Activation in Drosophila", "abstract": "Apparent defects in cell polarity are often seen in human cancer. However, the underlying mechanisms of how cell polarity disruption contributes to tumor progression are unknown. Here, using a Drosophila genetic model for Ras-induced tumor progression, we show a molecular link between loss of cell polarity and tumor malignancy. Mutation of different apicobasal polarity genes activates c-Jun N-terminal kinase (JNK) signaling and downregulates the E-cadherin/beta-catenin adhesion complex, both of which are necessary and sufficient to cause oncogenic Ras(V12)-induced benign tumors in the developing eye to exhibit metastatic behavior. Furthermore, activated JNK and Ras signaling cooperate in promoting tumor growth cell autonomously, as JNK signaling switches its proapoptotic role to a progrowth effect in the presence of oncogenic Ras. Our finding that such context-dependent alterations promote both tumor growth and metastatic behavior suggests that metastasis-promoting mutations may be selected for based primarily on their growth-promoting capabilities. Similar oncogenic cooperation mediated through these evolutionarily conserved signaling pathways could contribute to human cancer progression.", "corpus_id": 827852, "score": 0 }, { "doc_id": "11612800", "title": "JNK‐ and Fos‐regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila", "abstract": "Loss of the epithelial polarity gene scribble in clones of Drosophila imaginal disc cells can cooperate with Ras signaling to induce malignant tumors. Such mutant tissue overproliferates, resists apoptosis, leaves its place of origin and invades other organs, ultimately causing lethality. We show that increased Jun N‐terminal kinase (JNK) signaling resulting from the loss of scribble promotes the movement of transformed cells to secondary sites. This effect requires Fos‐dependent transcriptional activation of a matrix metalloprotease gene mmp1 downstream of JNK. Expression of the Mmp inhibitor Timp or Mmp RNAi knockdown suppresses cell invasiveness. The proinvasive function of the JNK pathway is revealed in a tumor context when active Ras signaling prevents the apoptotic response to JNK activity as it occurs in nontransformed cells. Based on these results, we present a model that explains the oncogenic cooperation between JNK and Ras, and describes how aberrant regulation of cell survival, proliferation and mobilization cooperate to incite malignant tumor formation.", "corpus_id": 11612800, "score": 0 }, { "doc_id": "5197746", "title": "Drosophila endocytic neoplastic tumor suppressor genes regulate Sav/Wts/Hpo signaling and the c-Jun N-terminal kinase pathway", "abstract": "Genetic screens in the fruit fly Drosophila melanogaster have identified a class of neoplastic tumor suppressor genes (endocytic nTSGs), which encode proteins that localize to endosomes and facilitate the trafficking of membrane-bound receptors and adhesion molecules into the degradative lysosome. Loss of endocytic nTSGs transforms imaginal disc epithelia into highly proliferative, invasive tissues that fail to differentiate and display defects in cellular apicobasal polarity, adhesion and tissue architecture. As vertebrate homologs of some Drosophila nTSGs are linked to tumor formation, identifying molecular changes in signaling associated with nTSG loss could inform understanding of neoplastic transformation in vertebrates. Here we show that mutations in genes that act at multiple steps of the endolysosomal pathway lead to autonomous activation of the Sav/Wts/Hpo (SWH) transcriptional effector Yki (YAP/TAZ in vertebrates) and the Jun N-terminal kinase (JNK), which is known to promote Yki activity in cells with disrupted polarity. Yki and JNK activity are elevated by mutations at multiple steps in the endolysosomal pathway including mutations in the AP-2σ gene, which encodes a component of the AP-2 adaptor complex that recruits cargoes into clathrin-coated pits for subsequent internalization. Moreover, reduction of JNK activity can decrease elevated Yki-signaling caused by altered endocytosis. These studies reveal a broad requirement for components of the endocytic pathway in regulating SWH and JNK outputs, and place Drosophila endocytic nTSGs into a network that involving two major signaling pathways implicated in oncogenesis.", "corpus_id": 5197746, "score": 0 }, { "doc_id": "464801", "title": "Influence of Fat-Hippo and Notch signaling on the proliferation and differentiation of Drosophila optic neuroepithelia", "abstract": "The Drosophila optic lobe develops from neuroepithelial cells, which function as symmetrically dividing neural progenitors. We describe here a role for the Fat-Hippo pathway in controlling the growth and differentiation of Drosophila optic neuroepithelia. Mutation of tumor suppressor genes within the pathway, or expression of activated Yorkie, promotes overgrowth of neuroepithelial cells and delays or blocks their differentiation; mutation of yorkie inhibits growth and accelerates differentiation. Neuroblasts and other neural cells, by contrast, appear unaffected by Yorkie activation. Neuroepithelial cells undergo a cell cycle arrest before converting to neuroblasts; this cell cycle arrest is regulated by Fat-Hippo signaling. Combinations of cell cycle regulators, including E2f1 and CyclinD, delay neuroepithelial differentiation, and Fat-Hippo signaling delays differentiation in part through E2f1. We also characterize roles for Jak-Stat and Notch signaling. Our studies establish that the progression of neuroepithelial cells to neuroblasts is regulated by Notch signaling, and suggest a model in which Fat-Hippo and Jak-Stat signaling influence differentiation by their acceleration of cell cycle progression and consequent impairment of Delta accumulation, thereby modulating Notch signaling. This characterization of Fat-Hippo signaling in neuroepithelial growth and differentiation also provides insights into the potential roles of Yes-associated protein in vertebrate neural development and medullablastoma.", "corpus_id": 464801, "score": 0 }, { "doc_id": "4505909", "title": "Notch Signaling Activates Yorkie Non-Cell Autonomously in Drosophila", "abstract": "In Drosophila imaginal epithelia, cells mutant for the endocytic neoplastic tumor suppressor gene vps25 stimulate nearby untransformed cells to express Drosophila Inhibitor-of-Apoptosis-Protein-1 (DIAP-1), conferring resistance to apoptosis non-cell autonomously. Here, we show that the non-cell autonomous induction of DIAP-1 is mediated by Yorkie, the conserved downstream effector of Hippo signaling. The non-cell autonomous induction of Yorkie is due to Notch signaling from vps25 mutant cells. Moreover, activated Notch in normal cells is sufficient to induce non-cell autonomous Yorkie activity in wing imaginal discs. Our data identify a novel mechanism by which Notch promotes cell survival non-cell autonomously and by which neoplastic tumor cells generate a supportive microenvironment for tumor growth.", "corpus_id": 4505909, "score": 0 }, { "doc_id": "42355752", "title": "Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila.", "abstract": "We have found that the Drosophila gene vps25 possesses several properties of a tumor suppressor. First, vps25 mutant cells activate Notch and Dpp receptor signaling, inducing ectopic organizers in developing eyes and limbs and consequent overproliferation of both mutant and nearby wild-type cells. Second, as the mutant cells proliferate, they lose their epithelial organization and undergo apoptosis. Strikingly, when apoptosis of mutant cells is blocked, tumor-like overgrowths are formed that are capable of metastasis. vps25 encodes a component of the ESCRT-II complex, which sorts membrane proteins into multivesicular bodies during endocytic trafficking to the lysosome. Activation of Notch and Dpp receptor signaling in mutant cells results from an endocytic blockage that causes accumulation of these receptors and other signaling components in endosomes. These results highlight the importance of endocytic trafficking in regulating signaling and epithelial organization and suggest a possible role for ESCRT components in human cancer.", "corpus_id": 42355752, "score": 0 }, { "doc_id": "12717688", "title": "vps25 mosaics display non-autonomous cell survival and overgrowth, and autonomous apoptosis", "abstract": "Appropriate cell-cell signaling is crucial for proper tissue homeostasis. Protein sorting of cell surface receptors at the early endosome is important for both the delivery of the signal and the inactivation of the receptor, and its alteration can cause malignancies including cancer. In a genetic screen for suppressors of the pro-apoptotic gene hid in Drosophila, we identified two alleles of vps25, a component of the ESCRT machinery required for protein sorting at the early endosome. Paradoxically, although vps25 mosaics were identified as suppressors of hid-induced apoptosis, vps25 mutant cells die. However, we provide evidence that a non-autonomous increase of Diap1 protein levels, an inhibitor of apoptosis, accounts for the suppression of hid. Furthermore, before they die, vps25 mutant clones trigger non-autonomous proliferation through a failure to downregulate Notch signaling, which activates the mitogenic JAK/STAT pathway. Hid and JNK contribute to apoptosis of vps25 mutant cells. Inhibition of cell death in vps25 clones causes dramatic overgrowth phenotypes. In addition, Hippo signaling is increased in vps25 clones, and hippo mutants block apoptosis in vps25 clones. In summary, the phenotypic analysis of vps25 mutants highlights the importance of receptor downregulation by endosomal protein sorting for appropriate tissue homeostasis, and may serve as a model for human cancer.", "corpus_id": 12717688, "score": 0 }, { "doc_id": "37386939", "title": "Kicking it up a Notch for the best in show: Scalloped leads Yorkie into the haematopoietic arena", "abstract": "Maintenance and differentiation of progenitor cells is essential for proper organ development and adaptation to environmental stress and injury. In Drosophila melanogaster, the haematopietic system serves as an ideal model for interrogating the function of signaling pathways required for progenitor maintenance and cell fate determination. Here we focus on the role of the Hippo pathway effectors Yorkie and Scalloped in mediating and facilitating Notch signaling-mediated lineage specification in the lymph gland, the primary center for haematopoiesis within the developing larva. We discuss the regulatory mechanisms which promote Notch activity during normal haematopoiesis and its modulation during immune challenge conditions. We provide additional evidence establishing the hierarchy of signaling events during crystal cell formation, highlighting the relationship between Yorkie, Scalloped and Lozenge, while expanding on the role of Yorkie in promoting hemocyte survival and the developmental regulation of Notch and its ligand, Serrate, within the lymph gland. Finally, we propose additional areas of exploration that may provide mechanistic insight into the environmental and non-cell autonomous regulation of cell fate in the blood system.", "corpus_id": 37386939, "score": 0 }, { "doc_id": "18786105", "title": "Warts Is Required for PI3K-Regulated Growth Arrest, Autophagy, and Autophagic Cell Death in Drosophila", "abstract": "BACKGROUND\nCell growth arrest and autophagy are required for autophagic cell death in Drosophila. Maintenance of growth by expression of either activated Ras, Dp110, or Akt is sufficient to inhibit autophagy and cell death in Drosophila salivary glands, but the mechanism that controls growth arrest is unknown. Although the Warts (Wts) tumor suppressor is a critical regulator of tissue growth in animals, it is not clear how this signaling pathway controls cell growth.\n\n\nRESULTS\nHere, we show that genes in the Wts pathway are required for salivary gland degradation and that wts mutants have defects in cell growth arrest, caspase activity, and autophagy. Expression of Atg1, a regulator of autophagy, in salivary glands is sufficient to rescue wts mutant salivary gland destruction. Surprisingly, expression of Yorkie (Yki) and Scalloped (Sd) in salivary glands fails to phenocopy wts mutants. By contrast, misexpression of the Yki target bantam was able to inhibit salivary gland cell death, even though mutations in bantam fail to suppress the wts mutant salivary gland-persistence phenotype. Significantly, wts mutant salivary glands possess altered phosphoinositide signaling, and decreased function of the class I PI3K-pathway genes chico and TOR suppressed wts defects in cell death.\n\n\nCONCLUSIONS\nAlthough we have previously shown that salivary gland degradation requires genes in the Wts pathway, this study provides the first evidence that Wts influences autophagy. Our data indicate that the Wts-pathway components Yki, Sd, and bantam fail to function in salivary glands and that Wts regulates salivary gland cell death in a PI3K-dependent manner.", "corpus_id": 18786105, "score": 0 }, { "doc_id": "17195001", "title": "TOR Signaling in Growth and Metabolism", "abstract": "The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.", "corpus_id": 17195001, "score": 0 }, { "doc_id": "44516708", "title": "Mechanisms of growth and homeostasis in the Drosophila wing.", "abstract": "Animal shape and size is controlled with amazing precision during development. External factors such as nutrient availability and crowding can alter overall animal size, but individual body parts scale reproducibly to match the body even with challenges from a changing environment. How is such precision achieved? Here, we review selected research from the last few years in Drosophila--arguably the premier genetic model for the study of animal growth--that sheds light on how body and tissue size are regulated by forces intrinsic to individual organs. We focus on two topics currently under intense study: the influence of pattern regulators on organ and tissue growth and the role of local competitive interactions between cells in tissue homeostasis and final size.", "corpus_id": 44516708, "score": 0 }, { "doc_id": "21935984", "title": "YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29", "abstract": "Organ development is a complex process governed by the interplay of several signalling pathways that have critical functions in the regulation of cell growth and proliferation. Over the past years, the Hippo pathway has emerged as a key regulator of organ size. Perturbation of this pathway has been shown to play important roles in tumorigenesis. YAP, the main downstream target of the mammalian Hippo pathway, promotes organ growth, yet the underlying molecular mechanism of this regulation remains unclear. Here we provide evidence that YAP activates the mammalian target of rapamycin (mTOR), a major regulator of cell growth. We have identified the tumour suppressor PTEN, an upstream negative regulator of mTOR, as a critical mediator of YAP in mTOR regulation. We demonstrate that YAP downregulates PTEN by inducing miR-29 to inhibit PTEN translation. Last, we show that PI(3)K–mTOR is a pathway modulated by YAP to regulate cell size, tissue growth and hyperplasia. Our studies reveal a functional link between Hippo and PI(3)K–mTOR, providing a molecular basis for the coordination of these two pathways in organ size regulation.", "corpus_id": 21935984, "score": 0 }, { "doc_id": "17628783", "title": "An innate immune response of blood cells to tumors and tissue damage in Drosophila", "abstract": "SUMMARY Studies in mice and humans have demonstrated a role for the immune system in preventing the growth of tumors. Deciphering the mechanisms involved in the immune response to tumors is essential to our understanding of immune recognition and cancer progression. Here we report an innate immune response to tumors in Drosophila melanogaster. We found that circulating blood cells, termed hemocytes, adhere to tumors upon detection of basement membrane disruption, and subsequently counter their growth. Basement membrane components are remarkably conserved throughout the animal kingdom, providing a unique structure for the immune system to sense tissue integrity. Further, we show that tissue damage activates JNK signaling in both tumors and aseptic wounds, causing expression of JAK/STAT-activating cytokines. Cytokine secretion from the injured tissue is amplified into a systemic response through the induction of additional cytokine expression in the hemocytes and the fat body, resulting in hemocyte proliferation. Our findings reveal common mechanisms in the response to tumors and wounds in flies. A similar innate reaction may underlie the response to tumors and tissue damage in vertebrates and humans.", "corpus_id": 17628783, "score": 0 }, { "doc_id": "4431344", "title": "Interaction between RasV12 and scribble clones induces tumour growth and invasion", "abstract": "Human tumours have a large degree of cellular and genetic heterogeneity. Complex cell interactions in the tumour and its microenvironment are thought to have an important role in tumorigenesis and cancer progression. Furthermore, cooperation between oncogenic genetic lesions is required for tumour development; however, it is not known how cell interactions contribute to oncogenic cooperation. The genetic techniques available in the fruitfly Drosophila melanogaster allow analysis of the behaviour of cells with distinct mutations, making this the ideal model organism with which to study cell interactions and oncogenic cooperation. In Drosophila eye-antennal discs, cooperation between the oncogenic protein RasV12 (ref. 5) and loss-of-function mutations in the conserved tumour suppressor scribbled (scrib) gives rise to metastatic tumours that display many characteristics observed in human cancers. Here we show that clones of cells bearing different mutations can cooperate to promote tumour growth and invasion in Drosophila. We found that the RasV12 and scrib- mutations can also cause tumours when they affect different adjacent epithelial cells. We show that this interaction between RasV12 and scrib- clones involves JNK signalling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines, a compensatory growth mechanism for tissue homeostasis. The development of RasV12 tumours can also be triggered by tissue damage, a stress condition that activates JNK signalling. Given the conservation of the pathways examined here, similar cooperative mechanisms could have a role in the development of human cancers.", "corpus_id": 4431344, "score": 0 }, { "doc_id": "4420533", "title": "Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila", "abstract": "Mitochondrial respiratory function is frequently impaired in human cancers. However, the mechanisms by which mitochondrial dysfunction contributes to tumour progression remain elusive. Here we show in Drosophila imaginal epithelium that defects in mitochondrial function potently induce tumour progression of surrounding tissue in conjunction with oncogenic Ras. Our data show that Ras activation and mitochondrial dysfunction cooperatively stimulate production of reactive oxygen species, which causes activation of c-Jun amino (N)-terminal kinase (JNK) signalling. JNK cooperates with oncogenic Ras to inactivate the Hippo pathway, leading to upregulation of its targets Unpaired (an interleukin-6 homologue) and Wingless (a Wnt homologue). Mitochondrial dysfunction in Ras-activated cells further cooperates with Ras signalling in neighbouring cells with normal mitochondrial function, causing benign tumours to exhibit metastatic behaviour. Our findings provide a mechanistic basis for interclonal tumour progression driven by mitochondrial dysfunction and oncogenic Ras.", "corpus_id": 4420533, "score": 0 }, { "doc_id": "2294", "title": "Apical deficiency triggers JNK-dependent apoptosis in the embryonic epidermis of Drosophila", "abstract": "Epithelial homeostasis and the avoidance of diseases such as cancer require the elimination of defective cells by apoptosis. Here, we investigate how loss of apical determinants triggers apoptosis in the embryonic epidermis of Drosophila. Transcriptional profiling and in situ hybridisation show that JNK signalling is upregulated in mutants lacking Crumbs or other apical determinants. This leads to transcriptional activation of the pro-apoptotic gene reaper and to apoptosis. Suppression of JNK signalling by overexpression of Puckered, a feedback inhibitor of the pathway, prevents reaper upregulation and apoptosis. Moreover, removal of endogenous Puckered leads to ectopic reaper expression. Importantly, disruption of the basolateral domain in the embryonic epidermis does not trigger JNK signalling or apoptosis. We suggest that apical, not basolateral, integrity could be intrinsically required for the survival of epithelial cells. In apically deficient embryos, JNK signalling is activated throughout the epidermis. Yet, in the dorsal region, reaper expression is not activated and cells survive. One characteristic of these surviving cells is that they retain discernible adherens junctions despite the apical deficit. We suggest that junctional integrity could restrain the pro-apoptotic influence of JNK signalling.", "corpus_id": 2294, "score": 0 }, { "doc_id": "59259425", "title": "Wingless modulates activator protein-1-mediated tumor invasion", "abstract": "Metastasis begins with a subset of local tumor cells acquiring the potential to invade into surrounding tissues, and remains to be a major obstacle for cancer treatments. More than 90% of cancer patients died from tumor metastasis, instead of primary tumor growth. The canonical Wnt/β-catenin pathway plays essential roles in promoting tumor formation, yet its function in regulating tumor metastasis and the underlying mechanisms remain controversial. Here we employed well-established Drosophila tumor models to investigate the regulating mechanism of Wingless (Wg) pathway in tumor invasion. Our results showed that Wg signaling is necessary and sufficient for cell polarity disruption-induced cell migration and molecular changes reminiscent of epithelial-mesenchymal transition (EMT). Moreover, reducing Wg signaling suppressed lgl−/−/RasV12-induced tumor invasion, and cooperation between Arm and RasV12 is sufficient to induce tumor invasion. Mechanistically, we found that cell polarity disruption activates JNK signaling, which in turn upregulate wg expression through transcription factor activator protein-1 (AP-1). We identified a consensus AP-1 binding site located in the 2nd intron of wg, and confirmed that it is essential for AP-1 induced wg transcription both in vitro and in vivo. Lastly, we confirmed that the transcriptional activation of WNT by AP-1 is conserved in human cancer cells. These evidences reveal a positive role of Wnt/β-catenin pathway in tumor invasion, and provide a conserved mechanism that connects JNK and Wnt signaling in regulating tumor progression.", "corpus_id": 59259425, "score": 0 }, { "doc_id": "12353308", "title": "Src controls tumorigenesis via JNK‐dependent regulation of the Hippo pathway in Drosophila", "abstract": "Cell–cell interactions within the tumour microenvironment have crucial roles in epithelial tumorigenesis. Using Drosophila genetics, we show that the oncoprotein Src controls tumour microenvironment by Jun N‐terminal kinase (JNK)‐dependent regulation of the Hippo pathway. Clones of cells with elevated Src expression activate the Rac‐Diaphanous and Ras‐mitogen‐activated protein kinase (MAPK) pathways, which cooperatively induce F‐actin accumulation, thereby leading to activation of the Hippo pathway effector Yorkie (Yki). Simultaneously, Src activates the JNK pathway, which antagonizes the autonomous Yki activity and causes propagation of Yki activity to neighbouring cells, resulting in the overgrowth of surrounding tissue. Our data provide a mechanism to explain how oncogenic mutations regulate tumour microenvironment through cell–cell communication.", "corpus_id": 12353308, "score": 0 }, { "doc_id": "4928080", "title": "The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila.", "abstract": "Similar to the mammalian intestine, the Drosophila adult midgut has resident stem cells that support growth and regeneration. How the niche regulates intestinal stem cell activity in both mammals and flies is not well understood. Here, we show that the conserved germinal center protein kinase Misshapen restricts intestinal stem cell division by repressing the expression of the JAK-STAT pathway ligand Upd3 in differentiating enteroblasts. Misshapen, a distant relative to the prototypic Warts activating kinase Hippo, interacts with and activates Warts to negatively regulate the activity of Yorkie and the expression of Upd3. The mammalian Misshapen homolog MAP4K4 similarly interacts with LATS (Warts homolog) and promotes inhibition of YAP (Yorkie homolog). Together, this work reveals that the Misshapen-Warts-Yorkie pathway acts in enteroblasts to control niche signaling to intestinal stem cells. These findings also provide a model in which to study requirements for MAP4K4-related kinases in MST1/2-independent regulation of LATS and YAP.", "corpus_id": 4928080, "score": 0 }, { "doc_id": "35739930", "title": "Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade.", "abstract": "In Drosophila and mammals, the canonical Hippo kinase cascade is mediated by Hpo/Mst acting through the intermediary kinase Wts/Lats to phosphorylate the transcriptional coactivator Yki/YAP/TAZ. Despite recent reports linking Yki/YAP/TAZ activity to the actin cytoskeleton, the underlying mechanisms are poorly understood and/or controversial. Using Drosophila imaginal discs as an in vivo model, we show that Wts, but not Hpo, is genetically indispensable for cytoskeleton-mediated subcellular localization of Yki. Through a systematic screen, we identify the Ste-20 kinase Happyhour (Hppy) and its mammalian counterpart MAP4K1/2/3/5 as an alternative kinase that phosphorylates the hydrophobic motif of Wts/Lats in a similar manner as Hpo/Mst. Consistent with their redundant function as activating kinases of Wts/Lats, combined loss of Hpo/Mst and Hppy/MAP4K abolishes cytoskeleton-mediated regulation of Yki/YAP subcellular localization, as well as YAP cytoplasmic translocation induced by contact inhibition. These Hpo/Mst-like kinases provide an expanded view of the Hippo kinase cascade in development and physiology.", "corpus_id": 35739930, "score": 0 }, { "doc_id": "34331480", "title": "Drosophila Schip1 Links Expanded and Tao-1 to Regulate Hippo Signaling.", "abstract": "Regulation of organ size is essential in animal development, and Hippo (Hpo) signaling is a major conserved mechanism for controlling organ growth. In Drosophila, Hpo and Warts kinases are core components of this pathway and function as tumor suppressors by inhibiting Yorkie (Yki). Expanded (Ex) is a regulator of the Hpo activity, but how they are linked is unknown. Here, we show that Schip1, a Drosophila homolog of the mammalian Schwannomin interacting protein 1 (SCHIP1), provides a link between Ex and Hpo. Ex is required for apical localization of Schip1 in imaginal discs. Schip1 is necessary for promoting membrane localization and phosphorylation of Hpo by recruiting the Hpo kinase Tao-1. Taking these findings together, we conclude that Schip1 directly links Ex to Hpo signaling by recruiting Tao-1. This study provides insights into the mechanism of Tao-1 regulation and a potential growth control function for SCHIP1 in mammals.", "corpus_id": 34331480, "score": 0 } ]

{ "doc_id": "215238818", "title": "To mask or not to mask: Modeling the potential for face mask use by the general public to curtail the COVID-19 pandemic", "abstract": "\n Abstract\n \n Face mask use by the general public for limiting the spread of the COVID-19 pandemic is controversial, though increasingly recommended, and the potential of this intervention is not well understood. We develop a compartmental model for assessing the community-wide impact of mask use by the general, asymptomatic public, a portion of which may be asymptomatically infectious. Model simulations, using data relevant to COVID-19 dynamics in the US states of New York and Washington, suggest that broad adoption of even relatively ineffective face masks may meaningfully reduce community transmission of COVID-19 and decrease peak hospitalizations and deaths. Moreover, mask use decreases the effective transmission rate in nearly linear proportion to the product of mask effectiveness (as a fraction of potentially infectious contacts blocked) and coverage rate (as a fraction of the general population), while the impact on epidemiologic outcomes (death, hospitalizations) is highly nonlinear, indicating masks could synergize with other non-pharmaceutical measures. Notably, masks are found to be useful with respect to both preventing illness in healthy persons and preventing asymptomatic transmission. Hypothetical mask adoption scenarios, for Washington and New York state, suggest that immediate near universal (80%) adoption of moderately (50%) effective masks could prevent on the order of 17–45% of projected deaths over two months in New York, while decreasing the peak daily death rate by 34–58%, absent other changes in epidemic dynamics. Even very weak masks (20% effective) can still be useful if the underlying transmission rate is relatively low or decreasing: In Washington, where baseline transmission is much less intense, 80% adoption of such masks could reduce mortality by 24–65% (and peak deaths 15–69%), compared to 2–9% mortality reduction in New York (peak death reduction 9–18%). Our results suggest use of face masks by the general public is potentially of high value in curtailing community transmission and the burden of the pandemic. The community-wide benefits are likely to be greatest when face masks are used in conjunction with other non-pharmaceutical practices (such as social-distancing), and when adoption is nearly universal (nation-wide) and compliance is high.\n \n", "corpus_id": 215238818 }

[ { "doc_id": "17398411", "title": "SARS Transmission, Risk Factors, and Prevention in Hong Kong", "abstract": "We analyzed information obtained from 1,192 patients with probable severe acute respiratory syndrome (SARS) reported in Hong Kong. Among them, 26.6% were hospital workers, 16.1% were household members of SARS patients and had probable secondary infections, 14.3% were Amoy Garden residents, 4.9% were inpatients, and 20.1% were contacts of SARS patients who were not family members. The remaining 347 case-patients (29.1%) did not have “known” sources of infection. Excluding those <16 years of age, 330 patients with cases from “undefined” sources were used in a 1:2 matched case-control study. Multivariate analysis of this case-control study showed that having visited mainland China, hospitals, or the Amoy Gardens were risk factors (odds ratio [OR] 1.95 to 7.63). In addition, frequent mask use in public venues, frequent hand washing, and disinfecting the living quarters were significant protective factors (OR 0.36 to 0.58). In Hong Kong, therefore, community-acquired infection did not make up most transmissions, and public health measures have contributed substantially to the control of the SARS epidemic.", "corpus_id": 17398411, "score": 0 }, { "doc_id": "214748504", "title": "COVID-19 epidemic: disentangling the re-emerging controversy about medical facemasks from an epidemiological perspective", "abstract": "COVID-19 epidemic: disentangling the re-emerging controversy about medical facemasks from an epidemiological perspective Ka Hung Chan * and Kwok-Yung Yuen Clinical Trial Service and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK, Public Health Research Collaborative, Hong Kong SAR and, Department of Clinical Microbiology and Infection Control, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR", "corpus_id": 214748504, "score": 0 }, { "doc_id": "212740627", "title": "Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2)", "abstract": "Undetected cases The virus causing coronavirus disease 2019 (COVID-19) has now become pandemic. How has it managed to spread from China to all around the world within 3 to 4 months? Li et al. used multiple sources to infer the proportion of early infections that went undetected and their contribution to virus spread. The researchers combined data from Tencent, one of the world's largest social media and technology companies, with a networked dynamic metapopulation model and Bayesian inference to analyze early spread within China. They estimate that ∼86% of cases were undocumented before travel restrictions were put in place. Before travel restriction and personal isolation were implemented, the transmission rate of undocumented infections was a little more than half that of the known cases. However, because of their greater numbers, undocumented infections were the source for ∼80% of the documented cases. Immediately after travel restrictions were imposed, ∼65% of cases were documented. These findings help to explain the lightning-fast spread of this virus around the world. Science, this issue p. 489 Prior to travel restrictions, most SARS-CoV-2 infections went undocumented and substantially contributed to global virus spread. Estimation of the prevalence and contagiousness of undocumented novel coronavirus [severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2)] infections is critical for understanding the overall prevalence and pandemic potential of this disease. Here, we use observations of reported infection within China, in conjunction with mobility data, a networked dynamic metapopulation model, and Bayesian inference, to infer critical epidemiological characteristics associated with SARS-CoV-2, including the fraction of undocumented infections and their contagiousness. We estimate that 86% of all infections were undocumented [95% credible interval (CI): 82–90%] before the 23 January 2020 travel restrictions. The transmission rate of undocumented infections per person was 55% the transmission rate of documented infections (95% CI: 46–62%), yet, because of their greater numbers, undocumented infections were the source of 79% of the documented cases. These findings explain the rapid geographic spread of SARS-CoV-2 and indicate that containment of this virus will be particularly challenging.", "corpus_id": 212740627, "score": 1 }, { "doc_id": "9903269", "title": "Effectiveness of facemasks to reduce exposure hazards for airborne infections among general populations", "abstract": "Facemasks are widely used as a protective measure by general public to prevent inhalation of airborne pathogens including seasonal, swine and other forms of influenza and severe acute respiratory syndrome (SARS), etc. However, scientific data on effectiveness of facemasks in reducing infections in the community are extremely limited and even inconsistent. In this work, two manikins labelled as ‘source’ and ‘susceptible’ were used to measure the protection provided by facemasks under various emission scenarios. The source was modified to generate polydisperse ultrafine particles, whereas the susceptible was modified to mimic a realistic breathing pattern. The facemask was challenged by both pseudo-steady and highly transient emissions generated by an expiratory process where parameters, such as separation distance between manikins, emission velocity and expiratory duration, were controlled and measured systematically. Performances of four different types of facemask fits, varying from ideal to normal wearing practice, were also investigated. Under the pseudo-steady concentration environment, facemask protection was found to be 45 per cent, while under expiratory emissions, protection varied from 33 to 100 per cent. It was also observed that the separation between the source and the manikin was the most influential parameter affecting facemask protection.", "corpus_id": 9903269, "score": 1 }, { "doc_id": "19367258", "title": "Testing the Efficacy of Homemade Masks: Would They Protect in an Influenza Pandemic?", "abstract": "Abstract Objective This study examined homemade masks as an alternative to commercial face masks. Methods Several household materials were evaluated for the capacity to block bacterial and viral aerosols. Twenty-one healthy volunteers made their own face masks from cotton t-shirts; the masks were then tested for fit. The number of microorganisms isolated from coughs of healthy volunteers wearing their homemade mask, a surgical mask, or no mask was compared using several air-sampling techniques. Results The median-fit factor of the homemade masks was one-half that of the surgical masks. Both masks significantly reduced the number of microorganisms expelled by volunteers, although the surgical mask was 3 times more effective in blocking transmission than the homemade mask. Conclusion Our findings suggest that a homemade mask should only be considered as a last resort to prevent droplet transmission from infected individuals, but it would be better than no protection. (Disaster Med Public Health Preparedness. 2013;0:1–6)", "corpus_id": 19367258, "score": 1 }, { "doc_id": "13617338", "title": "The efficacy of medical masks and respirators against respiratory infection in healthcare workers", "abstract": "We aimed to examine the efficacy of medical masks and respirators in protecting against respiratory infections using pooled data from two homogenous randomised control clinical trials (RCTs).", "corpus_id": 13617338, "score": 1 }, { "doc_id": "10565052", "title": "Effectiveness of Masks and Respirators Against Respiratory Infections in Healthcare Workers: A Systematic Review and Meta-Analysis", "abstract": "In this systematic review and meta-analysis, we found evidence for a protective effect of facemasks and respirators against clinical respiratory infection among healthcare workers, and limited evidence for superiority of respirators. However, the existing evidence is sparse and findings inconsistent.", "corpus_id": 10565052, "score": 1 }, { "doc_id": "14231151", "title": "Face Mask Use and Control of Respiratory Virus Transmission in Households", "abstract": "Mask use is associated with low adherence, but adherent mask users are significantly protected against seasonal disease.", "corpus_id": 14231151, "score": 0 }, { "doc_id": "12336999", "title": "Surgical Mask to Prevent Influenza Transmission in Households: A Cluster Randomized Trial", "abstract": "Background Facemasks and respirators have been stockpiled during pandemic preparedness. However, data on their effectiveness for limiting transmission are scarce. We evaluated the effectiveness of facemask use by index cases for limiting influenza transmission by large droplets produced during coughing in households. Methodology and Principal Findings A cluster randomized intervention trial was conducted in France during the 2008–2009 influenza season. Households were recruited during a medical visit of a household member with a positive rapid influenza A test and symptoms lasting less than 48 hours. Households were randomized either to the mask or control group for 7 days. In the intervention arm, the index case had to wear a surgical mask from the medical visit and for a period of 5 days. The trial was initially intended to include 372 households but was prematurely interrupted after the inclusion of 105 households (306 contacts) following the advice of an independent steering committee. We used generalized estimating equations to test the association between the intervention and the proportion of household contacts who developed an influenza-like illness during the 7 days following the inclusion. Influenza-like illness was reported in 24/148 (16.2%) of the contacts in the intervention arm and in 25/158 (15.8%) of the contacts in the control arm and the difference between arms was 0.40% (95%CI: −10% to 11%, P = 1.00). We observed a good adherence to the intervention. In various sensitivity analyses, we did not identify any trend in the results suggesting effectiveness of facemasks. Conclusion This study should be interpreted with caution since the lack of statistical power prevents us to draw formal conclusion regarding effectiveness of facemasks in the context of a seasonal epidemic. Trial Registration clinicaltrials.gov NCT00774774", "corpus_id": 12336999, "score": 0 }, { "doc_id": "12683569", "title": "Professional and Home-Made Face Masks Reduce Exposure to Respiratory Infections among the General Population", "abstract": "Background Governments are preparing for a potential influenza pandemic. Therefore they need data to assess the possible impact of interventions. Face-masks worn by the general population could be an accessible and affordable intervention, if effective when worn under routine circumstances. Methodology We assessed transmission reduction potential provided by personal respirators, surgical masks and home-made masks when worn during a variety of activities by healthy volunteers and a simulated patient. Principal Findings All types of masks reduced aerosol exposure, relatively stable over time, unaffected by duration of wear or type of activity, but with a high degree of individual variation. Personal respirators were more efficient than surgical masks, which were more efficient than home-made masks. Regardless of mask type, children were less well protected. Outward protection (mask wearing by a mechanical head) was less effective than inward protection (mask wearing by healthy volunteers). Conclusions/Significance Any type of general mask use is likely to decrease viral exposure and infection risk on a population level, in spite of imperfect fit and imperfect adherence, personal respirators providing most protection. Masks worn by patients may not offer as great a degree of protection against aerosol transmission.", "corpus_id": 12683569, "score": 1 }, { "doc_id": "43851274", "title": "The Effect of Mask Use on the Spread of Influenza During a Pandemic", "abstract": "Face masks have traditionally been used in general infection control, but their efficacy at the population level in preventing transmission of influenza viruses has not been studied in detail. Data from published clinical studies indicate that the infectivity of influenza A virus is probably very high, so that transmission of infection may involve low doses of virus. At low doses, the relation between dose and the probability of infection is approximately linear, so that the reduction in infection risk is proportional to the reduction in exposure due to particle retention of the mask. A population transmission model was set up to explore the impact of population‐wide mask use, allowing estimation of the effects of mask efficacy and coverage (fraction of the population wearing masks) on the basic reproduction number and the infection attack rate. We conclude that population‐wide use of face masks could make an important contribution in delaying an influenza pandemic. Mask use also reduces the reproduction number, possibly even to levels sufficient for containing an influenza outbreak.", "corpus_id": 43851274, "score": 0 }, { "doc_id": "214680715", "title": "Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19.", "abstract": "This JAMA Insights Clinical Update discusses the need to better understand the dynamics of respiratory disease transmission by better characterizing transmission routes, the role of patient physiology in shaping them, and best approaches for source control in the context of the COVID-19 outbreak", "corpus_id": 214680715, "score": 1 }, { "doc_id": "212752423", "title": "Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1", "abstract": "Aerosol and Surface Stability of SARS-CoV-2 In this research letter, investigators report on the stability of SARS-CoV-2 and SARS-CoV-1 under experimental conditions. The viability of the two virus...", "corpus_id": 212752423, "score": 0 }, { "doc_id": "212408365", "title": "Air, Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) From a Symptomatic Patient.", "abstract": "This study documents results of SARS-CoV-2 polymerase chain reaction (PCR) testing of environmental surfaces and personal protective equipment surrounding 3 COVID-19 patients in isolation rooms in a Singapore hospital.", "corpus_id": 212408365, "score": 0 }, { "doc_id": "51706385", "title": "Face Masks Reduce the Release of Pseudomonas aeruginosa Cough Aerosols When Worn for Clinically Relevant Periods", "abstract": "We recruited 25 people with CF and chronic P. aeruginosa infection (6) from the Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Brisbane, Australia. Ten healthy volunteers were recruited from hospital and research staff to assess mask comfort and mask weight change. All participants performed up to five randomly ordered tests in a validated cough system (7): uncovered cough, coughing with surgical mask worn for 10 minutes, coughing with surgical mask worn for 20 minutes, coughing with surgical mask worn for 40 minutes, and coughing with N95 mask worn for 20 minutes (3, 7). The N95 test was an optional test based on the poor comfort ratings observed in our earlier mask study (3).", "corpus_id": 51706385, "score": 0 }, { "doc_id": "15280548", "title": "Respiratory source control using a surgical mask: An in vitro study", "abstract": "ABSTRACT Cough etiquette and respiratory hygiene are forms of source control encouraged to prevent the spread of respiratory infection. The use of surgical masks as a means of source control has not been quantified in terms of reducing exposure to others. We designed an in vitro model using various facepieces to assess their contribution to exposure reduction when worn at the infectious source (Source) relative to facepieces worn for primary (Receiver) protection, and the factors that contribute to each. In a chamber with various airflows, radiolabeled aerosols were exhaled via a ventilated soft-face manikin head using tidal breathing and cough (Source). Another manikin, containing a filter, quantified recipient exposure (Receiver). The natural fit surgical mask, fitted (SecureFit) surgical mask and an N95-class filtering facepiece respirator (commonly known as an “N95 respirator”) with and without a Vaseline-seal were tested. With cough, source control (mask or respirator on Source) was statistically superior to mask or unsealed respirator protection on the Receiver (Receiver protection) in all environments. To equal source control during coughing, the N95 respirator must be Vaseline-sealed. During tidal breathing, source control was comparable or superior to mask or respirator protection on the Receiver. Source control via surgical masks may be an important adjunct defense against the spread of respiratory infections. The fit of the mask or respirator, in combination with the airflow patterns in a given setting, are significant contributors to source control efficacy. Future clinical trials should include a surgical mask source control arm to assess the contribution of source control in overall protection against airborne infection.", "corpus_id": 15280548, "score": 1 }, { "doc_id": "17898113", "title": "A cluster randomised trial of cloth masks compared with medical masks in healthcare workers", "abstract": "Editor's Note The authors of this article, published in 2015, have written a response to their work in light of the COVID-19 pandemic. We urge our readers to consider the response when reading the article. https://bmjopen.bmj.com/content/5/4/e006577.responses#covid-19-shortages-of-masks-and-the-use-of-cloth-masks-as-a-last-resort Objective The aim of this study was to compare the efficacy of cloth masks to medical masks in hospital healthcare workers (HCWs). The null hypothesis is that there is no difference between medical masks and cloth masks. Setting 14 secondary-level/tertiary-level hospitals in Hanoi, Vietnam. Participants 1607 hospital HCWs aged ≥18 years working full-time in selected high-risk wards. Intervention Hospital wards were randomised to: medical masks, cloth masks or a control group (usual practice, which included mask wearing). Participants used the mask on every shift for 4 consecutive weeks. Main outcome measure Clinical respiratory illness (CRI), influenza-like illness (ILI) and laboratory-confirmed respiratory virus infection. Results The rates of all infection outcomes were highest in the cloth mask arm, with the rate of ILI statistically significantly higher in the cloth mask arm (relative risk (RR)=13.00, 95% CI 1.69 to 100.07) compared with the medical mask arm. Cloth masks also had significantly higher rates of ILI compared with the control arm. An analysis by mask use showed ILI (RR=6.64, 95% CI 1.45 to 28.65) and laboratory-confirmed virus (RR=1.72, 95% CI 1.01 to 2.94) were significantly higher in the cloth masks group compared with the medical masks group. Penetration of cloth masks by particles was almost 97% and medical masks 44%. Conclusions This study is the first RCT of cloth masks, and the results caution against the use of cloth masks. This is an important finding to inform occupational health and safety. Moisture retention, reuse of cloth masks and poor filtration may result in increased risk of infection. Further research is needed to inform the widespread use of cloth masks globally. However, as a precautionary measure, cloth masks should not be recommended for HCWs, particularly in high-risk situations, and guidelines need to be updated. Trial registration number Australian New Zealand Clinical Trials Registry: ACTRN12610000887077.", "corpus_id": 17898113, "score": 0 }, { "doc_id": "210989295", "title": "Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study", "abstract": "\n Summary\n \n Background\n Since Dec 31, 2019, the Chinese city of Wuhan has reported an outbreak of atypical pneumonia caused by the 2019 novel coronavirus (2019-nCoV). Cases have been exported to other Chinese cities, as well as internationally, threatening to trigger a global outbreak. Here, we provide an estimate of the size of the epidemic in Wuhan on the basis of the number of cases exported from Wuhan to cities outside mainland China and forecast the extent of the domestic and global public health risks of epidemics, accounting for social and non-pharmaceutical prevention interventions.\n \n \n Methods\n We used data from Dec 31, 2019, to Jan 28, 2020, on the number of cases exported from Wuhan internationally (known days of symptom onset from Dec 25, 2019, to Jan 19, 2020) to infer the number of infections in Wuhan from Dec 1, 2019, to Jan 25, 2020. Cases exported domestically were then estimated. We forecasted the national and global spread of 2019-nCoV, accounting for the effect of the metropolitan-wide quarantine of Wuhan and surrounding cities, which began Jan 23–24, 2020. We used data on monthly flight bookings from the Official Aviation Guide and data on human mobility across more than 300 prefecture-level cities in mainland China from the Tencent database. Data on confirmed cases were obtained from the reports published by the Chinese Center for Disease Control and Prevention. Serial interval estimates were based on previous studies of severe acute respiratory syndrome coronavirus (SARS-CoV). A susceptible-exposed-infectious-recovered metapopulation model was used to simulate the epidemics across all major cities in China. The basic reproductive number was estimated using Markov Chain Monte Carlo methods and presented using the resulting posterior mean and 95% credibile interval (CrI).\n \n \n Findings\n In our baseline scenario, we estimated that the basic reproductive number for 2019-nCoV was 2·68 (95% CrI 2·47–2·86) and that 75 815 individuals (95% CrI 37 304–130 330) have been infected in Wuhan as of Jan 25, 2020. The epidemic doubling time was 6·4 days (95% CrI 5·8–7·1). We estimated that in the baseline scenario, Chongqing, Beijing, Shanghai, Guangzhou, and Shenzhen had imported 461 (95% CrI 227–805), 113 (57–193), 98 (49–168), 111 (56–191), and 80 (40–139) infections from Wuhan, respectively. If the transmissibility of 2019-nCoV were similar everywhere domestically and over time, we inferred that epidemics are already growing exponentially in multiple major cities of China with a lag time behind the Wuhan outbreak of about 1–2 weeks.\n \n \n Interpretation\n Given that 2019-nCoV is no longer contained within Wuhan, other major Chinese cities are probably sustaining localised outbreaks. Large cities overseas with close transport links to China could also become outbreak epicentres, unless substantial public health interventions at both the population and personal levels are implemented immediately. Independent self-sustaining outbreaks in major cities globally could become inevitable because of substantial exportation of presymptomatic cases and in the absence of large-scale public health interventions. Preparedness plans and mitigation interventions should be readied for quick deployment globally.\n \n \n Funding\n Health and Medical Research Fund (Hong Kong, China).\n \n", "corpus_id": 210989295, "score": 0 }, { "doc_id": "214728024", "title": "A Modified SIR Model for the COVID-19 Contagion in Italy", "abstract": "The purpose of this work is to give a contribution to the understanding of the COVID-19 contagion in Italy. To this end, we developed a modified Susceptible-Infected-Recovered (SIR) model for the contagion, and we used official data of the pandemic up to March 30th, 2020 for identifying the parameters of this model. The non standard part of our approach resides in the fact that we considered as model parameters also the initial number of susceptible individuals, as well as the proportionality factor relating the detected number of positives with the actual (and unknown) number of infected individuals. Identifying the contagion, recovery and death rates as well as the mentioned parameters amounts to a non-convex identification problem that we solved by means of a two-dimensional grid search in the outer loop, with a standard weighted least-squares optimization problem as the inner step.", "corpus_id": 214728024, "score": 0 }, { "doc_id": "214667952", "title": "A simple Stochastic SIR model for COVID 19 Infection Dynamics for Karnataka: Learning from Europe", "abstract": "In this short note we model the region-wise trends of the evolution to COVID-19 infections using a stochastic SIR model. The SIR dynamics are expressed using \\textit{Ito-stochastic differential equations}. We first derive the parameters of the model from the available daily data from European regions based on a 24-day history of infections, recoveries and deaths. The derived parameters have been aggregated to project future trends for the Indian subcontinent, which is currently at an early stage in the infection cycle. The projections are meant to serve as a guideline for strategizing the socio-political counter measures to mitigate COVID-19.", "corpus_id": 214667952, "score": 0 }, { "doc_id": "214774969", "title": "Inferring COVID-19 spreading rates and potential change points for case number forecasts", "abstract": "As COVID-19 is rapidly spreading across the globe, short-term modeling forecasts provide time-critical information for decisions on containment and mitigation strategies. A main challenge for short-term forecasts is the assessment of key epidemiological parameters and how they change as first governmental intervention measures are showing an effect. By combining an established epidemiological model with Bayesian inference, we analyze the time dependence of the effective growth rate of new infections. For the case of COVID-19 spreading in Germany, we detect change points in the effective growth rate which correlate well with the times of publicly announced interventions.Thereby, we can (a) quantify the effects of recent governmental measures to mitigating the disease spread, and (b) incorporate analogue change points to forecast future scenarios and case numbers.Our code is freely available and can be readily adapted to any country or region.", "corpus_id": 214774969, "score": 0 }, { "doc_id": "212781727", "title": "Statistics based predictions of coronavirus 2019-nCoV spreading in mainland China", "abstract": "Background. The epidemic outbreak cased by coronavirus 2019-nCoV is of great interest to researches because of the high rate of spread of the infection and the significant number of fatalities. A detailed scientific analysis of the phenomenon is yet to come, but the public is already interested in the questions of the duration of the epidemic, the expected number of patients and deaths. For long time predictions, the complicated mathematical models are necessary which need many efforts for unknown parameters identification and calculations. In this article, some preliminary estimates will be presented. Objective. Since the reliable long time data are available only for mainland China, we will try to predict the epidemic characteristics only in this area. We will estimate some of the epidemic characteristics and present the most reliable dependences for victim numbers, infected and removed persons versus time. Methods. In this study we use the known SIR model for the dynamics of an epidemic, the known exact solution of the linear equations and statistical approach developed before for investigation of the children disease, which occurred in Chernivtsi (Ukraine) in 1988-1989. Results. The optimal values of the SIR model parameters were identified with the use of statistical approach. The numbers of infected, susceptible and removed persons versus time were predicted. Conclusions. Simple mathematical model was used to predict the characteristics of the epidemic caused by coronavirus 2019-nCoV in mainland China. The further research should focus on updating the predictions with the use of fresh data and using more complicated mathematical models.", "corpus_id": 212781727, "score": 0 }, { "doc_id": "214728110", "title": "COVID-19 infection and recovery in various countries: Modeling the dynamics and evaluating the non-pharmaceutical mitigation scenarios.", "abstract": "The coronavirus disease 2019 (COVID-19) pandemic radically impacts our lives, while the transmission/infection and recovery dynamics of COVID-19 remain obscure. A time-dependent Susceptible, Exposed, Infectious, and Recovered (SEIR) model was proposed and applied to fit and then predict the time series of COVID-19 evolution observed in the last three months (till 3/22/2020) in various provinces and metropolises in China. The model results revealed the space dependent transmission/infection rate and the significant spatiotemporal variation in the recovery rate, likely due to the continuous improvement of screening techniques and public hospital systems, as well as full city lockdowns in China. The validated SEIR model was then applied to predict COVID-19 evolution in United States, Italy, Japan, and South Korea which have responded differently to monitoring and mitigating COVID-19 so far, although these predictions contain high uncertainty due to the intrinsic change of the maximum infected population and the infection/recovery rates within the different countries. In addition, a stochastic model based on the random walk particle tracking scheme, analogous to a mixing-limited bimolecular reaction model, was developed to evaluate non-pharmaceutical strategies to mitigate COVID-19 spread. Preliminary tests using the stochastic model showed that self-quarantine may not be as efficient as strict social distancing in slowing COVID-19 spread, if not all of the infected people can be promptly diagnosed and quarantined.", "corpus_id": 214728110, "score": 0 }, { "doc_id": "214743536", "title": "Controlling the Transmission Dynamics of COVID-19", "abstract": "The outbreak of COVID-19 caused by SARS-CoV-2 in Wuhan and other cities in China in 2019 has become a global pandemic as declared by World Health Organization (WHO) in the first quarter of 2020 . The delay in diagnosis, limited hospital resources and other treatment resources leads to rapid spread of COVID-19. In this article, we consider an optimal control COVID-19 transmission model and assess the impact of some control measures that can lead to the reduction of exposed and infectious individuals in the population. We investigate three control strategies for this deadly infectious disease using personal protection, treatment with early diagnosis, treatment with delay diagnosis and spraying of virus in the environment as time-dependent control functions in our dynamical model to curb the disease spread.", "corpus_id": 214743536, "score": 0 }, { "doc_id": "212725094", "title": "Covid-19 spread: Reproduction of data and prediction using a SIR model on Euclidean network.", "abstract": "We study the datafor the cumulative as well as daily number of cases in the Covid-19 outbreak in China. The cumulative data can be fit to an empirical form obtained from a Susceptible-Infected-Removed (SIR) model studied on an Euclidean network previously. Plotting the number of cases against the distance from the epicenter for both China and Italy, we find an approximate power law variation with an exponent $\\sim 1.85$ showing strongly that the spatial dependence plays a key role, a factor included in the model. We report here that the SIR model on the Eucledean network can reproduce with a high accuracy the data for China for given parameter values, and can also predict when the epidemic, at least locally, can be expected to be over.", "corpus_id": 212725094, "score": 0 }, { "doc_id": "214611746", "title": "Modelling transmission and control of the COVID-19 pandemic in Australia", "abstract": "There is a continuing debate on relative benefits of various mitigation and suppression strategies aimed to control the spread of COVID-19. Here we report the results of agent-based modelling using a fine-grained computational simulation of the ongoing COVID-19 pandemic in Australia. This model is calibrated to match key characteristics of COVID-19 transmission. An important calibration outcome is the age-dependent fraction of symptomatic cases, with this fraction for children found to be one-fifth of such fraction for adults. We apply the model to compare several intervention strategies, including restrictions on international air travel, case isolation, home quarantine, social distancing with varying levels of compliance, and school closures. School closures are not found to bring decisive benefits unless coupled with high level of social distancing compliance. We report several trade-offs, and an important transition across the levels of social distancing compliance, in the range between 70% and 80% levels, with compliance at the 90% level found to control the disease within 13–14 weeks, when coupled with effective case isolation and international travel restrictions.", "corpus_id": 214611746, "score": 0 }, { "doc_id": "214729892", "title": "Why is it difficult to accurately predict the COVID-19 epidemic?", "abstract": "\n Abstract\n \n Since the COVID-19 outbreak in Wuhan City in December of 2019, numerous model predictions on the COVID-19 epidemics in Wuhan and other parts of China have been reported. These model predictions have shown a wide range of variations. In our study, we demonstrate that nonidentifiability in model calibrations using the confirmed-case data is the main reason for such wide variations. Using the Akaike Information Criterion (AIC) for model selection, we show that an SIR model performs much better than an SEIR model in representing the information contained in the confirmed-case data. This indicates that predictions using more complex models may not be more reliable compared to using a simpler model. We present our model predictions for the COVID-19 epidemic in Wuhan after the lockdown and quarantine of the city on January 23, 2020. We also report our results of modeling the impacts of the strict quarantine measures undertaken in the city after February 7 on the time course of the epidemic, and modeling the potential of a second outbreak after the return-to-work in the city.\n \n", "corpus_id": 214729892, "score": 0 }, { "doc_id": "212656559", "title": "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study", "abstract": "\n Summary\n \n Background\n Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.\n \n \n Methods\n In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.\n \n \n Findings\n 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days.\n \n \n Interpretation\n The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.\n \n \n Funding\n Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.\n \n ", "corpus_id": 212656559, "score": 0 }, { "doc_id": "213095057", "title": "Novel coronavirus 2019-nCoV: early estimation of epidemiological parameters and epidemic predictions", "abstract": "Since first identified, the epidemic scale of the recently emerged novel coronavirus (2019-nCoV) in Wuhan, China, has increased rapidly, with cases arising across China and other countries and regions. using a transmission model, we estimate a basic reproductive number of 3.11 (95%CI, 2.39-4.13); 58-76% of transmissions must be prevented to stop increasing; Wuhan case ascertainment of 5.0% (3.6-7.4); 21022 (11090-33490) total infections in Wuhan 1 to 22 January.", "corpus_id": 213095057, "score": 0 } ]

{ "doc_id": "118975283", "title": "Chiral 2D “strange metals” from N=4$$ \\mathcal{N}=4 $$ SYM", "abstract": "A bstractFamiliar field theories may contain closed subsectors made out of only fermions, which can be used to explore new and unusual phases of matter in lower dimensions. We focus on the fermionic su(1, 1) sector in N=4$$ \\mathcal{N}=4 $$ SYM and on its ground states, which are Fermi surface states/operators. By computing their spectrum to order (gYM2N)2, we argue that fluctuations around this Fermi surface, within the sector and in the limit kF → ∞, are governed by a chiral 1+1 dimensional sector of the “strange metal” coset SU(N )N ⊗ SU(N )N /SU(N )2N . On the gravity side, the conjectured dual configuration is an S = 0 degeneration of a rotating black hole. On general grounds we expect that the near horizon excitations of (S = 0, Ω = 1, J → ∞) degenerations of black holes will be governed by a chiral sector of a 1+1 CFT.", "corpus_id": 118975283 }

[ { "doc_id": "126363487", "title": "The Large N limit of superconformal field theories and supergravity", "abstract": "We show that the large-N limits of certainconformal field theories in various dimensions includein their Hilbert space a sector describing supergravityon the product of anti-de Sitter spacetimes, spheres, and other compact manifolds. This is shown bytaking some branes in the full M/string theory and thentaking a low-energy limit where the field theory on thebrane decouples from the bulk. We observe that, in this limit, we can still trust thenear-horizon geometry for large N. The enhancedsupersymmetries of the near-horizon geometry correspondto the extra supersymmetry generators present in thesuperconformal group (as opposed to just the super-Poincaregroup). The 't Hooft limit of 3 + 1 N = 4 super-Yang–Mills at the conformal pointis shown to contain strings: they are IIB strings. Weconjecture that compactifications of M/string theory on various anti-de Sitterspacetimes is dual to various conformal field theories.This leads to a new proposal for a definition ofM-theory which could be extended to include fivenoncompact dimensions.", "corpus_id": 126363487, "score": 0 }, { "doc_id": "10882387", "title": "Anti-de Sitter space and holography", "abstract": "Recently, it has been proposed by Maldacena that large $N$ limits of certain conformal field theories in $d$ dimensions can be described in terms of supergravity (and string theory) on the product of $d+1$-dimensional $AdS$ space with a compact manifold. Here we elaborate on this idea and propose a precise correspondence between conformal field theory observables and those of supergravity: correlation functions in conformal field theory are given by the dependence of the supergravity action on the asymptotic behavior at infinity. In particular, dimensions of operators in conformal field theory are given by masses of particles in supergravity. As quantitative confirmation of this correspondence, we note that the Kaluza-Klein modes of Type IIB supergravity on $AdS_5\\times {\\bf S}^5$ match with the chiral operators of ${\\cal N}=4$ super Yang-Mills theory in four dimensions. With some further assumptions, one can deduce a Hamiltonian version of the correspondence and show that the ${\\cal N}=4$ theory has a large $N$ phase transition related to the thermodynamics of $AdS$ black holes.", "corpus_id": 10882387, "score": 0 }, { "doc_id": "3265656", "title": "Strange Metals in One Spatial Dimension", "abstract": "We consider 1+1 dimensional SU(N) gauge theory coupled to a multiplet of massive Dirac fermions transforming in the adjoint representation of the gauge group. The only global symmetry of this theory is a U(1) associated with the conserved Dirac fermion number, and we study the theory at variable, nonzero densities. The high density limit is characterized by a deconfined Fermi surface state with Fermi wave vector equal to that of free gauge-charged fermions. Its low energy fluctuations are described by a coset conformal field theory with central charge c=(N2-1)/3 and an emergent N=(2,2) supersymmetry: the U(1) fermion number symmetry becomes an R-symmetry. We determine the exact scaling dimensions of the operators associated with Friedel oscillations and pairing correlations. For N>2, we find that the symmetries allow relevant perturbations to this state. We discuss aspects of the N→∞ limit, and its possible dual description in AdS3 involving string theory or higher-spin gauge theory. We also discuss the low density limit of the theory by computing the low lying bound state spectrum of the large N gauge theory numerically at zero density, using discretized light cone quantization.", "corpus_id": 3265656, "score": 1 }, { "doc_id": "15583645", "title": "Weakly Renormalized Near 1/16 SUSY Fermi Liquid Operators in N = 4 SYM", "abstract": "We discuss a class of Fermi Liquid Operators in N = 4 SYM. We show that these operators are eigenstates of the full quantum dilatation operator. We compute their 1 and 2 loop anomalous dimensions, and show that, similar to Fermi liquids in condensed matter systems, these corrections are suppressed by an arbitrarily small parameter, which is the equivalent of one over the Fermi energy. These operators are, at the classical level, descendants of 1/16 BPS operators, with some scaling properties similar to those of the 1/16 Black Holes in AdS_5.", "corpus_id": 15583645, "score": 1 }, { "doc_id": "118641685", "title": "Degenerate rotating black holes, chiral CFTs and Fermi surfaces I — Analytic results for quasinormal modes", "abstract": "A bstractIn this work we discuss charged rotating black holes in AdS5 × S5 that degenerate to extremal black holes with zero entropy. These black holes have scaling properties between charge and angular momentum similar to those of Fermi surface operators in a subsector of $ \\mathcal{N} = 4 $ SYM. We add a massless uncharged scalar to the five dimensional supergravity theory, such that it still forms a consistent truncation of the type IIB ten dimensional supergravity and analyze its quasinormal modes. Separating the equation of motion to a radial and angular part, we proceed to solve the radial equation using a matched asymptotic expansion method applied to Heun’s equation with two nearby singularities. We use the continued fraction method for the angular Heun equation and obtain numerical results for the quasinormal modes. In the case of the near-supersymmetric black hole we present some analytic results for the decay rates of the scalar perturbations. The spectrum of quasinormal modes obtained is similar to that of a chiral 1 + 1 CFT, which is consistent with the conjectured field-theoretic dual. In addition, some of the modes can be found analytically.", "corpus_id": 118641685, "score": 1 }, { "doc_id": "11624487", "title": "New rotating non-extremal black holes in D=5 maximal gauged supergravity", "abstract": "Abstract We obtain new non-extremal rotating black hole solutions in maximal five-dimensional gauged supergravity. They are characterised by five parameters, associated with the mass, the two angular momenta, and two independently-specifiable charge parameters. Two of the three charges associated with the U ( 1 ) 3 Cartan subgroup of the SO ( 6 ) gauge group are equal, whilst the third can be independently specified. These new solutions generalise all the previously-known non-extremal rotating solutions in five-dimensional gauged supergravity with independent angular momenta. They describe regular black holes, provided the parameters lie in appropriate ranges so that naked singularities and closed-timelike curves (CTCs) are avoided. We also construct the BPS limit, and show that regular supersymmetric black holes or topological solitons arise if the parameters are further restricted in an appropriate manner.", "corpus_id": 11624487, "score": 1 }, { "doc_id": "125210680", "title": "Five-Dimensional Gauged Supergravity Black Holes with Independent Rotation Parameters", "abstract": "We construct new non-extremal rotating black hole solutions in SO(6) gauged fivedimensional supergravity. Our solutions are the first such examples in which the two rotation parameters are independently specifiable, rather than being set equal. The black holes carry charges for all three of the gauge fields in the U(1) 3 subgroup of SO(6), albeit with only one independent charge parameter. We discuss the BPS limits, showing in particular that these include the first examples of regular supersymmetric black holes with independent angular momenta in gauged supergravity. We also find non-singular BPS solitons. Finally, we obtain another independent class of new rotating non-extremal black hole solutions with just one non-vanishing rotation parameter, and one non-vanishing charge.", "corpus_id": 125210680, "score": 0 }, { "doc_id": "14628213", "title": "AdS dual of the critical O(N) vector model", "abstract": "Abstract We suggest a general relation between theories of infinite number of higher-spin massless gauge fields in AdS d +1 and large N conformal theories in d dimensions containing N -component vector fields. In particular, we propose that the singlet sector of the well-known critical 3-d O ( N ) model with the ( φ a φ a ) 2 interaction is dual, in the large N limit, to the minimal bosonic theory in AdS 4 containing massless gauge fields of even spin.", "corpus_id": 14628213, "score": 0 }, { "doc_id": "118959569", "title": "W symmetry in conformal field theory", "abstract": "Abstract We review various aspects of W algebra symmetry in two-dimensional conformal field theory and string theory. We pay particular attention to the construction of W algebras through the quantum Drinfeld-Sokolov reduction and through the coset construction.", "corpus_id": 118959569, "score": 0 }, { "doc_id": "15125974", "title": "An AdS_3 Dual for Minimal Model CFTs", "abstract": "We propose a duality between the 2d W{sub N} minimal models in the large N't Hooft limit, and a family of higher spin theories on AdS{sub 3}. The 2d conformal field theories (CFTs) can be described as Wess-Zumino-Witten coset models, and include, for N=2, the usual Virasoro unitary series. The dual bulk theory contains, in addition to the massless higher spin fields, two complex scalars (of equal mass). The mass is directly related to the 't Hooft coupling constant of the dual CFT. We give convincing evidence that the spectra of the two theories match precisely for all values of the 't Hooft coupling. We also show that the renormalization group flows in the 2d CFT agree exactly with the usual AdS/CFT prediction of the gravity theory. Our proposal is in many ways analogous to the Klebanov-Polyakov conjecture for an AdS{sub 4} dual for the singlet sector of large N vector models.", "corpus_id": 15125974, "score": 0 }, { "doc_id": "118634257", "title": "Minimal model holography", "abstract": "We review the duality relating 2D WN minimal model conformal field theories, in a large-N ’t Hooft like limit, to higher spin gravitational theories on AdS3. This article is part of a special issue of Journal of Physics A: Mathematical and Theoretical devoted to ‘Higher spin theories and holography’.", "corpus_id": 118634257, "score": 0 }, { "doc_id": "13949235", "title": "= 4 SYM to two loops: compact expressions for the non-compact symmetry algebra of the (1,1|2) sector", "abstract": "We begin a study of higher-loop corrections to the dilatation generator of = 4 SYM in non-compact sectors. In these sectors, the dilatation generator contains infinitely many interactions, and therefore one expects very complicated higher-loop corrections. Remarkably, we find a short and simple expression for the two-loop dilatation generator. Our solution for the non-compact (1,1|2) sector consists of nested commutators of four (g1) generators and one simple auxiliary generator. Moreover, the solution does not require the planar limit; we conjecture that it is valid for any gauge group. To obtain the two-loop dilatation generator, we find the complete (g3) symmetry algebra for this sector, which is also given by concise expressions. We check our solution using published results of direct field theory calculations. By applying the expression for the two-loop dilatation generator to compute selected anomalous dimensions and the bosonic (2) sector internal S-matrix, we confirm recent conjectures of the higher-loop Bethe ansatz of hep-th/0412188.", "corpus_id": 13949235, "score": 1 }, { "doc_id": "15838211", "title": "On symmetry enhancement in the (1, 1|2) sector of = 4 SYM", "abstract": "Strong evidence indicates that the spectrum of planar anomalous dimensions of = 4 super Yang-Mills theory is given asymptotically by Bethe equations. A curious observation is that the Bethe equations for the (1, 1|2) subsector lead to very large degeneracies of 2M multiplets, which apparently do not follow from conventional integrable structures. In this article, we explain such degeneracies by constructing suitable conserved nonlocal generators acting on the spin chain. We propose that they generate a subalgebra of the loop algebra for the (2) automorphism of (1, 1|2). Then the degenerate multiplets of size 2M transform in irreducible tensor products of M two-dimensional evaluation representations of the loop algebra.", "corpus_id": 15838211, "score": 1 }, { "doc_id": "118488341", "title": "Horizons, holography and condensed matter", "abstract": "The holographic correspondence creates an interface between classical gravitational physics and the dynamics of strongly interacting quantum field theories. This chapter will relate the physics of charged, asymptotically Anti-de Sitter spacetimes to the phenomenology of low temperature critical phases of condensed matter. Common essential features will characterise both the gravitational and field theoretic systems. Firstly, an emergent scaling symmetry at the lowest energy scales appears as an emergent isometry in the interior, `near horizon' regime of the spacetime. Secondly, the field theoretic distinction between fractionalized and mesonic phases appears as the presence or absence of a charge-carrying horizon in the spacetime. A perspective grounded in these two characteristics allows a unified presentation of `holographic superconductors', `electron stars' and `charged dilatonic spacetimes'.", "corpus_id": 118488341, "score": 0 }, { "doc_id": "233207", "title": "Holographic non-Fermi-liquid fixed points", "abstract": "Techniques arising from string theory can be used to study assemblies of strongly interacting fermions. Via this ‘holographic duality’, various strongly coupled many-body systems are solved using an auxiliary theory of gravity. Simple holographic realizations of finite density exhibit single-particle spectral functions with sharp Fermi surfaces, of a form distinct from those of the Landau theory. The self-energy is given by a correlation function in an infrared (IR) fixed-point theory that is represented by a two-dimensional anti de Sitter space (AdS2) region in the dual gravitational description. Here, we describe in detail the gravity calculation of this IR correlation function.", "corpus_id": 233207, "score": 0 }, { "doc_id": "55231045", "title": "Infinite Chiral Symmetry in Four Dimensions", "abstract": "We describe a new correspondence between four-dimensional conformal field theories with extended supersymmetry and two-dimensional chiral algebras. The meromorphic correlators of the chiral algebra compute correlators in a protected sector of the four-dimensional theory. Infinite chiral symmetry has far-reaching consequences for the spectral data, correlation functions, and central charges of any four-dimensional theory with $${\\mathcal{N}=2}$$N=2 superconformal symmetry.", "corpus_id": 55231045, "score": 0 }, { "doc_id": "118480845", "title": "EVH black holes, AdS3 throats and EVH/CFT proposal", "abstract": "Within class of generic black holes there are extremal black holes (with vanishing Hawking temperature T) and vanishing horizon area Ah, but with finite Ah/T ratio, the Extremal Vanishing Horizon (EVH) black holes. We study the near horizon limit of a four dimensional EVH black hole solution to a generic (gauged) Einstein-Maxwell dilaton theory and show that in the near horizon limit they develop a throat which is a pinching orbifold limit of AdS3. This is an extension of the well known result for extremal black holes the near horizon limit of which contains an AdS2 throat. We show that in the near EVH near horizon limit the pinching AdS3 factor turns to a pinching BTZ black hole and that this near horizon limit is indeed a decoupling limit. We argue that the pinching AdS3 or BTZ orbifold is resolved if the near horizon limit is accompanied by taking the 4d Newton constant G4 to zero such that the Bekenstein-Hawking entropy S = Ah/(4G4) remains finite. We propose that in this limit the near horizon EVH black hole is dual to a 2d CFT. We provide pieces of evidence in support of the EVH/CFT correspondence and comment on its connection to the Kerr/CFT proposal and speculation show the EVH/CFT maybe used to study generic e.g. Schwarzchild-type black holes.", "corpus_id": 118480845, "score": 0 }, { "doc_id": "15010088", "title": "Kerr/CFT Correspondence", "abstract": "Quantum gravity in the region very near the horizon of an extreme Kerr black hole (whose angular momentum and mass are related by J=GM{sup 2}) is considered. It is shown that consistent boundary conditions exist, for which the asymptotic symmetry generators form one copy of the Virasoro algebra with central charge c{sub L}=(12J/({Dirac_h}/2{pi})). This implies that the near-horizon quantum states can be identified with those of (a chiral half of) a two-dimensional conformal field theory (CFT). Moreover, in the extreme limit, the Frolov-Thorne vacuum state reduces to a thermal density matrix with dimensionless temperature T{sub L}=(1/2{pi}) and conjugate energy given by the zero mode generator, L{sub 0}, of the Virasoro algebra. Assuming unitarity, the Cardy formula then gives a microscopic entropy S{sub micro}=(2{pi}J/({Dirac_h}/2{pi})) for the CFT, which reproduces the macroscopic Bekenstein-Hawking entropy S{sub macro}=(Area/4({Dirac_h}/2{pi})G). The results apply to any consistent unitary quantum theory of gravity with a Kerr solution. We accordingly conjecture that extreme Kerr black holes are holographically dual to a chiral two-dimensional conformal field theory with central charge c{sub L}=(12J/({Dirac_h}/2{pi})), and, in particular, that the near-extreme black hole GRS 1915+105 is approximately dual to a CFT with c{sub L}{approx}2x10{sup 79}.", "corpus_id": 15010088, "score": 0 }, { "doc_id": "118600898", "title": "Hidden Conformal Symmetry of the Kerr Black Hole", "abstract": "Extreme and very-near-extreme spin $J$ Kerr black holes have been conjectured to be holographically dual to two-dimensional (2D) conformal field theories (CFTs) with left and right central charges ${c}_{L}={c}_{R}=12J$. In this paper it is observed that the 2D conformal symmetry of the scalar wave equation at low frequencies persists for generic nonextreme values of the mass $M\\ensuremath{\\ne}\\sqrt{J}$. Interestingly, this conformal symmetry is not derived from a conformal symmetry of the spacetime geometry except in the extreme limit. The $2\\ensuremath{\\pi}$ periodic identification of the azimuthal angle $\\ensuremath{\\phi}$ is shown to correspond to a spontaneous breaking of the conformal symmetry by left and right temperatures ${T}_{L}={M}^{2}/2\\ensuremath{\\pi}J$ and ${T}_{R}=\\sqrt{{M}^{4}\\ensuremath{-}{J}^{2}}/2\\ensuremath{\\pi}J$. The well-known low-frequency scalar-Kerr scattering amplitudes coincide with correlators of a 2D CFT at these temperatures. Moreover, the CFT microstate degeneracy inferred from the Cardy formula agrees exactly with the Bekenstein-Hawking area law for all $M$ and $J$. These observations provide evidence for the conjecture that the Kerr black hole is dual to a ${c}_{L}={c}_{R}=12J$ 2D CFT at temperatures (${T}_{L},{T}_{R}$) for every value of $M$ and $J$.", "corpus_id": 118600898, "score": 0 }, { "doc_id": "55669946", "title": "Emergent IR dual 2d CFTs in charged AdS5 black holes", "abstract": "We study the possible dynamical emergence of IR conformal invariance describing the low energy excitations of near-extremal R-charged global AdS5 black holes. We find interesting behavior especially when we tune parameters in such a way that the relevant extremal black holes have classically vanishing horizon area, i.e. no classical ground-state entropy, and when we combine the low energy limit with a large N limit of the dual gauge theory. We consider both near-BPS and non-BPS regimes and their near horizon limits, emphasize the differences between the local AdS3 throats emerging in either case, and discuss potential dual IR 2d CFTs for each case. We compare our results with the predictions obtained from the Kerr/CFT correspondence, and obtain a natural quantization for the central charge of the near-BPS emergent IR CFT which we interpret in terms of the open strings stretched between giant gravitons.", "corpus_id": 55669946, "score": 0 }, { "doc_id": "119279543", "title": "Near-extremal vanishing horizon AdS5 black holes and their CFT duals", "abstract": "A bstractWe consider families of charged rotating asymptotically AdS5 Extremal black holes with Vanishing Horizon (EVH black holes) whose near horizon geometries develop locally AdS3 throats. Using the AdS3/CFT2 duality, we propose an EVH/CFT2 correspondence to describe the near-horizon low energy IR dynamics of near-EVH black holes involving a specific large N limit of the 4d $ \\mathcal{N}=4 $ SYM. We give a map between the UV and IR near-EVH excitations, showing that the ‘UV first law’ of thermodynamics reduces to the ‘IR first law’ satisfied by the near horizon BTZ black holes in this near-EVH limit. We also discuss the connection between our EVH/CFT proposal and the Kerr/CFT correspondence in the cases where the two overlap.", "corpus_id": 119279543, "score": 0 }, { "doc_id": "9287169", "title": "Determinant Formulae and Unitarity for the N=2 Superconformal Algebras in Two-Dimensions or Exact Results on String Compactification", "abstract": "Determinant formulae are presented for the periodic, antiperiodic and twisted N = 2 superconformal algebras in two dimensions, and a classification is derived of the unitary highest weight representations. Physical realisations of several of these representations are discussed. In particular, it is noted that the unitarity constraints apply to string compactification, giving results which are nonperturbative in the compactification radius.", "corpus_id": 9287169, "score": 0 }, { "doc_id": "55379283", "title": "Chiral primaries in strange metals", "abstract": "Abstract It was suggested recently that the study of 1-dimensional QCD with fermions in the adjoint representation could lead to an interesting toy model for strange metals and their holographic formulation. In the high density regime, the infrared physics of this theory is described by a constrained free fermion theory with an emergent N = ( 2 , 2 ) superconformal symmetry. In order to narrow the choice of potential holographic duals, we initiate a systematic search for chiral primaries in this model. We argue that the bosonic part of the superconformal algebra can be extended to a coset chiral algebra of the form W N = SO ( 2 N 2 − 2 ) 1 / SU ( N ) 2 N . In terms of this algebra the spectrum of the low energy theory decomposes into a finite number of sectors which are parametrized by special necklaces. We compute the corresponding characters and partition functions and determine the set of chiral primaries for N ≤ 5 .", "corpus_id": 55379283, "score": 0 }, { "doc_id": "10140656", "title": "3d Higher-spin Gauge Theories with Matter †", "abstract": "This paper is a letter-type version of hep-th/9806236. We discuss properties of non-linear equations of motion which describe higher-spin gauge interactions for massive spin-0 and spin-1/2 matter fields in 2+1 dimensional anti-de Sitter space. The model is shown to have N = 2 supersymmetry and to describe higher-spin interactions of d3 N = 2 massive hypermultiplets. An integrating flow is found which reduces the full non-linear system to the free field equations via a non-local Bäcklund-Nicolai–type mapping.", "corpus_id": 10140656, "score": 0 }, { "doc_id": "118949332", "title": "The Dilatation Operator of N=4 Super Yang-Mills Theory and Integrability", "abstract": "Abstract In this work we review recent progress in four-dimensional conformal quantum field theories and scaling dimensions of local operators. Here we consider the example of maximally supersymmetric gauge theory and present techniques to derive, investigate and apply the dilatation operator which measures the scaling dimensions. We construct the dilatation operator by purely algebraic means: Relying on the symmetry algebra and structural properties of Feynman diagrams we are able to bypass involved, higher-loop field theory computations. In this way we obtain the complete one-loop dilatation operator and the planar, three-loop deformation in an interesting subsector. These results allow us to address the issue of integrability within a planar four-dimensional gauge theory: We prove that the complete dilatation generator is integrable at one loop and present the corresponding Bethe ansatz. We furthermore argue that integrability extends to three loops and beyond. Assuming that it holds indeed, we finally construct a novel spin chain model at five loops and propose a Bethe ansatz which might be valid at arbitrary loop order!", "corpus_id": 118949332, "score": 0 }, { "doc_id": "73652073", "title": "The continuous orbifold of N$$ \\mathcal{N} $$ = 2 minimal model holography", "abstract": "A bstractFor the N$$ \\mathcal{N} $$ = 2 Kazama-Suzuki models that appear in the duality with a higher spin theory on AdS3 it is shown that the large level limit can be interpreted as a continuous orbifold of 2N free bosons and fermions by the group U(N ). In particular, we show that the subset of coset representations that correspond to the perturbative higher spin degrees of freedom are precisely described by the untwisted sector of this U(N ) orbifold. We furthermore identify the twisted sector ground states of the orbifold with specific coset representations, and give various pieces of evidence in favour of this identification.", "corpus_id": 73652073, "score": 0 }, { "doc_id": "15902919", "title": "Iterative structure of the = 4 SYM spin chain", "abstract": "We develop algebraic methods for finding loop corrections to the = 4 SYM dilatation generator, within the noncompact (1, 1|2) sector. This sector gives a 't Hooft coupling λ-dependent representation of (1, 1|2) × (1|1)2. At first working independently of the representation, we present an all-order algebraic ansatz for the λ-dependence of this Lie algebra's generators. The ansatz solves the symmetry constraints if an auxiliary generator, , satisfies certain simple commutation relations with the Lie algebra generators. Applying this to the (1, 1|2) sector leads to an iterative solution for the planar three-loop dilatation generator in terms of leading order symmetry generators and , which passes a thorough set of spectral tests. We argue also that this algebraic ansatz may be applicable to the nonplanar theory as well.", "corpus_id": 15902919, "score": 1 } ]

{ "doc_id": "37587320", "title": "Performance of FDG PET/CT in the clinical management of breast cancer.", "abstract": "In this analysis, the role of metabolic imaging with fluorine 18 fluorodeoxyglucose (FDG) in breast cancer is reviewed. The analysis was limited to recent works by using state-of-the-art positron emission tomography (PET)/computed tomography (CT) technology. The strengths and limitations of FDG PET/CT are examined in various clinical settings, and the following questions are answered: Is FDG PET/CT useful to differentiate malignant from benign breast lesions? Can FDG PET/CT replace sentinel node biopsy for axillary staging? What is the role of FDG PET/CT in initial staging of inflammatory or locally advanced breast cancer? What is the role of FDG PET/CT in initial staging of clinical stage IIA and IIB and primary operable stage IIIA breast cancer? How does FDG PET/CT compare with conventional techniques in the restaging of cancer in patients who are suspected of having disease recurrence? What is the role of FDG PET/CT in the assessment of early response to neoadjuvant therapy and of response to therapy for metastatic disease? Some recommendations for clinical practice are given.", "corpus_id": 37587320 }

[ { "doc_id": "2516461", "title": "SUV varies with time after injection in (18)F-FDG PET of breast cancer: characterization and method to adjust for time differences.", "abstract": "UNLABELLED\nThe purpose of this study was to measure how (18)F-FDG PET standardized uptake values (SUVs) change over time in breast cancer and to examine the feasibility of a method to adjust for modest variations in the time of uptake measurement experienced in clinical practice.\n\n\nMETHODS\n(18)F-FDG PET was performed as 60-min dynamic imaging with an additional image acquired at approximately 75 min after injection. For 20 newly diagnosed, untreated, locally advanced breast cancer patients, both the maximum SUV and the average SUV within the lesion were calculated with and without correction for blood glucose concentration. A linear regression analysis of the portion of the time-activity curves starting at 27 min after injection was used to estimate the rate of SUV change per minute during the interval from 27 to 75 min. The rate of SUV change with time was compared with the instantaneous SUV obtained at different times from 27 to 75 min.\n\n\nRESULTS\nIn untreated breast cancer, (18)F-FDG SUV values changed approximately linearly after 27 min at a rate ranging from -0.02 to 0.15 per minute. In addition, the rate of SUV change was linearly correlated with the instantaneous SUV measured at different times after injection (r(2) ranged from 0.82 to 0.94; P < 0.001). Using this information, an empirical linear model of SUV variation with time from injection to uptake measurement was formulated. The comparison method was then applied prospectively to a second set of 20 locally advanced breast cancer lesions not included in the initial analysis. The average percent error using the method to adjust for time differences was 8% and 5% for maximum SUVs and average SUVs ranging from 2 to 12.\n\n\nCONCLUSION\nIn untreated breast cancer, the SUV at any time point approximately predicts the rate of change of SUV over time. A comparison method based on this finding appears feasible and may improve the usefulness of the SUV by providing a means of comparing SUV acquired at different times after injection.", "corpus_id": 2516461, "score": 0 }, { "doc_id": "35281644", "title": "Time Course of Tumor SUV in 18F-FDG PET of Breast Cancer: Presentation of a Simple Model Using a Single Reference Point for Time Corrections of Tumor SUVs", "abstract": "Tumor standardized uptake values (SUVs) vary with the interval between 18F-FDG injection and image acquisition. This paper presents a simple method using a single reference point to make appropriate time corrections for tumor SUVs. Methods: The reference point method was algebraically deduced from observations made by Beaulieu et al., who found that tumor SUVs behaved linearly over time (∼30 to 75 min after 18F-FDG injection). Eighteen patients with breast cancer were dynamically examined with PET/CT (∼60 and 80 min after 18F-FDG injection). Maximum SUV was calculated by applying 2 different iterative reconstruction methods (high-definition reconstruction and attenuation-weighted ordered-subsets expectation maximization). Reference points for time corrections were given, and errors for corrections obtained with the reference point method were calculated. Results: Variations in the reconstruction algorithm strongly influenced the coordinates of the reference point. Time corrections using the reference point method were more accurate at higher tumor SUVs (>8 at high-definition reconstruction and >6 at attenuation-weighted ordered-subsets expectation maximization) than at lower ones. Conclusion: A common origin of tumor SUVs over time exists in breast cancer. In combination with the linear behavior of tumor SUVs between approximately 30 and 80 min, such a reference point allows for straightforward time corrections of tumor SUVs. Parameters for image reconstruction must be considered because they influence the coordinates of the reference point.", "corpus_id": 35281644, "score": 0 }, { "doc_id": "26210582", "title": "Dual-Modality Imaging: Combining Anatomy and Function*", "abstract": "The extensive development of image fusion techniques over the past 20 y has shown that the fusion of images from complementary modalities offers a more complete and accurate assessment of disease than do images from a single modality. Although software techniques have been successful in fusing images of the brain from different modalities, they have achieved rather limited success for other parts of the body. The recent introduction of technology that can acquire both anatomic and functional images in a single scan has addressed many of the limitations of software fusion. The combination of CT and PET was introduced commercially in 2001, followed by CT and SPECT in 2004. Clinical adoption of PET/CT has been surprisingly rapid, and despite continuing debate, the new technology has advanced the use of clinical molecular imaging, particularly for oncology.", "corpus_id": 26210582, "score": 0 }, { "doc_id": "21460606", "title": "PET/CT: form and function.", "abstract": "Functional imaging with positron emission tomography (PET) is playing an increasingly important role in the diagnosis and staging of malignant disease, image-guided therapy planning, and treatment monitoring. PET with the labeled glucose analogue fluorine 18 fluorodeoxyglucose (FDG) is a relatively recent addition to the medical technology for imaging of cancer, and FDG PET complements the more conventional anatomic imaging modalities of computed tomography (CT) and magnetic resonance imaging. CT is complementary in the sense that it provides accurate localization of organs and lesions, while PET maps both normal and abnormal tissue function. When combined, the two modalities can help both identify and localize functional abnormalities. Attempts to align CT and PET data sets with fusion software are generally successful in the brain; other areas of the body is more challenging, owing to the increased number of degrees of freedom between the two data sets. These challenges have recently been addressed by the introduction of the combined PET/CT scanner, a hardware-oriented approach to image fusion. With such a device, accurately registered anatomic and functional images can be acquired for each patient in a single scanning session. Currently, over 800 combined PET/CT scanners are installed in medical institutions worldwide, many of them for the diagnosis and staging of malignant disease and increasingly for monitoring of the response to therapy. This review will describe some of the most recent technologic developments in PET/CT instrumentation and the clinical indications for which combined PET/CT has been shown to be more useful than PET and CT performed separately.", "corpus_id": 21460606, "score": 0 }, { "doc_id": "40156836", "title": "The evolving role of PET/CT in breast cancer", "abstract": "Departments of Nuclear Medicine, Medical Oncology, Breast Diseases Unit, Saint-Louis Hospital, EAD Imagerie Moléculaire Diagnostique et Ciblage Thérapeutique, IUH, University of Paris VII, Paris, France, Department of Nuclear Medicine, Santa Maria della Misericordia, Rovigo Hospital, Rovigo, Italy and Department of Nuclear Medicine, Imperial College Healthcare, Hammersmith Hospital, London, UK Correspondence to Domenico Rubello, MD, Department of Nuclear Medicine, PET/CT Centre, Medical Physics, Radiology, Santa Maria della Misericordia Hospital, Rovigo, Italy Tel: + 39 320 7985599; fax: + 39 42 5394434; e-mail: domenico.rubello@libero.it", "corpus_id": 40156836, "score": 0 }, { "doc_id": "38779637", "title": "The Effects of Estrogen, Progesterone, and C-erbB-2 Receptor States on 18F-FDG Uptake of Primary Breast Cancer Lesions", "abstract": "The purpose of this prospective study was to investigate whether correlations exist between 18F-FDG uptake of primary breast cancer lesions and predictive and prognostic factors such as estrogen receptor (ER), progesterone receptor (PR), and C-erbB-2 receptor (C-erbB-2R) states. Methods: Before undergoing partial or total mastectomy, 213 patients with newly diagnosed breast cancer underwent 18F-FDG PET (5.2 MBq/kg of body weight). The maximum standardized uptake value (SUV) of the primary lesion was measured in each patient. Standard immunohistochemistry was performed on a surgical specimen of the cancer lesion to characterize the receptor state of the tumor cells. Pearson χ2 tests were performed on the cross-tables of different receptor states to test any association that may exist among ER, PR, and C-erbB-2R. Maximum SUV measurements for different receptor states were compared using factorial ANOVA in a completely random design. Results: After exclusion of certain lesions, 118 lesions were analyzed for this study. The mean maximum SUVs of ER-positive and ER-negative lesions were 3.03 ± 0.26 and 5.64 ± 0.75, whereas those of PR were 3.24 ± 0.29 and 4.89 ± 0.67, respectively, and those of C-erbB-2R were 4.64 ± 0.70 and 3.70 ± 0.35, respectively. χ2 tests for ER and PR showed that if one is positive then the other tends to be positive as well (χ2 = 71.054, P < 0.01). For ER and C-erbB-2R states, if ER is positive, C-erbB-2R will more likely be negative (χ2 = 13.026, P < 0.01). No relationship was detected between PR and C-erbB-2R states (χ2 = 3.695, P > 0.05). ANOVAs showed that PR state alone (F = 0.095, P > 0.05) and C-erbB-2R state alone (F = 0.097, P > 0.05) had no effect on 18F-FDG uptake but ER state alone had an effect (F = 9.126, P < 0.01). ER and PR being together had no additional effect on 18F-FDG uptake. Our study also demonstrated that interactions exist between ER and C-erbB-2R state and between PR and C-erbB-2R state. Conclusion: SUV measurements may provide valuable information about the state of ER, PR, and C-erbB-2R and the associated glucose metabolism as measured by 18F-FDG uptake of the primary breast cancer lesions. Such an association may be of importance to treatment planning and outcome in these patients.", "corpus_id": 38779637, "score": 1 }, { "doc_id": "27959850", "title": "Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography.", "abstract": "PURPOSE\nVariable uptake of the glucose analog (18)fluorodeoxyglucose (FDG) has been noticed in positron emission tomography (PET) studies of breast cancer patients, with low uptake occurring especially in lobular cancer. At present, no satisfactory biologic explanation exists for this phenomenon. This study compared (18)FDG uptake in vivo with biomarkers expected to be involved in the underlying biologic mechanisms.\n\n\nPATIENTS AND METHODS\nPreoperative (18)FDG-PET scans were performed in 55 patients. (18)FDG activity was assessed visually by three observers using a four-point score. Tumor sections were stained by immunohistochemistry for glucose transporter-1 (Glut-1); Hexokinase (HK) I, II, and III; macrophages; hypoxia-inducible factor-1-alfa (HIF-1alpha); vascular endothelial growth factor (VEGF(165)); and microvessels. Mitotic activity index (MAI), amount of necrosis, number of lymphocytes, and tumor cells/volume were assessed.\n\n\nRESULTS\nThere were positive correlations between (18)FDG uptake and Glut-1 expression (P <.001), MAI (P =.001), amount of necrosis (P =.010), number of tumor cells/volume (P =.009), expression of HK I (P =.019), number of lymphocytes (P =.032), and microvessel density (r =.373; P =.005). HIF-1alpha, VEGF(165), HK II, HK III, and macrophages showed no univariate correlation with (18)FDG. In logistic regression, however, HIF-1alpha and HK II added value to MAI and Glut-1.\n\n\nCONCLUSION\n(18)FDG uptake in breast cancer is a function of microvasculature for delivering nutrients, Glut-1 for transportation of (18)FDG into the cell, HK for entering (18)FDG into glycolysis, number of tumor cells/volume, proliferation rate (also reflected in necrosis), number of lymphocytes (not macrophages), and HIF-1alpha for upregulating Glut-1. Together, these features explain why breast cancers vary in (18)FDG uptake and elucidate the low uptake in lobular breast cancer.", "corpus_id": 27959850, "score": 0 }, { "doc_id": "32131345", "title": "Overexpression of glut‐1 glucose transporter in human breast cancer an immunohistochemical study", "abstract": "Background. Breast cancers have higher than normal glucose metabolism, but the mechanism of glucose entry into these tumors is not well understood.", "corpus_id": 32131345, "score": 0 }, { "doc_id": "45240998", "title": "Breast imaging with positron emission tomography and fluorine-18 fluorodeoxyglucose: use and limitations.", "abstract": "PURPOSE\nTo evaluate the diagnostic value of positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) for the diagnosis of primary breast cancer.\n\n\nPATIENTS AND METHODS\nPreoperatively, 144 patients with masses suggestive of breast cancer underwent PET imaging of the breast. To identify breast cancer by increased metabolic activity, parametric FDG-PET images were analyzed for increased tracer uptake applying conventional image reading (CIR) and sensitive image reading (SIR). One hundred eighty-five breast tumors were evaluated by histology, revealing 132 breast carcinomas and 53 benign masses.\n\n\nRESULTS\nBreast carcinomas were identified with an overall sensitivity of 64.4% (CIR) and 80.3% (SIR). The increase in sensitivity (SIR) resulted in a noticeable decrease in specificity, from 94.3% (CIR) to 75.5% (SIR). At stage pT1, only 30 (68.2%) of 44 breast carcinomas were detected, compared with 57 (91.9%) of 62 at stage pT2. A higher percentage of invasive lobular carcinomas were false-negative (65.2%) compared with invasive ductal carcinomas (23.7%). Nevertheless, positive PET scans provided a high positive-predictive value (96.6%) for breast cancer.\n\n\nCONCLUSION\nPartial volume effects and varying metabolic activity (dependent on tumor type) seem to represent the most significant limitations for the routine diagnostic application of PET. The number of invasive procedures is therefore unlikely to be significantly reduced by PET imaging in patients presenting with abnormal mammography. However, the high positive-predictive value, resulting from the increased metabolic activity of malignant tissue, may be used with carefully selected subsets of patients as well as to determine the extent of disease or to assess therapy response.", "corpus_id": 45240998, "score": 0 }, { "doc_id": "26164444", "title": "Clinicopathologic factors associated with false negative FDG–PET in primary breast cancer", "abstract": "Summary The present study was aimed to determine the clinicopathologic factors that predict false negative (FN) PET results in these patients.MethodsA total of 116 breast lesions in 111 patients (pre-menopausal 45; perimenopausal 15; post-menopausal 51) with known or suspicious of breast cancer who underwent FDG–PET scans for staging, were included in this study. The median age was 52±11 years (range 32–79 years). All PET studies results were correlated with follow-up surgical pathology results. A cut off value of 2.5 was considered for positive or negative PET results. Univariate and multivariate analyses were performed to identify factors associated with FN results.ResultsOf 116 breast lesions, 85 were malignant and 31 were benign on histopathology. Of the 85 malignant lesions, 41 were true positive (TP) and 44 were FN. Among the 31 benign lesions, 30 were true negative and one was false positive. There was significant difference in the tumor size (p=0.003) and tumor grade (p=0.001) in patients with TP and FN PET results. Multivariate logistic regression demonstrated that tumor size (≤10 mm) and low tumor grade were independently associated with FN results. No significant relationship of FN PET results was found with age, menopausal status, tumor type, c-erbB-2, estrogen and progesterone receptors, sentinel lymph node or distant metastasis, parenchymal density and multifocality of primary breast tumor.ConclusionIn present study, tumor size and tumor grade are independent factors that predict FDG–PET results. Smaller tumors (≤10 mm) and low-grade tumors are strong predictor of FN FDG–PET results.", "corpus_id": 26164444, "score": 1 }, { "doc_id": "29802068", "title": "[PET/CT in breast cancer: an update].", "abstract": "The authors discuss the various roles of 18F-FDG PET/CT in the management of breast cancer. Roles of new tracers such as F-18 fluoro-L-thymidine (a marker of cell proliferation), 18-fluoro-17-B-estradiol (marker of estrogen receptor) and sodium fluoride (marker of bone matrix) are also mentioned. There is little justification for the use of FDG-PET/CT in patient with clinically T1 (< or = 2 cm) N0 tumours. Notably, it cannot be used as a substitute to SLNB \"sentinel lymph node biopsy\" for axillary staging due to limited sensitivity for the detection of small metastases. The case is different in higher risk patients, and especially so in patients with locally advanced disease. FDG-PET/CT in these patients might depict lymph node involvement in the level III of Berg or in supraclavicular or internal mammary basins. It might also uncover occult distant metastases, notably, early osteomedullary infiltration. Thus, for these tumors, initial PET/CT can enable better intramodality treatment planning or a change in treatment. PET/CT as a whole-body examination is also very efficient in case of suspicion of recurrence. On the other hand, many studies show that this functional imaging could be used to assess early response to neoadjuvant chemotherapy or to chemotherapy of metastatic disease. 18FDG-PET/CT could thus become an unavoidable modality to answer various clinical situations.", "corpus_id": 29802068, "score": 0 }, { "doc_id": "26096148", "title": "18F‐fluorodeoxyglucose positron emission tomography/computed tomography (FDG‐PET/CT) imaging in the staging and prognosis of inflammatory breast cancer", "abstract": "To prospectively assess fluorodeoxyglucose positron emission tomography/computed tomography (FDG‐PET/CT) staging and prognosis value in patients with suspected inflammatory breast cancer (IBC).", "corpus_id": 26096148, "score": 1 }, { "doc_id": "205510148", "title": "Association between [18F]fluorodeoxyglucose uptake and prognostic parameters in breast cancer", "abstract": "This study analysed the correlation between [18F]fluorodeoxyglucose (FDG) uptake assessed by positron emission tomography (PET) in breast tumours, and histopathological and inmunohistochemical prognostic factors.", "corpus_id": 205510148, "score": 1 }, { "doc_id": "210817", "title": "Association between [18F]fluorodeoxyglucose uptake and postoperative histopathology, hormone receptor status, thymidine labelling index and p53 in primary breast cancer: a preliminary observation", "abstract": "Abstract. To investigate the possible role of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) in the prognostic evaluation of primary breast cancer, we studied 86 patients with T1–3 (TNM classification) breast tumours before surgery and compared the tumour FDG uptake, calculated as a standardized uptake value (SUV), with postoperative histopathological findings, steroid hormone receptor status of the tumour, thymidine labelling index (LI) and tissular expression of p53. SUV was significantly higher in infiltrating ductal carcinomas (n = 68; median SUV = 5.6) than in lobular ones (n = 18; median SUV = 3.8), and in grade 3 carcinomas (n = 26; median SUV = 6.2) than in grade 1–2 ones (n = 60; median SUV = 4.9). Moreover, SUV was significantly higher in carcinomas with high levels of p53 (n = 12; median SUV = 9.5) than in those with low levels (n = 48; median SUV = 4.25). By contrast, there was no significant correlation between SUV and the steroid hormone receptor status or LI of tumours. Our data demonstrate that FDG uptake, expressed as SUV, is associated with certain prognostic factors in breast cancer, such as histopathological grading and p53 expression, which can be assessed only by means of postoperative in vitro examinations. Hence, the information provided by FDG-PET is to some extent related to relevant information on tumour biology. The clinical value of these data will have to be confirmed by analysis of the independence of SUV from other prognostic factors by means of a multivariate analysis performed on a larger series of patients with adequate follow-up. If SUV is confirmed as an independent variable, FDG-PET could assume an important role in the determination of appropriate therapeutic strategies for primary breast cancer.", "corpus_id": 210817, "score": 0 }, { "doc_id": "26058004", "title": "Standardized Uptake Values for Breast Carcinomas Assessed by Fluorodeoxyglucose-Positron Emission Tomography Correlate with Prognostic Factors", "abstract": "Several studies have revealed the diagnostic value of fluorodeoxyglucose-positron emission tomography for breast carcinomas. However, breast carcinomas display considerable variation in 18F-labeled 2-fluoro-2-deoxy-D-glucose uptake, and few papers have reported the clinical utility of the standardized uptake values (SUV). The purpose of this study is to investigate the relationship between SUV assessed by positron emission tomography (PET) and the clinicopathological characteristics of breast carcinoma. We reviewed 52 breast carcinomas of 45 patients presented at our department between January 2004 and July 2005. We compared the histopathological findings of the breast carcinomas with the preoperative SUV. Of the 52 breast carcinomas, 49 (94%) were detected by preoperative PET. A positive correlation was found between the SUV and tumor size (P < 0.01), histological grade (P < 0.01), the expression of the estrogen receptor (P < 0.001), progesterone receptor (P < 0.01), and p53 (P < 0.01). The number of metastatic axillary lymph nodes (r = 0.73; P < 0.0001) and the MIB-1 labeling rates (r = 0.5; P < 0.01) correlated with the SUV of the breast carcinomas. No relationship existed between the SUV and the following: histological tumor types (P = 0.07), human epidermal growth factor receptor-2 status (P = 0.10), and the presence of metastatic lymph nodes (P = 0.10). The SUV of the breast carcinomas correlate with several histopathological and immunohistochemical prognostic factors. We can obtain information on the degree of malignancy of the carcinoma and prognostic factors by preoperative PET examination.", "corpus_id": 26058004, "score": 1 }, { "doc_id": "24100936", "title": "FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters", "abstract": "Abstract. The aim of this study was to evaluate the possible correlation between preoperative FDG-PET results in human breast cancer and the prognostic markers Ki-67, c-erb B2, p53, oestrogen/progesterone receptor status, axillary lymph node status, tumour size and tumour grading. Seventy-five female patients with breast cancer were included in this prospective study. Patient selection was independent of tumour size and the suspected clinical stage of disease. A high-resolution full-ring scanner (Siemens ECAT HR+) was used for PET imaging. The FDG uptake of breast tumours was calculated as the tumour to background ratio (TBR). In resected cancer tissue specimens, the proliferative fraction was evaluated by Ki-67 immunostaining. Additionally, immunostaining of the prognostic markers c-erb B2, p53, and progesterone and oestrogen receptors was performed. Haematoxylin and eosin-stained sections were used for tumour grading. Correlations between FDG uptake and prognostic markers were assumed to be significant at P<0.05 using the Mann-Whitney U test. In ductal breast cancer, mean TBR was 17.3 (median 7.7, range 1.6–122.7), while in lobular cancer it was 6.5 (median 3.7, range 1.4–22.7). Mean proliferative fraction (% Ki-67 positive tumour cells) was 15%±13.8% (median 10%, range 0%–60%). Twenty-three carcinomas showed <5% Ki-67 positive tumour cells. Statistical analysis indicated a positive correlation between FDG uptake and proliferative index in ductal breast cancer (P<0.0001, r=0.63). By contrast, there was no correlation between FDG uptake and c-erb B2 (P=0.79), p53 (P=0.92), tumour grading (P=0.09), oestrogen receptor status (P=0.41), progesterone receptor status (P=0.34), axillary lymph node status (P=0.90) and tumour size (P=0.3). It is concluded that FDG uptake is significantly higher in ductal breast cancer than in lobular cancer (P<0.05). FDG uptake correlates with proliferative activity assessed by Ki-67 immunostaining (P<0.05). A significant correlation with the other prognostic markers, however, could not be demonstrated.", "corpus_id": 24100936, "score": 1 }, { "doc_id": "11457148", "title": "Correlation of high 18F-FDG uptake to clinical, pathological and biological prognostic factors in breast cancer", "abstract": "PurposeThe aim of this study was to determine the impact of the main clinicopathological and biological prognostic factors of breast cancer on 18F-fluorodeoxyglucose (FDG) uptake. Only women with tumours larger than 20 mm (T2–T4) were included in order to minimize bias of partial volume effect.MethodsIn this prospective study, 132 consecutive women received FDG PET/CT imaging before starting neoadjuvant chemotherapy. Maximum standardized uptake values (SUVmax) were compared to tumour characteristics as assessed on core biopsy.ResultsThere was no influence of T and N stage on SUV. Invasive ductal carcinoma showed higher SUV than lobular carcinoma. However, the highest uptake was found for metaplastic tumours, representing 5% of patients in this series. Several biological features usually considered as bad prognostic factors were associated with an increase in FDG uptake: the median of SUVmax was 9.7 for grade 3 tumours vs 4.8 for the lower grades (p < 0.0001); negativity for oestrogen receptors (ER) was associated with higher SUV (ER+ SUV = 5.5; ER− SUV = 7.6; p = 0.003); triple-negative tumours (oestrogen and progesterone receptor negative, no overexpression of c-erbB-2) had an SUV of 9.2 vs 5.8 for all others (p = 0005); p53 mutated tumours also had significantly higher SUV (7.8 vs 5.0; p < 0.0001). Overexpression of c-erbB-2 had no effect on the SUV value.ConclusionKnowledge of the factors influencing uptake is important when interpreting FDG PET/CT scans. Also, findings that FDG uptake is highest in those patients with poor prognostic features (high grade, hormone receptor negativity, triple negativity, metaplastic tumours) is helpful to determine who are the best candidates for baseline staging.", "corpus_id": 11457148, "score": 0 }, { "doc_id": "9861846", "title": "Glucose metabolism of breast cancer assessed by 18F-FDG PET: histologic and immunohistochemical tissue analysis.", "abstract": "UNLABELLED\nBreast cancer is characterized by elevated glucose consumption resulting in increased uptake of 18F-FDG. However, tracer uptake varies considerably among tumors imaged with PET. This study compared histologic and immunohistochemical tissue analysis of breast carcinomas with preoperative FDG uptake assessed by PET to identify tumor characteristics that define the degree of tracer accumulation.\n\n\nMETHODS\nFDG uptake in breast tumors was quantified by calculating standardized uptake values (SUVs) corrected for partial-volume effect and normalized to blood glucose level at the time of tracer injection. The histologic sections of 50 invasive and 6 noninvasive breast carcinomas were analyzed for histologic type, microscopic tumor growth pattern, percentage of tumor cells, presence of inflammatory cells, density of blood vessels, histopathologic grading, tumor cell proliferation (mitotic rate and antibody binding of MIB-1), expression of estrogen and progesterone receptors, and expression of the glucose transporter protein Glut-1.\n\n\nRESULTS\nA positive correlation was found between FDG uptake and histologic tumor type (ductal vs. lobular; P = 0.003), microscopic tumor growth pattern (nodular vs. diffuse; P = 0.007), and tumor cell proliferation (MIB-1; P = 0.009). Tumors with diffuse growth patterns had significantly lower SUVs compared with clearly defined tumors. A weak relationship was found between FDG uptake and the percentage of tumor cells (P = 0.06). Lower densities of blood vessels corresponded to higher FDG uptakes (P = 0.08). However, even significant correlations showed poor correlation coefficients. No relationship was found between FDG uptake and the following: tumor size; axillary lymph node status; percentage of necrotic, fibrotic, and cystic compounds; presence of inflammatory cells; steroid receptor status; and expression of Glut-1.\n\n\nCONCLUSION\nHistologic and immunohistochemical tissue analysis was unable to sufficiently explain the variation of FDG uptake in breast cancer. The degree of metabolic changes after malignant transformation is most likely explained by a complex interaction between cellular energy demand and tumoral microenvironment. Therefore, FDG PET imaging may not be used to estimate tumor biologic behavior of breast cancer such as differentiation, histopathologic grading, cell proliferation, or axillary lymph node status.", "corpus_id": 9861846, "score": 0 }, { "doc_id": "5365559", "title": "Utility of 18F-fluoro-deoxyglucose emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in combination with ultrasonography for axillary staging in primary breast cancer", "abstract": "BackgroundAccurate evaluation of axillary lymph node (ALN) involvement is mandatory before treatment of primary breast cancer. The aim of this study is to compare preoperative diagnostic accuracy between positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG PET/CT) and axillary ultrasonography (AUS) for detecting ALN metastasis in patients having operable breast cancer, and to assess the clinical management of axillary 18F-FDG PET/CT for therapeutic indication of sentinel node biopsy (SNB) and preoperative systemic chemotherapy (PSC).MethodsOne hundred eighty-three patients with primary operable breast cancer were recruited. All patients underwent 18F-FDG PET/CT and AUS followed by SNB and/or ALN dissection (ALND). Using 18F-FDG PET/CT, we studied both a visual assessment of 18F-FDG uptake and standardized uptake value (SUV) for axillary staging.ResultsIn a visual assessment of 18F-FDG PET/CT, the diagnostic accuracy of ALN metastasis was 83% with 58% in sensitivity and 95% in specificity, and when cut-off point of SUV was set at 1.8, sensitivity, specificity, and accuracy were 36, 100, and 79%, respectively. On the other hand, the diagnostic accuracy of AUS was 85% with 54% in sensitivity and 99% in specificity. By the combination of 18F-FDG PET/CT and AUS to the axilla, the sensitivity, specificity, and accuracy were 64, 94, and 85%, respectively. If either 18F-FDG PET uptake or AUS was positive in allixa, the probability of axillary metastasis was high; 50% (6 of 12) in 18F-FDG PET uptake only, 80% (4 of 5) in AUS positive only, and 100% (28 of 28) in dual positive. By the combination of AUS and 18F-FDG PET/CT, candidates of SNB were more appropriately selected. The axillary 18F-FDG uptake was correlated with the maximum size and nuclear grade of metastatic foci (p = 0.006 and p = 0.03).ConclusionThe diagnostic accuracy of 18F-FDG PET/CT was shown to be nearly equal to ultrasound, and considering their limited sensitivities, the high radiation exposure by 18F-FDG PET/CT and also costs of the examination, it is likely that AUS will be more cost-effective in detecting massive axillary tumor burden. However, when we cannot judge the axillary staging using AUS alone, metabolic approach of 18F-FDG PET/CT for axillary staging would enable us a much more confident diagnosis.", "corpus_id": 5365559, "score": 0 }, { "doc_id": "20186767", "title": "Biological characterisation of breast cancer by means of PET", "abstract": "Breast cancer is associated with increased glucose consumption and can therefore be visualised with the glucose analogue [18F]2-deoxy-2-fluoro-d-glucose (FDG) and positron emission tomography (PET). FDG uptake in the primary tumour can vary substantially, and specific tumour characteristics have been demonstrated to determine the degree of glucose metabolism. Factors with a major influence on FDG uptake in breast cancer comprise expression of glucose transporter Glut-1 and hexokinase I, number of viable tumour cells per volume, histological subtype, tumour grading, microvessel density and proliferative activity. Recently, an association between high FDG uptake and a worse prognosis was suggested. Several studies have been performed correlating FDG uptake with a variety of prognostic and molecular biomarkers as well as parameters predicting tumour response to therapy. However, a correlation with important clinical prognostic markers such as axillary lymph node status and size of the primary tumour, expression of oestrogen and progesterone receptors, proto-oncogene c-erbB-2 or VEGF could not be demonstrated. The lack of correlation with important markers of prognosis does not suggest that FDG uptake might be used as a prognostic criterion in breast cancer. Innovative radiotracers for specific imaging of tumoural perfusion ([15O]H2O), hormone receptor expression ([18F]FES), protein synthesis ([11C]methionine), proliferation rate ([18F]FLT) or bone mineralisation ([18F]fluoride) may provide additional information compared with that provided by FDG PET.", "corpus_id": 20186767, "score": 0 }, { "doc_id": "207406238", "title": "18F-FDG PET of Locally Invasive Breast Cancer and Association of Estrogen Receptor Status with Standardized Uptake Value: Microarray and Immunohistochemical Analysis", "abstract": "PET imaging is useful for evaluating locally advanced primary breast cancer. Expression of specific molecular markers in these cancers, such as estrogen receptor (ER), progesterone receptor (PR), and HER2 status, has direct prognostic and therapeutic implications in patient management. This study aimed to determine whether a relationship exists between tumor glucose use and important molecular markers in invasive breast cancer. For our purposes, tumor glucose use is quantified by the PET-derived parameter maximum standardized uptake value (SUV). Methods: Breast tumors from 36 patients were excised and examined histologically after PET. ER, PR, and HER2 status were determined for all lesions histopathologically. In addition, genomewide expression for a subset of 20 tumors was analyzed using the human genome U133A oligonucleotide microarray. Results: A significant association was found between estrogen ER status and lesion SUV. ER-negative tumors (n = 17; median SUV, 8.5) demonstrated a significantly higher maximum SUV than did ER-positive tumors (n = 19; median SUV, 4.0) (P < 0.001). No significant association existed between SUV and PR status, HER2/neu status, lymph node involvement, or tumor size. Unsupervised hierarchic clustering of the 20 genetically profiled cancers segregated tumor samples into 2 primary groups of 10 patients each, largely corresponding to ER status. Conclusion: In locally invasive primary breast cancer, ER-negative tumors display higher 18F-FDG uptake than ER-positive tumors. Microarray analysis confirms these data and identifies genes associated with increased glucose use as measured by PET. These genes significantly overlap those of a previously validated ER-status molecular phenotype. These preliminary data support a growing body of evidence that ER-positive and ER-negative breast cancers have distinct disease-specific patterns. Further validation prospectively and with larger numbers will be required to establish a robust molecular signature for metabolic uptake and patterns of aggressive behavior in advanced breast cancer.", "corpus_id": 207406238, "score": 0 }, { "doc_id": "1224803", "title": "FDG PET/CT and diffusion-weighted imaging for breast cancer: prognostic value of maximum standardized uptake values and apparent diffusion coefficient values of the primary lesion", "abstract": "PurposeTo correlate both primary lesion 18F-fluorodeoxyglucose (FDG) maximum standardized uptake value (SUVmax) and diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) with clinicopathological prognostic factors and compare the prognostic value of these indexes in breast cancer.MethodsThe study population consisted of 44 patients with 44 breast cancers visible on both preoperative FDG PET/CT and DWI images. The breast cancers included 9 ductal carcinoma in situ (DCIS) and 35 invasive ductal carcinomas (IDC). The relationships between both SUVmax and ADC and clinicopathological prognostic factors were evaluated by univariate and multivariate regression analysis and the degree of correlation was determined by Spearman’s rank test. The patients were divided into a better prognosis group (n = 24) and a worse prognosis group (n = 20) based upon invasiveness (DCIS or IDC) and upon their prognostic group (good, moderate or poor) determined from the modified Nottingham prognostic index. Their prognostic values were examined by receiver operating characteristic analysis.ResultsBoth SUVmax and ADC were significantly associated (p<0.05) with histological grade (independently), nodal status and vascular invasion. Significant associations were also noted between SUVmax and tumour size (independently), oestrogen receptor status and human epidermal growth factor receptor-2 status, and between ADC and invasiveness. SUVmax and ADC were negatively correlated (ρ=−0.486, p = 0.001) and positively and negatively associated with increasing of histological grade, respectively. The threshold values for predicting a worse prognosis were ≥4.2 for SUVmax (with a sensitivity, specificity and accuracy of 80%, 75% and 77%, respectively) and ≤0.98 for ADC (with a sensitivity, specificity and accuracy of 90%, 67% and 77%, respectively).ConclusionSUVmax and ADC correlated with several of pathological prognostic factors and both indexes may have the same potential for predicting the prognosis of breast cancer.", "corpus_id": 1224803, "score": 0 }, { "doc_id": "12518602", "title": "Clinicopathological and prognostic relevance of uptake level using 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in primary breast cancer.", "abstract": "OBJECTIVE\nUsing integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT), the clinical significance of 18F-FDG uptake was evaluated in patients with primary breast cancer.\n\n\nMETHODS\nClinicopathological correlation with the level of maximum standardized uptake values (SUV) 60 min obtained from preoperative 18F-FDG PET/CT were examined in 152 patients with primary breast cancer. The prognostic impact of the level of SUV was explored using simulated prognosis derived from computed program Adjuvant! in 136 (89%) patients with invasive ductal carcinoma (IDC).\n\n\nRESULTS\nHigh SUV level was significantly correlated with tumor invasive size (< or = 2 cm) (P < 0.0001), higher score of nuclear grade (P < 0.0001), nuclear atypia (P < 0.0001) and mitosis counts (P < 0.0001), negative hormone receptor status (P = 0.001), high score of c-erbB-2 expression (P = 0.006), lymph node metastasis (P = 0.002), and IDC in comparison with invasive lobular carcinoma (P = 0.004). Multivariate analyses showed tumor invasive size, nuclear grade and estrogen receptor negativity were significantly correlated with SUV in primary breast cancer (P < 0.0001,< 0.0001, and < 0.012, respectively), and nuclear grade was significantly correlated with SUV in tumors of invasive size 2 cm or less (P < 0.0001). Tumors with high SUV (cutoff value 4.0) showed higher relapse and mortality rate compared to those with low SUV (P < 0.0001).\n\n\nCONCLUSIONS\nHigh uptake of 18F-FDG would be predictive of poor prognosis in patients with primary breast cancer, and aggressive features of cancer cells in patients with early breast cancer. 18F-FDG PET/CT could be a useful tool to pre-therapeutically predict biological characteristics and baseline risk of breast cancer.", "corpus_id": 12518602, "score": 0 }, { "doc_id": "22245107", "title": "Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis.", "abstract": "PURPOSE\nSentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) are used to assess axillary nodal status in breast cancer, but are invasive procedures associated with morbidity, including lymphoedema. This systematic review evaluates the diagnostic accuracy of positron emission tomography (PET), with or without computed tomography (CT), for assessment of axillary nodes in early breast cancer.\n\n\nMETHODS\nEleven databases including MEDLINE, EMBASE and the Cochrane Library, plus research registers and conference proceedings, were searched in April 2009. Study quality was assessed using the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. Sensitivity and specificity were meta-analysed using a bivariate random effects approach.\n\n\nRESULTS\nAcross 26 studies evaluating PET or PET/CT (n = 2591 patients), mean sensitivity was 63% (95% CI: 52-74%; range 20-100%) and mean specificity 94% (95% CI: 91-96%; range 75-100%). Across 7 studies of PET/CT (n = 862), mean sensitivity was 56% (95% CI: 44-67%) and mean specificity 96% (90-99%). Across 19 studies of PET-only (n = 1729), mean sensitivity was 66% (50-79%) and mean specificity 93% (89-96%). Mean sensitivity was 11% (5-22%) for micrometastases (≤2 mm; five studies; n = 63), and 57% (47-66%) for macrometastases (>2 mm; four studies; n = 111).\n\n\nCONCLUSIONS\nPET had lower sensitivity and specificity than SLNB. Therefore, replacing SLNB with PET would avoid the adverse effects of SLNB, but lead to more false negative patients at risk of recurrence and more false positive patients undergoing unnecessary ALND. The present evidence does not support the routine use of PET or PET-CT for the assessment of the clinically negative axilla.", "corpus_id": 22245107, "score": 0 }, { "doc_id": "12328417", "title": "Positron emission tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary lymph node metastases in early breast cancer: systematic review and economic evaluation.", "abstract": "BACKGROUND\nBreast cancer is the most common type of cancer in women. Evaluation of axillary lymph node metastases is important for breast cancer staging and treatment planning.\n\n\nOBJECTIVES\nTo evaluate the diagnostic accuracy, cost-effectiveness and effect on patient outcomes of positron emission tomography (PET), with or without computed tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of axillary lymph node metastases in patients with newly diagnosed early-stage breast cancer.\n\n\nDATA SOURCES\nA systematic review of literature and an economic evaluation were carried out. Key databases (including MEDLINE, EMBASE and nine others) plus research registers and conference proceedings were searched for relevant studies up to April 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK.\n\n\nREVIEW METHODS\nOne reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies were resolved by discussion. Quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist, applied by one reviewer and checked by a second.\n\n\nRESULTS\nForty-five citations relating to 35 studies were included in the clinical effectiveness review: 26 studies of PET and nine studies of MRI. Two studies were included in the cost-effectiveness review: one of PET and one of MRI. Of the seven studies evaluating PET/CT (n = 862), the mean sensitivity was 56% [95% confidence interval (CI) 44% to 67%] and mean specificity 96% (95% CI 90% to 99%). Of the 19 studies evaluating PET only (n = 1729), the mean sensitivity was 66% (95% CI 50% to 79%) and mean specificity 93% (95% CI 89% to 96%). PET performed less well for small metastases; the mean sensitivity was 11% (95% CI 5% to 22%) for micrometastases (≤ 2 mm; five studies; n = 63), and 57% (95% CI 47% to 66%) for macrometastases (> 2 mm; four studies; n = 111). The smallest metastatic nodes detected by PET measured 3 mm, while PET failed to detect some nodes measuring > 15 mm. Studies in which all patients were clinically node negative showed a trend towards lower sensitivity of PET compared with studies with a mixed population. Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), the mean sensitivity was 98% (95% CI 61% to 100%) and mean specificity 96% (95% CI 72% to 100%). Across three studies of gadolinium-enhanced MRI (n = 187), the mean sensitivity was 88% (95% CI 78% to 94%) and mean specificity 73% (95% CI 63% to 81%). In the single study of in vivo proton magnetic resonance spectroscopy (n = 27), the sensitivity was 65% (95% CI 38% to 86%) and specificity 100% (95% CI 69% to 100%). USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity than gadolinium-enhanced MRI. Results of the decision modelling suggest that the MRI replacement strategy is the most cost-effective strategy and dominates the baseline 4-node sampling (4-NS) and sentinel lymph node biopsy (SLNB) strategies in most sensitivity analyses undertaken. The PET replacement strategy is not as robust as the MRI replacement strategy, as its cost-effectiveness is significantly affected by the utility decrement for lymphoedema and the probability of relapse for false-negative (FN) patients.\n\n\nLIMITATIONS\nNo included studies directly compared PET and MRI.\n\n\nCONCLUSIONS\nStudies demonstrated that PET and MRI have lower sensitivity and specificity than SLNB and 4-NS but are associated with fewer adverse events. Included studies indicated a significantly higher mean sensitivity for MRI than for PET, with USPIO-enhanced MRI providing the highest sensitivity. However, sensitivity and specificity of PET and MRI varied widely between studies, and MRI studies were relatively small and varied in their methods; therefore, results should be interpreted with caution. Decision modelling based on these results suggests that the most cost-effective strategy may be MRI rather than SLNB or 4-NS. This strategy reduces costs and increases quality-adjusted life-years (QALYs) because there are fewer adverse events for the majority of patients. However, this strategy leads to more FN cases at higher risk of cancer recurrence and more false- positive (FP) cases who would undergo unnecessary axillary lymph node dissection. Adding MRI prior to SLNB or 4-NS has little effect on QALYs, though this analysis is limited by lack of available data. Future research should include large, well-conducted studies of MRI, particularly using USPIO; data on the long-term impacts of lymphoedema on cost and patient utility; studies of the comparative effectiveness and cost-effectiveness of SLNB and 4-NS; and more robust UK cost data for 4-NS and SLNB as well as the cost of MRI and PET techniques.\n\n\nFUNDING\nThis study was funded by the Health Technology Assessment programme of the National Institute of Health Research.", "corpus_id": 12328417, "score": 0 }, { "doc_id": "196415717", "title": "A comparative study on the value of FDG-PET and sentinel node biopsy to identify occult axillary", "abstract": "metastases. Patients and Methods: In all, 236 patients with breast cancer and clinically negative axilla were enrolled in the study. 18-FDG-PET was carried out before surgery, using a positron emission tomography (PET)/computed tomography scanner. In all patients, SNB was carried out after identification through lymphoscintigraphy. Patients underwent axillary lymph nodes dissection (ALND) in cases of positive FDG-PET or positive SNB. The results of PET scan were compared with histopathology of SNB and ALND. Results: In all, 103 out of the 236 patients (44%) had metastases in axillary nodes. Sensitivity of FDG-PET scan for detection of axillary lymph node metastases in this series was low (37%); however, specificity and positive predictive values were acceptable (96% and 88%, respectively). Conclusions: The high specificity of PET imaging indicates that patients who have a PET-positive axilla should have an ALND rather than an SNB for axillary staging. In contrast, FDG-PET showed poor sensitivity in the detection of axillary metastases, confirming the need for SNB in cases where PET is negative in the axilla.", "corpus_id": 196415717, "score": 1 }, { "doc_id": "8340505", "title": "Diagnostic value of full-dose FDG PET/CT for axillary lymph node staging in breast cancer patients", "abstract": "PurposeThe aims of this study were (1) to evaluate FDG PET/CT and CT for the detection of axillary lymph node metastases in breast cancer (BC) patients and (2) to evaluate FDG PET/CT as a pre-test for the triage to sentinel lymph node biopsy (SLNB) versus axillary lymph node dissection (ALND).MethodsThe sensitivity, specificity, positive and negative predictive value (PPV, NPV), and accuracy of FDG PET/CT and CT for axillary lymph node metastases were determined in 61 patients (gold standard: histopathology). According to the equation “NPV = specificity ∙ (1-prevalence) / [specificity ∙ (1-prevalence) + (1-sensitivity) ∙ prevalence]” FDG PET/CT was evaluated as a triage tool for SLNB versus ALND.ResultsThe sensitivity, specificity, PPV, NPV and accuracy of FDG PET/CT was 58, 92, 82, 77 and 79% and of CT 46, 89, 72, 71 and 72%, respectively. Patients with an up to ~60% risk for axillary lymph node metastases appear to be candidates for SLNB provided that the axilla is unremarkable on FDG PET/CT.ConclusionFDG PET/CT cannot replace invasive approaches for axillary staging but may extend the indication for SLNB.", "corpus_id": 8340505, "score": 0 }, { "doc_id": "23624878", "title": "The Sentinel Node Procedure in Breast Cancer: Nuclear Medicine as the Starting Point", "abstract": "Axillary node status is a major prognostic factor in early breast cancer. Staging with sentinel node biopsy (SNB) leads to a substantial reduction in surgical morbidity. Recent multiinstitutional studies revealed SNB false-negative rates ranging from 5.5% to 16.7%, higher than the target (<5%) set by the 2005 guidelines of the American Society of Clinical Oncology. These alarming data point to the necessity of optimization. Dual mapping with radiotracer and blue dye, combining 2 different injection sites, and routinely using lymphoscintigraphy may improve accuracy. Factors associated with decreased sensitivity, such as prior excisional biopsy or neoadjuvant chemotherapy, should be recognized. The use of SNB in situations with a high prevalence of node positivity (large tumor, multifocality) is controversial. The risk of missed disease after negative SNB ranges from 1% to 4% in patients with T1 tumor and up to 15% in patients with T3. With peritumoral injection, internal mammary drainage is seen in about 20% of cases. Patients combining internal mammary drainage with a positive axillary sentinel node have close to a 50% probability of internal mammary involvement. Lymphoscintigraphy might thus be helpful in selecting patients for whom internal mammary radiation has a high benefit-to-risk ratio.", "corpus_id": 23624878, "score": 0 }, { "doc_id": "31834991", "title": "Prospective multicenter study of axillary nodal staging by positron emission tomography in breast cancer: a report of the staging breast cancer with PET Study Group.", "abstract": "PURPOSE\nTo determine the accuracy of positron emission tomography with fluorine-18-labeled 2-fluoro-2-deoxy-d-glucose (FDG-PET) in detecting axillary nodal metastases in women with primary breast cancer.\n\n\nPATIENTS AND METHODS\nIn this prospective multicenter study, 360 women with newly diagnosed invasive breast cancer underwent FDG-PET. Images were blindly interpreted by three experienced readers for abnormally increased axillary FDG uptake. Imaging results from 308 assessable axillae were compared with axillary node pathology.\n\n\nRESULTS\nFor detecting axillary nodal metastasis, the mean estimated area under the receiver operator curve for the three readers was 0.74 (range, 0.70 to 0.76). If at least one probably or definitely abnormal axillary focus was considered positive, the mean (and range) sensitivity, specificity, and positive and negative predictive values for PET were 61% (54% to 67%), 80% (79% to 81%), 62% (60% to 64%), and 79% (76% to 81%), respectively. False-negative axillae on PET had significantly smaller and fewer tumor-positive lymph nodes (2.7) than true-positive axillae (5.1; P <.005). Semiquantitative analysis of axillary FDG uptake showed that a nodal standardized uptake value (lean body mass) more than 1.8 had a positive predictive value of 90%, but a sensitivity of only 32%. Finding two or more intense foci of tracer uptake in the axilla was highly predictive of axillary metastasis (78% to 83% positive predictive value), albeit insensitive (27%).\n\n\nCONCLUSION\nFDG-PET has moderate accuracy for detecting axillary metastasis but often fails to detect axillae with small and few nodal metastases. Although highly predictive for nodal tumor involvement when multiple intense foci of tracer uptake are identified, FDG-PET is not routinely recommended for axillary staging of patients with newly diagnosed breast cancer.", "corpus_id": 31834991, "score": 0 }, { "doc_id": "8646391", "title": "Breast Cancer Staging in a Single Session: Whole-Body PET/CT Mammography", "abstract": "Our objective was to compare the diagnostic accuracy of an all-in-one protocol of whole-body 18F-FDG PET/CT and integrated 18F-FDG PET/CT mammography with the diagnostic accuracy of a multimodality algorithm for initial breast cancer staging. Methods: Forty women (mean age, 58.3 y; range, 30.8–78.4 y; SD, 12 y) with suspected breast cancer were included. For the primary tumor, we compared 18F-FDG PET/CT mammography versus MRI mammography; for axillary lymph node status, 18F-FDG PET/CT versus clinical investigation and ultrasound; and for distant metastases, 18F-FDG PET/CT versus a multimodality staging algorithm. Histopathology and clinical follow-up served as the standard of reference. The Fisher exact test evaluated the significance of differences (P < 0.05). Alterations in patient management caused by 18F-FDG PET/CT were documented. Results: No significant differences were found in the detection rate of breast cancer lesions (18F-FDG PET/CT, 95%; MRI, 100%; P = 1). 18F-FDG PET/CT correctly classified lesion focality significantly more often than did MRI (18F-FDG PET/CT, 79%; MRI, 73%; P < 0.001). MRI correctly defined the T stage significantly more often than did 18F-FDG PET/CT (MRI, 77%; 18F-FDG PET/CT, 54%; P = 0.001). 18F-FDG PET/CT detected axillary lymph node metastases in 80% of cases; clinical investigation/ultrasound, in 70%. This difference was not statistically significant (P = 0.067). Distant metastases were detected with 18F-FDG PET/CT in 100% of cases, and the multimodality algorithm identified distant metastases in 70%. This difference was not statistically significant (P = 1). Three patients had extraaxillary lymph node metastases that were detected only by PET/CT (cervical, retroperitoneal, mediastinal/internal mammary group). 18F-FDG PET/CT changed patient management in 12.5% of cases. Conclusion: Our data suggest that a whole-body 18F-FDG PET/CT mammography protocol may be used for staging breast cancer in a single session. This initial assessment of the 18F-FDG PET/CT protocol indicates similar accuracy to MRI for the detection of breast cancer lesions. Although MRI seems to be more accurate when assessing the T stage of the tumor, 18F-FDG PET/CT seems able to more accurately define lesion focality. Although 18F-FDG PET/CT mammography was able to detect axillary lymph node metastases with a high sensitivity, this method cannot soon be expected to replace the combination of clinical examination, ultrasound, and sentinel lymph node biopsy for axillary assessment.", "corpus_id": 8646391, "score": 0 }, { "doc_id": "24794535", "title": "Unexpected foci of 18F-FDG uptake in the breast detected by PET/CT: incidence and clinical significance", "abstract": "PurposeThe aim of this study was to evaluate the frequency and clinical significance of unexpected focal 18F-fluorodeoxyglucose (FDG) uptake localized by PET/CT within the breast.MethodsThe files of 4,038 consecutive female cancer patients referred for FDG PET/CT over a period of 74 months were retrospectively reviewed. Patients with breast cancer were excluded from the study. The incidence of focal sites of increased FDG uptake localized by PET/CT to the breast was determined. The intensity of uptake was measured using the lean body mass maximum standard uptake value (LBM SUVmax), and the presence and patterns of morphologic changes on CT were assessed. The etiology and clinical significance of findings were confirmed histologically or with imaging and clinical follow-up.ResultsUnexpected FDG foci in the breast were identified in 33 of 4,038 patients (0.82%). Follow-up data were available for 30 patients. Malignancy was diagnosed in 17 patients (histology 12, clinical 5) and excluded in 13 patients (histology 9, clinical 4). There was a borderline statistically significant difference in FDG uptake (LBM SUVmax) between malignant (3.13 ± 2.25) and benign (1.85 ± 1.18) lesions (p = 0.05). Focal lesions were seen on CT in 23 patients (malignant 11, benign 12), and CT was negative in 7 patients (malignant 6, benign 1).ConclusionAlthough rare, incidental focal abnormal FDG uptake in the breast may represent malignant lesions in up to 57% of patients. Breast incidentalomas on PET/CT warrant further assessment including tissue sampling to define the etiology of these unexpected FDG-avid foci.", "corpus_id": 24794535, "score": 0 }, { "doc_id": "31323894", "title": "AJCC Cancer Staging Manual", "abstract": "General Information on Cancer Staging and End-Results Reporting.- Purposes and Principles of Cancer Staging.- Cancer Survival Analysis.- Head and Neck.- Lip and Oral Cavity.- Pharynx.- Larynx.- Nasal Cavity and Paranasal Sinuses.- Major Salivary Glands.- Thyroid.- Mucosal Melanoma of the Head and Neck.- Digestive System.- Esophagus and Esophagogastric Junction.- Stomach.- Small Intestine.- Colon and Rectum.- Anus.- Gastrointestinal Stromal Tumor.- Neuroendocrine Tumors.- Liver.- Intrahepatic Bile Ducts.- Gallbladder.- Perihilar Bile Ducts.- Distal Bile Duct.- Ampulla of Vater.- Exocrine and Endocrine Pancreas.- Thorax.- Lung.- Pleural Mesothelioma.- Musculoskeletal Sites.- Bone.- Soft Tissue Sarcoma.- Skin.- Cutaneous Squamous Cell Carcinoma and Other Cutaneous Carcinomas.- Merkel Cell Carcinoma.- Melanoma of the Skin.- Breast.- Breast.- Gynecologic Sites.- Vulva.- Vagina.- Cervix Uteri.- Corpus Uteri.- Ovary and Primary Peritoneal Carcinoma.- Fallopian Tube.- Gestational Trophoblastic Tumors.- Genitourinary Sites.- Penis.- Prostate.- Testis.- Kidney.- Renal Pelvis and Ureter.- Urinary Bladder.- Urethra.- Adrenal.- Ophthalmic Sites.- Carcinoma of the Eyelid.- Carcinoma of the Conjunctiva.- Malignant Melanoma of the Conjunctiva.- Malignant Melanoma of the Uvea.- Retinoblastoma.- Carcinoma of the Lacrimal Gland.- Sarcoma of the Orbit.- Ocular Adnexal Lymphoma.- Central Nervous System.- Brain and Spinal Cord.- Lymphoid Neoplasms.- Lymphoid Neoplasms.", "corpus_id": 31323894, "score": 0 }, { "doc_id": "1004233", "title": "Retrospective Study of 18F-FDG PET/CT in the Diagnosis of Inflammatory Breast Cancer: Preliminary Data", "abstract": "Our objective was to retrospectively evaluate 18F-FDG PET/CT in the initial staging of inflammatory breast cancer (IBC). Methods: The institutional review board waived informed consent and approved this study, which was compliant with the Health Insurance Portability and Accountability Act. The cases of 41 women with a mean age of 50 y (range, 25–71 y) and newly diagnosed IBC who underwent 18F-FDG PET/CT at diagnosis were retrospectively reviewed. All PET/CT images were analyzed visually and semiquantitatively by 2 physicians. The maximum standardized uptake value in the primary breast, regional nodes (axillary, subpectoral, supraclavicular, internal mammary), and extranodal regions was documented. The accuracy of PET/CT image interpretation was assessed by histopathologic analysis, if available; concurrent or subsequent imaging findings (contrast-enhanced CT, contrast-enhanced MRI, sonography, or PET/CT follow-up); or clinical follow-up. Results: All patients presented with unilateral IBC. PET/CT showed hypermetabolic uptake in the skin in all patients, in the affected breast in 40 (98%), in the ipsilateral axillary nodes in 37 (90%), and in the ipsilateral subpectoral nodes in 18 (44%). Twenty patients (49%) were found to have distant metastases at staging, 7 (17%) of whom were not known to have metastases before undergoing PET/CT. Disease sites included bone, liver, contralateral axilla, lung, chest wall, pelvis, and the subpectoral, supraclavicular, internal mammary, mediastinal, and abdominal nodes. Conclusion: PET/CT should be considered in the initial staging of IBC, as the technique provided valuable information on locoregional and distant disease in this preliminary retrospective study.", "corpus_id": 1004233, "score": 0 }, { "doc_id": "11542753", "title": "Inflammatory breast cancer: PET/CT, MRI, mammography, and sonography findings", "abstract": "PurposeTo describe the role of Positron Emission Tomography/Computed Tomography (PET/CT), Magnetic Resonance Imaging (MRI), sonography, and mammography in patients with inflammatory breast cancer (IBC).Materials and methodsPatients who had been newly diagnosed with IBC and who had undergone mammography, sonography, MRI, PET/CT, or a combination of these were included in this study. The visibility of breast parenchymal lesion (BPLs), skin abnormalities, regional (axillary, supraclavicular, or internal mammary) nodal disease, and distant metastatic disease was documented with the imaging techniques.ResultsEighty patients (median age, 51 years, [range, 25–78 years]) were included in this study: 75 (94%) had undergone mammography, 76 (95%) sonography, 33 (41%) MRI, and 24 (30%) PET/CT. A primary BPL was found in 60 patients (80%) on mammography (mass or calcifications), 72 (95%) on sonography (mass or architectural distortion), 23 (96%) on PET/CT (hypermetabolic BPL), and 33 (100%) on MRI (enhancing BPL). Regional axillary nodal disease was found in 74 patients (93%) by histologic or cytologic examination, in 71 patients (93%) on sonography, in 21 (88%) on PET/CT, in 29 (88%) on MRI, and in 34 (45%) on mammography. Distant metastases in the bone, liver, and contralateral lymph nodes were diagnosed in nine patients (38%) on PET/CT.ConclusionMRI was the most accurate imaging technique in detecting a primary BPL in IBC patients. Sonography can be useful in diagnosing regional nodal disease. PET/CT provides additional information on distant metastasis, and it should be considered in the initial staging of IBC.", "corpus_id": 11542753, "score": 0 }, { "doc_id": "205354976", "title": "Effect of (18)F-FDG PET/CT imaging in patients with clinical Stage II and III breast cancer.", "abstract": "PURPOSE\nTo investigate the potential effect of using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in the initial assessment of patients with clinical Stage II or III breast cancer.\n\n\nMETHODS AND MATERIALS\nDuring 14 consecutive months, 39 patients (40 tumors) who presented with Stage II or III breast cancer on the basis of a routine extension assessment were prospectively included in this study. PET/CT was performed in addition to the initial assessment.\n\n\nRESULTS\nIn 3 cases, PET/CT showed extra-axillary lymph node involvement that had not been demonstrated with conventional techniques. Two of these patients had hypermetabolic lymph nodes in the subpectoral and infraclavicular regions, and the third had a hypermetabolic internal mammary node. PET/CT showed distant uptake in 4 women. Of these 4 women, 1 had pleural involvement and 3 had bone metastasis. Overall, of the 39 women, the PET/CT results modified the initial stage in 7 (18%). The modified staging altered the treatment plan for 5 patients (13%). It led to radiotherapy in 4 patients (bone metastasis, pleural lesion, subpectoral lymph nodes, and internal mammary nodes) and excision of, and radiotherapy to, the infraclavicular lymph nodes in 1 patient.\n\n\nCONCLUSIONS\nPET/CT can provide information on extra-axillary lymph node involvement and can uncover occult distant metastases in a significant percentage of patients. Therefore, initial PET/CT could enable better treatment planning for patients with Stage II and III breast cancer.", "corpus_id": 205354976, "score": 0 }, { "doc_id": "205668199", "title": "Additional Value of PET–CT in Staging of Clinical Stage IIB and III Breast Cancer", "abstract": "Abstract:  To evaluate retrospectively the accuracy of integrated PET/CT, against PET, CT, or conventional staging in breast cancer. Seventy consecutive biopsy proven clinical stage IIB and III breast cancer patients were included. Descriptive statistics of integrated PET/CT for the primary tumor, nodal status and metastasis detection were compared to PET, CT with contrast, and conventional staging (biochemistry, chest X‐ray, liver ultrasound, and bone scintigraphy). Sensitivity of PET/CT for primary tumor and nodal status was 97.1% and 62.5%, respectively. Specificity and negative predictive value for nodal status were 100% and 66.6%, respectively. The values for conventional staging for nodal involvement were 100% and 85.7% with a sensitivity of 87.5%. PET/CT showed metastatic disease in seven women despite normal conventional staging. PET/CT is able to visualize most clinical stage IIB and III primary breast cancers. PET/CT is superior to conventional staging for detecting internal mammary chain nodes and metastatic disease, but not for axillary staging. Future studies will have to test whether therapy adjustment based on PET/CT has the potential to improve survival.", "corpus_id": 205668199, "score": 1 }, { "doc_id": "8005711", "title": "Preoperative staging of large primary breast cancer with [18F]fluorodeoxyglucose positron emission tomography/computed tomography compared with conventional imaging procedures.", "abstract": "PURPOSE\nTo evaluate the utility of positron emission tomography (PET) and [(18)F]fluorodeoxyglucose in the initial staging of large primary breast tumors.\n\n\nPATIENTS AND METHODS\nThis prospective study was approved by the ethics committee, and all patients gave their informed consent before enrollment. Sixty consecutive patients with large (> 3 cm) primary breast cancer diagnosed by clinical examination and breast magnetic resonance imaging (MRI) were entered onto the study. The mean age was 57 +/- 13 years. Chest computed tomography (CT), liver ultrasonography, bone scan, and PET/CT were performed in all patients. All findings were histologically confirmed, and/or at least 1 year of follow-up was required. Correlation between parameters was calculated using Pearson's correlation coefficient. P < .05 was considered statistically significant.\n\n\nRESULTS\nPrimary tumor was identified by both PET/CT and MRI in all patients. Multifocal and/or multicentric tumors were found in 19 patients by MRI. Axillary lymph node metastases were found in 20 of 52 patients. Extra-axillary metastatic lymph nodes were also found in three patients. One patient showed an infiltrated lymph node in the contralateral axilla. The sensitivity and specificity for PET/CT to detect axillary lymph nodes metastases were 70% and 100%, respectively. PET/CT diagnosed all extra-axillary lymph nodes. The overall sensitivity and specificity of PET/CT in detecting distant metastases were 100% and 98%, respectively; whereas the sensitivity and specificity of conventional imaging were 60% and 83%, respectively. PET led to a change in the initial staging in 42% of patients.\n\n\nCONCLUSION\nPET/CT underestimates locoregional lymph node staging in large primary breast cancer patients. PET/CT is a valuable tool to discard unsuspected extra-axillary lymph nodes and distant metastases.", "corpus_id": 8005711, "score": 0 }, { "doc_id": "35472516", "title": "Pitfalls of FDG-PET for the diagnosis of osteoblastic bone metastases in patients with breast cancer", "abstract": "PurposeThe purpose of this study was to investigate the pitfalls of using 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the evaluation of osteoblastic bone metastases in patients with breast cancer by comparing it with 99mTc-hydroxymethylene diphosphonate bone scintigraphy.MethodsAmong the 89 breast cancer patients (mean age 59±15 years) who had undergone both FDG-PET and bone scintigraphy within 1 month between September 2003 and December 2004, 55 with bone metastases were studied. The bone metastases were visually classified by multi-slice CT into four types according to their degree of osteosclerosis and osteolysis—osteoblastic, osteolytic, mixed and invisible—and compared in terms of tracer uptake on FDG-PET or bone scintigraphy and SUVmean on FDG-PET. Differences in the rate of detection on bone scintigraphy and FDG-PET were analysed for significance by the McNemar test.ResultsThe sensitivity, specificity and accuracy of bone scintigraphy were 78.2%, 82.4% and 79.8% respectively, and those of FDG-PET were 80.0%, 88.2% and 83.1%, respectively, revealing no significant differences. According to the CT image type, the visualisation rate of bone scintigraphy/FDG-PET was 100%/55.6% for the blastic type, 70.0%/100.0% for the lytic type, 84.2%/94.7% for the mixed type and 25.0%/87.5% for the invisible type. The visualisation rates of bone scintigraphy for the blastic type and FDG-PET for the invisible type were significantly higher. The SUVmean of the blastic, lytic, mixed and invisible types were 1.72±0.28, 4.14±2.20, 2.97±1.98 and 2.25±0.80, respectively, showing that the SUVmean tended to be higher for the lytic type than for the blastic type.ConclusionFDG-PET showed a low visualisation rate in respect of osteoblastic bone metastases. Although FDG-PET is useful for detection of bone metastases from breast cancer, it is apparent that it suffers from some limitations in depicting metastases of the osteoblastic type.", "corpus_id": 35472516, "score": 0 }, { "doc_id": "30940972", "title": "Detection of Bone Metastases in Breast Cancer by Positron Emission Tomography.", "abstract": "Positron emission tomography (PET) is able to demonstrate changes in the metabolism of malignant tumors and metastases before they become visible on anatomical imaging. The skeleton is the most common site of distant metastases of breast cancer. There is convincing evidence that FDG-PET is more sensitive in detecting osteolytic metastases than bone scintigraphy, whereas bone scintigraphy is more sensitive in detecting osteoblastic metastases. Because both types of metastases can occur in breast cancer, bone scintigraphy and FDG-PET should be considered as complementary and can currently be regarded as standard of care for staging in breast cancer patients, whereas the decision to use F-18 fluoride PET should be made individually for each patient, depending on the expected change of therapy management.", "corpus_id": 30940972, "score": 0 }, { "doc_id": "34029289", "title": "Integrated positron emission tomography/computed tomography may render bone scintigraphy unnecessary to investigate suspected metastatic breast cancer.", "abstract": "PURPOSE\nAlthough the accurate detection of osseous metastases in the evaluation of patients with suspected metastatic breast cancer (MBC) has significant prognostic and therapeutic implications, the ideal diagnostic approach is uncertain. In this retrospective, single-institution study, we compare the diagnostic performance of integrated positron emission tomography/computed tomography (PET/CT) and bone scintigraphy (BSc) in women with suspected MBC.\n\n\nPATIENTS AND METHODS\nWomen with suspected MBC evaluated with PET/CT and BSc (within 30 days) between January 1, 2003 and June 30, 2008, were identified through institutional databases. Electronic medical records were reviewed, and radiology reports were classified as positive/negative/equivocal for osseous metastases. A nuclear medicine radiologist (blinded to correlative and clinical end points) reviewed all equivocal PET/CT and BSc images and reclassified some reports. Final PET/CT and BSc classifications were compared. Baseline patient/tumor characteristics and bone pathology were recorded and compared to the final imaging results.\n\n\nRESULTS\nWe identified 163 women who had a median age of 52 years (range, 30 to 90 years); 32% had locally advanced breast cancer, 42% had been diagnosed with breast cancer less than 12 weeks before identification. Twenty studies were originally deemed equivocal (five with PET/CT, and 15 with BSc), and 13 (65%) of these studies were reclassified after radiology review. Overall, PET/CT and BSc were highly concordant for reporting osseous metastases with 132 paired studies (81%); 32 (20%) were positive, and 100 (61%) were negative. Thirty-one occurrences (19%) were discordant. Twelve of these (39%) had pathology confirming osseous metastases: nine (of 18) were PET/CT positive and BSc negative; one (of three) was PET/CT positive and BSc equivocal; and two (of two) were PET/CT equivocal and BSc negative.\n\n\nCONCLUSION\nThis study supports the use of PET/CT in detecting osseous metastases for suspected MBC. Whether PET/CT may supplant BSc in this setting is unknown.", "corpus_id": 34029289, "score": 0 }, { "doc_id": "25380706", "title": "Diagnostic value of diffusion-weighted magnetic resonance imaging (DWI) compared to FDG PET/CT for whole-body breast cancer staging", "abstract": "PurposeThe aim of the study was to prospectively compare the diagnostic value of whole-body diffusion-weighted imaging (DWI) and FDG PET/CT for breast cancer (BC) staging.MethodsTwenty BC patients underwent whole-body FDG PET/CT and 1.5-T DWI. Lesions with qualitatively elevated signal intensity on DW images (b = 800 s/mm2) were rated as suspicious for tumour and mapped to individual lesions and different compartments (overall 552 lesions). The apparent diffusion coefficient (ADC) value was determined for quantitative evaluation. Histopathology, MRI findings, bone scan findings, concordant findings between FDG PET/CT and DWI, CT follow-up scans and plausibility served as the standards of reference defining malignancy.ResultsAccording to the standards of reference, breasts harboured malignancy in 11, regional lymph nodes in 4, M1 lymph nodes in 3, bone in 7, lung in 2, liver in 3 and other tissues in 3 patients. On a compartment basis, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) for the detection of malignancies were 94, 99, 98, 97 and 98% for FDG PET/CT and 91, 72, 76, 50 and 96% for DWI, respectively. Of the lesions seen on DWI only, 348 (82%) turned out to be false-positive compared to 23 (11%) on FDG PET/CT. The average lesion ADC was 820 ± 300 with true-positive lesions having 929 ± 252 vs 713 ± 305 in false-positive lesions (p < 0.0001).ConclusionBased on these initial data DWI seems to be a sensitive but unspecific modality for the detection of locoregional or metastatic BC disease. There was no possibility to quantitatively distinguish lesions using ADC. DWI alone may not be recommended as a whole-body staging alternative to FDG PET(/CT). Further studies are necessary addressing the question of whether full-body MRI including DWI may become an alternative to FDG PET/CT for whole-body breast cancer staging.", "corpus_id": 25380706, "score": 0 }, { "doc_id": "20944828", "title": "Integrated contrast-enhanced diagnostic whole-body PET/CT as a first-line restaging modality in patients with suspected metastatic recurrence of breast cancer.", "abstract": "OBJECTIVE(S)\nOnly few information exist about the diagnostic accuracy of PET/CT for restaging patients with metastatic recurrence of breast carcinoma. Therefore, our study hypothesis was to perform diagnostic contrast enhanced CT (ce-CT) and FDG-PET in a one-step investigation, to prove sensitivity of each modality and to determine whether diagnostic PET/CT adds information over PET or contrast enhanced CT alone for restaging of patients with suspected recurrence of breast cancer.\n\n\nMETHODS\nFifty-two patients with suspected recurrence of breast cancer were included in our study. All of them were free of metastasis after the first line therapy. Indications for restaging were: Elevated tumor markers n=32, clinical deterioration n=16 and/or suspicious findings on other imaging studies n=48. Integrated PET/CT was performed using contrast-enhanced diagnostic CT for attenuation correction.\n\n\nRESULTS\nPET was correct in 44/52 patients (85%), ce-CT in 38/52 patients (73%) and PET/CT in 50/52 patients (96%). Sensitivity and specificity of lesion detection of PET, CT and PET/CT were 84%, 66% and 93%, and 100%, 92%, and 100%, respectively.\n\n\nDISCUSSION\nPET/CT can improve staging and alter therapeutic options in patients suspected to have breast cancer recurrence and distant metastatic disease, primarily by demonstrating local or distant nodal involvement occult at other imaging studies. The added value of FDG-PET/CT over other diagnostic modalities is mainly expressed by the fact that a noninvasive whole-body evaluation is possible in a single examination.", "corpus_id": 20944828, "score": 1 }, { "doc_id": "24399941", "title": "The role of FDG‐PET/CT in suspected recurrence of breast cancer", "abstract": "Early diagnosis of recurrent breast cancer is crucial to selection of the most appropriate therapy. The current study evaluated the role of FDG‐PET/CT in the assessment of suspected recurrent breast cancer in patients who presented with elevated serum tumor markers.", "corpus_id": 24399941, "score": 0 }, { "doc_id": "3052208", "title": "The role of FDG PET/CT in patients with locoregional breast cancer recurrence: a comparison to conventional imaging techniques.", "abstract": "PURPOSE\nThe aim of this study was to evaluate the impact of (18)F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) on clinical management in patients with locoregional breast cancer recurrence amenable for locoregional treatment and to compare the PET/CT results with the conventional imaging data.\n\n\nPATIENTS AND METHODS\nFrom January 2006 to August 2008, all patients with locoregional breast cancer recurrence underwent whole-body PET/CT. PET/CT findings were compared with results of the conventional imaging techniques and final pathology. The impact of PET/CT results on clinical management was evaluated based on clinical decisions obtained from patient files.\n\n\nRESULTS\n56 patients were included. In 32 patients (57%) PET/CT revealed additional tumour localisations. Distant metastases were detected in 11 patients on conventional imaging and in 23 patients on PET/CT images (p < 0.01). In 25 patients (45%), PET/CT detected additional lesions not visible on conventional imaging. PET/CT had an impact on clinical management in 27 patients (48%) by detecting more extensive locoregional disease or distant metastases. In 20 patients (36%) extensive surgery was prevented and treatment was changed to palliative treatment. The sensitivity, specificity, accuracy, positive and negative predictive values of FDG PET/CT were respectively 97%, 92%, 95%, 94% and 96%.\n\n\nCONCLUSIONS\nPET/CT, in addition to conventional imaging techniques, plays an important role in staging patients with locoregional breast cancer recurrence since its result changed the clinical management in almost half of the patients. PET/CT could potentially replace conventional staging imaging in patients with a locoregional breast cancer recurrence.", "corpus_id": 3052208, "score": 0 }, { "doc_id": "37197683", "title": "18F-FDG-PET/CT in patients with breast cancer and rising Ca 15-3 with negative conventional imaging: a multicentre study.", "abstract": "OBJECTIVES\nBreast cancer is the second cause of death in women in Europe and North America. The mortality of this disease can be reduced with effective therapy and regular follow up to detect early recurrence. Tumor markers are sensitive in detecting recurrent or residual disease but imaging is required to customize the therapeutic option. Rising tumor markers and negative conventional imaging (US, X-mammography, CT and MR) poses a management problem. Our aim is to assess the role of 18F-FDG-PET/CT in the management of post-therapy patients with rising markers but negative conventional imaging.\n\n\nMATERIALS AND METHODS\nIn the period from January 2008 to September 2009, 89 female patients with breast cancer who developed post-therapy rising markers (serum Ca 15-3 levels=64.8±16.3 U/mL) but negative clinical examination and conventional imaging were investigated with 18F-FDG-PET/CT.\n\n\nRESULTS\nTumor deposits were detected in 40/89 patients in chest wall, internal mammary nodes, lungs, liver and skeleton. The mean SUVmax value calculated in these lesions was 6.6±1.7 (range 3.1-12.8). In 23/40 patients solitary small lesion were amenable to radical therapy. In 7 out of these 23 patients a complete disease remission lasting more than 1 year was observed.\n\n\nCONCLUSIONS\n18F-FDG-PET/CT may have a potential role in asymptomatic patients with rising markers and negative conventional imaging. Our findings agree with other studies in promoting regular investigations such as tumor markers and 18F-FDG-PET/CT rather than awaiting the developments of physical symptoms as suggested by current guidelines since the timely detection of early recurrence may have a major impact on therapy and survival.", "corpus_id": 37197683, "score": 0 }, { "doc_id": "207406868", "title": "The Yield of 18F-FDG PET/CT in Patients with Clinical Stage IIA, IIB, or IIIA Breast Cancer: A Prospective Study", "abstract": "The purpose of this study was to prospectively evaluate the role of 18F-FDG PET/CT in patients with stage IIA, IIB, or IIIA breast cancer. Methods: During 56 mo, 131 consecutive patients with large (>2 cm) breast cancer and clinical stage IIA, IIB, or IIIA (based on clinical examination, mammography, breast MRI, and ultrasonography) underwent 18F-FDG PET/CT. The nuclear physician was unaware of the results of any other procedure (bone scan, chest radiography, liver ultrasound, or thoracoabdominal CT scan). Results: Of the 131 examined patients, 36 had clinical stage IIA (34 T2N0 and 2 T1N1), 48 stage IIB (20 T3N0 and 28 T2N1), and 47 stage IIIA (29 T3N1, 9 T2N2, and 9 T3N2). 18F-FDG PET/CT modified staging for 5.6% of stage IIA patients, for 14.6% of stage IIB patients, and for 27.6% of stage IIIA patients. However, within stage IIIA, the yield was specifically high among the 18 patients with N2 disease (56% stage modification). When considering stage IIB and primary operable IIIA (T3N1) together, the yield of 18F-FDG PET/CT was 13% (10/77); extraaxillary regional lymph nodes were detected in 5 and distant metastases in 7 patients. In this series, 18F-FDG PET/CT outperformed bone scanning, with only 1 misclassification versus 8 for bone scanning (P = 0.036). Conclusion: 18F-FDG PET/CT provided useful information in 13% of patients with clinical T3N0, T2N1, or T3N1 disease. The yield was more modest in patients with stage IIA. The high yield in the case of N2 disease demonstrates that stage IIIA comprises 2 quite distinct groups of patients.", "corpus_id": 207406868, "score": 0 }, { "doc_id": "10349388", "title": "F-18-Fluoro-2-Deoxyglucose Positron Emission Tomography/Computed Tomography in the Follow-up of Breast Cancer With Elevated Levels of Tumor Markers", "abstract": "Objective The value of combined positron emission tomography (PET)/computed tomography (CT) in the follow-up of patients with breast cancer with elevated tumor markers but without proven metastases or local recurrence was assessed. Methods Thirty-four women underwent PET/CT. The PET and CT images were first analyzed separately; fused findings were then interpreted, blinded to the results of the other modalities. The results of CT, PET, and PET/CT were compared with each other and correlated to the final diagnosis. Results The PET/CT identified 149 malignant foci in 24 patients (71%). The CT detected 96 of these foci in 18 patients, whereas PET identified 124 foci in 17 patients. Differences between CT and PET were not significant. Differences between PET/CT and CT (P < 0.01) and PET/CT and PET (P < 0.01) were significant. The person-based sensitivity of PET/CT, PET, and CT was 96%, 88% and 96%, respectively. Specificity of PET/CT, PET, and CT was 89%, 78%, and 78%, respectively. Conclusions The PET/CT is a valuable modality for the follow-up of patients with breast cancer and elevated levels of tumor markers.", "corpus_id": 10349388, "score": 0 }, { "doc_id": "652680", "title": "FDG-PET and other imaging modalities for the evaluation of breast cancer recurrence and metastases: a meta-analysis", "abstract": "Background and purposeBreast carcinoma is the most common cancer in female patients with a propensity for recurrence and metastases. The accuracy of ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), scintimammography (SMM) and positron emission tomography (PET) in diagnosing the recurrent and/or breast cancer has never been systematically assessed, and present systematic review was aimed at this issue.MethodsMEDLINE and EMBASE were searched for articles dealt with detection of recurrent and/or metastatic breast cancer by US, CT, MRI, SMM or PET whether interpreted with or without the use of CT. Histopathologic analysis and/or close clinical and imaging follow-up for at least 6 months were used as golden reference. We extracted data to calculate sensitivity, specificity, summary receiver operating characteristic curves and area under the curve and to test for heterogeneity.ResultIn 42 included studies, US and MRI had highest pooled specificity (0.962 and 0.929, respectively); MRI and PET had highest pooled sensitivity (0.9500 and 0.9530, respectively). The AUC of US, CT, MRI, SMM and PET was 0.9251, 0.8596, 0.9718, 0.9386 and 0.9604, respectively. Results of pairwise comparison between each modality demonstrated that AUC of MRI and PET was higher than that of US or CT, p < 0.05. No statistical significance was found between MRI and PET. There was heterogeneity among studies and evidence of publication bias.ConclusionIn conclusion, MRI seemed to be a more useful supplement to current surveillance techniques to assess patients with suspected recurrent and/or metastatic breast cancer. If MRI shows an indeterminate or benign lesion or MRI was not applicable, FDG-PET could be performed in addition.", "corpus_id": 652680, "score": 0 }, { "doc_id": "37156046", "title": "A systematic review of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence.", "abstract": "BACKGROUND\nBreast cancer (BC) accounts for one-third of all cases of cancer in women in the UK. Current strategies for the detection of BC recurrence include computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy. Positron emission tomography (PET) and, more recently, positron emission tomography/computed tomography (PET/CT) are technologies that have been shown to have increasing relevance in the detection and management of BC recurrence.\n\n\nOBJECTIVE\nTo review the accuracy of PET and PET/CT for the diagnosis of BC recurrence by assessing their value compared with current practice and compared with each other.\n\n\nDATA SOURCES\nMEDLINE and EMBASE were searched from inception to May 2009.\n\n\nSTUDY SELECTION\nStudies were included if investigations used PET or PET/CT to diagnose BC recurrence in patients with a history of BC and if the reference standard used to define the true disease status was histological diagnosis and/or long-term clinical follow-up. Studies were excluded if a non-standard PET or PET/CT technology was used, investigations were conducted for screening or staging of primary breast cancer, there was an inadequate or undefined reference standard, or raw data for calculation of diagnostic accuracy were not available.\n\n\nSTUDY APPRAISAL\nQuality assessment and data extraction were performed independently by two reviewers. Direct and indirect comparisons were made between PET and PET/CT and between these technologies and methods of conventional imaging, and meta-analyses were carried out. Analysis was conducted separately on patient- and lesion-based data. Subgroup analysis was conducted to investigate variation in the accuracy of PET in certain populations or contexts and sensitivity analysis was conducted to examine the reliability of the primary outcome measures.\n\n\nRESULTS\nOf the 28 studies included in the review, 25 presented patient-based data and 7 presented lesion-based data for PET and 5 presented patient-based data and 1 presented patient- and lesion-based data for PET/CT; 16 studies conducted direct comparisons with 12 comparing the accuracy of PET or PET/CT with conventional diagnostic tests and 4 with MRI. For patient-based data (direct comparison) PET had significantly higher sensitivity [89%, 95% confidence interval (CI) 83% to 93% vs 79%, 95% CI 72% to 85%, relative sensitivity 1.12, 95% CI 1.04 to 1.21, p = 0.005] and significantly higher specificity (93%, 95% CI 83% to 97% vs 83%, 95% CI 67% to 92%, relative specificity 1.12, 95% CI 1.01 to 1.24, p = 0.036) compared with conventional imaging tests (CITs)--test performance did not appear to vary according to the type of CIT tested. For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with CT (95%, 95% CI 88% to 98% vs 80%, 95% CI 65% to 90%, relative sensitivity 1.19, 95% CI 1.03 to 1.37, p = 0.015), but the increase in specificity was not significant (89%, 95% CI 69% to 97% vs 77%, 95% CI 50% to 92%, relative specificity 1.15, 95% CI 0.95 to 1.41, p = 0.157). For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with PET (96%, 95% CI 90% to 98% vs 85%, 95% CI 77% to 91%, relative sensitivity 1.11, 95% CI 1.03 to 1.18, p = 0.006), but the increase in specificity was not significant (89%, 95% CI 74% to 96% vs 82%, 95% CI 64% to 92%, relative specificity 1.08, 95% CI 0.94 to 1.20, p = 0.267). For patient-based data there were no significant differences in the sensitivity or specificity of PET when compared with MRI, and, in the one lesion based study, there was no significant differences in the sensitivity or specificity of PET/CT when compared with MRI.\n\n\nLIMITATIONS\nStudies reviewed were generally small and retrospective and this may have limited the generalisability of findings. Subgroup analysis was conducted on the whole set of studies investigating PET and was not restricted to comparative studies. Conventional imaging studies that were not compared with PET or PET/CT were excluded from the review.\n\n\nCONCLUSIONS\nAvailable evidence suggests that for the detection of BC recurrence PET, in addition to conventional imaging techniques, may generally offer improved diagnostic accuracy compared with current standard practice. However, uncertainty remains around its use as a replacement for, rather than an add-on to, existing imaging technologies. In addition, PET/CT appeared to show clear advantage over CT and PET alone for the diagnosis of BC recurrence.\n\n\nFUTURE WORK\nFuture research should include: prospective studies with patient populations clearly defined with regard to their clinical presentation; a study of diagnostic accuracy of PET/CT compared with conventional imaging techniques; a study of PET/CT compared with whole-body MRI; studies investigating the possibility of using PET/CT as a replacement for rather than an addition to CITs; and using modelling of the impact of PET/CT on patient outcomes to inform the possibility of conducting large-scale intervention trials.", "corpus_id": 37156046, "score": 1 }, { "doc_id": "23918025", "title": "Performance of 2-Deoxy-2-[F-18]fluoro-d-glucose Positron Emission Tomography and Integrated PET/CT in Restaged Breast Cancer Patients", "abstract": "PurposeThis study was conducted to compare the clinical stage derived from 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) positron emission tomography (PET) to that of integrated PET/computed tomography (CT) in restaged breast cancer patients.ProceduresFifty-eight female patients (age range 29–80 years, mean age ±SD, 53.3 ± 11.7 years) underwent PET/CT restaging for breast cancer. Two experienced nuclear medicine physicians interpreted PET images. A radiologist was added for reading PET/CT studies. A patient-based analysis was performed. Histopathological findings, correlative imaging studies, changes in number, size, and hypermetabolic activity of suspicious lesions and/or patient outcome served as standard of reference for determining the diagnostic accuracy of both modalities.ResultsPET staged 79.3% (46/58) of the patients correctly, overstaged seven (12.1%), and understaged five patients (8.6%). Integrated PET/CT staged 89.7% (52/58) of the patients correctly, overstaged four (6.9%), and understaged two patients (3.4%). The staging accuracy of PET/CT was not significantly better than that of PET alone (p = 0.059). Lesions exhibiting mild hypermetabolic activity, benign inflammatory lesions, and physiological variants largely explained incorrect PET findings.ConclusionIntegrated PET/CT only marginally improves the restaging accuracy over PET alone (p = 0.059) in breast cancer patients.", "corpus_id": 23918025, "score": 0 }, { "doc_id": "19291420", "title": "FDG-PET/CT in restaging of patients with recurrent breast cancer: possible impact on staging and therapy.", "abstract": "We aimed to compare the value of combined positron emission tomography (PET)/CT, PET+CT (viewed side by side), CT alone and PET alone concerning the rTNM stage and influence on therapy in patients with recurrent breast cancer. 44 patients with suspicion of recurrent breast cancer underwent whole-body [18F]-2-fluoro-2-deoxy-d-glucose (FDG)-PET/CT. Images of combined PET/CT, PET+CT, PET alone and CT alone were evaluated by four blinded reader teams. Diagnostic accuracies and influence on therapy were compared. Histology and a mean clinical follow up of 456 days served as the standard of reference. Differences between the staging procedures were tested for statistical significance by McNemar's test. Overall TNM tumour stage was correctly determined in 40/44 patients with PET/CT, in 38/44 with PET+CT, in 36/44 with PET alone and in 36/44 patients with CT alone. No statistically significant difference was detected between all tested imaging modalities. PET/CT changed the therapy in two patients compared with PET+CT, in four patients compared with PET alone and in five patients compared with CT alone. Combined PET/CT appeared to be more accurate in assessing the rTNM and showed a moderate impact on therapy over PET and CT. Minor improvements were noted when compared with PET+CT. Experienced readers might therefore be able to provide accurate staging results for further therapy from separately acquired studies.", "corpus_id": 19291420, "score": 0 }, { "doc_id": "20814280", "title": "Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.", "abstract": "PURPOSE\nTo determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies.\n\n\nPATIENTS AND METHODS\nWomen (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response.\n\n\nRESULTS\nThere was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model.\n\n\nCONCLUSION\nPreoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.", "corpus_id": 20814280, "score": 0 }, { "doc_id": "207018818", "title": "Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27.", "abstract": "PURPOSE\nNational Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively. Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response rates, DFS, and OS.\n\n\nPATIENTS AND METHODS\nAnalyses were limited to eligible patients. In B-18, 751 patients were assigned to receive preoperative AC, and 742 patients were assigned to receive postoperative AC. In B-27, 784 patients were assigned to receive preoperative AC followed by surgery, 783 patients were assigned to AC followed by T and surgery, and 777 patients were assigned to AC followed by surgery and then T.\n\n\nRESULTS\nResults from B-18 show no statistically significant differences in DFS and OS between the two groups. However, there were trends in favor of preoperative chemotherapy for DFS and OS in women less than 50 years old (hazard ratio [HR] = 0.85, P = .09 for DFS; HR = 0.81, P = .06 for OS). DFS conditional on being event free for 5 years also demonstrated a strong trend in favor of the preoperative group (HR = 0.81, P = .053). Protocol B-27 results demonstrated that the addition of T to AC did not significantly impact DFS or OS. Preoperative T added to AC significantly increased the proportion of patients having pathologic complete responses (pCRs) compared with preoperative AC alone (26% v 13%, respectively; P < .0001). In both studies, patients who achieved a pCR continue to have significantly superior DFS and OS outcomes compared with patients who did not.\n\n\nCONCLUSION\nB-18 and B-27 demonstrate that preoperative therapy is equivalent to adjuvant therapy. B-27 also showed that the addition of preoperative taxanes to AC improves response.", "corpus_id": 207018818, "score": 0 }, { "doc_id": "2481210", "title": "Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27.", "abstract": "PURPOSE\nThis study was designed to determine the effect of adding docetaxel (T) to preoperative doxorubicin and cyclophosphamide (AC) on breast cancer response rates and disease-free survival (DFS) and overall survival (OS).\n\n\nPATIENTS AND METHODS\nWomen with operable breast cancer (N = 2,411) were randomly assigned to receive preoperative AC followed by surgery, AC followed by T and surgery, or AC followed by surgery and then T. Tamoxifen was initiated concurrently with chemotherapy. Median time on study for 2,404 patients with follow-up was 77.9 months.\n\n\nRESULTS\nAddition of T to AC did not significantly impact DFS or OS. There were trends toward improved DFS with addition of T. The addition of T reduced the incidence of local recurrences as first events (P = .0034). Preoperative T, but not postoperative T, significantly improved DFS in patients who had a clinical partial response after AC (hazard ratio [HR] = 0.71; 95% CI, 0.55 to 0.91; P = .007). Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR = 0.33; 95% CI, 0.23 to 0.47; P < .0001). Pathologic nodal status after chemotherapy was a significant predictor of OS (P < .0001).\n\n\nCONCLUSION\nThe addition of preoperative or postoperative T after preoperative AC did not significantly affect OS, slightly improved DFS, and decreased the incidence of local recurrences. The sample size of this study was not sufficient to yield significance for the moderate DFS improvement. Concurrent use of tamoxifen may have limited the impact of adding T.", "corpus_id": 2481210, "score": 0 }, { "doc_id": "5973454", "title": "Early monitoring of response to neoadjuvant chemotherapy in breast cancer with 18F-FDG PET/CT: defining a clinical aim", "abstract": "In Europe, in 2008, it was estimated that 421,000 new cases of breast cancer were diagnosed; 129,000 women died from breast cancer in the same year [1]. Neoadjuvant chemotherapy (NAC), initially used only for locally advanced breast cancer, is now commonly used in patients with operable but large breast cancer. This strategy allows patients to undergo breast-conserving surgery (BCS) and gives information on the efficacy of chemotherapy [2]. Long-term outcomes are significantly correlated with pathological tumour response rates [3]. In the present paper we here focus on what could be the role of an early evaluation with F-FDG PET/CT of the response to NAC in patients with operable breast cancer.", "corpus_id": 5973454, "score": 0 }, { "doc_id": "25666874", "title": "Positron emission tomography using [(18)F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy.", "abstract": "PURPOSE\nTo determine whether [(18)F]-fluorodeoxy-D-glucose ([(18)F]-FDG) positron emission tomography (PET) can predict the pathologic response of primary and metastatic breast cancer to chemotherapy.\n\n\nPATIENTS AND METHODS\nThirty patients with noninflammatory, large (> 3 cm), or locally advanced breast cancers received eight doses of primary chemotherapy. Dynamic PET imaging was performed immediately before the first, second, and fifth doses and after the last dose of treatment. Primary tumors and involved axillary lymph nodes were identified, and the [(18)F]-FDG uptake values were calculated (expressed as semiquantitative dose uptake ratio [DUR] and influx constant [K]). Pathologic response was determined after chemotherapy by evaluation of surgical resection specimens.\n\n\nRESULTS\nThirty-one primary breast lesions were identified. The mean pretreatment DUR values of the eight lesions that achieved a complete microscopic pathologic response were significantly (P =.037) higher than those from less responsive lesions. The mean reduction in DUR after the first pulse of chemotherapy was significantly greater in lesions that achieved a partial (P =.013), complete macroscopic (P =.003), or complete microscopic (P =.001) pathologic response. PET after a single pulse of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph node metastases. Mean pretreatment DUR values in the metastatic lesions that responded did not differ significantly from those that failed to respond (P =.076). However, mean pretreatment K values were significantly higher in ultimately responsive cancers (P =.037). The mean change in DUR and K after the first pulse of chemotherapy was significantly greater in responding lesions (DUR, P =.038; K, P =.012).\n\n\nCONCLUSION\n[(18)F]-FDG PET imaging of primary and metastatic breast cancer after a single pulse of chemotherapy may be of value in the prediction of pathologic treatment response.", "corpus_id": 25666874, "score": 0 }, { "doc_id": "46505522", "title": "Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron emission tomography.", "abstract": "PURPOSE\nThis study aimed to assess prospectively the efficacy of sequential [18F]fluorodeoxyglucose positron emission tomography (FDG PET) to evaluate early response to neoadjuvant chemotherapy in stage II and III breast cancer patients.\n\n\nPATIENTS AND METHODS\nImages were acquired with a PET/computed tomography scanner in 64 patients after administration of FDG (5 MBq/kg) at baseline and after the first, second, third, and sixth course of chemotherapy. Ultrasound and mammography were used to assess tumor size. Decrease in the standardized uptake value (SUV) with PET was compared with the pathologic response.\n\n\nRESULTS\nSurgery was performed after six courses of chemotherapy and pathologic analysis revealed gross residual disease in 28 patients and minimal residual disease in 36 patients. Although SUV data did not vary much in nonresponders (based on pathology findings), they decreased markedly to background levels in 94% (34 of 36) of responders. When using 60% of SUV at baseline as the cutoff value, the sensitivity, specificity, and negative predictive value of FDG PET were 61%, 96%, and 68% after one course of chemotherapy, 89%, 95%, and 85% after two courses, and 88%, 73%, and 83% after three courses, respectively. The same parameters with ultrasound (US) and mammography were 64%, 43%, and 55%, and 31%, 56%, and 45%, respectively. Assessment of tumor response with US or mammography was never significant whatever the cutoff.\n\n\nCONCLUSION\nPathologic response to neoadjuvant chemotherapy in stage II and III breast cancer can be predicted accurately by FDG PET after two courses of chemotherapy.", "corpus_id": 46505522, "score": 1 }, { "doc_id": "31947122", "title": "[18F]FDG-PET predicts complete pathological response of breast cancer to neoadjuvant chemotherapy", "abstract": "PurposeTo evaluate, in breast cancer patients treated by neoadjuvant chemotherapy, the predictive value of reduction in FDG uptake with regard to complete pathological response (pCR).MethodsForty-seven women with non-metastatic, non-inflammatory, large or locally advanced breast cancer were included. Tumour uptake of FDG was evaluated before and after the first course of neoadjuvant chemotherapy. Four indices were used: maximal and average SUV without or with correction by body surface area and glycaemia (SUVmax, SUVavg, SUVmax-BSA-G and SUVavg-BSA-G, respectively). The predictive value of reduction in FDG uptake with respect to pCR was studied by logistic regression analysis. Relationships between baseline [18F]FDG uptake and prognostic parameters were assessed.ResultsThe relative decrease in FDG uptake (ΔSUV) after the first course of neoadjuvant chemotherapy was significantly greater in the pCR group than in the non-pCR group (p < 0.000066). The four FDG uptake indices were all strongly correlated with each other. A decrease in SUVmax-BSA-G of 85.4% ± 21.9% was found in pCR patients, versus 22.6% ± 36.6% in non-pCR patients. ΔSUVmax-BSA-G <−60% predicted the pCR with an accuracy of 87% and ΔSUVs were found to be only factors predictive of the pCR at multivariate analysis. An elevated baseline SUV was associated with high mitotic activity (p < 0.0016), tumour grading (p < 0.004), high nuclear pleomorphism score (p < 0.03) and negative hormonal receptor status (p < 0.005).ConclusionIn breast cancer patients, after only one course of neoadjuvant chemotherapy the reduction in FDG uptake is an early and powerful predictor of pCR.", "corpus_id": 31947122, "score": 0 }, { "doc_id": "39709430", "title": "Monitoring primary breast cancer throughout chemotherapy using FDG-PET", "abstract": "We have compared 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography (FDG-PET) images of large or locally advanced breast cancers (LABC) acquired during Anthracycline-based chemotherapy. The purpose was to determine whether there is an optimal method for defining tumour volume and an optimal imaging time for predicting pathologic chemotherapy response. Method: PET data were acquired before the first and second cycles, at the midpoint and at the endpoint of neoadjuvant chemotherapy. FDG uptake was quantified using the mean and maximum standardized uptake values (SUV) and the coefficient of variation within a region of interest. Receiver-operator characteristic (ROC) analysis was used to determine the discrimination between tumours demonstrating a high pathological response (i.e. those with greater than 90% reduction in viable tumour cells) and low pathological response. Results: Only tumours with an initial tumour to background ratio (TBR) of greater than five showed a difference between response categories. In terms of response discrimination, there was no statistically significant advantage of any of the methods used for image quantification or any of the time points. The best discrimination was measured for mean SUV at the midpoint of therapy, which identified 77% of low responding tumours whilst correctly identifying 100% of high responding tumours and had an ROC area of 0.93. Conclusion: FDG-PET is efficacious for predicting the pathologic response of most primary breast tumours throughout the duration of a neoadjuvant chemotherapy regimen. However, this technique is ineffective for tumours with low image contrast on pre-therapy PET scans.", "corpus_id": 39709430, "score": 0 }, { "doc_id": "6398981", "title": "18F-FDG PET/CT for early prediction of response to neoadjuvant chemotherapy in breast cancer", "abstract": "PurposeThe aim of this study was to prospectively evaluate 18F-FDG PET/CT in predicting response to neoadjuvant chemotherapy in large primary breast cancer.MethodsFifty consecutive patients underwent PET/CT at baseline and after the second cycle. Baseline MRI was performed to establish tumour size. All findings were confirmed by histopathological analysis. Changes in maximum standardized uptake value (SUVmax) between baseline study and after two cycles of neoadjuvant chemotherapy (epirubicin + cyclophosphamide + taxanes) were compared using response evaluation criteria in solid tumours (RECIST) criteria and the Miller and Payne (M&P) scale.ResultsThe mean tumour size was 4.3 ± 1.4 cm. Forty patients were considered responders and ten as non-responders. SUVmax changes in patients with good prognosis (M&P grades 4–5) were higher than in patients with bad prognosis (M&P grades 1–3) (p = 0.025). SUVmax changes between responders and non-responders following RECIST criteria were also statistically significant (p = 0.0028). A cut-off ΔSUV value of 40% differentiates both groups, with a sensitivity of 77% and a specificity of 80%.Conclusion18F-FDG PET/CT can predict response to neoadjuvant chemotherapy at an early stage.", "corpus_id": 6398981, "score": 0 }, { "doc_id": "25014125", "title": "The role of 18F-FDG PET/CT in evaluation of early response to neoadjuvant chemotherapy in patients with locally advanced breast cancer", "abstract": "We evaluated the role of 18F-FDG PET/CT for the assessment of response after two cycles of neo-adjuvant chemotherapy (NACT) for breast cancer. Twenty-three women with locally advanced breast cancer were included in this study. Early response to NACT was evaluated after two cycles using clinical examination, CT, and 18F-FDG PET/CT. Final histopathology following surgery after six cycles of NACT served as reference. Baseline PET/CT demonstrated a total of 26 lesions in 23 patients. The size of the primary tumor ranged from 1.90 cm to 11.60 cm, and the maximum value of the standardized uptake value of FDG (SUVmax) ranged from 3.6 to 38.6 (mean, 11.7). Post-chemotherapy PET/CT examinations were done after two cycles of NACT. The size of the primary tumor on follow-up PET/CT examinations ranged from 0.0 cm to 7.6 cm, and SUVmax ranged from 0.0 to 12.0 (mean, 3.96). On clinical, CT, and PET/CT examinations, 50% reduction in the parameters was taken as the cutoff value to differentiate between responders and non-responders. Post-NACT PET/CT demonstrated that 16 patients were responders and 7 non-responders. Among 16 responders on PET/CT scan, 14 were true positive and 2 were false positive when compared with histopathology. Among seven non-responder patients, six were true negative, and one was false negative. The sensitivity, specificity, and accuracy of PET/CT in detecting responders were 93%, 75%, and 87%, respectively. In conclusion, 18F-FDG PET/CT can differentiate responders from non-responders with high accuracy after two cycles of NACT in patients with LABC.", "corpus_id": 25014125, "score": 0 }, { "doc_id": "40193369", "title": "Early 18F‐2‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography may identify a subset of patients with estrogen receptor‐positive breast cancer who will not respond optimally to preoperative chemotherapy", "abstract": "A pathologic complete response (pCR) and minimal residual disease (pMRD) after preoperative chemotherapy (PCT) for early stage or locally advanced breast cancer (BC) correlates with a good prognosis.", "corpus_id": 40193369, "score": 0 }, { "doc_id": "30720927", "title": "FDG-PET and beyond: molecular breast cancer imaging.", "abstract": "Positron emission tomography (PET) scanning has gained widespread acceptance for the diagnosis, staging, and management of a variety of malignancies, including breast cancer. This has heralded an exciting new era of molecular imaging research of which using FDG as the primary PET tracer is only the beginning. The fundamental strength of PET over conventional imaging is the ability to convey functional information that even the most exquisitely detailed anatomic image cannot provide. As the standard PET radiotracer in current clinical use, FDG is a glucose analog that is taken up by cells in proportion to their rate of glucose metabolism. The increased glycolytic rate and glucose avidity of malignant cells in comparison to normal tissue is the basis of the ability of FDG-PET imaging to accurately differentiate cancer from benign tissue irregardless of morphology. The level or intensity of FDG uptake on PET is semiquantified and reported as the standardized uptake value (SUV). A multitude of new PET tracers are under development, many of which are aimed at targeting cellular processes that are more specific than glucose metabolism. In relation to breast cancer, these tracers include thymidine analogs such as [F-18]fluoro-L-thymidine (FLT) that target DNA replication as a measure of cell proliferation, annexin V derivatives that evaluate apoptosis, estrogen receptor (ER) tracers such as 16 -[F-18]fluoroestradiol-17 (FES), and engineered antibody fragments that directly target HER-2/neu receptors. In addition to new tracers, scanner technology is also rapidly evolving. Chief among these is the advent of the dual modality PET/CT scanner, which at the very least increases patient convenience by permitting PET and computed tomography (CT) imaging in a single appointment. But perhaps more importantly, initial studies indicate that the sum of the two modalities is better than either used separately and also may be an extremely useful tool in preradiation therapy planning. Other new scanning devices are also being developed, including small gantry PET scanners designed specifically for breast imaging, and handheld PET probes for direct intraoperative localization of tracer-avid tumor foci.", "corpus_id": 30720927, "score": 0 }, { "doc_id": "21555525", "title": "Positron emission tomographic assessment of ”metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy", "abstract": "Abstract. We have investigated whether increased tumor uptake of fluorine-18 fluorodeoxyglucose (FDG) detected with positron emission tomography (PET) early after initiating tamoxifen therapy (”metabolic flare”) predicts a hormonally responsive breast cancer. Eleven postmenopausal women with biopsy-proved estrogen receptor-positive (ER+) metastatic breast cancer were studied by PET with FDG and 16α[18F]fluoro-17β-estradiol (FES) before and 7–10 days after initiation of tamoxifen therapy. FDG and FES uptake was evaluated semiquantitatively in 21 lesions. The PET results were correlated with follow-up evaluation, continued until the patient became unresponsive to hormone therapy (3–24 months). There were seven responders and four nonresponders based on clinical follow-up. None of the responders had a clinical flare reaction, but all demonstrated metabolic flare, with a mean ± standard deviation increase in tumor standardized uptake value (SUV) for FDG of 1.4±0.7. No evidence for flare was noted in the nonresponders (change in SUV for FDG –0.1±0.4; P = 0.008 vs. responders). The degree of ER blockade by tamoxifen was greater in responders (mean decrease in SUV 2.7±1.7) than in nonresponders (mean decrease 0.8±0.5) (P = 0.04). The lesions of responders had higher baseline SUVs for FES than did those of three of four nonresponders (≥2.2 vs ≤1.7). The findings of a metabolic flare by FDG-PET and the degree of ER blockade by FES-PET early after institution of tamoxifen treatment appear to predict responsiveness to antiestrogen therapy in patients with ER+ metastatic breast cancer.", "corpus_id": 21555525, "score": 0 }, { "doc_id": "27437", "title": "PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer", "abstract": "Purpose To determine if response to endocrine therapy of breast cancer can be predicted by either a metabolic “flare reaction” detected by positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxyglucose (FDG), induced by an estradiol challenge, or by estrogen-receptor (ER) status, determined by PET with the estrogen analog 16α-[18F]fluoroestradiol-17β (FES). Methods Fifty-one post-menopausal women with advanced estrogen-receptor positive breast cancer were studied. Patients underwent FES-PET and FDG-PET at baseline and repeat FDG-PET after 30 mg estradiol. Tracer uptakes was measured as the standardized uptake value (SUV). Patients were subsequently treated with either an aromatase inhibitor or fulvestrant. A prospectively defined cut-off SUV ≥ 2 for FES was considered positive for ER expression. A cutoff of ≥12% increase in SUV for FDG, determined by ROC analysis, represented metabolic flare. PET results were correlated with responsiveness to endocrine therapy. Results Seventeen patients responded and 34 patients did not respond to endocrine therapy. Four responders and one non-responder had a clinical flare reaction, while only the responders demonstrated metabolic flare. After estradiol challenge, a significantly higher mean (±SD) percent change in SUV for FDG was noted in responders (20.9 ± 24.2) compared with non-responders (−4.3 ± 11.0, P < 0.0001). On FES-PET, a higher tumor SUV was noted in responders (3.5 ± 2.5) compared with non-responders (2.1 ± 1.8, P = 0.0049). There was significantly longer overall survival in patients with metabolic flare than in those without flare regardless of type of endocrine therapy (P = 0.0062). Conclusion Baseline tumor FES uptake and metabolic flare after an estradiol challenge are both predictive of responsiveness to endocrine therapy in ER+ breast cancer.", "corpus_id": 27437, "score": 0 }, { "doc_id": "21128790", "title": "Metabolic flare: indicator of hormone responsiveness in advanced breast cancer.", "abstract": "PURPOSE\nThe purpose of this study was to investigate whether positron emission tomography (PET) with the glucose analog [(18)F]fluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-[(18)F]fluoroestradiol-17 beta (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (metabolic flare) and changes in available levels of estrogen receptor (ER). In addition, we investigated whether these PET findings would predict hormonally responsive breast cancer.\n\n\nPATIENTS AND METHODS\nForty women with biopsy-proved advanced ER-positive (ER(+)) breast cancer underwent PET with FDG and FES before and 7 to 10 days after initiation of tamoxifen therapy; 70 lesions were evaluated. Tumor FDG and FES uptake were assessed semiquantitatively by the standardized uptake value (SUV) method. The PET results were correlated with response to hormonal therapy.\n\n\nRESULTS\nIn the responders, the tumor FDG uptake increased after tamoxifen by 28.4% +/- 23.3% (mean +/- SD); only five of these patients had evidence of a clinical flare reaction. In nonresponders, there was no significant change in tumor FDG uptake from baseline (mean change, 10.1% +/- 16.2%; P =.0002 v responders). Lesions of responders had higher baseline FES uptake (SUV, 4.3 +/- 2.4) than those of nonresponders (SUV, 1.8 +/- 1.3; P =.0007). All patients had evidence of blockade of the tumor ERs 7 to 10 days after initiation of tamoxifen therapy; however, the degree of ER blockade was greater in the responders (mean percentage decrease, 54.8% +/- 14.2%) than in the nonresponders (mean percentage decrease, 19.4% +/- 17.3%; P =.0003).\n\n\nCONCLUSION\nThe functional status of tumor ERs can be characterized in vivo by PET with FDG and FES. The results of PET are predictive of responsiveness to tamoxifen therapy in patients with advanced ER(+) breast cancer.", "corpus_id": 21128790, "score": 0 }, { "doc_id": "36560174", "title": "Preoperative evaluation of prognosis in breast cancer patients by [18F]2-Deoxy-2-fluoro-D-glucose-positron emission tomography", "abstract": "Purpose [18F]2-Deoxy-2-fluoro-D-glucose (FDG)-positron emission tomography (PET) was applied to breast cancer patients for the purpose of preoperative evaluation of patient prognosis with more accuracy than conventional TNM staging.Methods FDG-PET was performed preoperatively in 81 patients with breast cancer, and the maximum standardized uptake value (SUVmax) of tumors as well as the focal accumulation of FDG in the axillary region (PET-N status) were investigated in their association with patient prognosis.Results The SUVmax high group (n=40) showed a significantly (P=0.011) poorer prognosis than the SUVmax low group (n=41) (5-year disease-free survival (DFS) rates; 75.0% vs 95.1%). FDG-PET was more accurate in the diagnosis of axillary lymph node status than physical examination, i.e., diagnostic accuracy was 80% and 70% for FDG-PET and physical examination, respectively. The combination of high SUVmax and positive PET-N (+) was shown to be a highly significant risk factor being independent of the clinical T and N factors, i.e., patients with high SUVmax and positive PET-N (+) showed a significantly (P<0.001) poorer prognosis than the other patients (5-year DFS rates; 44.4% vs 96.8%).Conclusions These results suggest that FDG-PET is useful in the preoperative evaluation of prognosis in breast cancer patients with more accuracy than conventional TNM staging. It is expected that the indication of neoadjuvant chemotherapy can be decided more precisely by the preoperative evaluation of patient prognosis with FDG-PET due to a possible elimination of overtreatment for those who have good prognosis and, thus, need not to be treated with chemotherapy.", "corpus_id": 36560174, "score": 0 }, { "doc_id": "11632365", "title": "Predicting the prognoses of breast carcinoma patients with positron emission tomography using 2‐deoxy‐2‐fluoro[18F]‐D‐glucose", "abstract": "Positron emission tomography (PET) with 2‐deoxy‐2‐fluoro[18F]‐D‐glucose (FDG) can provide quantitative information about tumor glucose metabolism. The prognostic value of this technique was evaluated for breast carcinoma patients.", "corpus_id": 11632365, "score": 0 }, { "doc_id": "207411569", "title": "Comparison of FDG PET and MRI for evaluating the tumor extent of breast cancer and the impact of FDG PET on the systemic staging and prognosis of patients who are candidates for breast-conserving therapy", "abstract": "BackgroundFDG PET has not yet found a role in the clinical evaluation of the tumor extent of breast cancer. FDG PET has been reported to be useful for evaluating the prognoses of breast cancer patients with more accuracy than conventional imaging modalities. The purpose of this study was to compare the accuracy of FDG PET and MRI for the preoperative assessment of the tumor extent of breast cancer, for evaluating the impact of FDG PET on systemic staging, and also for predicting the prognosis of patients who are candidates for breast-conserving therapy.MethodsThe study was a prospective series of 23 breasts with breast cancer that underwent both FDG PET and MRI before surgery. Systemic staging with FDG PET was also performed. The correlation between the results of these examinations and histological findings was thus examined. The maximum standardized uptake value (SUVmax) of the tumors was investigated in association with the patient prognoses.ResultsWhen evaluating the local tumor extent, the accuracy of FDG PET (43.5%) was significantly lower than that of MRI (91%) (P < 0.001). The sensitivity, specificity, and accuracy of FDG PET regarding the nodal status were 60, 94, and 87%, respectively. No patients demonstrated any distant metastasis, whereas FDG PET gave a false positive in one patient. The mean follow-up period was 61 months. The SUVmax value of the worse prognosis patient group was significantly higher than that of the good prognosis patient group (P = 0.032).ConclusionsFDG PET is not a breast imaging modality for evaluating the local tumor extent, but it is useful for predicting the prognoses of patients who are candidates for breast-conserving therapy.", "corpus_id": 207411569, "score": 0 }, { "doc_id": "25410221", "title": "Sequential Positron Emission Tomography Using [18F]Fluorodeoxyglucose for Monitoring Response to Chemotherapy in Metastatic Breast Cancer", "abstract": "Purpose: To evaluate the clinical value of positron emission tomography (PET) for monitoring chemotherapy in metastatic breast cancer. Experimental Design: Twenty patients with hormonorefractory or hormonoreceptor-negative multimetastatic breast cancer were prospectively included. PET studies were done at baseline, at day 21 after the first cycle and at day 21 after the third cycle of chemotherapy. Metabolic response was defined based on visual and various modes of standardized uptake value (SUV) analysis of sequential PET studies. Results: After one cycle, PET indicated a partial response in 12 patients, stable disease in 7 patients, and progressive disease in 1 patient, according to the visual analysis. After three cycles, PET showed a complete response in 5 patients, partial response in 11 patients, stable disease in 3 patients, and progressive disease in 1 patient. Seventy-five percent of the patients showing a metabolic response on visual analysis effectively responded to the treatment. The average SUV decreased on both the second and the third PET study, but only changes measured after three cycles of chemotherapy predicted the clinical response to chemotherapy and the overall survival. All methods for calculating the SUV (normalized for body weight, body surface area, or lean body mass) provided similar results. Conclusion: Semiquantitative analysis of [18F]fluorodeoxyglucose-PET studies done after three cycles of chemotherapy is useful for monitoring the response to chemotherapy in metastatic breast cancer.", "corpus_id": 25410221, "score": 0 }, { "doc_id": "20598390", "title": "Serial 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) to monitor treatment of bone-dominant metastatic breast cancer predicts time to progression (TTP)", "abstract": "BackgroundThe response of bone-dominant (BD) breast cancer to therapy is difficult to assess by conventional imaging. Our preliminary studies have shown that quantitative serial 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) correlates with therapeutic response of BD breast cancer, but the relationship to long-term outcome measures is unknown. Our goal was to evaluate the prognostic power of serial FDG PET in BD breast cancer patients undergoing treatment.MethodsWe reviewed medical records of 405 consecutive breast cancer patients referred for FDG PET. Of these, 28 demonstrated metastatic BD breast cancer, were undergoing treatment, had at least 2 serial PET scans, and had abnormal FDG uptake on the first scan. Standardized uptake value (SUV) for the most conspicuous bone lesion at the initial scan, absolute change in SUV over an interval of 1–17 months, and percent change in SUV were considered as predictors of time-to-progression (TTP) and time to skeletal-related event (t-SRE).ResultsUsing proportional hazards regression, smaller percentage decreases in SUV (or increases in SUV) were associated with a shorter TTP (P < 0.006). A patient with no change in SUV was twice as likely to progress compared to a patient with a 42% median decrease in SUV. A higher SUV on the initial FDG PET predicted a shorter t-SRE (hazard ratio = 1.30, P < 0.02).ConclusionsChanges in serial FDG PET may predict TTP in BD metastatic breast cancer patients. However, larger prospective trials are needed to validate changes in FDG PET as a surrogate endpoint for treatment response.", "corpus_id": 20598390, "score": 0 }, { "doc_id": "32504957", "title": "Early prediction of response to chemotherapy in metastatic breast cancer using sequential 18F-FDG PET.", "abstract": "UNLABELLED\nChemotherapy is currently the treatment of choice for patients with high-risk metastatic breast cancer. Clinical response is determined after several cycles of chemotherapy by changes in tumor size as assessed by conventional imaging procedures including CT, MRI, plain film radiography, or ultrasound. The aim of this study was to evaluate the use of sequential 18F-FDG PET to predict response after the first and second cycles of standardized chemotherapy for metastatic breast cancer.\n\n\nMETHODS\nEleven patients with 26 metastatic lesions underwent 31 (18)F-FDG PET examinations (240-400 MBq of 18F-FDG; 10-min 2-dimensional emission and transmission scans). Clinical response, as assessed by conventional imaging after completion of chemotherapy, served as the reference. 18F-FDG PET images after the first and second cycles of chemotherapy were analyzed semiquantitatively for each metastatic lesion using standardized uptake values (SUVs) normalized to patients' blood glucose levels. In addition, whole-body 18F-FDG PET images were viewed for overall changes in the 18F-FDG uptake pattern of metastatic lesions within individual patients and compared with conventional imaging results after the third and sixth cycles of chemotherapy.\n\n\nRESULTS\nAfter completion of chemotherapy, 17 metastatic lesions responded, as assessed by conventional imaging procedures. In those lesions, SUV decreased to 72% +/- 21% after the first cycle and 54% +/- 16% after the second cycle, when compared with the baseline PET scan. In contrast, 18F-FDG uptake in lesions not responding to chemotherapy (n = 9) declined only to 94% +/- 19% after the first cycle and 79% +/- 9% after the second cycle. The differences between responding and nonresponding lesions were statistically significant after the first (P = 0.02) and second (P = 0.003) cycles. Visual analysis of 18F-FDG PET images correctly predicted the response in all patients as early as after the first cycle of chemotherapy. As assessed by 18F-FDG PET, the overall survival in nonresponders (n = 5) was 8.8 mo, compared with 19.2 mo in responders (n = 6).\n\n\nCONCLUSION\nIn patients with metastatic breast cancer, sequential 18F-FDG PET allowed prediction of response to treatment after the first cycle of chemotherapy. The use of 18F-FDG PET as a surrogate endpoint for monitoring therapy response offers improved patient care by individualizing treatment and avoiding ineffective chemotherapy.", "corpus_id": 32504957, "score": 0 }, { "doc_id": "22914308", "title": "Bone metastases in patients with metastatic breast cancer: morphologic and metabolic monitoring of response to systemic therapy with integrated PET/CT.", "abstract": "PURPOSE\nTo retrospectively compare morphologic and metabolic changes in bone metastases in response to systemic therapy in patients with metastatic breast cancer (MBC) with integrated positron emission tomography (PET)/computed tomography (CT).\n\n\nMATERIALS AND METHODS\nThe institutional review board waived the requirement for informed consent and approved this HIPAA-compliant study. A retrospective analysis was performed with 102 women (mean age, 55 years) with MBC who received systemic treatment. All patients underwent integrated PET/CT before and after treatment. Two reviewers analyzed the images in consensus. Morphologic changes, including morphologic patterns, and lesion attenuation were evaluated. Standardized uptake value (SUV) and total lesion glycolysis (TLG) were analyzed to evaluate metabolic changes. Uni- and multivariate analyses were performed to identify factors that enabled response duration (RD) to be predicted.\n\n\nRESULTS\nAt baseline, the morphologic patterns of the target lesions were lytic (n = 33), sclerotic (n = 22), mixed (n = 42), and unclassified (n = 5). Progression of sclerotic change after treatment was identified in 49 patients (48%). After treatment, the mean attenuation of the lesion increased, whereas the mean SUV and TLG decreased. Increases in attenuation correlated significantly with decreases in SUV (r = -0.510, P < .001) and TLG (r = -0.491, P < . 001). Univariate analysis revealed that the increase in attenuation and the decrease in SUV were potential predictors of RD. Multivariate analysis revealed that an increase in the change in SUV was a significant predictor of RD (relative risk, 2.4; P = .003).\n\n\nCONCLUSION\nA decrease in SUV after treatment was an independent predictor of RD in patients with MBC who had bone metastases.", "corpus_id": 22914308, "score": 0 }, { "doc_id": "2955537", "title": "Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group.", "abstract": "[18F]-fluorodeoxyglucose ([18F]-FDG) uptake is enhanced in most malignant tumours which in turn can be measured using positron emission tomography (PET). A number of small clinical trials have indicated that quantification of the change in tumour [18F]-FDG uptake may provide an early, sensitive, pharmacodynamic marker of the tumoricidal effect of anticancer drugs. This may allow for the introduction of subclinical response for anticancer drug evaluation in early clinical trials and improvements in patient management. For comparison of results from smaller clinical trials and larger-scale multicentre trials a consensus is desirable for: (i) common measurement criteria; and (ii) reporting of alterations in [18F]-FDG uptake with treatment. This paper summarises the current status of the technique and recommendations on the measurement of [18F]-FDG uptake for tumour response monitoring from a consensus meeting of the European Organization for Research and Treatment of Cancer (EORTC) PET study group held in Brussels in February 1998 and confirmed at a subsequent meeting in March 1999.", "corpus_id": 2955537, "score": 0 }, { "doc_id": "15656065", "title": "From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors", "abstract": "The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with 18F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0. Methods: PubMed searches, including searches for the terms RECIST, positron, WHO, FDG, cancer (including specific types), treatment response, region of interest, and derivative references, were performed. Abstracts and articles judged most relevant to the goals of this report were reviewed with emphasis on limitations and strengths of the anatomic and PET approaches to treatment response assessment. On the basis of these data and the authors' experience, draft criteria were formulated for PET tumor response to treatment. Results: Approximately 3,000 potentially relevant references were screened. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria is widely applied but still has limitations in response assessments. For example, despite effective treatment, changes in tumor size can be minimal in tumors such as lymphomas, sarcoma, hepatomas, mesothelioma, and gastrointestinal stromal tumor. CT tumor density, contrast enhancement, or MRI characteristics appear more informative than size but are not yet routinely applied. RECIST criteria may show progression of tumor more slowly than WHO criteria. RECIST 1.1 criteria (assessing a maximum of 5 tumor foci, vs. 10 in RECIST) result in a higher complete response rate than the original RECIST criteria, at least in lymph nodes. Variability appears greater in assessing progression than in assessing response. Qualitative and quantitative approaches to 18F-FDG PET response assessment have been applied and require a consistent PET methodology to allow quantitative assessments. Statistically significant changes in tumor standardized uptake value (SUV) occur in careful test–retest studies of high-SUV tumors, with a change of 20% in SUV of a region 1 cm or larger in diameter; however, medically relevant beneficial changes are often associated with a 30% or greater decline. The more extensive the therapy, the greater the decline in SUV with most effective treatments. Important components of the proposed PERCIST criteria include assessing normal reference tissue values in a 3-cm-diameter region of interest in the liver, using a consistent PET protocol, using a fixed small region of interest about 1 cm3 in volume (1.2-cm diameter) in the most active region of metabolically active tumors to minimize statistical variability, assessing tumor size, treating SUV lean measurements in the 1 (up to 5 optional) most metabolically active tumor focus as a continuous variable, requiring a 30% decline in SUV for “response,” and deferring to RECIST 1.1 in cases that do not have 18F-FDG avidity or are technically unsuitable. Criteria to define progression of tumor-absent new lesions are uncertain but are proposed. Conclusion: Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria have limitations, particularly in assessing the activity of newer cancer therapies that stabilize disease, whereas 18F-FDG PET appears particularly valuable in such cases. The proposed PERCIST 1.0 criteria should serve as a starting point for use in clinical trials and in structured quantitative clinical reporting. Undoubtedly, subsequent revisions and enhancements will be required as validation studies are undertaken in varying diseases and treatments.", "corpus_id": 15656065, "score": 0 }, { "doc_id": "20153161", "title": "Triple-Negative Breast Cancer: Early Assessment with 18F-FDG PET/CT During Neoadjuvant Chemotherapy Identifies Patients Who Are Unlikely to Achieve a Pathologic Complete Response and Are at a High Risk of Early Relapse", "abstract": "Triple-negative breast cancer, an aggressive subtype, represents 15% of invasive breast tumors. This prospective study investigated whether early changes in 18F-FDG tumor uptake during neoadjuvant chemotherapy (NAC) can predict outcomes. Methods: Twenty (M0) patients underwent 18F-FDG PET/CT at baseline and after the second cycle. NAC was continued irrespective of PET results. Results: At surgery, 6 patients had a pathologic complete response, whereas 14 had residual tumor. Four patients showed early relapse (in the 2 y after surgery). There were 11 metabolic responders and 9 nonresponders using a 42% decrease in maximum standardized uptake value as a cutoff. In nonresponding patients, the risk of residual tumor at surgery was 100% (vs. 45% in responders; P = 0.014), and the risk of early relapse was 44% (vs. 0%; P = 0.024). Conclusion: A less than 42% decrease in 18F-FDG uptake at 2 cycles means residual tumor at the end of NAC and a high risk of early relapse.", "corpus_id": 20153161, "score": 0 }, { "doc_id": "23149409", "title": "Magnetic resonance imaging response monitoring of breast cancer during neoadjuvant chemotherapy: relevance of breast cancer subtype.", "abstract": "PURPOSE\nTo evaluate the relevance of breast cancer subtypes for magnetic resonance imaging (MRI) markers for monitoring of therapy response during neoadjuvant chemotherapy (NAC).\n\n\nPATIENTS AND METHODS\nMRI examinations were performed in 188 women before and during NAC. MRI interpretation included lesion morphology at baseline, changes in morphology, size, and contrast uptake kinetics (initial and late enhancement). By using immunohistochemistry, tumors were divided into three subtypes: triple negative, human epidermal growth factor receptor 2 (HER2) positive, and estrogen receptor (ER) positive/HER2 negative. Tumor response was assessed dichotomously (ie, presence or absence of residual tumor in the surgical specimen). Complementary, a continuous scale assessment was used (the breast response index [BRI], representing the relative change in tumor stage). Multivariate regression analysis and receiver operating characteristic analysis were employed to establish significant associations.\n\n\nRESULTS\nResidual tumor at pathology was present in 31 (66%) of 47 triple-negative tumors, 23 (61%) of 38 HER2-positive tumors, and 96 (93%) of 103 ER-positive/HER2-negative tumors. Multivariate analysis of residual disease showed significant associations between breast cancer subtype and MRI (area under the curve [AUC], 0.84; P < .001). BRI also showed significant correlation among breast cancer subtype, MRI, and age (Pearson's r = 0.465; P < .001). In subset analysis, this was only significant for triple-negative tumors (P < .001) and HER2-positive tumors (P < .05). Residual tumor after NAC in the triple-negative and HER2-positive group is significantly associated with the change in largest diameter of late enhancement during NAC (AUC, 0.76; P < .001). No associations were found for ER-positive/HER2-negative tumors.\n\n\nCONCLUSION\nMRI during NAC to monitor response is effective in triple-negative or HER2-positive disease but is inaccurate in ER-positive/HER2-negative breast cancer.", "corpus_id": 23149409, "score": 0 }, { "doc_id": "36893518", "title": "New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.", "abstract": "Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.", "corpus_id": 36893518, "score": 0 }, { "doc_id": "36879985", "title": "[New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)].", "abstract": "This paper is an overview of the new response evaluation criteria in solid tumours: revised RECIST guideline (version 1. 1), with a focus on updated contents.", "corpus_id": 36879985, "score": 0 }, { "doc_id": "31763493", "title": "Powerful prognostic stratification by [18F]fluorodeoxyglucose positron emission tomography in patients with metastatic breast cancer treated with high-dose chemotherapy.", "abstract": "PURPOSE\nThis study examines the use of [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the evaluation of the therapeutic response for patients treated with high-dose chemotherapy (HDC) with autologous stem cell transplantation for metastatic breast cancer (MBC) focusing on prognostic stratification.\n\n\nPATIENTS AND METHODS\nForty-seven patients with MBC were treated with a maximum of three cycles of HDC. Therapeutic response was assessed with conventional imaging (CImg; including a computed tomography in all cases and ultrasound, mammography, and bone scanning as clinically indicated) and by FDG-PET study performed after the last cycle of HDC. Parameters analyzed for predicting survival were FDG-PET and CImg results, pattern of disease, prior treatment, and HDC regimen.\n\n\nRESULTS\nComplete responses were observed in 16 patients (37%) with CImg and 34 patients (72%) with FDG-PET. The FDG-PET result was the most powerful and independent predictor of survival; patients with a negative post-treatment FDG-PET had a longer median survival than patients with a positive FDG-PET (24 months v 10 months; P < .001). By multivariate analysis the relative risk (RR) of death was higher in patients with FDG-PET-positive disease (RR, 5.3), prior anthracycline treatment (RR, 3.3), or with visceral metastasis (RR, 2.4).\n\n\nCONCLUSION\nA single FDG-PET study performed after completion of HDC for MBC can powerfully stratify for survival. This may have implications for how we should assess outcome after conventional-dose therapy for MBC and warrants additional study.", "corpus_id": 31763493, "score": 0 } ]

{ "doc_id": "15897720", "title": "The analgesic efficacy of remifentanil for labour. Systematic review of the recent literature.", "abstract": "BACKGROUND AND AIMS\nAlthough epidural analgesia is still regarded as the gold standard for labour analgesia due to its efficacy, in cases of contraindication, systemic remifentanil is an alternative. Since the first demonstration of the safety of remifentanil in obstetric analgesia in 1996, this has been repeatedly confirmed for both mother and newborn. The aim of this meta-analysis is to evaluate recently published studies (up to December 2014) on the analgesic efficacy of remifentanil during labour (as a Visual Analogue Scale (VAS) decrease in the first hour by 2 or more).\n\n\nMETHODS\nSearch of the US National Library of Medicine, National Institutes of Health (www.pubmed.gov), SCOPUS database (www.scopus.com) and Web of Science database (www.webofknowledge.com) using the key words \"labour\" and \"remifentanil\". 44 identified articles were included in the review and 15 published randomised controlled studies were incorporated into the meta-analysis. This was based on the fixed model and described by differences in the VAS between t=0 and t=1 hour after remifentanil administration using the 95% confidence interval (CI). The analysis was computed using the Comprehensive meta-analysis version 2.2.064.\n\n\nRESULTS\nThe combined data from the meta-analysis showed a statistically significant decrease in VAS in the remifentanil group. From a comparison of the CIs of summary estimates with a cut-off decrease of VAS 2, for the fixed model, there was a statistically significantly greater decrease in VAS than the cut-off. In the systematic review, we describe possible modes of application, dosage and side-effects for mother, fetus/ newborn.\n\n\nCONCLUSION\nThe meta-analysis presented here confirms that remifentanil for labour analgesia is effective but questions remain which can only be answered by further randomized trials.", "corpus_id": 15897720 }

[ { "doc_id": "205556540", "title": "[Peripartum period and hemophilia carriers].", "abstract": "Women who are carriers for hemophilia are usually considered as safe carriers. However, they can present hemorragic symptoms associated with low factor VIII or IX levels. During pregancy, factor VIII increases whereas factor IX does not. The peripartum period is at risk of increased bleeding in these women. Here are presented reports of clinical data concerning two hemophilia carriers with low factor VIII or IX (30-40%) during the peripartum period. They received remifentanil and ketamine for labor pain management because of contraindication of epidural and spinal analgesia. Delivery occured quickly but they presented immediate moderate postpartum haemorrage. They did not necessitate blood transfusion. The one with hemophilia A received desmopressin just after delivery and the other one received factor IX when she arrived in delivery room. Blood factor VIII or IX has to be assessed in these women with familial history of hemophilia and bleeding. During pregnancy, factor VIII increases and can be assessed many times during pregnancy expecting a level over 50%. Factor IX does not really increase during pregancy and hemorrage can occur. Epidural and spinal anesthesia seem to be contraindicated as far as recommandations are concerned. Coagulation factor substitution is a mean of increasing factor level before these anaesthesias and can be discussed for each case.", "corpus_id": 205556540, "score": 0 }, { "doc_id": "73274943", "title": "Intravenous patient-controlled analgesia for labour: a survey of UK practice", "abstract": "Background Although regional techniques offer superior analgesia during labour, many women receive other methods of pain relief. Furthermore, there is a specific need for analgesia in a small population of labouring women for whom regional techniques are contraindicated, unavailable or impossible to perform. We surveyed current UK practice of labour analgesia for such patients, with particular reference to the use of intravenous patient-controlled analgesia. Methods Following approval from the Obstetric Anaesthetists' Association, a questionnaire was sent to the lead anaesthetic consultants of 243 obstetric units in the United Kingdom. The questionnaire evaluated the availability of methods of pain relief other than regional blocks. Information was sought on patient-controlled intravenous analgesia regimens and patient monitoring. Results A total of 159 questionnaires were returned giving a response rate of 65.4%. The majority of units that responded (95.5%) used either intramuscular pethidine or diamorphine. Nearly half (49%) offered patient-controlled intravenous analgesia for labour pain. One third of units (36%) had an analgesic protocol for women in whom regional anaesthetic techniques were contraindicated. With patient-controlled intravenous analgesia, remifentanil (34.6%) was the most commonly used opioid for live births while morphine (35.5%) was used more commonly for deliveries involving intrauterine deaths. Conclusion The survey demonstrated that, when regional techniques were contraindicated, patient-controlled intravenous opioid analgesia was employed in almost half of the units responding to the questionnaire.", "corpus_id": 73274943, "score": 0 }, { "doc_id": "115992912", "title": "[Obstetric analgesia in German clinics. Remifentanil as alternative to regional analgesia].", "abstract": "OBJECTIVE\nEpidural regional analgesia is still recommended as the gold standard for obstetric analgesia due to its high efficacy and less depressing effects to the central nervous system. However, if absolute or relative contraindications for a regional anesthetic technique are present, there is a need for an effective and safe alternative. This survey investigates the current use of intravenous opioids, with a focus on remifentanil as patient-controlled intravenous analgesia (PCIA), in obstetrics in German hospitals.\n\n\nMETHODS\nA questionnaire was sent to 930 anesthesia units. Data were collected and analyzed using SPSS statistical package (PASW Statistics 18.0). The questionnaire requested statistics on births, the existing alternative labor analgesic techniques, intramuscular or intravenous opioids, PCIA or other options. Furthermore, the questions focused on details regarding the use of intravenous opioids in conjunction with PCIA techniques.\n\n\nRESULTS\nReplies were received from 343 anesthetic departments (response rate 37%) and 281 clinics had an obstetric department and were included for further analysis. All clinics provided a 24 h epidural service and the most commonly used opioids were pethidine (19%), meptazinol (17%) and piritramide (16%) for intermittent intravenous/intramuscular administration. Only 0.9% of the clinics offered nitrous oxide as an alternative analgesic technique and 22 (8%) of the responding anesthetic departments offered PCIA. Remifentanil was the most popular choice in conjunction with PCIA (68%) for labor analgesia. Most hospitals offering PCIA continuously monitor oxygen saturation (91%) and the blood pressure (95%), whereas continuous electrocardiograms (18%) and clinical observation of the respiratory frequency (19%) were less commonly reported. However, most clinics offered one-to-one nursing for the parturient using an opioid PCIA.\n\n\nCONCLUSIONS\nThis survey revealed that pethidine, meptazinol and piritramide are the most common opioids for opioid-based systemic labor pain relief in Germany. If PCIA is offered, remifentanil is the most popular opioid. However, only a few clinics are routinely using PCIA for obstetric analgesia. Furthermore the study showed that the current monitoring standards seem to have room for improvement with respect to safe administration of an opioid PCIA. The safety standards require continuous observation of the oxygen saturation, the possibility for oxygen supply, one-to-one nursing for a close clinical observation of the mother and the presence of an anesthetist during the initial titration phase to safely apply this technique. Applying these safety standards PCIA may prove a useful alternative for central neuraxial labor analgesia in those women who either do not want, cannot have or do not need epidural analgesia.", "corpus_id": 115992912, "score": 0 }, { "doc_id": "32207442", "title": "Neonatal depression after obstetrical analgesia with pethidine. the role of the injection‐delivery time interval and of the plasma concentrations of pethidine and norpethidine", "abstract": "Pethidine (100 mg) was administered i.m. to women in labor at different times before delivery. The interval before respiration in the newborn became sustained was shorter if pethidine was given less than one hour before delivery. The respiratory rate of the newborn increased after naloxone injection in 40 per cent of the cases, mostly when intrauterine exposure to pethidine exceeded one hour. The plasma concentrations of pethidine and norpethidine were measured in mother and newborn. The concentrations in the umbilical vein and artery indicated a continuous net transfer of pethidine from mother to fetus for approximately two hours. This correlates with the clinical finding of maximal neonatal depression 2–3 hours after maternal injection. The concentrations of norpethidine increased with a longer time interval between injection and delivery, but were probably too low to have any effect on the newborn. Neonatal depression seems to be related to the amount of unmetabolized pethidine that has been transferred from mother to fetus but not to norpethidine as had been suspected earlier.", "corpus_id": 32207442, "score": 0 }, { "doc_id": "24128955", "title": "Disposition of meperidine and normeperidine following multiple doses during labor. II. Fetus and neonate.", "abstract": "It has been suggested that continued diffusion gradients from mother to fetus would exist and that both meperidine and normeperidine would accumulate in the fetus following multiple doses of meperidine to the mother during labor. However, no pharmacokinetic data are available. Therefore, the purpose of this study was to document the disposition of meperidine and normeperidine in the fetus and neonate following multiple doses of meperidine to the mother over long time periods. Twelve infants were studied. The results show surprisingly high concentrations of both meperidine and normeperidine in fetal blood at delivery. In addition, the amount of normeperidine increased with time in umbilical cord blood, the ratio of normeperidine to meperidine increased with time, and the umbilical artery-to-vein ratio of meperidine (but not normeperidine) was greater than one following long drug-to-delivery intervals. The data also suggest that with long drug-to-delivery intervals the levels of normeperidine may become clinically important and that the elimination of both compounds by the neonate is prolonged. The study suggests that multiple doses to the mother over long time periods result in maximum accumulation of both meperidine and normeperidine in fetal tissues.", "corpus_id": 24128955, "score": 0 }, { "doc_id": "45764311", "title": "Effectiveness of intravenous meperidine for pain relief in the first stage of labour.", "abstract": "OBJECTIVE\nTo determine the effectiveness and side effects of intravenous meperidine in labour pain relief.\n\n\nMATERIAL AND METHOD\nA double blind, randomized controlled trial was conducted in 84 parturients, using normal saline as control. Visual analogue scale, postpartum parturients' opinion of effectiveness, sedative scores, nausea/vomiting, dizziness, delivery method, Apgar scores, and naloxone prescription were assessed.\n\n\nRESULT\nThere were no statistically significant differences between the mean and median of visual analogue scale of meperidine and control group. In addition, the sedative scores, nausea/vomiting and dizziness in the meperidine group occurred more than those in the control group significantly. Even mean of the pain increment in the meperidine group was less than those in the control group (p < 0.05). The parturients' opinion on the effectiveness of pain relief during labor within 24 hours of the first postpartum day was only 23.80 per cent in the meperidine group, however, it was statistically significantly different when compared to 7.10 per cent in the control group.\n\n\nCONCLUSION\nIntravenous meperidine exhibited the effectiveness of pain relief of only 23.80 per cent of the subjects, in addition, it may cause many side effects.", "corpus_id": 45764311, "score": 0 }, { "doc_id": "44343669", "title": "Lack of analgesic effect of systemically administered morphine or pethidine on labour pain", "abstract": "severe early onset pre-eclampsia. Magnesium levels were used to add a safety factor when the protocol was formulated in our unit, We find that serum levels of magnesium provide objective data about the therapy and now function more to assess undertreatment than overdose with subsequent adjustment of the infusion rate. We do not find a problem with the processing of the samples. The theoretical problem for the clinician who uses lower limb reflexes to assess toxicity of magnesium still exists when the epidural block may obliterate the tendon the reflexes and confound the diagnosis. The patient was not eclamptic and therefore we do not feel that it is necessary to provide evidence for serum monitoring of magnesium therapy. In fact, since its inception in our unit we have observed only two eclamptic fits in more than 20,000 deliveries. In addition, ldama and Lindow are under the misconception that we performed induction of labour in the reported case. To the contrary, this was a case of induced abortion with synthetic prostaglandins, which do not produce a physiological labour.", "corpus_id": 44343669, "score": 0 }, { "doc_id": "20616759", "title": "Preliminary Pharmacokinetics and Pharmacodynamics of an Ultra‐Short‐Acting Opioid: Remifentanil (GI87084B)", "abstract": "Remifentanil is a newly synthesized 4-anilidopiperidine with an ester side chain susceptible to esterase metabolism. We evaluated the safety, analgesic efficacy, and pharmacokinetics of remifentanil in 48 male volunteers. Volunteers were randomized to receive increasing doses of remifentanil, alfentanil, or placebo. Analgesic efficacy was evaluated by increasing tolerance to a spring-loaded rod measured at the tibia and sternum at multiple time points. Respiratory depression was measured by changes in arterial blood gas tensions and peripheral hemoglobin oxygen saturation. Hemodynamics were continuously monitored by means of an intra-arterial catheter. Both remifentanil and alfentanil produced a dose-dependent increase in analgesia and respiratory depression. Remifentanil was 20 to 30 times more potent (milligram to milligram) than alfentanil when assessed by either analgesic efficacy or respiratory measures. The pharmacokinetics of remifentanil were best described by a biexponential decay curve. Remifentanil had a small volume of distribution of 0.39 (SD, ±0.25) L/kg (alfentanil, 0.52 ± 2 L/kg), with a rapid distribution phase of 0.94 (SD, ±0. 57) min and an extremely short elimination half-life of 9.5 (SD, ±4) min compared with an elimination half-life of alfentanil of 58 (SD, ±7.6) min. The t1/2 ke0 (half-time for equilibration between plasma and the effect compartment) of remifentanil for analgesia was calculated as 1.3 min. Thus, remifentanil appears to have a pharmacologic profile similar to other potent μ agonists, but with exceptionally short-lasting pharmacokinetics, which is likely to make it a very useful opioid for clinical practice.", "corpus_id": 20616759, "score": 0 }, { "doc_id": "29923396", "title": "A Comparison of Remifentanil Parturient-Controlled Intravenous Analgesia with Epidural Analgesia: A Meta-Analysis of Randomized Controlled Trials", "abstract": "BACKGROUND:Epidural analgesia is generally accepted as the most effective form of pain relief during labor. Remifentanil patient-controlled IV analgesia (PCIA), which is less invasive than epidural analgesia, may be an attractive alternative. In this meta-analysis, we compared the efficacy and safety of the 2 analgesic techniques for labor pain. METHODS:Databases of PubMed, EMBASE, and Cochrane Library were searched independently by 2 reviewers to retrieve eligible randomized controlled clinical trials. The primary end points were pain scores at 1 and 2 hours, and the secondary end points were nausea, vomiting, pruritus, and umbilical artery pH values. Mean difference (MD) or risk ratio with 95% confidence intervals (CIs) were calculated for each end point. GRADE profiler was applied to assess the quality of evidence. RESULTS:Five eligible trials were retrieved and analyzed. We found that parturients with remifentanil PCIA had higher visual analog scale (10-cm scale) pain scores than those who received epidural analgesia at 1 hour (MD = 1.9 cm; 95% CI, 0.5–3.3; I2 = 94%) and 2 hours (MD = 3.0 cm; 95% CI, 0.7–5.2; I2 = 89%) after initiation of analgesia. There was no statistical difference between epidural analgesia and remifentanil PCIA in the incidence of nausea, vomiting, pruritus, or umbilical artery pH values. However, the CIs are quite wide and contain clinically significant differences. According to GRADE profiler, most end points had moderate quality except that pain scores at 1 hour were of low quality. CONCLUSIONS:This meta-analysis suggests that remifentanil PCIA is not superior to epidural analgesia in analgesic efficacy during labor. Given the wide CIs of the pooled results for secondary maternal and neonatal outcomes, definite conclusions cannot be drawn for those outcomes. Further studies are still warranted to validate these conclusions.", "corpus_id": 29923396, "score": 1 }, { "doc_id": "18416072", "title": "Comparison of parturient - controlled remifentanil with epidural bupivacain and sufentanil for labour analgesia: randomised controlled trial.", "abstract": "INTRODUCTION\nEpidural analgesia (EA) has significant contraindications including coagulation disorders and parturient refusal. One alternative is intravenous self-administered analgesia using the ultra short-acting opioid remifentanil (rPCA). We compared the efficiency and safety of standard epidural analgesia with parturient-controlled intravenous analgesia using remifentanil as well as personal satisfaction.\n\n\nMATERIALS AND METHODS\nWe enrolled twelve ASA I classified women with singleton pregnancy who delivered vaginally in the period 3/2010-5/2010 and who received rPCA (n=12) in standard analgesic protocol: 20 µg boluses using PCA pump with a lockout interval of 3 min. The control group consisted of 12 pregnant women who received EA (n=12): 0.125% bupivacaine with sufentanil 0.5 µg/mL in top-up boluses every hour until delivery. Data were acquired from standard Acute Pain Service (APS) form and patient medical records (demographic, labour course parameters), Visual Analogue Scale (VAS), Bromage Scale (BS) and adverse effects of analgesia.\n\n\nRESULTS\nThere were no demographic or labour course parameter differences between groups (P>0.05). The differences in VAS decrease (P=0.056) and parturient satisfaction (P=0.24) during the whole analgesia administration were statistically insignificant. The main limitation of the study was small sample and enrolment of healthy singleton pregnant women only.\n\n\nCONCLUSION\nRemifentanil use in obstetric analgesia is a viable alternative to EA, especially in cases of EA contraindications and parturient disapproval.", "corpus_id": 18416072, "score": 1 }, { "doc_id": "23854808", "title": "Intravenous Remifentanil: Placental Transfer, Maternal and Neonatal Effects", "abstract": "Background Remifentanil has not been studied in obstetric patients. This study evaluates the placental transfer of remifentanil and the neonatal effects when administered as an intravenous infusion. Methods Nineteen parturients underwent nonemergent cesarean section with epidural anesthesia and received 0.1 [micro sign]g [middle dot] kg‐1 [middle dot] min‐1 remifentanil intravenously, which was continued until skin closure. Maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood samples were obtained at delivery for analysis of drug concentrations of remifentanil, its metabolite, and blood gases. Maternal vital signs were monitored continuously, and pain and sedation levels were assessed intermittently. Apgar scores were obtained at 1, 5, 10, and 20 min, and Neonatal and Adaptive Capacity Scores were noted 30 and 60 min after delivery. Parturients and newborns were observed for at least 24 h after surgery for side effects. Results The means and SDs of UV:MA and UA:UV ratios for remifentanil were 0.88 +/‐ 0.78 and 0.29 +/‐ 0.07, respectively. Mean clearance was 93 ml [middle dot] min‐1 [middle dot] kg‐1. The mean UV:MA and UA:MV ratios for remifentanil acid were 0.56 +/‐ 0.29 and 1.23 +/‐ 0.89, respectively. The mean MA (remifentanil acid):MA (remifentanil) ratio was 2.92 +/‐ 3.65. There were no adverse effects on the neonates, but there was a sedative effect and respiratory depressant effect on the mothers. Conclusions Remifentanil crosses the placenta but appears to be rapidly metabolized, redistributed, or both. Maternal sedation and respiratory changes occur, but without adverse neonatal or maternal effects.", "corpus_id": 23854808, "score": 0 }, { "doc_id": "76065418", "title": "A Randomized Controlled Trial of the Efficacy and Respiratory Effects of Patient-controlled Intravenous Remifentanil Analgesia and Patient-controlled Epidural Analgesia in Laboring Women", "abstract": "BACKGROUND:Safe and effective alternatives are required in labor when epidural analgesia is not appropriate. We hypothesized that patient-controlled IV remifentanil labor analgesia would not be inferior to patient-controlled epidural labor analgesia.METHODS:This randomized nonblinded controlled noni", "corpus_id": 76065418, "score": 1 }, { "doc_id": "32729328", "title": "[French national survey on remifentanil utilisation for obstetrical peridural analgesia].", "abstract": "OBJECTIVES\nThe last French survey on alternatives to neuraxial anaesthesia for labour pain was published in 1997. However, intravenous remifentanil has become increasingly used as an option for labour analgesia. We evaluated the use of remifentanil as an alternative to epidural analgesia in level 2 and 3 French maternities in 2009.\n\n\nSTUDY DESIGN\nThis was an internet-based French survey performed in 2009 including all level 2 and 3 maternities. Data recorded were maternity unit characteristic, alternatives to neuraxial analgesia used, and remifentanil administration protocols.\n\n\nRESULTS\nTwo hundred and forty maternity units received the survey and 103 responses were completed. A written institutional alternative analgesia protocol for labour pain was present in 78%. Alternative labour analgesia included intermittent nitrous oxide inhalation (58%), intravenous nalbuphine (52%), patient-controlled intravenous administration of remifentanil (52%) and sufentanil (46%). Pethidine administration was reported by one maternity unit (1%). The bolus dose of remifentanil scheduled, and background infusion varied widely between maternity units. The analgesic efficacy of remifentanil used for labour pain was evaluated as moderate (55%) or good (43%). Two serious adverse events were reported.\n\n\nCONCLUSION\nIntravenous administration of remifentanil was largely reported as an alternative to neuraxial anaesthesia for labour pain. Although remifentanil administration was most often based on a local written protocol, bolus dose and background infusion varied widely between maternity units.", "corpus_id": 32729328, "score": 0 }, { "doc_id": "25041646", "title": "Patient-controlled intravenous analgesia as an alternative to epidural analgesia during labor: questioning the use of the short-acting opioid remifentanil. Survey in the French part of Belgium (Wallonia and Brussels).", "abstract": "Childbirth ranks among the most intense experiences of acute pain. Neuraxial analgesia (i.e. epidural or combined spinal-epidural technique) is the most effective way to relieve that pain but it is contraindicated or impossible to perform for some parturients. We designed a survey of the current use of analgesic alternatives to epidural analgesia (EA) for labor pain, specifically the use of opioid patient-controlled intravenous analgesia (PCIA), in the French part of Belgium (Wallonia and Brussels). A questionnaire was mailed to the departmental chair of the hospitals with an obstetric unit, both in university and non-university centers (total of 53 centers). The questionnaire evaluated the availability of EA, the alternatives used when EA was contraindicated, the use of opioid-based PCIA for labor analgesia as well as opioid preference and doses, and finally the reasons for not using opioid PCIA. The response rate was 67.5% (36 centers). Among the responding hospitals, EA was available for 68% (range 25-85%) of labors and deliveries. When EA was not available or contraindicated, a parenteral opioid (piritramide, tramadol or pethidine) was proposed in 19% (7/36) of the centers, Entonox in 11% (4/36), a pudendal block by obstetricians in 28% (10/36) and non-pharmacologic alternatives (i.e. hypnosis, sophrology, baths and massages) in 19% (7/36). In 28% (10/36) of the centers however, no analgesic alternative was proposed. Opioid PCIA was employed in 36% (13/36) of the centers and for an additional 11% (4/36) only in case of intrauterine death. Remifentanil was the first choice (76.5% of the PCIA), followed by sufentanil (23.5%). Other opioids (piritramide, morphine, fentanyl) and ketamine were also administered by PCIA. Forty-five percents of the centers reported never using opioid PCIA by either lack of knowledge (7%), fear of maternal or fetal side effects (48%) and unability to provide a correct supervision of the parturient during PCIA use (48%), opposition from the pediatricians or obstetricians (17%) or because they considered the technique as ineffective to relieve labor pain (17%). In conclusion, the survey demonstrated that, when EA is contraindicated, systemic opioid administered by PCIA is used in almost half of the centers (47%) and that remifentanil is the first choice, particularly when a live birth is expected.", "corpus_id": 25041646, "score": 0 }, { "doc_id": "23277946", "title": "Remifentanil Patient-Controlled Analgesia for Labour: A Complete Audit Cycle", "abstract": "Remifentanil patient-controlled analgesia (PCA) was introduced to a small maternity unit where an extensive epidural service was difficult to provide. This was a new service and the New Zealand College of Midwives had serious doubts about the efficacy and safety of remifentanil, so auditing its use was important. In a two-stage audit, clinical notes of 244 consecutive remifentanil users were studied between January 2008 and November 2009. We developed a questionnaire to assess the parturients’ satisfaction with remifentanil PCA and designed a proforma to evaluate it against four standards of best practice. During the two audit periods, timely commencement of PCA was achieved in 65% and 82% of cases, respectively. A 70% compliance rate with monitoring standards fell to 10% after the withdrawal of supervision by an acute pain team, but improved to 91% following implementation of regular midwifery training sessions and a redesigned partogram and prescription flowchart. Ninety-four percent of women rated remifentanil PCA as excellent, very good or good. Maternal side-effects were nausea, pruritus and drowsiness. A comparison of Apgar scores of consecutive neonates born by normal vaginal delivery to women receiving no analgesia, with those born to women using remifentanil PCA, demonstrated no difference. As a result of our audit, remifentanil PCA is now viewed by our midwives as an effective and safe method when accompanied by 1:1 care and appropriate monitoring. With our input other maternity units have introduced it, especially where epidural service provision is limited, and for patients in whom epidural analgesia is contraindicated.", "corpus_id": 23277946, "score": 0 }, { "doc_id": "37452204", "title": "Remifentanil patient-controlled analgesia for labour: optimizing drug delivery regimens", "abstract": "PurposeA pilot study was undertaken to compare the efficacy of two regimens of intravenous patient-controlled analgesia (PCA) with remifentanil for labour analgesia.MethodsTwenty term parturients requesting labour analgesia were randomized to receive one of two regimens of intravenous remifentanil. The initial settings in both groups consisted of an infusion of 0.025 μg·kg-1·min-1, a PCA bolus of 0.25 μg·kg-1 and a lockout interval of two minutes. In Group A, the infusion was increased in a stepwise manner from 0.025 to 0.05, 0.075 and 0.1 μg·kg-1·min-1 as required; the bolus was kept constant at 0.25 μg·kg-1. In Group B, the bolus was increased from 0.25 to 0.5, 0.75 and 1 μg·kg-1 as necessary; the infusion was kept constant at 0.025 μg·kg-1·min-1. Maternal pain, satisfaction and sedation scores, remifentanil requirement, and side effects were recorded.ResultsMean pain and patient satisfaction scores, and cumulative doses of remifentanil were similar in the two groups. The overall incidence of side effects was greater in Group B (P = 0.0007), with drowsiness observed in 100% of patients, as compared to 30% in Group A (P = 0.003). The minimum oxygen saturation levels were 94.3% ± 2.6% and 92.2% ± 3.8% in Groups A and B respectively (P = 0.19).ConclusionsAlthough pain and satisfaction scores were similar in both groups, the regimen used in Group A was associated with fewer side effects compared to the Group B dosing regimen. This pilot study suggests that remifentanil intravenous PCA is efficacious for labour analgesia as a bolus of 0.25 μg·kg-1, with a lockout interval of two minutes and continuous infusion of 0.025-0.1 μg·kg-1·min-1. The potential for respiratory depression mandates close respiratory monitoring. Large-scale trials to evaluate safety issues are warranted.RésuméObjectifUne étude pilote a été entreprise afin de comparer l’efficacité de deux régimes intraveineux d’analgésie contrôlée par le patient (ACP) avec du rémifentanil pour le travail obstétrical.MéthodeVingt parturientes à terme demandant une analgésie pour le travail ont été randomisées à recevoir l’un de deux régimes de rémifentanil intraveineux. Les réglages de base dans les deux groupes consistaient en une perfusion de 0,025 μg·kg-1 ·min-1, un bolus ACP de 0,25 μg·kg-1 et un intervalle d’interdiction de deux minutes. Dans le groupe A, la perfusion a été augmentée par paliers de 0,025 à 0,05, 0,075 et 0,1 μg·kg-1 ·min-1 au besoin; le bolus a été maintenu constant à 0,25 μg·k-1. Dans le groupe B, le bolus a été augmenté de 0,25 à 0,5, 0,75 et 1 μg·kg-1 au besoin; la perfusion a été maintenue constante à 0,025 μg·kg-1·min-1. Les douleurs maternelles, les scores de satisfaction et de sédation, les besoins en rémifentanil et les effets secondaires ont été enregistrés.RésultatLes scores moyens de douleur et de satisfaction des patientes ainsi que les doses cumulatives de rémifentanil ont atteint des résultats similaires dans les deux groupes. L’incidence totale d’effets secondaires était plus élevée dans le groupe B(P = 0,007), avec des cas de somnolence chez 100 % des patientes comparativement à 30 % dans le groupe A (P = 0,003). Le minimum de saturation en oxygène était de 94,3 % ± 2,6% et 92,2 % ± 3,8 % dans les groupes A et B respectivement (P = 0,19).ConclusionBien que les scores de douleur et de satisfaction étaient similaires dans les deux groupes, le régime utilisé par le groupe A a été associé à moins d’effets secondaires que le régime de dosage du groupe B. Cette étude pilote suggère que l’ACP intraveineuse au rémifentanil est efficace pour l’analgésie pour le travail en bolus de 0,25 μg·kg-1, avec un intervalle d’interdiction de deux minutes et une perfusion continue de 0,025 - 0,1 μg·kg-1 ·min-1. Toutefois, un monitorage respiratoire attentif est nécessaire en raison du potentiel de développement de dépressions respiratoires. Des essais à grande échelle pour évaluer les questions d’innocuité sont requis.", "corpus_id": 37452204, "score": 1 }, { "doc_id": "5931104", "title": "Patient-controlled intravenous analgesia with remifentanil in nulliparous subjects in labor", "abstract": "Objective: in this study we controlled the efficiency and safety of using remifentanil combined with two different supplementary background infusions for labor analgesia in nulliparous patients. Research design and methods: 60 subjects were allocated to two groups. After programming the patient-controlled analgesia device to deliver a fixed load and demand doses of intravenous remifentanil for all subjects, group r (n = 30) received a background infusion of remifentanil 0.1 μg/kg/min and group R (n = 30) received a supplementary infusion of remifentanil 0.15 μg/kg/min. Visual analogue scale for analgesia, hemodynamic parameters, sedation scales and fetal heart rates were recorded at the 5th, 10th, 20th and 30th min of the study and measurements continued every 15 min during 90 min of labor and delivery. Side effects, Apgar and satisfaction scores were obtained for every subject. Results: visual analogue scale scores of group R were significantly lower than those of group r throughout labor and delivery (p < 0.05). Hemodynamic parameters and fetal heart rates of the two groups were not different (p > 0.05). Most subjects were awake and only nausea was obtained (p > 0.05). The increase in the Apgar and satisfaction scores was not statistically significant (p > 0.05). Conclusion: it was determined that remifentanil with a 15-μg demand dose and 0.15 μg/kg/min supplementary continuous infusion is an effective choice for patient-controlled analgesia during labor in nulliparous subjects.", "corpus_id": 5931104, "score": 0 }, { "doc_id": "43915619", "title": "Patient controlled analgesia for labour: a comparison of remifentanil with pethidine *", "abstract": "We compared the analgesic efficacy and safety of remifentanil and pethidine via patient controlled analgesia for women in established uncomplicated labour. Women received either remifentanil 40 μg with a 2‐min lockout (n = 20) or pethidine 15 mg with a 10‐min lockout (n = 19). Visual analogue scores for pain during the study and for overall pain were similar for both groups (mean (SD) 6.4 (1.5) cm for remifentanil and 6.9 (1.7) cm for pethidine). The area under the curve for visual analogue scores of satisfaction with analgesia was higher for remifentanil than for pethidine (p = 0.001). Maternal arterial oxygen saturation was similar in both groups. Neurologic and Adaptive Capacity Scores at 30 min were higher for remifentanil than for pethidine (median (interquartile range [range]) 36 (34.5–37 [32–39]) vs 34 (33–35 [30–35]), respectively; p = 0.003).", "corpus_id": 43915619, "score": 1 }, { "doc_id": "24223950", "title": "Obstetric analgesia: a comparison of patient-controlled meperidine, remifentanil, and fentanyl in labour.", "abstract": "BACKGROUND\nTo compare the analgesic efficacy of remifentanil with meperidine and fentanyl in a patient-controlled setting (patient-controlled analgesia, PCA).\n\n\nMETHODS\nParturients (n=159) were randomly assigned to receive remifentanil (n=52), meperidine (n=53), or fentanyl (n=54). Pain scores and an observer sedation scores were assessed hourly. Fetal outcome was evaluated with Apgar score, cord blood gas analysis and the Neurologic and Adaptive Capacity Score.\n\n\nRESULTS\nPain scores decreased in all groups, the decrease varying from mild to moderate, average pain scores remaining above 4.5 cm in all groups. Remifentanil PCA was associated with the greatest decrease in pain scores, but the difference was significant only at 1 h. Pain scores returned towards baseline over time; 3 h after the initiation of treatment, pain scores no longer differed significantly from baseline values in any of the groups. Significantly more parturients receiving meperidine crossed over to epidural analgesia. Overall satisfaction scores were higher with remifentanil, but remifentanil produced more sedation and itching. More periods of desaturation (Sa(o(2)) <95%) were observed during administration of remifentanil and fentanyl. There were no significant differences in fetal outcome between the three groups.\n\n\nCONCLUSIONS\nThe efficacy of meperidine, fentanyl, and remifentanil PCA for labour analgesia varied from mild to moderate. Remifentanil PCA provided better analgesia than meperidine and fentanyl PCA, but only during the first hour of treatment. In all groups, pain scores returned to pre-treatment values within 3 h after the initiation of treatment.", "corpus_id": 24223950, "score": 1 }, { "doc_id": "205302581", "title": "A randomised comparison of intravenous remifentanil patient-controlled analgesia with epidural ropivacaine/sufentanil during labour.", "abstract": "BACKGROUND\nThe μ-opioid agonist remifentanil has a rapid onset and offset and a short half-life making it an attractive option for intravenous patient-controlled labour analgesia. We aimed to compare the efficacy of intravenous remifentanil patient-controlled analgesia with epidural ropivacaine/sufentanil during labour.\n\n\nMETHODS\nParturients were randomly assigned to receive intravenous patient-controlled analgesia with remifentanil (n=10) or epidural analgesia (n=10). Pain and satisfaction scores were assessed every hour by means of visual analogue scale, together with an observer sedation score. Side effects and neonatal outcome were noted.\n\n\nRESULTS\nAfter one hour, visual analogue pain scores had decreased significantly in both groups (remifentanil: -3.8 ± 2.6, P<0.01; epidural -6.7 ± 2.0, P<0.01). The decrease in pain scores in the epidural group was significantly greater than the remifentanil group at all time intervals. The decrease in pain scores was sustained in the epidural group whereas in the remifentanil group pain scores increased over time. Oxygen saturation was significantly lower in the remifentanil group after one hour of treatment compared to the epidural group (95.2 ± 2.4% vs. 99.0 ± 1.1%, P<0.01). Patient satisfaction scores during and after delivery were similar in both groups. No differences were found in neonatal outcome.\n\n\nCONCLUSIONS\nIn the 20 patients recruited to this study, pain relief in labour with epidural ropivacaine/sufentanil was more effective than with intravenous remifentanil patient-controlled analgesia.", "corpus_id": 205302581, "score": 1 }, { "doc_id": "8930991", "title": "Labor analgesia in preeclampsia: remifentanil patient controlled intravenous analgesia versus epidural analgesia.", "abstract": "BACKGROUND\nEpidural analgesia is considered to be the preferred method of labor analgesia in preeclamptic patients. Systemic opioids are another good effective, easy to administer alternative but may cause maternal and fetal respiratory depression. Remifentanil's rapid onset and offset of effects, should make it an ideal drug for the intermittent painful contraction during labor. Method. 30 preeclamptic patients were randomly assigned to one of two equal groups; Epidural Group: received epidural analgesia according to a standardized protocol using bupivacaine plus fentanyl. REMIFENTANIL GROUP: PCA was set up to deliver remlfentanil 0.5 microg/kg as a loading bolus infused over 20 seconds, lockout time of 5 minutes, PCA bolus of 0.25 microg/kg, continuous background infusion of 0.05 microg/kg/min, and maximum dose is 3 mg in 4 hours. Women were advised to start the PCA bolus when they feel the signs of a coming uterine contraction.\n\n\nRESULTS\nAll women demonstrated a significant decrease in VAS score in the first hour after administration of analgesia (P < 0.05). Analgesic quality as regard Visual Analog Pain Scores, sedation score, and post-delivery patient satisfaction in both groups, are comparable (P > 0.05). PCA remifentanil infusion until time of delivery produce no observable maternal, fetal or neonatal side effects (P < 0.05).\n\n\nCONCLUSION\nPCA intravenous remifentanil is an effective option for pain relief with minimal maternal and neonatal side effects in labor for preeclamptic patients with contraindications to epidural analgesia or requesting opioid analgesia.", "corpus_id": 8930991, "score": 0 }, { "doc_id": "604768", "title": "The effects of remifentanil or acetaminophen with epidural ropivacaine on body temperature during labor", "abstract": "PurposeEpidural analgesia is associated with hyperthermia during labor and presumably causes it, although no convincing mechanism has been postulated. It seems likely that fever associated with pyrogenic factors related to labor is suppressed by opioids, whereas it is expressed normally in patients given epidural analgesia. We examined this hypothesis and the possible etiology of temperature elevation in labor.MethodsIn this prospective, randomized, controlled study, we assessed 201 parturients during spontaneous labor. Analgesia was randomly provided with one of four treatment groups: (1) epidural ropivacaine alone, (2) IV remifentanil alone, (3) epidural ropivacaine plus IV remifentanil, and (4) epidural ropivacaine plus IV acetaminophen. At randomization, patients were normothermic. Intrapartum hyperthermia (≥38°C) was correlated to the analgesic technique.ResultsThe maximum increase in oral temperature was greatest in the ropivacaine group (0.7 ± 0.6°C) and least in the remifentanil group (0.3 ± 0.4°C; P = 0.013). The percentage of patients who became hyperthermic (≥38°C) during the first 6 h of labor was greatest in the ropivacaine group (14%) and least in the remifentanil-alone group (2%), but the difference was not statistically significant. The maximum forearm-finger gradients were lower (less vasoconstriction) in the remifentanil group when compared to the gradients in patients with epidural analgesia (1.4 ± 1.8 vs 3.0 ± 1.7, respectively; P < 0.001).ConclusionOur results are consistent with the theory that low-dose opioids inhibit fever in patients not given epidural analgesia. However, in view of the negative results, the hypothesis of epidural-induced hyperthermia may be questionable.", "corpus_id": 604768, "score": 1 }, { "doc_id": "8665372", "title": "Remifentanil: A Novel Systemic Analgesic for Labor Pain", "abstract": "In a double-blind, randomized, controlled clinical trial, we compared the analgesic effect of remifentanil in patient-controlled IV analgesia (PCIA) during labor and delivery with the effect of an IV infusion of meperidine. Eighty-eight healthy term parturients who requested IV analgesia for labor pain were enrolled in the study and were randomly assigned to receive either increasing doses (0.27–0.93 &mgr;g/kg per bolus) of PCIA remifentanil (n = 43) or an IV infusion of meperidine 150 mg (range, 75–200 mg) per patient (n = 45). Remifentanil by the PCIA device was more effective and reliable analgesia for labor and delivery than IV infusion of meperidine. The visual analog score was lower (35.8 ± 10.2 versus 58.8 ± 12.8; P < 0.001) and the patient satisfaction score higher (3.9 ± 0.6 versus 1.9 ± 0.4; P < 0.001), with less of a sedative effect (1.2 ± 0.1 versus 2.9 ± 0.1; P < 0.001) and less hemoglobin desaturation (97.5% ± 1.0 versus 94.2% ± 1.5; P < 0.007). The percentage of analgesia failure (the rate of crossover from opiate to epidural analgesia) was less for remifentanil compared with meperidine (10.8% versus 38.8%; P < 0.007). There were no significant differences between groups in the mode of delivery or neonatal outcome. There were fewer nonreassuring abnormal fetal heart rate patterns, i.e., higher variability and reactivity with fewer decelerations, under remifentanil therapy as compared with meperidine (P < 0.001). In conclusion, an intermittent incremental regimen with repeated small-dose PCIA boluses of remifentanil provided effective and reliable analgesia during labor and delivery.", "corpus_id": 8665372, "score": 0 }, { "doc_id": "33648918", "title": "Neuraxial analgesia versus intravenous remifentanil for pain relief in early labor in nulliparous women", "abstract": "ObjectiveTo assess if there is a difference in duration of labor, the mode of delivery, average Visual Analog Scale (VAS) pain scores, maternal overall satisfaction with analgesia, side effects and neonatal outcomes in nulliparous women who received early labor analgesia with either epidural, patient-controlled IV analgesia (PCIA) with remifentanil or combined spinal–epidural (CSE) techniques.Study designThis is a prospective randomized interventional study.Subjects and methodsThe study included 1,140 healthy nulliparous women (with term, singleton pregnancies) early in labor, requesting labor analgesia, during the period from September 2009 to August 2011 at TAIBA Hospital in Kuwait. The participants were randomized to receive either epidural analgesia (Group I), or PCIA with remifentanil (Group II) or CSE analgesia (Group III). The primary outcome was the rate of cesarean delivery.ResultsCSE analgesia was associated with a statistically highly significant decrease in labor duration (from analgesia to vaginal delivery), duration of latent and active phases of the first stage, and duration of the second stage of labor, average VAS pain scores, and a highest maternal overall satisfaction score with analgesia (P < 0.01) as compared to epidural analgesia or PCIA with remifentanil.ConclusionIn terms of labor duration, average VAS pain scores, and maternal overall satisfaction score with analgesia, CSE analgesia is superior to that provided by epidural analgesia or PCIA with remifentanil for pain relief in early labor in nulliparous women. However, there were no differences in the mode of delivery, side effects or neonatal outcomes between the three techniques.", "corpus_id": 33648918, "score": 0 }, { "doc_id": "11629688", "title": "A double‐blind randomised comparison of intravenous patient‐controlled remifentanil with intramuscular pethidine for labour analgesia *", "abstract": "In a prospective, double‐blind, randomised controlled trial, we compared the efficacy of patient‐controlled analgesia using remifentanil (25–30 μg per bolus) with intramuscular pethidine (50–75 mg) for labour analgesia in 69 parturients. Parturients receiving patient‐controlled analgesia reported less pain than those receiving intramuscular pethidine throughout the study period (p < 0.001), with maximal reduction in visual analogue pain score at 2 h after commencement of analgesia (mean (SD) 20 (17) in the patient‐controlled analgesia group and 36 (22) in the intramuscular pethidine group. The median (95% CI) time to the first request for rescue analgesics was significantly longer with patient‐controlled analgesia (8.0 (6.8–9.2) h) compared with intramuscular pethidine (4.9 (3.8–5.4) h, p < 0.001). Maternal satisfaction scores were also higher with remifentanil compared with intramuscular pethidine (p= 0.001). There was no report of sedation, aponea or oxygen desaturation in either group, and Apgar scores were similar between groups. We conclude that patient‐controlled analgesia with remifentanil provides better labour analgesia and maternal satisfaction than intramuscular pethidine. At this dose, maternal and fetal side effects were uncommon.", "corpus_id": 11629688, "score": 1 }, { "doc_id": "701422", "title": "Remifentanil by patient-controlled analgesia compared with intramuscular meperidine for pain relief in labour.", "abstract": "BACKGROUND\nThe pharmacokinetics of remifentanil suggests that it may be suitable for analgesia during labour.\n\n\nMETHODS\nIn an open pilot study, 36 women requesting meperidine for analgesia were recruited early in labour and randomized to receive either meperidine i.m. or remifentanil given as patient-controlled analgesia (PCA). Pain severity, sedation and anxiety were assessed with visual analogue scales and overall effective analgesia was assessed by the woman and midwife.\n\n\nRESULTS\nThe pain scores were lower in the remifentanil group: median pain score at 60 min was 72 mm for meperidine and 48 mm for remifentanil (P=0.004) and median maximum pain score during the first 2 h was 82.5 mm for the meperidine group and 66.5 mm for the remifentanil group (P=0.009). Both the midwives' and the women's assessments of overall effective analgesia were higher in the remifentanil group [Likert scale (5 = excellent to 1 = poor): chi2=12.10, P=0.002 for mothers' assessment; chi2=12.80, P=0.002 for midwives' assessment].\n\n\nCONCLUSION\nIn this pilot study, remifentanil by PCA gave better pain relief to mothers in labour than intramuscular meperidine. However, remifentanil is a potent respiratory depressant and adequate continuous monitoring is necessary.", "corpus_id": 701422, "score": 0 }, { "doc_id": "22520850", "title": "Labour analgesia: a randomised, controlled trial comparing intravenous remifentanil and epidural analgesia with ropivacaine and fentanyl", "abstract": "Background and objective To compare the analgesic efficacy and side-effects of remifentanil intravenous patient-controlled analgesia (IVPCA) with walking epidural analgesia (EDA) during labour. Methods Thirty-nine parturient patients of mixed parity, with normal singleton pregnancies, were randomised to receive either remifentanil IVPCA (RA group) or EDA (EA group). The epidural solution contained ropivacaine 1 mg ml−1 and fentanyl 2 &mgr;g ml−1, and the initial dose was 10 ml h−1. Starting bolus of remifentanil was 0.15 &mgr;g kg−1, with subsequent steps of 0.15 &mgr;g kg−1. Lock-out time was 2 min, bolus infusion speed 2 ml min−1 (100 &mgr;g min−1) and there was no background infusion. Visual analogue scale was used for pain assessment. Maternal heart rate, blood pressure, oxygen saturation, respiratory rate, sedation, nausea/vomiting, itching, satisfaction and fetal/neonatal outcome were recorded. Results Thirty-seven parturient patients were analysed. Both treatments provided good analgesia, but with higher pain scores in the RA group. Pain reduction at the end of first and during second stage and maximum pain reduction were similar (RA/EA group): 27/26 (P = 0.920), 31/29 (P = 0.909) and 61/59 (P = 0.855), respectively. Maternal satisfaction was similar. Two parturients receiving remifentanil (6%) converted to epidural, one because of inadequate analgesia. Remifentanil produced more maternal sedation, desaturation (SaO2 < 92%) and need for supplemental oxygen. Neonatal outcome was reassuring. Highest mean total dose of remifentanil was 0.70 &mgr;g kg−1 (range 0.30–1.05). Conclusion Remifentanil IVPCA and epidural provided effective analgesia, with high maternal satisfaction scores and reassuring neonatal outcome. Remifentanil produced more maternal sedation and oxygen desaturation. Close monitoring is, therefore, mandatory.", "corpus_id": 22520850, "score": 1 }, { "doc_id": "11667284", "title": "A comparison of pethidine and remifentanil patient-controlled analgesia in labour.", "abstract": "We conducted a double-blind randomised controlled trial comparing the efficacy of analgesia during labour of remifentanil and pethidine. Nine women were randomised to receive an i.v. bolus of remifentanil 0.5 microg.kg(-1)with a lockout period of 2 min and eight women were randomised to receive a bolus of pethidine 10 mg with a lockout period of 5 min. A visual analogue scale (VAS) scoring system was used to assess the level of pain hourly throughout the first and second stages of labour and a score was recorded within half an hour of delivery for the level of pain overall throughout labour (post delivery score). The study was terminated after 17 subjects, on agreement with the local ethics committee, due to concern with the poor Apgar scores in the pethidine group. With the data available, we demonstrated significantly lower mean hourly and post delivery VAS scores for pain in the remifentanil group (P < 0.05). The 1 and 5 min Apgar scores were significantly lower in the pethidine group compared with the remifentanil group (P < 0.05). This preliminary study suggests that remifentanil may have a use as patient-controlled analgesia for women in labour.", "corpus_id": 11667284, "score": 0 }, { "doc_id": "26019843", "title": "Comparison of remifentanil and nitrous oxide in labour analgesia", "abstract": "Background:  We compared the efficacy and side‐effects of remifentanil with those of nitrous oxide during the first stage of labour.", "corpus_id": 26019843, "score": 0 }, { "doc_id": "6729685", "title": "Intravenous remifentanil vs. epidural levobupivacaine with fentanyl for pain relief in early labour: a randomised, controlled, double‐blinded study", "abstract": "Background: We hypothesised that intravenous patient‐controlled analgesia (IV PCA) with remifentanil could provide as satisfactory pain relief for labour as epidural analgesia.", "corpus_id": 6729685, "score": 1 }, { "doc_id": "24984147", "title": "A Comparison Between Remifentanil and Meperidine for Labor Analgesia: A Systematic Review", "abstract": "BACKGROUND:Remifentanil is an ultrashort-acting opioid with favorable pharmacokinetic properties that make it suitable as a labor analgesic. Although it crosses the placenta freely, it is eliminated quickly in the neonate by rapid metabolism and redistribution. We aimed to determine whether remifentanil compared with meperidine is effective in reducing pain scores in laboring parturients. Other effects on the mother, the labor process, and the neonate were also examined. METHODS:MEDLINE, CINAHL, Embase, Cochrane CENTRAL, and Maternity and Infant Care databases were searched without language restriction using multiple keywords for labor analgesia, remifentanil, and meperidine. Published abstracts from 5 key research meetings and references from retrieved articles were examined for additional studies. Randomized controlled trials in laboring parturients comparing remifentanil with meperidine were selected. Risk of bias was assessed using criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed for adequacy of sequence generation, allocation concealment, blinding, and completeness of follow-up. Data were extracted from each study using a standardized data collection form. The primary outcome was reduction in pain scores (visual analog scale [VAS], 0–100 mm). We also evaluated maternal side effects (sedation, oxygen desaturation, and bradypnea) and effects on the neonate (Apgar scores, umbilical cord pH, and Neurologic and Adaptive Capacity Scores). RESULTS:Seven studies (349 patients) were identified for inclusion; only 3 studies were suitable for quantitative synthesis in a meta-analysis (233 patients). We found that remifentanil reduces the mean VAS score at 1 hour by 25 mm more than meperidine (P < 0.001) (95% confidence interval = 19–31 mm). Limited conclusions can be made regarding the side-effect profile of remifentanil because of insufficient data. CONCLUSION:Compared with meperidine, remifentanil is superior in reducing mean VAS scores for labor pain after 1 hour.", "corpus_id": 24984147, "score": 0 }, { "doc_id": "7567296", "title": "Remifentanil in obstetrics", "abstract": "Purpose of review The present study summarizes the knowledge to date of the use of remifentanil in obstetric anaesthesia and analgesia. Recent findings Modest labour analgesia, particularly for the first stage, can be achieved using a patient-controlled analgesia bolus of 40 μg with a 2-min lockout. Neonatal effects are minimal; however, maternal desaturation is a possibility and requires one-to-one supervision and appropriate monitoring. Background infusions can improve analgesia, but maternal desaturation or even apnoea is more likely. Remifentanil is effective at obtunding responses to airway manipulation and surgery under general anaesthesia. Neonatal effects are more pronounced and 50% of neonates may need assisted ventilation, and occasionally naloxone. Summary Remifentanil has a place in obstetric anaesthesia and analgesia. Further studies are needed to confirm if background infusions are safe in addition to patient-controlled analgesia. Studies are needed to establish a dose range under general anaesthesia that prevents neonatal respiratory depression at birth.", "corpus_id": 7567296, "score": 0 }, { "doc_id": "23830474", "title": "Alternatives to neuraxial analgesia for labor", "abstract": "Purpose of review Although millions of parturients profit from neuraxial analgesia for labor, there are far more of those who do not have this choice for one reason or another. They need alternative ways to relieve labor pain. Recent findings Paracervical block gives less efficient analgesia compared with single-shot spinal in a sample of multiparae at active labor but is associated with better umbilical artery pH. Use of a neurostimulator may increase success in pudendal block. It is possible to reduce nitrous oxide occupational exposure by a developed scavenging system. Intravenous remifentanil gives less efficient pain relief than epidural analgesia. The maternal satisfaction, however, may be comparable. Summary Paracervical block with modern technique is a viable option for selected cases. It is rapid and does not affect the course of labor, but its efficacy is only modest. Pudendal block can be used in the second stage of labor or for episiotomy tear repair and pain. Intravenous remifentanil is currently becoming an established method, although its safety is still an issue. Nitrous oxide is a useful method to be used alone or together with the other methods.", "corpus_id": 23830474, "score": 0 }, { "doc_id": "884327", "title": "Maternal and neonatal side-effects of remifentanil patient-controlled analgesia in labour.", "abstract": "BACKGROUND\nRemifentanil has been suggested as an ideal opioid for patient-controlled analgesia (PCA) in labour, but the safety profile has not been established. The aims of this preliminary prospective observational study were to investigate the maternal side-effects and early neonatal effects, and to assess the placental transfer of remifentanil PCA during labour.\n\n\nMETHODS\nWomen with no known obstetric complications or contraindication to remifentanil were recruited (n=50). Remifentanil was administered at a bolus dose of 0.5 microg kg(-1) and a lockout period of 2 min. A visual analogue scale was used to assess pain, nausea and itching. Maternal observations were recorded hourly and fetal heart rate trace was assessed every 2 h. Umbilical cord gases, 1 and 5 min Apgar scores and neurological evaluation of the neonate were recorded. Maternal venous blood and umbilical artery and vein cord blood samples were collected for analysis of remifentanil concentration.\n\n\nRESULTS\nFifty women enrolled in the study (24 multiparous, 26 primiparous). There was no evidence of cardiovascular instability or respiratory depression. Pain scores decreased significantly, but there was no significant change in nausea after initiating the PCA. A statistically significant increase in itching was found to be clinically mild and 22 women were slightly drowsy (95% confidence interval [CI], 30-58.7%) but alert to voice. Ten fetal heart rate traces demonstrated changes in the first 20 min, but did not require intervention (95% CI, 10-33.7%). The median 1 and 5 min Apgar scores were 9. The mean umbilical cord gases and neurological examination were within normal limits. Maternal vein and umbilical vein cord samples demonstrated placental transfer of remifentanil, and small amounts were detected in umbilical artery samples.\n\n\nCONCLUSIONS\nAt the bolus dose used remifentanil PCA has an acceptable level of maternal side-effects and minimal effect on the neonate. Remifentanil crosses the placenta and appears to be either rapidly metabolized or redistributed in the neonate.", "corpus_id": 884327, "score": 1 }, { "doc_id": "634319", "title": "Patient-controlled analgesia for labour using remifentanil: a feasibility study.", "abstract": "We have investigated the efficacy and safety of remifentanil in a patient-controlled analgesia device for labour in 21 women. Remifentanil was available in increasing doses (bolus doses 0.25-1.0 microg x kg(-1)) with and without a background infusion (0.025-0.05 microg x kg(-1) x min(-1)). A lockout time of 2 min was used. Thirteen out of 21 (62%) women chose to continue using remifentanil up to and during delivery. Nineteen out of 21 (90%) achieved a reduction in pain score from baseline. Using a VAS of 0-10 cm the median maximum reduction in pain score was 3 cm (range 0-8 cm). There was a significant reduction (P<0.05) from baseline pain scores (median= 8 cm) to scores at bolus doses in the range 0.25-0.5 microg x kg(-1) (median=5 cm). There were no significant reductions in the fetal heart rate. Apgar scores and cord blood gas analyses remained within normal limits. We conclude that a remifentanil patient-controlled analgesia system (bolus doses 0.25-0.5 microg x kg(-1), without a background infusion) may safely provide worthwhile, although incomplete, analgesia for labour.", "corpus_id": 634319, "score": 1 }, { "doc_id": "36693389", "title": "Remifentanil in Obstetric Analgesia: A Dose-Finding Study", "abstract": "IV patient-controlled analgesia (PCA) with remifentanil is a new approach in systemic opioid analgesia during labor. We determined the minimum effective dose of IV remifentanil by increasing the PCA bolus from 0.2 &mgr;g/kg with 0.2 &mgr;g/kg increments during a 60-min study period until the analgesia was considered adequate by the parturient. Twenty healthy parturients with singleton pregnancies participated in the study during the first stage of labor. Remifentanil hydrochloride was given IV via PCA over 1 min with a lockout time of 1 min. The parturient started the PCA bolus at the first subjective sign of uterine contraction. All 17 patients who completed the study reached adequate pain relief. The median effective PCA bolus was 0.4 &mgr;g/kg and consumption was 0.066 &mgr;g · kg−1 · min−1, with wide individual variation (0.2–0.8 &mgr;g/kg and 0.027–0.207 &mgr;g · kg−1 · min−1, respectively). The pain scores were reduced by a median of 4.2 (25th–75th percentiles, 3.1–5.2;P < 0.001) on an 11-point numeric scale. Although there was a wide individual variation in the dose required, remifentanil seems effective for labor analgesia. However, maternal oxygen desaturation, sedation, and reduced fetal heart rate beat-to-beat variability were observed frequently. There was wide individual variation in the dose required for effective labor analgesia. Potentially serious side effects, which were observed frequently during remifentanil analgesia, may limit remifentanil’s use in obstetrics.", "corpus_id": 36693389, "score": 1 }, { "doc_id": "2152507", "title": "Knowledge-Assisted Sequential Pattern Analysis With Heuristic Parameter Tuning for Labor Contraction Prediction", "abstract": "The optimal dosing regimen of remifentanil for relieving labor pain should achieve maximal efficacy during contractions and little effect between contractions. Toward such a need, we propose a knowledge-assisted sequential pattern analysis with heuristic parameter tuning to predict the changes in intrauterine pressure, which indicates the occurrence of labor contractions. This enables giving the drug shortly before each contraction starts. A sequential association rule mining based patient selection strategy is designed to dynamically select data for training regression models. A novel heuristic parameter tuning method is proposed to decide the appropriate value ranges and searching strategies for both the regularization factor and the Gaussian kernel parameter of least-squares support vector machine with radial basis function (RBF) kernel, which is used as the regression model for time series prediction. The parameter tuning method utilizes information extracted from the training dataset, and it is adaptive to the characteristics of time series. The promising experimental results show that the proposed framework is able to achieve the lowest prediction errors as compared to some existing methods.", "corpus_id": 2152507, "score": 0 }, { "doc_id": "33430776", "title": "Respiratory arrest in an obstetric patient using remifentanil patient‐controlled analgesia *", "abstract": "Remifentanil patient‐controlled analgesia is well established in many centres and provides satisfactory pain relief for many women in labour. We describe a patient using remifentanil patient‐controlled analgesia who suffered a respiratory arrest requiring a brief period of ventilation. In our institution, remifentanil patient‐controlled analgesia has been offered to women in labour since 2009. Up to this point, we had not observed any critical incidents in over 130 patients using this mode of analgesia in our labour suite.", "corpus_id": 33430776, "score": 0 }, { "doc_id": "6033314", "title": "Maternal and Neonatal Effects of Remifentanil at Induction of General Anesthesia for Cesarean Delivery: A Randomized, Double-blind, Controlled Trial", "abstract": "Background:Use of remifentanil during general anesthesia for cesarean delivery has been described, but its maternal and neonatal effects have not been investigated by a controlled study. Methods:In a randomized, double-blind, controlled study, patients undergoing elective cesarean delivery received an intravenous bolus of 1 &mgr;g/kg remifentanil (n = 20) or saline (n = 20) immediately before induction of general anesthesia. The authors compared maternal hemodynamic changes and neonatal condition and measured plasma concentrations of remifentanil. Results:The maximum increase in systolic arterial pressure from baseline after induction was smaller in the remifentanil group (median, 9 [range, −17 to 31] mmHg) compared with the control group (42 [6–73] mmHg, median difference, 33 mmHg; 95% confidence interval of difference, 23–45 mmHg; P < 0.0001). Maximum recorded values were smaller in the remifentanil group compared with the control group for systolic and mean arterial pressure and maternal heart rate. Apgar scores and time to sustained respiration were similar between groups. Two neonates in the remifentanil group were considered clinically depressed at birth and were given a single dose of naloxone. Remifentanil crossed the placenta with an umbilical venous/maternal arterial concentration ratio of 0.73 (SD, 0.17) and an umbilical arterial/umbilical venous concentration ratio of 0.60 (0.23). Conclusions:A single bolus of 1 &mgr;g/kg remifentanil effectively attenuated hemodynamic changes after induction and tracheal intubation. However, remifentanil crosses the placenta and may cause mild neonatal depression and thus should be used for clear maternal indications when adequate facilities for neonatal resuscitation are available.", "corpus_id": 6033314, "score": 0 }, { "doc_id": "25804016", "title": "The Pharmacodynamic Effect of a Remifentanil Bolus on Ventilatory Control", "abstract": "Background In doses typically administered during conscious sedation, remifentanil may be associated with ventilatory depression. However, the time course of ventilatory depression after an initial dose of remifentanil has not been determined previously. Methods In eight healthy volunteers, the authors determined the time course of the ventilatory response to carbon dioxide using the dual isohypercapnic technique. Subjects breathed via mask from a to-and-fro circuit with variable carbon dioxide absorption, allowing the authors to maintain end-tidal pressure of carbon dioxide (PETCO2) at approximately 46 or 56 mmHg (alternate subjects). After 6 min of equilibration, subjects received 0.5 &mgr;g/kg remifentanil over 5 s, and minute ventilation (&OV0312;E) was recorded during the next 20 min. Two hours later, the study was repeated using the other carbon dioxide tension (56 or 46 mmHg). The &OV0312;E data were used to construct two-point carbon dioxide response curves at 30-s intervals after remifentanil administration. Using published pharmacokinetic values for remifentanil and the method of collapsing hysteresis loops, the authors estimated the effect-site equilibration rate constant (keo), the effect-site concentration producing 50% respiratory depression (EC50), and the shape parameter of the concentration–response curve (&ggr;). Results The slope of the carbon dioxide response decreased from 0.99 [95% confidence limits 0.72 to 1.26] to a nadir of 0.27 l · min−1 · mmHg−1 [−0.12 to 0.66] 2 min after remifentanil (P < 0.001); within 5 min, it recovered to approximately 0.6l · min−1 · mmHg−1, and within 15 min of injection, slope returned to baseline. The computed ventilation at PET = 50 mmHg (&OV0312;E50) decreased from 12.9 [9.8 to 15.9] to 6.1 l/min [4.8 to 7.4] 2.5 min after remifentanil injection (P < 0.001). This was caused primarily by a decrease in tidal volume rather than in respiratory rate. Estimated pharmacodynamic parameters based on computed mean values of &OV0312;E50 included keo = 0.24 min−1 (T1/2 = 2.9 min), EC50 = 1.12 ng/ml, and &ggr; = 1.74. Conclusions After administration of 0.5 &mgr;g/kg remifentanil, there was a decrease in slope and downward shift of the carbon dioxide ventilatory response curve. This reached its nadir approximately 2.5 min after injection, consistent with the computed onset half-time of 2.9 min. The onset of respiratory depression appears to be somewhat slower than previously reported for the onset of remifentanil-induced electroencephalographic slowing. Recovery of ventilatory drive after a small dose essentially was complete within 15 min.", "corpus_id": 25804016, "score": 0 }, { "doc_id": "37522322", "title": "Timing of intravenous patient‐controlled remifentanil bolus during early labour", "abstract": "Background: Remifentanil labour analgesia is superior to nitrous oxide but less potent than epidural analgesia. The short onset and offset times of effect suggest that the timing of the bolus in the contraction cycle could have importance. We hypothesised that administering a remifentanil bolus during contraction pause would improve analgesia in early labour.", "corpus_id": 37522322, "score": 0 }, { "doc_id": "40404138", "title": "The effects of Entonox and epidural analgesia on arterial oxygen saturation of women in labour", "abstract": "The arterial oxygen saturation of 40 mothers in the first stage of labour was monitored using pulse oximetry. Half the mothers received epidural analgesia and the rest inhaled Entonox for pain relief. Eight mothers in the Entonox group and six in the epidural group had at least one episode of significant hypoxia (saturation < 90%). There was little difference in the number of hypoxic episodes experienced by either group (29 in the Entonox and 21 in the epidural) although their mean duration and severity was greater in the Entonox group. Women in labour who inhale Entonox have an appreciable incidence of arterial desaturation. Epidural analgesia reduces the severity of hypoxic episodes although it does not eliminate them.", "corpus_id": 40404138, "score": 0 }, { "doc_id": "19541966", "title": "Maternal hypoxaemia during labour and delivery: the influence of analgesia and effect on neonatal outcome", "abstract": "The effect of analgesia on the incidence of hypoxaemia was assessed in an unrandomised trial in 51 parturients from the last hour of the first stage of labour until delivery. Women were retrospectively divided into four groups: no analgesia, pethidine with intermittent Entonox, extradural bupivacaine (either infusion of 0.125% or top‐ups of 10ml of 0.25%): and extradural infusion of 0.1% bupivacaine with 2 μg.ml ‐1fentanyl. The lowest median incidence of desaturation (Spo2< 94%) was in the extradural bupivacaine group: 0 min.h‐1 in the last hour of the first stage and 0.1 min.h‐1 in the second stage. The incidence was significantly lower than in the pethidine I Entonox group (1.4min.h‐1) in the last hour of the first stage (p < 0.001) and the extradural bupivacaine /fentanyl group (0.9 min.h‐1 and no analgesia group (3min.h‐1) in the second stage (p < 0.05 in both cases). There was no correlation between maternal oxygenation during the second stage and measures of neonatal outcome including Apgar score and umbilical artery and vein blood gases.", "corpus_id": 19541966, "score": 0 }, { "doc_id": "6271877", "title": "Must we press on until a young mother dies? Remifentanil patient controlled analgesia in labour may not be suited as a “poor man’s epidural”", "abstract": "BackgroundThe epidural route is still considered the gold standard for labour analgesia, although it is not without serious consequences when incorrect placement goes unrecognized, e.g. in case of intravascular, intrathecal and subdural placements. Until now there has not been a viable alternative to epidural analgesia especially in view of the neonatal outcome and the need for respiratory support when long-acting opioids are used via the parenteral route. Pethidine and meptazinol are far from ideal having been described as providing rather sedation than analgesia, affecting the cardiotocograph (CTG), causing fetal acidosis and having active metabolites with prolonged half-lives especially in the neonate. Despite these obvious shortcomings, intramuscular and intravenously administered pethidine and comparable substances are still frequently used in delivery units.Since the end of the 90ths remifentanil administered in a patient-controlled mode (PCA) had been reported as a useful alternative for labour analgesia in those women who either don’t want, can’t have or don’t need epidural analgesia.DiscussionIn view of the need for conversion to central neuraxial blocks and the analgesic effect remifentanil has been demonstrated to be superior to pethidine. Despite being less effective in terms of the resulting pain scores, clinical studies suggest that the satisfaction with analgesia may be comparable to that obtained with epidural analgesia. Owing to this fact, remifentanil has gained a place in modern labour analgesia in many institutions.However, the fact that remifentanil may cause harm should not be forgotten when the use of this potent mu-agonist is considered for the use in labouring women. In the setting of one-to-one midwifery care, appropriate monitoring and providing that enough experience exists with this potent opioid and the treatment of potential complications, remifentanil PCA is a useful option in addition to epidural analgesia and other central neuraxial blocks. Already described serious consequences should remind us not refer to remifentanil PCA as a “poor man’s epidural” and to safely administer remifentanil with an appropriate indication.SummaryTherefore, the authors conclude that economic considerations and potential cost-savings in conjunction with remifentanil PCA may not be appropriate main endpoints when studying this valuable method for labour analgesia.", "corpus_id": 6271877, "score": 0 } ]

{ "doc_id": "565501", "title": "Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway", "abstract": "The control of cell division is essential for normal development and the maintenance of cellular homeostasis. Abnormal cell proliferation is associated with multiple pathological states, including cancer. Although the Hippo/YAP signaling pathway was initially thought to control organ size and growth, increasing evidence indicates that this pathway also plays a major role in the control of proliferation independent of organ size control. In particular, accumulating evidence indicates that the Hippo/YAP signaling pathway functionally interacts with multiple other cellular pathways and serves as a central node in the regulation of cell division, especially in cancer cells. Here, recent observations are highlighted that connect Hippo/YAP signaling to transcription, the basic cell-cycle machinery, and the control of cell division. Furthermore, the oncogenic and tumor-suppressive attributes of YAP/TAZ are reviewed, which emphasizes the relevance of the Hippo pathway in cancer. Mol Cancer Res; 14(2); 127–40. ©2015 AACR.", "corpus_id": 565501 }

[ { "doc_id": "14967252", "title": "Elucidation of a Universal Size-Control Mechanism in Drosophila and Mammals", "abstract": "Coordination of cell proliferation and cell death is essential to attain proper organ size during development and for maintaining tissue homeostasis throughout postnatal life. In Drosophila, these two processes are orchestrated by the Hippo kinase cascade, a growth-suppressive pathway that ultimately antagonizes the transcriptional coactivator Yorkie (Yki). Here we demonstrate that a single phosphorylation site in Yki mediates the growth-suppressive output of the Hippo pathway. Hippo-mediated phosphorylation inactivates Yki by excluding it from the nucleus, whereas loss of Hippo signaling leads to nuclear accumulation and therefore increased Yki activity. We further delineate a mammalian Hippo signaling pathway that culminates in the phosphorylation of YAP, the mammalian homolog of Yki. Using a conditional YAP transgenic mouse model, we demonstrate that the mammalian Hippo pathway is a potent regulator of organ size, and that its dysregulation leads to tumorigenesis. These results uncover a universal size-control mechanism in metazoan.", "corpus_id": 14967252, "score": 0 }, { "doc_id": "11091575", "title": "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.", "abstract": "The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.", "corpus_id": 11091575, "score": 0 }, { "doc_id": "26737825", "title": "The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation.", "abstract": "Yes-associated protein (YAP) is a potent transcription coactivator acting via binding to the TEAD transcription factor, and plays a critical role in organ size regulation. YAP is phosphorylated and inhibited by the Lats kinase, a key component of the Hippo tumor suppressor pathway. Elevated YAP protein levels and gene amplification have been implicated in human cancer. In this study, we report that YAP is inactivated during embryonic stem (ES) cell differentiation, as indicated by decreased protein levels and increased phosphorylation. Consistently, YAP is elevated during induced pluripotent stem (iPS) cell reprogramming. YAP knockdown leads to a loss of ES cell pluripotency, while ectopic expression of YAP prevents ES cell differentiation in vitro and maintains stem cell phenotypes even under differentiation conditions. Moreover, YAP binds directly to promoters of a large number of genes known to be important for stem cells and stimulates their expression. Our observations establish a critical role of YAP in maintaining stem cell pluripotency.", "corpus_id": 26737825, "score": 1 }, { "doc_id": "12848583", "title": "Metabolic control of YAP and TAZ by the mevalonate pathway", "abstract": "The YAP and TAZ mediators of the Hippo pathway (hereafter called YAP/TAZ) promote tissue proliferation and organ growth. However, how their biological properties intersect with cellular metabolism remains unexplained. Here, we show that YAP/TAZ activity is controlled by the SREBP/mevalonate pathway. Inhibition of the rate-limiting enzyme of this pathway (HMG-CoA reductase) by statins opposes YAP/TAZ nuclear localization and transcriptional responses. Mechanistically, the geranylgeranyl pyrophosphate produced by the mevalonate cascade is required for activation of Rho GTPases that, in turn, activate YAP/TAZ by inhibiting their phosphorylation and promoting their nuclear accumulation. The mevalonate–YAP/TAZ axis is required for proliferation and self-renewal of breast cancer cells. In Drosophila melanogaster, inhibition of mevalonate biosynthesis and geranylgeranylation blunts the eye overgrowth induced by Yorkie, the YAP/TAZ orthologue. In tumour cells, YAP/TAZ activation is promoted by increased levels of mevalonic acid produced by SREBP transcriptional activity, which is induced by its oncogenic cofactor mutant p53. These findings reveal an additional layer of YAP/TAZ regulation by metabolic cues.", "corpus_id": 12848583, "score": 0 }, { "doc_id": "14139806", "title": "The Hippo Signaling Pathway Coordinately Regulates Cell Proliferation and Apoptosis by Inactivating Yorkie, the Drosophila Homolog of YAP", "abstract": "Coordination between cell proliferation and cell death is essential to maintain homeostasis in multicellular organisms. In Drosophila, these two processes are regulated by a pathway involving the Ste20-like kinase Hippo (Hpo) and the NDR family kinase Warts (Wts; also called Lats). Hpo phosphorylates and activates Wts, which in turn, through unknown mechanisms, negatively regulates the transcription of cell-cycle and cell-death regulators such as cycE and diap1. Here we identify Yorkie (Yki), the Drosophila ortholog of the mammalian transcriptional coactivator yes-associated protein (YAP), as a missing link between Wts and transcriptional regulation. Yki is required for normal tissue growth and diap1 transcription and is phosphorylated and inactivated by Wts. Overexpression of yki phenocopies loss-of-function mutations of hpo or wts, including elevated transcription of cycE and diap1, increased proliferation, defective apoptosis, and tissue overgrowth. Thus, Yki is a critical target of the Wts/Lats protein kinase and a potential oncogene.", "corpus_id": 14139806, "score": 0 }, { "doc_id": "34550340", "title": "Herding Hippos: regulating growth in flies and man.", "abstract": "Control of cell number requires the coordinate regulation of cell proliferation and cell death. Studies in both the fly and mouse have identified the Hippo kinase pathway as a key signaling pathway that controls cell proliferation and apoptosis. Several studies have implicated the Hippo pathway in a variety of cancers. Recent studies have also revealed a role for the Hippo pathway in the control of cell fate decisions during development. In this review, we will cover the current model of Hippo signaling in development. We will explore the differences between the Hippo pathway in invertebrates and mammals, and focus on recent advances in understanding how this conserved pathway is regulated.", "corpus_id": 34550340, "score": 0 }, { "doc_id": "10566416", "title": "TAZ: a novel transcriptional co‐activator regulated by interactions with 14‐3‐3 and PDZ domain proteins", "abstract": "The highly conserved and ubiquitously expressed 14‐3‐3 proteins regulate differentiation, cell cycle progression and apoptosis by binding intracellular phosphoproteins involved in signal transduction. By screening in vitro translated cDNA pools for the ability to bind 14‐3‐3, we identified a novel transcriptional co‐activator, TAZ (transcriptional co‐activator with PDZ‐binding motif) as a 14‐3‐3‐binding molecule. TAZ shares homology with Yes‐associated protein (YAP), contains a WW domain and functions as a transcriptional co‐activator by binding to the PPXY motif present on transcription factors. 14‐3‐3 binding requires TAZ phosphorylation on a single serine residue, resulting in the inhibition of TAZ transcriptional co‐activation through 14‐3‐3‐mediated nuclear export. The C‐terminus of TAZ contains a highly conserved PDZ‐binding motif that localizes TAZ into discrete nuclear foci and is essential for TAZ‐stimulated gene transcription. TAZ uses this same motif to bind the PDZ domain‐containing protein NHERF‐2, a molecule that tethers plasma membrane ion channels and receptors to cytoskeletal actin. TAZ may link events at the plasma membrane and cytoskeleton to nuclear transcription in a manner that can be regulated by 14‐3‐3.", "corpus_id": 10566416, "score": 0 }, { "doc_id": "9671692", "title": "YAP/TAZ Incorporation in the β-Catenin Destruction Complex Orchestrates the Wnt Response", "abstract": "The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression.", "corpus_id": 9671692, "score": 0 }, { "doc_id": "43100100", "title": "The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway.", "abstract": "The Hippo pathway senses cell density information to control tissue growth by regulating the localization of the transcriptional regulators TAZ and YAP (TAZ/YAP). TAZ/YAP also regulate TGF-β-SMAD signaling, but whether this role is linked to cell density sensing is unknown. Here we demonstrate that TAZ/YAP dictate the localization of active SMAD complexes in response to cell density-mediated formation of polarity complexes. In high-density cell cultures, the Hippo pathway drives cytoplasmic localization of TAZ/YAP, which sequesters SMAD complexes, thereby suppressing TGF-β signaling. We show that during mouse embryogenesis, this is reflected by differences in TAZ/YAP localization, which define regions of active SMAD2/3 complexes. Interfering with TAZ/YAP phosphorylation drives nuclear accumulation of TAZ/YAP and SMAD2/3. Furthermore, we demonstrate that the Crumbs polarity complex interacts with TAZ/YAP, which relays cell density information by promoting TAZ/YAP phosphorylation, cytoplasmic retention, and suppressed TGF-β signaling. Accordingly, disruption of the Crumbs complex enhances TGF-β signaling and predisposes cells to TGF-β-mediated epithelial-to-mesenchymal transitions.", "corpus_id": 43100100, "score": 1 }, { "doc_id": "12737132", "title": "TEAD mediates YAP-dependent gene induction and growth control.", "abstract": "The YAP transcription coactivator has been implicated as an oncogene and is amplified in human cancers. Recent studies have established that YAP is phosphorylated and inhibited by the Hippo tumor suppressor pathway. Here we demonstrate that the TEAD family transcription factors are essential in mediating YAP-dependent gene expression. TEAD is also required for YAP-induced cell growth, oncogenic transformation, and epithelial-mesenchymal transition. CTGF is identified as a direct YAP target gene important for cell growth. Moreover, the functional relationship between YAP and TEAD is conserved in Drosophila Yki (the YAP homolog) and Scalloped (the TEAD homolog). Our study reveals TEAD as a new component in the Hippo pathway playing essential roles in mediating biological functions of YAP.", "corpus_id": 12737132, "score": 0 }, { "doc_id": "10853391", "title": "The Hippo pathway: regulators and regulations.", "abstract": "Control of cell number is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation or organ degeneration. The Hippo pathway in both Drosophila and mammals regulates cell number by modulating cell proliferation, cell death, and cell differentiation. Recently, numerous upstream components involved in the Hippo pathway have been identified, such as cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. Actin cytoskeleton or cellular tension appears to be the master mediator that integrates and transmits upstream signals to the core Hippo signaling cascade. Here, we review regulatory mechanisms of the Hippo pathway and discuss potential implications involved in different physiological and pathological conditions.", "corpus_id": 10853391, "score": 1 }, { "doc_id": "14181458", "title": "Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene.", "abstract": "Hippo-Lats-Yorkie signaling regulates tissue overgrowth and tumorigenesis in Drosophila. We show that the Mst1 and Mst2 protein kinases, the mammalian Hippo orthologs, are cleaved and constitutively activated in the mouse liver. Combined Mst1/2 deficiency in the liver results in loss of inhibitory Ser127 phosphorylation of the Yorkie ortholog, Yap1, massive overgrowth, and hepatocellular carcinoma (HCC). Reexpression of Mst1 in HCC-derived cell lines promotes Yap1 Ser127 phosphorylation and inactivation and abrogates their tumorigenicity. Notably, Mst1/2 inactivates Yap1 in liver through an intermediary kinase distinct from Lats1/2. Approximately 30% of human HCCs show low Yap1(Ser127) phosphorylation and a majority exhibit loss of cleaved, activated Mst1. Mst1/2 inhibition of Yap1 is an important pathway for tumor suppression in liver relevant to human HCC.", "corpus_id": 14181458, "score": 0 }, { "doc_id": "206542155", "title": "Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry.", "abstract": "Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ∼ 83% and ∼ 6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy.", "corpus_id": 206542155, "score": 0 }, { "doc_id": "16588717", "title": "The Hippo Transducer TAZ Confers Cancer Stem Cell-Related Traits on Breast Cancer Cells", "abstract": "Cancer stem cells (CSCs) are proposed to drive tumor initiation and progression. Yet, our understanding of the cellular and molecular mechanisms that underlie CSC properties is limited. Here we show that the activity of TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in breast CSCs. TAZ protein levels and activity are elevated in prospective CSCs and in poorly differentiated human tumors and have prognostic value. Gain of TAZ endows self-renewal capacity to non-CSCs. In epithelial cells, TAZ forms a complex with the cell-polarity determinant Scribble, and loss of Scribble--or induction of the epithelial-mesenchymal transition (EMT)--disrupts the inhibitory association of TAZ with the core Hippo kinases MST and LATS. This study links the CSC concept to the Hippo pathway in breast cancer and reveals a mechanistic basis of the control of Hippo kinases by cell polarity.", "corpus_id": 16588717, "score": 0 }, { "doc_id": "21958283", "title": "Pro-Invasive Activity of the Hippo Pathway Effectors YAP and TAZ in Cutaneous Melanoma", "abstract": "YAP and its paralog protein TAZ are downstream effectors of the Hippo pathway. Both are amplified in many human cancers and promote cell proliferation and epithelial–mesenchymal transition. Little is known about the status of the Hippo pathway in cutaneous melanoma. We profiled Hippo pathway component expression in a panel of human melanoma cell lines and melanocytic lesions, and characterized the capacity of YAP and TAZ to control melanoma cell behavior. YAP and TAZ immuno-staining in human samples revealed mixed cytoplasmic and nuclear staining for both proteins in benign nevi and superficial spreading melanoma. TAZ was expressed at higher levels than YAP1/2 in all cell lines and in those with high invasive potential. Stable YAP or TAZ knockdown dramatically reduced the expression of the classical Hippo target CCN2/connective-tissue growth factor (CTGF), as well as anchorage-independent growth, capacity to invade Matrigel, and ability form lung metastases in mice following tail-vein injection. YAP knockdown also reduced invasion in a model of skin reconstruct. Inversely, YAP overexpression increased melanoma cell invasiveness, associated with increased TEA domain–dependent transcription and CCN2/CTGF expression. Together, these results demonstrate that both YAP and TAZ contribute to the invasive and metastatic capacity of melanoma cells and may represent worthy targets for therapeutic intervention.", "corpus_id": 21958283, "score": 0 }, { "doc_id": "951100", "title": "The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma.", "abstract": "Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression and aberrant osteoblastic and chondrocytic differentiation in a TEAD-dependent fashion. Using chromatin immunoprecipitation (ChIP), we show that TAZ is directly recruited to a majority of MES gene promoters in a complex with TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with platelet-derived growth factor-B (PDGF-B) resulted in high-grade tumors with MES features in a murine model of glioma. Our studies uncover a direct role for TAZ and TEAD in driving the MES differentiation of malignant glioma.", "corpus_id": 951100, "score": 0 }, { "doc_id": "9532050", "title": "hippo Encodes a Ste-20 Family Protein Kinase that Restricts Cell Proliferation and Promotes Apoptosis in Conjunction with salvador and warts", "abstract": "The coordination between cell proliferation and cell death is essential to maintain homeostasis within multicellular organisms. The mechanisms underlying this regulation are yet to be completely understood. Here, we report the identification of hippo (hpo) as a gene that regulates both cell proliferation and cell death in Drosophila. hpo encodes a Ste-20 family protein kinase that binds to and phosphorylates the tumor suppressor protein Salvador (Sav), which is known to interact with the Warts (Wts) protein kinase. Loss of hpo results in elevated transcription of the cell cycle regulator cyclin E and the cell-death inhibitor diap1, leading to increased proliferation and reduced apoptosis. Further, we show that hpo, sav, and wts define a pathway that regulates diap1 at the transcriptional level. A human homolog of hpo completely rescues the overgrowth phenotype of Drosophila hpo mutants, suggesting that hpo might play a conserved role for growth control in mammals.", "corpus_id": 9532050, "score": 0 }, { "doc_id": "17894660", "title": "The Drosophila Mst Ortholog, hippo, Restricts Growth and Cell Proliferation and Promotes Apoptosis", "abstract": "Establishing and maintaining homeostasis is critical to the well-being of an organism and is determined by the balance of cell proliferation and death. Two genes that function together to regulate growth, proliferation, and apoptosis in Drosophila are warts (wts), encoding a serine/threonine kinase, and salvador (sav), encoding a WW domain containing Wts-interacting protein. However, the mechanisms by which sav and wts regulate growth and apoptosis are not well understood. Here, we describe mutations in hippo (hpo), which encodes a protein kinase most related to mammalian Mst1 and Mst2. Like wts and sav, hpo mutations result in increased tissue growth and impaired apoptosis characterized by elevated levels of the cell cycle regulator cyclin E and apoptosis inhibitor DIAP1. Hpo, Sav, and Wts interact physically and functionally, and regulate DIAP1 levels, likely by Hpo-mediated phosphorylation and subsequent degradation. Thus, Hpo links Sav and Wts to a key regulator of apoptosis.", "corpus_id": 17894660, "score": 0 }, { "doc_id": "2008641", "title": "The Hippo pathway and human cancer", "abstract": "The Hippo pathway controls organ size in diverse species, whereas pathway deregulation can induce tumours in model organisms and occurs in a broad range of human carcinomas, including lung, colorectal, ovarian and liver cancer. Despite this, somatic or germline mutations in Hippo pathway genes are uncommon, with only the upstream pathway gene neurofibromin 2 (NF2) recognized as a bona fide tumour suppressor gene. In this Review, we appraise the evidence for the Hippo pathway as a cancer signalling network, and discuss cancer-relevant biological functions, potential mechanisms by which Hippo pathway activity is altered in cancer and emerging therapeutic strategies.", "corpus_id": 2008641, "score": 0 }, { "doc_id": "16850012", "title": "Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer", "abstract": "Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.", "corpus_id": 16850012, "score": 1 }, { "doc_id": "4464124", "title": "Comprehensive genomic characterization of head and neck squamous cell carcinomas", "abstract": "The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.", "corpus_id": 4464124, "score": 0 }, { "doc_id": "36848574", "title": "Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma", "abstract": "The RASSF1A tumor suppressor is involved in regulation of apoptosis and cell cycle progression. RASSF1A is localized to microtubules and binds the apoptotic kinases MST1 and MST2. It has been shown that this interaction is mediated by the Sav‐RASSF‐Hpo domain, which is an interaction domain characterized for the Drosophila proteins Sav (human WW45), Hpo (human MST1 and MST2) and Warts/LATS (large tumor suppressor). Previously, we have reported that RASSF1A hypermethylation occurs frequently in soft tissue sarcoma and is associated with an unfavorable prognosis for cancer patients. In our study, we performed methylation analysis of the CpG island promoter of MST1, MST2, WW45, LATS1 and LATS2 in soft tissue sarcomas by methylation‐specific PCR. No or a very low methylation frequency was detected for WW45, LATS1 and LATS2 (<7%). In 19 out of 52 (37%) sarcomas, a methylated promoter of MST1 was detected and 12 out of 60 (20%) samples showed methylation of the MST2 promoter. Methylation status of MST1 was confirmed by bisulfite sequencing. In tumors harboring a methylated promoter of MST1, a reduction of MST1 expression was observed by RT‐PCR. In leiomyosarcomas, MST1 and MST2 or RASSF1A methylation were mutually exclusive (P = 0.007 and P = 0.025, respectively). Surprisingly, a significantly increased risk for tumor‐related death was found for patients with an unmethylated MST1 promoter (P = 0.036). In summary, our results suggest that alteration of the Sav‐RASSF1‐Hpo tumor suppressor pathway may occur through hypermethylation of the CpG island promoter of MST1, MST2 and/or RASSF1A in human sarcomas. © 2007 Wiley‐Liss, Inc.", "corpus_id": 36848574, "score": 0 }, { "doc_id": "17417104", "title": "Hippo Pathway Activity Influences Liver Cell Fate", "abstract": "The Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. Employing a combination of lineage tracing, clonal analysis, and organoid culture approaches, we demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level. We also identify the NOTCH-signaling pathway as a functional important effector downstream of the Hippo transducer YAP. Our findings uncover a potent role for Hippo/YAP signaling in controlling liver cell fate and reveal an unprecedented level of phenotypic plasticity in mature hepatocytes, which has implications for the understanding and manipulation of liver regeneration.", "corpus_id": 17417104, "score": 1 }, { "doc_id": "207153421", "title": "The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration", "abstract": "Identification of the signaling pathways that control the proliferation of stem cells (SCs), and whether they act in a cell or non-cell autonomous manner, is key to our understanding of tissue homeostasis and cancer. In the adult Drosophila midgut, the Jun N-Terminal Kinase (JNK) pathway is activated in damaged enterocyte cells (ECs) following injury. This leads to the production of Upd cytokines from ECs, which in turn activate the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway in Intestinal SCs (ISCs), stimulating their proliferation. In addition, the Hippo pathway has been recently implicated in the regulation of Upd production from the ECs. Here, we show that the Hippo pathway target, Yorkie (Yki), also plays a crucial and cell-autonomous role in ISCs. Activation of Yki in ISCs is sufficient to increase ISC proliferation, a process involving Yki target genes that promote division, survival and the Upd cytokines. We further show that prior to injury, Yki activity is constitutively repressed by the upstream Hippo pathway members Fat and Dachsous (Ds). These findings demonstrate a cell-autonomous role for the Hippo pathway in SCs, and have implications for understanding the role of this pathway in tumorigenesis and cancer stem cells.", "corpus_id": 207153421, "score": 0 }, { "doc_id": "1387654", "title": "The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program.", "abstract": "Although a developmental role for Hippo signaling in organ size control is well appreciated, how this pathway functions in tissue regeneration is largely unknown. Here we address this issue using a dextran sodium sulfate (DSS)-induced colonic regeneration model. We find that regenerating crypts express elevated Yes-associated protein (YAP) levels. Inactivation of YAP causes no obvious intestinal defects under normal homeostasis, but severely impairs DSS-induced intestinal regeneration. Conversely, hyperactivation of YAP results in widespread early-onset polyp formation following DSS treatment. Thus, the YAP oncoprotein must be exquisitely controlled in tissue regeneration to allow compensatory proliferation and prevent the intrinsic oncogenic potential of a tissue regeneration program.", "corpus_id": 1387654, "score": 0 }, { "doc_id": "32160217", "title": "Hippo signaling regulates differentiation and maintenance in the exocrine pancreas.", "abstract": "BACKGROUND & AIMS\nThe Hippo signaling pathway is a context-dependent regulator of cell proliferation, differentiation, and apoptosis in species ranging from Drosophila to humans. In this study, we investigated the role of the core Hippo kinases-Mst1 and Mst2-in pancreatic development and homeostasis.\n\n\nMETHODS\nWe used a Cre/LoxP system to create mice with pancreas-specific disruptions in Mst1 and Mst2 (Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice), the mammalian orthologs of Drosophila Hippo. We used a transgenic approach to overexpress Yap, the downstream mediator of Hippo signaling, in the developing pancreas of mice.\n\n\nRESULTS\nContrary to expectations, the pancreatic mass of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice was reduced compared with wild-type mice, largely because of postnatal de-differentiation of acinar cells into duct-like cells. Development of this phenotype coincided with postnatal reactivation of YAP expression. Ectopic expression of YAP during the secondary transition (a stage at which YAP is normally absent) blocked differentiation of the endocrine and exocrine compartments, whereas loss of a single Yap allele reduced acinar de-differentiation. The phenotype of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice recapitulated cellular and molecular changes observed during chemical-induced pancreatitis in mice.\n\n\nCONCLUSIONS\nThe mammalian Hippo kinases, and YAP, maintain postnatal pancreatic acinar differentiation in mice.", "corpus_id": 32160217, "score": 0 }, { "doc_id": "30852123", "title": "The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors.", "abstract": "How epithelial progenitor cells integrate local signals to balance expansion with differentiation during organogenesis is still little understood. Here, we provide evidence that the Hippo pathway effector Yap is a key regulator of this process in the developing lung. We show that when epithelial tubules are forming and branching, a nucleocytoplasmic shift in Yap localization marks the boundary between the airway and the distal lung compartments. At this transition zone, Yap specifies a transcriptional program that controls Sox2 expression and ultimately generates the airway epithelium. Without Yap, epithelial progenitors are unable to properly respond to local TGF-β-induced cues and control levels and distribution of Sox2 to form airways. Yap levels and subcellular localization also markedly influence Sox2 expression and differentiation of adult airway progenitors. Our data reveal a role for the Hippo-Yap pathway in integrating growth-factor-induced cues in the developing and adult lung potentially key for homeostasis and regeneration repair.", "corpus_id": 30852123, "score": 0 }, { "doc_id": "45823013", "title": "YAP and TAZ regulate skin wound healing.", "abstract": "The Hippo signaling pathway regulates organ size, tissue regeneration, and stem cell self-renewal. The two key downstream transcription coactivators in this pathway, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), mediate the major gene regulation and biological functions of the Hippo pathway. The biological functions of YAP and TAZ in many tissues are known; however, their roles in skin wound healing remain unclear. To analyze whether YAP and/or TAZ are required for cutaneous wound healing, we performed small interfering RNA (siRNA)-mediated knockdown of YAP/TAZ in full-thickness skin wounds. YAP is strongly expressed in the nucleus and cytoplasm in the epidermis and hair follicle. Interestingly, YAP is expressed in the nucleus in the dermis at 2 and 7 days after wounding. TAZ normally localizes to the cytoplasm in the dermis but is distributed in both the nucleus and cytoplasm at 1 day after wounding. The knockdown of YAP and TAZ markedly delayed the rate of wound closure and reduced the transforming growth factor-β1 (TGF-β1) expression in the wound. YAP and TAZ also modulate the expression of TGF-β1 signaling pathway components such as Smad-2, p21, and Smad-7. These results suggest that YAP and TAZ localization to the nucleus is required for skin wound healing.", "corpus_id": 45823013, "score": 0 }, { "doc_id": "9615855", "title": "Defects in Yolk Sac Vasculogenesis, Chorioallantoic Fusion, and Embryonic Axis Elongation in Mice with Targeted Disruption of Yap65", "abstract": "ABSTRACT YAP is a multifunctional adapter protein and transcriptional coactivator with several binding partners well described in vitro and in cell culture. To explore in vivo requirements for YAP, we generated mice carrying a targeted disruption of the Yap gene. Homozygosity for the Yap tm1Smil allele (Yap −/− ) caused developmental arrest around E8.5. Phenotypic characterization revealed a requirement for YAP in yolk sac vasculogenesis. Yolk sac endothelial and erythrocyte precursors were specified as shown by histology, PECAM1 immunostaining, and alpha globin expression. Nonetheless, development of an organized yolk sac vascular plexus failed in Yap −/− embryos. In striking contrast, vasculogenesis proceeded in both the allantois and the embryo proper. Mutant embryos showed patterned gene expression domains along the anteroposterior neuraxis, midline, and streak/tailbud. Despite this evidence of proper patterning and tissue specification, Yap −/− embryos showed developmental perturbations that included a notably shortened body axis, convoluted anterior neuroepithelium, caudal dysgenesis, and failure of chorioallantoic fusion. These results reveal a vital requirement for YAP in the developmental processes of yolk sac vasculogenesis, chorioallantoic attachment, and embryonic axis elongation.", "corpus_id": 9615855, "score": 0 }, { "doc_id": "8050101", "title": "Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver", "abstract": "How organ size is controlled in mammals is not currently understood. In Drosophila the Hippo signaling pathway functions to suppress growth in imaginal discs and has been suggested to control organ size. To investigate the role of hippo signaling in regulation of mammalian organ size we have generated conditional alleles of Sav1, mst1, and mst2, orthologs of Drosophila Salvador and hippo, respectively. Specific deletion of both mst1 and mst2 in hepatocytes results in significantly enlarged livers due to excessive proliferation. By the age of 5–6 months, mst1/2 conditional mutant livers have multiple foci of liver tumors, indicating that the combined activities of mst1 and mst2 act as redundant tumor suppressors in hepatocytes. Similar findings were obtained with liver-specific deletion of Sav1, a second core Hippo signaling component that facilitates activation of mst1 and mst2. Tumors from sav1 mutants exhibited varied morphology, suggesting a mixed-lineage origin of tumor-initiating cells. Transcriptional profiling of liver tissues from both mst1/2 and sav1 conditional mutants revealed a network of Hippo signaling regulated genes with specific enrichment for genes involved in immune and inflammatory responses. Histological and immunological characterization of mst1/2 double mutant liver tissues revealed abundant accumulation of adult facultative stem cells termed oval cells in periductal regions. Because oval cells induction is commonly associated with liver injury and tumor formation, it is likely that these cells contribute to the enlarged livers and hepatomas that we observe in sav1 and mst1/2 mutants. Taken together, our results demonstrate that the Hippo signaling pathway is a critical regulator of mammalian liver growth and a potent suppressor of liver tumor formation.", "corpus_id": 8050101, "score": 0 }, { "doc_id": "17056730", "title": "YAP1 Increases Organ Size and Expands Undifferentiated Progenitor Cells", "abstract": "The mechanisms that regulate mammalian organ size are poorly understood. It is unclear whether the pathways that control organ size also impinge on stem/progenitor cells. A highly expressed gene in stem cells is YAP1, the ortholog of Drosophila Yorkie, a downstream component of the Hippo pathway. Mutations in components of this pathway produce tissue overgrowth phenotypes in the fly whereas mammalian orthologs, like salvador, merlin, LATS, and YAP1, have been implicated in tumorigenesis. We report here that YAP1 increases organ size and causes aberrant tissue expansion in mice. YAP1 activation reversibly increases liver size more than 4-fold. In the intestine, expression of endogenous YAP1 is restricted to the progenitor/stem cell compartment, and activation of YAP1 expands multipotent undifferentiated progenitor cells, which differentiate upon cessation of YAP1 expression. YAP1 stimulates Notch signaling, and administration of gamma-secretase inhibitors suppressed the intestinal dysplasia caused by YAP1. Human colorectal cancers expressing higher levels of YAP1 share molecular aspects with YAP1-induced dysplastic growth in the mouse. Our data show that the Hippo signaling pathway regulates organ size in mammals and can act on stem cell compartments, indicating a potential link between stem/progenitor cells, organ size, and cancer.", "corpus_id": 17056730, "score": 0 }, { "doc_id": "27829224", "title": "Dual role of YAP and TAZ in renewal of the intestinal epithelium", "abstract": "The rapidly self-renewing intestinal epithelium represents an exquisite model for stem cell biology. So far, genetic studies in mice have uncovered crucial roles for several signalling pathways in the tissue. Here we show, by using intestine-specific gene transfer (iGT), that Hippo signalling effectors, YAP and TAZ, promote both the proliferation of intestinal stem/progenitor cells and their differentiation into goblet cells. These functions of YAP/TAZ are regulated by the upstream Hippo pathway kinases MST1/2 and LATS1/2. Moreover, we identify TEADs and Klf4 as partner transcription factors of YAP/TAZ in the proliferation and differentiation processes, respectively. These results indicate that Hippo signalling plays a dual role in renewal of the intestinal epithelium through the regulation of two different processes, stem/progenitor cell proliferation and differentiation into goblet cells, using two different types of transcription factor. Moreover, iGT should provide a robust platform to elucidate molecular mechanisms of intestinal epithelium self-renewal.", "corpus_id": 27829224, "score": 0 }, { "doc_id": "2896610", "title": "A crucial role of WW45 in developing epithelial tissues in the mouse", "abstract": "The role and molecular mechanisms of a new Hippo signalling pathway are not fully understood in mammals. Here, we generated mice that lack WW45 and revealed a crucial role for WW45 in cell‐cycle exit and epithelial terminal differentiation. Many organs in the mutant mouse embryos displayed hyperplasia accompanied by defects in terminal differentiation of epithelial progenitor cells owing to impaired proliferation arrest rather than intrinsic acceleration of proliferation during differentiation. Importantly, the MST1 signalling pathway is specifically activated in differentiating epithelial cells. Moreover, WW45 is required for MST1 activation and translocation to the nucleus for subsequent LATS1/2 activation upon differentiation signal. LATS1/2 phosphorylates YAP, which, in turn, translocates from the nucleus into the cytoplasm, resulting in cell‐cycle exit and terminal differentiation of epithelial progenitor cells. Collectively, these data provide compelling evidence that WW45 is a key mediator of MST1 signalling in the coordinate coupling of proliferation arrest with terminal differentiation for proper epithelial tissue development in mammals.", "corpus_id": 2896610, "score": 0 }, { "doc_id": "14914202", "title": "SOX2 regulates YAP1 to maintain stemness and determine cell fate in the osteo-adipo lineage.", "abstract": "The osteoblastic and adipocytic lineages arise from mesenchymal stem cells (MSCs), but few regulators of self-renewal and early cell-fate decisions are known. Here, we show that the Hippo pathway effector YAP1 is a direct target of SOX2 and can compensate for the self-renewal defect caused by SOX2 inactivation in osteoprogenitors and MSCs. Osteogenesis is blocked by high SOX2 or YAP1, accelerated by depletion of either one, and the inhibition of osteogenesis by SOX2 requires YAP1. SOX2 favors adipogenesis and induces PPARγ, but adipogenesis can only occur with moderate levels of YAP1. YAP1 induction by SOX2 is restrained in adipogenesis, and both YAP1 overexpression and depletion inhibit the process. YAP1 binds β-catenin and directly induces the Wnt antagonist Dkk1 to dampen pro-osteogenic Wnt signals. We demonstrate a Hippo-independent regulation of YAP1 by SOX2 that cooperatively antagonizes Wnt/β-catenin signals and regulates PPARγ to determine osteogenic or adipocytic fates.", "corpus_id": 14914202, "score": 0 }, { "doc_id": "2462355", "title": "Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells.", "abstract": "Our understanding of how stem cells are regulated to maintain appropriate tissue size and architecture is incomplete. We show that Yap (Yes-associated protein 1) is required for the actual maintenance of an adult mammalian stem cell. Without Yap, adult airway basal stem cells are lost through their unrestrained differentiation, resulting in the simplification of a pseudostratified epithelium into a columnar one. Conversely, Yap overexpression increases stem cell self-renewal and blocks terminal differentiation, resulting in epithelial hyperplasia and stratification. Yap overexpression in differentiated secretory cells causes them to partially reprogram and adopt a stem cell-like identity. In contrast, Yap knockdown prevents the dedifferentiation of secretory cells into stem cells. We then show that Yap functionally interacts with p63, the cardinal transcription factor associated with myriad epithelial basal stem cells. In aggregate, we show that Yap regulates all of the cardinal behaviors of airway epithelial stem cells and determines epithelial architecture.", "corpus_id": 2462355, "score": 0 }, { "doc_id": "4415223", "title": "Restriction of intestinal stem cell expansion and the regenerative response by YAP", "abstract": "A remarkable feature of regenerative processes is their ability to halt proliferation once an organ’s structure has been restored. The Wnt signalling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. However, the mechanisms that counterbalance Wnt-driven proliferation are poorly understood. Here we demonstrate in mice and humans that yes-associated protein 1 (YAP; also known as YAP1)—a protein known for its powerful growth-inducing and oncogenic properties—has an unexpected growth-suppressive function, restricting Wnt signals during intestinal regeneration. Transgenic expression of YAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss of YAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP restricts elevated Wnt signalling independently of the AXIN–APC–GSK-3β complex partly by limiting the activity of dishevelled (DVL). DVL signals in the nucleus of intestinal stem cells, and its forced expression leads to enhanced Wnt signalling in crypts. YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas, and that its expression can restrict the growth of colorectal carcinoma xenografts. Collectively, our work describes a novel mechanistic paradigm for how proliferative signals are counterbalanced in regenerating tissues. Additionally, our findings have important implications for the targeting of YAP in human malignancies.", "corpus_id": 4415223, "score": 1 }, { "doc_id": "206530480", "title": "Hippo Pathway Inhibits Wnt Signaling to Restrain Cardiomyocyte Proliferation and Heart Size", "abstract": "Heart size is controlled through an antagonistic interaction between Hippo and Wnt signaling pathways. Genetic regulation of mammalian heart size is poorly understood. Hippo signaling represents an organ-size control pathway in Drosophila, where it also inhibits cell proliferation and promotes apoptosis in imaginal discs. To determine whether Hippo signaling controls mammalian heart size, we inactivated Hippo pathway components in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecipitation revealed that Hippo signaling negatively regulates a subset of Wnt target genes. Genetic interaction studies indicated that β-catenin heterozygosity suppressed the Hippo cardiomyocyte overgrowth phenotype. Furthermore, the Hippo effector Yap interacts with β-catenin on Sox2 and Snai2 genes. These data uncover a nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size.", "corpus_id": 206530480, "score": 1 }, { "doc_id": "32037617", "title": "The Hippo pathway regulates Wnt/beta-catenin signaling.", "abstract": "Several developmental pathways contribute to processes that regulate tissue growth and organ size. The Hippo pathway has emerged as one such critical regulator. However, how Hippo signaling is integrated with other pathways to coordinate these processes remains unclear. Here, we show that the Hippo pathway restricts Wnt/beta-Catenin signaling by promoting an interaction between TAZ and DVL in the cytoplasm. TAZ inhibits the CK1delta/epsilon-mediated phosphorylation of DVL, thereby inhibiting Wnt/beta-Catenin signaling. Abrogation of TAZ levels or Hippo signaling enhances Wnt3A-stimulated DVL phosphorylation, nuclear beta-Catenin, and Wnt target gene expression. Mice lacking Taz develop polycystic kidneys with enhanced cytoplasmic and nuclear beta-Catenin. Moreover, in Drosophila, Hippo signaling modulates Wg target gene expression. These results uncover a cytoplasmic function of TAZ in regulating Wnt signaling and highlight the role of the Hippo pathway in coordinating morphogenetic signaling with growth control.", "corpus_id": 32037617, "score": 0 }, { "doc_id": "2144218", "title": "TAZ-mediated crosstalk between Wnt and Hippo signaling.", "abstract": "Previously, research addressing Hippo signaling focused on the inactivation of the proto-oncoproteins TAZ and YAP caused by the sequestration of supposedly inactive phospho-TAZ/YAP in the cytoplasm. In this issue of Developmental Cell, the Attisano laboratory now shows that cytoplasmic TAZ inhibits canonical Wnt signaling, thereby highlighting that the Hippo pathway can control other signaling cascades.", "corpus_id": 2144218, "score": 0 }, { "doc_id": "205741321", "title": "Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP.", "abstract": "The insulin/IGF signaling (IIS) pathway is a potent inducer of cell proliferation in normal development and in cancer. The mechanism by which this occurs, however, is not completely understood. The Hippo signaling pathway regulates cell proliferation via the transcriptional co-activator Yorkie/YAP, however the signaling inputs regulating Hippo activity are not fully elucidated. Here we present evidence linking these two conserved, oncogenic pathways in Drosophila and in mammalian cells. We find that activation of IIS and of Yorkie signaling correlate positively in hepatocellular carcinoma. We show that IIS activates Yorkie in vivo, and that Yorkie plays an important role in the ability of IIS to drive cell proliferation. Interestingly, we also find the converse--that Yorkie signaling activates components of the insulin/TOR pathway. In sum, this crosstalk between IIS and Yorkie leads to coordinated regulation of these two oncogenic pathways.", "corpus_id": 205741321, "score": 0 }, { "doc_id": "11594247", "title": "YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation.", "abstract": "Medulloblastoma is the most common solid malignancy of childhood, with treatment side effects reducing survivors' quality of life and lethality being associated with tumor recurrence. Activation of the Sonic hedgehog (Shh) signaling pathway is implicated in human medulloblastomas. Cerebellar granule neuron precursors (CGNPs) depend on signaling by the morphogen Shh for expansion during development, and have been suggested as a cell of origin for certain medulloblastomas. Mechanisms contributing to Shh pathway-mediated proliferation and transformation remain poorly understood. We investigated interactions between Shh signaling and the recently described tumor-suppressive Hippo pathway in the developing brain and medulloblastomas. We report up-regulation of the oncogenic transcriptional coactivator yes-associated protein 1 (YAP1), which is negatively regulated by the Hippo pathway, in human medulloblastomas with aberrant Shh signaling. Consistent with conserved mechanisms between brain tumorigenesis and development, Shh induces YAP1 expression in CGNPs. Shh also promotes YAP1 nuclear localization in CGNPs, and YAP1 can drive CGNP proliferation. Furthermore, YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly growing tumor cells. These findings implicate YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence.", "corpus_id": 11594247, "score": 0 }, { "doc_id": "39342916", "title": "Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma.", "abstract": "BACKGROUND & AIMS\nCancer cells often lose contact inhibition to undergo anchorage-independent proliferation and become resistant to apoptosis by inactivating the Hippo signaling pathway, resulting in activation of the transcriptional co-activator yes-associated protein (YAP). However, the oncogenic mechanisms of YAP activity are unclear.\n\n\nMETHODS\nBy using cross-species analysis of expression data, the Notch ligand Jagged-1 (Jag-1) was identified as a downstream target of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells. We analyzed the functions of YAP in HCC cells via overexpression and RNA silencing experiments. We used transgenic mice that overexpressed a constitutively activated form of YAP (YAP(S127A)), and measured protein levels in HCC, colorectal and pancreatic tumor samples from patients.\n\n\nRESULTS\nHuman HCC cell lines and mouse hepatocytes that overexpress YAP(S127A) up-regulated Jag-1, leading to activation of the Notch pathway and increased proliferation. Induction of Jag-1, activation of Notch, and cell proliferation required binding of YAP to its transcriptional partner TEA domain family member 4 (TEAD4); TEAD4 binding required the Mst1/2 but not β-catenin signaling. Levels of YAP correlated with Jag-1 expression and Notch signaling in human tumor samples and correlated with shorter survival times of patients with HCC or colorectal cancer.\n\n\nCONCLUSIONS\nThe transcriptional regulator YAP up-regulates Jag-1 to activate Notch signaling in HCC cells and mouse hepatocytes. YAP-dependent activity of Jag-1 and Notch correlate in human HCC and colorectal tumor samples with patient survival times, suggesting the use of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer. Transcript profiling: microarray information was deposited at the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jxepvsumwosqkve&acc=GSE35004).", "corpus_id": 39342916, "score": 1 }, { "doc_id": "13997392", "title": "Regulation of the Hippo-YAP Pathway by G-Protein-Coupled Receptor Signaling", "abstract": "The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR.", "corpus_id": 13997392, "score": 1 }, { "doc_id": "34496353", "title": "Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP.", "abstract": "Hippo signaling represents a tumor suppressor pathway that regulates organ size and tumorigenesis through phosphorylation and inhibition of the transcription coactivator YAP. Here, we show that serum deprivation dramatically induces YAP Ser127 phosphorylation and cytoplasmic retention, independent of cell-cell contact. Through chemical isolation and activity profiling, we identified serum-derived sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) as small molecule activators of YAP. S1P induces YAP nuclear localization through S1P(2) receptor, Rho GTPase activation, and F-actin polymerization, independent of the core Hippo pathway kinases. Bioinformatics studies also showed that S1P stimulation induces YAP target gene expression in mouse liver and human embryonic stem cells. These results revealed potent small molecule regulators of YAP and suggest that S1P and LPA might modulate cell proliferation and tumorigenesis through YAP activation.", "corpus_id": 34496353, "score": 0 }, { "doc_id": "24935841", "title": "Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP.", "abstract": "Uveal melanoma (UM) is the most common cancer in adult eyes. Approximately 80% of UMs harbor somatic activating mutations in GNAQ or GNA11 (encoding Gq or G11, respectively). Herein, we show in both cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G protein-coupled receptor signaling. YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations. This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11.", "corpus_id": 24935841, "score": 0 }, { "doc_id": "35978710", "title": "Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs).", "abstract": "The Hippo signaling pathway plays a crucial role in tissue growth and tumorigenesis. Core components of the Hippo pathway include the MST1/2 and Lats1/2 kinases. Acting downstream from the Hippo pathway are the YAP/TAZ transcription coactivators, which are inhibited through phosphorylation by Lats. However, upstream signals that regulate the Hippo pathway have not been well delineated. Here we report that stimulation of protease-activated receptors (PARs) activates YAP/TAZ by decreasing phosphorylation and increasing nuclear localization. PAR1 acts through G(12/13) and Rho GTPase to inhibit the Lats1/2 kinase. Our observations establish thrombin as a physiological signal for the Hippo pathway and implicate Hippo-YAP as a key downstream signaling branch of PAR activation.", "corpus_id": 35978710, "score": 0 }, { "doc_id": "1073547", "title": "Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1", "abstract": "The Hippo signaling pathway inhibits cell growth and regulates organ size through a kinase cascade that leads to the phosphorylation and nuclear exclusion of the growth-promoting transcriptional coactivator Yes-associated protein (YAP)/Yorkie. It mediates contact inhibition of cell growth downstream of cadherin adhesion molecules and other cell surface proteins. Contact inhibition is often antagonized by mitogenic growth factor signaling. We report an important mechanism for this antagonism, inhibition of Hippo pathway signaling by mitogenic growth factors. EGF treatment of immortalized mammary cells triggers the rapid translocation of YAP into the nucleus along with YAP dephosphorylation, both of which depend on Lats, the terminal kinase in the Hippo pathway. A small-molecule inhibitor screen of downstream effector pathways shows that EGF receptor inhibits the Hippo pathway through activation of PI3-kinase (PI3K) and phosphoinositide-dependent kinase (PDK1), but independent of AKT activity. The PI3K-PDK1 pathway also mediates YAP nuclear translocation downstream of lysophosphatidic acid and serum as a result of constitutive oncogenic activation of PI3K. PDK1 associates with the core Hippo pathway-kinase complex through the scaffold protein Salvador. The entire Hippo core complex dissociates in response to EGF signaling in a PI3K-PDK1–dependent manner, leading to inactivation of Lats, dephosphorylation of YAP, and YAP nuclear accumulation and transcriptional activation of its target gene, CTGF. These findings show that an important activity of mitogenic signaling pathways is to inactivate the growth-inhibitory Hippo pathway and provide a mechanism for antagonism between contact inhibition and growth factor action.", "corpus_id": 1073547, "score": 0 }, { "doc_id": "3235104", "title": "Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins.", "abstract": "EGFR and Hippo signaling pathways both control growth and, when dysregulated, contribute to tumorigenesis. We find that EGFR activates the Hippo pathway transcription factor Yorkie and demonstrate that Yorkie is required for the influence of EGFR on cell proliferation in Drosophila. EGFR regulates Yorkie through the influence of its Ras-MAPK branch on the Ajuba LIM protein Jub. Jub is epistatic to EGFR and Ras for Yorkie regulation, Jub is subject to MAPK-dependent phosphorylation, and EGFR-Ras-MAPK signaling enhances Jub binding to the Yorkie kinase Warts and the adaptor protein Salvador. An EGFR-Hippo pathway link is conserved in mammals, as activation of EGFR or RAS activates the Yorkie homolog YAP, and EGFR-RAS-MAPK signaling promotes phosphorylation of the Ajuba family protein WTIP and also enhances WTIP binding to the Warts and Salvador homologs LATS and WW45. Our observations implicate the Hippo pathway in EGFR-mediated tumorigenesis and identify a molecular link between these pathways.", "corpus_id": 3235104, "score": 0 }, { "doc_id": "24854468", "title": "YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway", "abstract": "The Hippo signalling pathway regulates cellular proliferation and survival, thus has profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP (yes-associated protein), a transcriptional co-activator amplified in mouse and human cancers, where it promotes epithelial to mesenchymal transition (EMT) and malignant transformation. So far, studies of YAP target genes have focused on cell-autonomous mediators; here we show that YAP-expressing MCF10A breast epithelial cells enhance the proliferation of neighbouring untransfected cells, implicating a non-cell-autonomous mechanism. We identify the gene for the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) as a transcriptional target of YAP, whose induction contributes to YAP-mediated cell proliferation and migration, but not EMT. Knockdown of AREG or addition of an EGFR kinase inhibitor abrogates the proliferative effects of YAP expression. Suppression of the negative YAP regulators LATS1 and 2 (large tumour suppressor 1 and 2) is sufficient to induce AREG expression, consistent with physiological regulation of AREG by the Hippo pathway. Genetic interaction between the Drosophila YAP orthologue Yorkie and Egfr signalling components supports the link between these two highly conserved signalling pathways. Thus, YAP-dependent secretion of AREG indicates that activation of EGFR signalling is an important non-cell-autonomous effector of the Hippo pathway, which has implications for the regulation of both physiological and malignant cell proliferation.", "corpus_id": 24854468, "score": 0 }, { "doc_id": "37215373", "title": "Neuregulin 1–activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration", "abstract": "Two pathways regulating tissue growth and oncogenic signaling are functionally linked. ERBB4 Signals to YAP Whereas the Hippo pathway limits cell growth in response to mechanical signals or cell-cell contact, growth factors are soluble signals that stimulate cell proliferation. Kinases in the Hippo pathway phosphorylate and inhibit YAP, sequestering YAP in the cytosol and limiting organ size and tissue growth. Neuregulin stimulates the cleavage of the epidermal growth factor receptor family member ERBB4. Haskins et al. found that the cleaved intracellular domain (ICD) of ERBB4 activated YAP-mediated transcription by interacting with YAP. In breast cancer cells, knocking down YAP prevented cell migration induced by neuregulin. These results suggest that in addition to receptor tyrosine kinase signaling, ERBB4 can promote tumor aggressiveness by stimulating YAP. The receptor tyrosine kinase ERBB4, a member of the epidermal growth factor receptor (EGFR) family, is unusual in that ERBB4 can undergo intramembrane proteolysis, releasing a soluble intracellular domain (ICD) that modulates transcription in the nucleus. We found that ERBB4 activated the transcriptional coactivator YAP, which promotes organ and tissue growth and is inhibited by the Hippo tumor-suppressor pathway. Overexpressing ERBB4 in cultured mammary epithelial cells or adding the ERBB4 ligand neuregulin 1 (NRG1) to breast cancer cell cultures promoted the expression of genes regulated by YAP, such as CTGF. Knocking down YAP or ERBB4 prevented the induction of CTGF expression by NRG1, as did treating cells with the ERBB inhibitors lapatinib or erlotinib, which reduced ERBB4 cleavage. NRG1 stimulated YAP activity to an extent comparable to that of EGF (epidermal growth factor) or LPA (lysophosphatidic acid), known activators of YAP. NRG1 stimulated YAP-dependent cell migration in breast cancer cell lines. These observations connect the unusual nuclear function of a growth factor receptor with a mechanosensory pathway and suggest that NRG1-ERBB4-YAP signaling contributes to the aggressive behavior of tumor cells.", "corpus_id": 37215373, "score": 0 }, { "doc_id": "475767", "title": "Integration of mechanical and chemical signals by YAP and TAZ transcription coactivators", "abstract": "YAP and TAZ are transcription coactivators and effectors of the Hippo pathway, which play a key role in organ size control. Through interaction with transcription factors such as TEADs, they activate gene transcription and thus promote cell proliferation, inhibit apoptosis, and regulate cell differentiation. Dysregulation of YAP/TAZ was found to correlate with human cancers. The oncogenic roles of these proteins were also demonstrated in animal models. The growth promoting activity of YAP/TAZ is limited by the Hippo tumor suppressor pathway through phosphorylation-induced cytoplasmic retention and destabilization. Recently, it was found that YAP and TAZ mediate responses to several extracellular signals including mechanical stress, GPCR signaling, and the Wnt signaling pathway. All these growth-regulating signals play important roles in normal development and cancer. In this review, we would like to discuss the function of YAP and TAZ as effectors of these physiological signals.", "corpus_id": 475767, "score": 0 }, { "doc_id": "8550887", "title": "YAP/TAZ as mechanosensors and mechanotransducers in regulating organ size and tumor growth", "abstract": "Organ size is controlled by the concerted action of biochemical and physical processes. Although mechanical forces are known to regulate cell and tissue behavior, as well as organogenesis, the precise molecular events that integrate mechanical and biochemical signals to control these processes are not fully known. The recently delineated Hippo‐tumor suppressor network and its two nuclear effectors, YAP and TAZ, shed light on these mechanisms. YAP and TAZ are proto‐oncogene proteins that respond to complex physical milieu represented by the rigidity of the extracellular matrix, cell geometry, cell density, cell polarity and the status of the actin cytoskeleton. Here, we review the current knowledge of how YAP and TAZ function as mechanosensors and mechanotransducers. We also suggest that by deciphering the mechanical and biochemical signals controlling YAP/TAZ function, we will gain insights into new strategies for cancer treatment and organ regeneration.", "corpus_id": 8550887, "score": 0 }, { "doc_id": "205225137", "title": "Role of YAP/TAZ in mechanotransduction", "abstract": "Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.", "corpus_id": 205225137, "score": 0 }, { "doc_id": "3377738", "title": "A Mechanical Checkpoint Controls Multicellular Growth through YAP/TAZ Regulation by Actin-Processing Factors", "abstract": "Key cellular decisions, such as proliferation or growth arrest, typically occur at spatially defined locations within tissues. Loss of this spatial control is a hallmark of many diseases, including cancer. Yet, how these patterns are established is incompletely understood. Here, we report that physical and architectural features of a multicellular sheet inform cells about their proliferative capacity through mechanical regulation of YAP and TAZ, known mediators of Hippo signaling and organ growth. YAP/TAZ activity is confined to cells exposed to mechanical stresses, such as stretching, location at edges/curvatures contouring an epithelial sheet, or stiffness of the surrounding extracellular matrix. We identify the F-actin-capping/severing proteins Cofilin, CapZ, and Gelsolin as essential gatekeepers that limit YAP/TAZ activity in cells experiencing low mechanical stresses, including contact inhibition of proliferation. We propose that mechanical forces are overarching regulators of YAP/TAZ in multicellular contexts, setting responsiveness to Hippo, WNT, and GPCR signaling.", "corpus_id": 3377738, "score": 0 }, { "doc_id": "1167227", "title": "Angiomotins link F-actin architecture to Hippo pathway signaling", "abstract": "Angiomotin proteins, together with LATS kinase, regulate the Hippo pathway transcriptional coactivator YAP in response to changes in the F-actin cytoskeleton. Competition between F-actin and YAP for binding to angiomotins makes YAP regulation responsive to F-actin levels. Phosphorylation by LATS can switch angiomotins from F-actin to YAP binding.", "corpus_id": 1167227, "score": 0 }, { "doc_id": "1897324", "title": "A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway", "abstract": "The Hippo–YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size. To identify components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes. One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases. Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1. Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies. In addition, our findings provide insight into upstream signals of the Hippo–YAP signalling cascade.", "corpus_id": 1897324, "score": 0 }, { "doc_id": "17479197", "title": "Cytokinesis Failure Triggers Hippo Tumor Suppressor Pathway Activation", "abstract": "Genetically unstable tetraploid cells can promote tumorigenesis. Recent estimates suggest that ∼37% of human tumors have undergone a genome-doubling event during their development. This potentially oncogenic effect of tetraploidy is countered by a p53-dependent barrier to proliferation. However, the cellular defects and corresponding signaling pathways that trigger growth suppression in tetraploid cells are not known. Here, we combine RNAi screening and in vitro evolution approaches to demonstrate that cytokinesis failure activates the Hippo tumor suppressor pathway in cultured cells, as well as in naturally occurring tetraploid cells in vivo. Induction of the Hippo pathway is triggered in part by extra centrosomes, which alter small G protein signaling and activate LATS2 kinase. LATS2 in turn stabilizes p53 and inhibits the transcriptional regulators YAP and TAZ. These findings define an important tumor suppression mechanism and uncover adaptive mechanisms potentially available to nascent tumor cells that bypass this inhibitory regulation.", "corpus_id": 17479197, "score": 0 }, { "doc_id": "221918", "title": "Spectrin regulates Hippo signaling by modulating cortical actomyosin activity", "abstract": "The Hippo pathway controls tissue growth through a core kinase cascade that impinges on the transcription of growth-regulatory genes. Understanding how this pathway is regulated in development remains a major challenge. Recent studies suggested that Hippo signaling can be modulated by cytoskeletal tension through a Rok-myosin II pathway. How cytoskeletal tension is regulated or its relationship to the other known upstream regulators of the Hippo pathway remains poorly defined. In this study, we identify spectrin, a contractile protein at the cytoskeleton-membrane interface, as an upstream regulator of the Hippo signaling pathway. We show that, in contrast to canonical upstream regulators such as Crumbs, Kibra, Expanded, and Merlin, spectrin regulates Hippo signaling in a distinct way by modulating cortical actomyosin activity through non-muscle myosin II. These results uncover an essential mediator of Hippo signaling by cytoskeleton tension, providing a new entry point to dissecting how mechanical signals regulate Hippo signaling in living tissues. DOI: http://dx.doi.org/10.7554/eLife.06567.001", "corpus_id": 221918, "score": 0 }, { "doc_id": "12711748", "title": "Remodelling the extracellular matrix in development and disease", "abstract": "The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.", "corpus_id": 12711748, "score": 0 }, { "doc_id": "12900829", "title": "Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling", "abstract": "Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.", "corpus_id": 12900829, "score": 0 }, { "doc_id": "3103365", "title": "Mechano-transduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer associated fibroblasts", "abstract": "To learn more about cancer-associated fibroblasts (CAFs), we have isolated fibroblasts from different stages of breast cancer progression and analysed their function and gene expression. These analyses reveal that activation of the YAP transcription factor is a signature feature of CAFs. YAP function is required for CAFs to promote matrix stiffening, cancer cell invasion and angiogenesis. Remodelling of the ECM and promotion of cancer cell invasion requires the actomyosin cytoskeleton. YAP regulates the expression of several cytoskeletal regulators, including ANLN and DIAPH3, and controls the protein levels of MYL9 (also known as MLC2). Matrix stiffening further enhances YAP activation, thus establishing a feed-forward self-reinforcing loop that helps to maintain the CAF phenotype. Actomyosin contractility and Src function are required for YAP activation by stiff matrices. Further, transient ROCK inhibition is able to disrupt the feed-forward loop, leading to a long-lasting reversion of the CAF phenotype.", "corpus_id": 3103365, "score": 0 }, { "doc_id": "15468669", "title": "The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis", "abstract": "Merlin, the protein product of the Neurofibromatosis type-2 gene, acts as a tumour suppressor in mice and humans. Merlin is an adaptor protein with a FERM domain and it is thought to transduce a growth-regulatory signal. However, the pathway through which Merlin acts as a tumour suppressor is poorly understood. Merlin, and its function as a negative regulator of growth, is conserved in Drosophila, where it functions with Expanded, a related FERM domain protein. Here, we show that Drosophila Merlin and Expanded are components of the Hippo signalling pathway, an emerging tumour-suppressor pathway. We find that Merlin and Expanded, similar to other components of the Hippo pathway, are required for proliferation arrest and apoptosis in developing imaginal discs. Our genetic and biochemical data place Merlin and Expanded upstream of Hippo and identify a pathway through which they act as tumour-suppressor genes.", "corpus_id": 15468669, "score": 0 }, { "doc_id": "22213499", "title": "Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded.", "abstract": "The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. Central to this pathway is a kinase cascade wherein Hippo (Hpo), in complex with Salvador (Sav), phosphorylates and activates Warts (Wts), which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein, known as the YAP coactivator in mammalian cells. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are upstream components that regulate Hpo activity through unknown mechanisms. Here we identify Kibra as another upstream component of the Hippo signaling pathway. We show that Kibra functions together with Mer and Ex in a protein complex localized to the apical domain of epithelial cells, and that this protein complex regulates the Hippo kinase cascade via direct binding to Hpo and Sav. These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis.", "corpus_id": 22213499, "score": 0 }, { "doc_id": "273070", "title": "Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein.", "abstract": "The Yes-associated protein (YAP) is a transcription coactivator that plays a crucial role in organ size control by promoting cell proliferation and inhibiting apoptosis. The Hippo tumor suppressor pathway inhibits YAP through phosphorylation-induced cytoplasmic retention and degradation. Here we report a novel mechanism of YAP regulation by angiomotin (AMOT) family proteins via a direct interaction. Knockdown of AMOT family protein AMOTL2 in polarized Madin-Darby canine kidney (MDCK) cells leads to YAP activation, as indicated by decreased YAP tight junction localization, attenuated YAP phosphorylation, accumulation of nuclear YAP, and induction of YAP target gene expression. Transcriptional coactivator with PDZ-binding motif (TAZ), the YAP paralog, is also regulated by AMOT in a similar fashion. Furthermore, AMOTL2 knockdown results in loss of cell contact inhibition in a manner dependent on the functions of YAP and TAZ. Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition.", "corpus_id": 273070, "score": 0 }, { "doc_id": "23360445", "title": "E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components", "abstract": "Contact inhibition of cell growth is essential for embryonic development and maintenance of tissue architecture in adult organisms, and the growth of tumors is characterized by a loss of contact inhibition of proliferation. The recently identified Hippo signaling pathway has been implicated in contact inhibition of proliferation as well as organ size control. The modulation of the phosphorylation and nuclear localization of Yes-associated protein (YAP) by the highly conserved kinase cascade of the Hippo signaling pathway has been intensively studied. However, cell-surface receptors regulating the Hippo signaling pathway in mammals are not well understood. In this study, we show that Hippo signaling pathway components are required for E-cadherin–dependent contact inhibition of proliferation. Knockdown of the Hippo signaling components or overexpression of YAP inhibits the decrease in cell proliferation caused by E-cadherin homophilic binding at the cell surface, independent of other cell–cell interactions. We also demonstrate that the E-cadherin/catenin complex functions as an upstream regulator of the Hippo signaling pathway in mammalian cells. Expression of E-cadherin in MDA-MB-231 cells restores the density-dependent regulation of YAP nuclear exclusion. Knockdown of β-catenin in densely cultured MCF10A cells, which mainly depletes E-cadherin–bound β-catenin, induces a decrease in the phosphorylation of S127 residue of YAP and its nuclear accumulation. Moreover, E-cadherin homophilic binding independent of other cell interactions is sufficient to control the subcellular localization of YAP. Therefore, Our results indicate that, in addition to its role in cell–cell adhesion, E-cadherin-mediated cell–cell contact directly regulates the Hippo signaling pathway to control cell proliferation.", "corpus_id": 23360445, "score": 0 }, { "doc_id": "86271406", "title": "Epithelial cell polarity, stem cells and cancer", "abstract": "Fernando Martin‑Belmonte 1 and Mirna Perez‑Moreno 2 Abstract | After years of extensive scientific discovery much has been learned about the networks that regulate epithelial homeostasis. Loss of expression or functional activity of cell adhesion and cell polarity proteins (including the PAR, crumbs (CRB) and scribble (SCRIB) complexes) is intricately related to advanced stages of tumour progression and invasiveness. But the key roles of these proteins in crosstalk with the Hippo and liver kinase B1 (LKB1)- AMPK pathways and in epithelial function and proliferation indicate that they may also be associated with the early stages of tumorigenesis. For example, deregulation of adhesion and polarity proteins can cause misoriented cell divisions and increased self-renewal of adult epithelial stem cells. In this Review, we highlight some advances in the understanding of how loss of epithelial cell polarity contributes to tumorigenesis.", "corpus_id": 86271406, "score": 0 }, { "doc_id": "14474049", "title": "Spatial Organization of Hippo Signaling at the Plasma Membrane Mediated by the Tumor Suppressor Merlin/NF2", "abstract": "Although Merlin/NF2 was discovered two decades ago as a tumor suppressor underlying Neurofibromatosis type II, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo/Mst. In contrast to the commonly depicted linear model of Merlin functioning through Hpo/Mst, here we show that in both Drosophila and mammals, Merlin promotes downstream Hippo signaling without activating the intrinsic kinase activity of Hpo/Mst. Instead, Merlin directly binds and recruits the effector kinase Wts/Lats to the plasma membrane. Membrane recruitment, in turn, promotes Wts phosphorylation by the Hpo-Sav kinase complex. We further show that disruption of the actin cytoskeleton promotes Merlin-Wts interactions, which implicates Merlin in actin-mediated regulation of Hippo signaling. Our findings elucidate an important molecular function of Merlin and highlight the plasma membrane as a critical subcellular compartment for Hippo signal transduction.", "corpus_id": 14474049, "score": 0 }, { "doc_id": "8695180", "title": "The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment", "abstract": "The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also have beneficial roles in stimulating tissue repair and regeneration following injury, so their activation may be therapeutically useful in these contexts. A complex network of intracellular and extracellular signalling pathways that modulate YAP and TAZ activities have recently been identified. Here, we review the regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators.", "corpus_id": 8695180, "score": 0 }, { "doc_id": "13292100", "title": "Disease implications of the Hippo/YAP pathway.", "abstract": "The Hippo signaling pathway is important for controlling organ size and tissue homeostasis. Originally identified in Drosophila melanogaster, the core components of the Hippo pathway are highly conserved in mammals. The Hippo pathway can be modulated by a wide range of stimuli, including G protein-coupled receptor (GPCR) signaling, changes in the actin cytoskeleton, cell-cell contact, and cell polarity. When activated, the Hippo pathway functions as a tumor suppressor to limit cell growth. However, dysregulation by genetic inactivation of core pathway components or amplification or gene fusion of its downstream effectors results in increased cell proliferation and decreased apoptosis and differentiation. Unsurprisingly, this can lead to tissue overgrowth, tumorigenesis, and many other diseases.", "corpus_id": 13292100, "score": 0 }, { "doc_id": "13225320", "title": "The emerging roles of YAP and TAZ in cancer", "abstract": "Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the major downstream effectors of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration and tumorigenesis. In this Progress article, we summarize the current understanding of the biological functions of YAP and TAZ, and how the regulation of these two proteins can be disrupted in cancer. We also highlight recent findings on their expanding role in cancer progression and describe the potential of these targets for therapeutic intervention.", "corpus_id": 13225320, "score": 0 }, { "doc_id": "13970062", "title": "Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus", "abstract": "Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth-inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4(DCAF1), and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 implement a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlin's ability to interact with or inhibit CRL4(DCAF1). Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4(DCAF1).", "corpus_id": 13970062, "score": 0 }, { "doc_id": "11356760", "title": "Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus.", "abstract": "It is currently unclear whether Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at the plasma membrane or by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. We found that derepressed CRL4(DCAF1) promotes YAP- and TEAD-dependent transcription by ubiquitylating and, thereby, inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2-mutant tumors. We conclude that derepressed CRL4(DCAF1) promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus.", "corpus_id": 11356760, "score": 0 }, { "doc_id": "206228145", "title": "Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver.", "abstract": "The molecular signals that control the maintenance and activation of liver stem/progenitor cells are poorly understood, and the role of liver progenitor cells in hepatic tumorigenesis is unclear. We report here that liver-specific deletion of the neurofibromatosis type 2 (Nf2) tumor suppressor gene in the developing or adult mouse specifically yields a dramatic, progressive expansion of progenitor cells throughout the liver without affecting differentiated hepatocytes. All surviving mice eventually developed both cholangiocellular and hepatocellular carcinoma, suggesting that Nf2(-/-) progenitors can be a cell of origin for these tumors. Despite the suggested link between Nf2 and the Hpo/Wts/Yki signaling pathway in Drosophila, and recent studies linking the corresponding Mst/Lats/Yap pathway to mammalian liver tumorigenesis, our molecular studies suggest that Merlin is not a major regulator of YAP in liver progenitors, and that the overproliferation of Nf2(-/-) liver progenitors is instead driven by aberrant epidermal growth factor receptor (EGFR) activity. Indeed, pharmacologic inhibition of EGFR blocks the proliferation of Nf2(-/-) liver progenitors in vitro and in vivo, consistent with recent studies indicating that the Nf2-encoded protein Merlin can control the abundance and signaling of membrane receptors such as EGFR. Together, our findings uncover a critical role for Nf2/Merlin in controlling homeostasis of the liver stem cell niche.", "corpus_id": 206228145, "score": 0 }, { "doc_id": "13074668", "title": "The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals.", "abstract": "The conserved Hippo signaling pathway regulates organ size in Drosophila and mammals. While a core kinase cascade leading from the protein kinase Hippo (Hpo) (Mst1 and Mst2 in mammals) to the transcription coactivator Yorkie (Yki) (YAP in mammals) has been established, upstream regulators of the Hippo kinase cascade are less well defined, especially in mammals. Using conditional knockout mice, we demonstrate that the Merlin/NF2 tumor suppressor and the YAP oncoprotein function antagonistically to regulate liver development. While inactivation of Yap led to loss of hepatocytes and biliary epithelial cells, inactivation of Nf2 led to hepatocellular carcinoma and bile duct hamartoma. Strikingly, the Nf2-deficient phenotypes in multiple tissues were largely suppressed by heterozygous deletion of Yap, suggesting that YAP is a major effector of Merlin/NF2 in growth regulation. Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2.", "corpus_id": 13074668, "score": 0 }, { "doc_id": "5193975", "title": "The Angiomotins – From discovery to function", "abstract": "Angiomotins were originally identified as angiostatin binding proteins and implicated in the regulation of endothelial cell migration. Recent studies have shed light on the role of Angiomotins and other members of the Motin protein family in epithelial cells and in pathways directly linked to the pathogenesis of cancer. In particular, Motins have been shown to play a role in signaling pathways regulated by small G‐proteins and the Hippo–YAP pathway. In this review the role of the Motin protein family in these signaling pathways will be described and open questions will be discussed.", "corpus_id": 5193975, "score": 0 }, { "doc_id": "42815617", "title": "Actin-binding and Cell Proliferation Activities of Angiomotin Family Members Are Regulated by Hippo Pathway-mediated Phosphorylation*", "abstract": "Background: LATS kinase, one of the core kinases of Hippo pathway, phosphorylates and inactivates the downstream coactivator YAP/TAZ. Results: The angiomotin (Amot) family members are phosphorylated by LATS kinase. Conclusion: Phosphorylation of Amots by LATS kinase inhibits actin-binding, stabilizes Amot, and inhibits cell proliferation. Significance: Besides phosphorylating YAP/TAZ, LATS kinase may phosphorylate other components of the Hippo pathway. Whether the Hippo pathway has downstream targets other than YAP and TAZ is unknown. In this report, we have identified angiomotin (Amot) family members as novel substrates of Hippo core kinases. The N-terminal regions of Amot proteins contain a conserved HXRXXS consensus site for LATS1/2-mediated phosphorylation. Phospho-specific antibodies showed that Hippo core kinases could mediate phosphorylation of endogenous as well as exogenous Amot family members. Knockdown of LATS1 and LATS2 endogenously reduced the phosphorylation of Amots detected by the phospho-specific antibodies. Mutation of the serine to alanine within this HXRXXS site in Amot and AmotL2 established that this site was essential for Hippo core kinase-mediated phosphorylation. Wild-type and non-phosphorylated Amot (Amot-S175A) were targeted to actin filaments, whereas phospho-mimic Amot (Amot-S175D) failed to be localized with actin. Overexpression of LATS2 caused dissociation of Amot from actin but not Amot-S175A. Mapping of the actin-binding site of Amot showed that serine 175 of Amot was important for the actin-binding activity. Amot-S175A promoted, whereas Amot and Amot-S175D inhibited, cell proliferation. These results collectively suggest that the Hippo pathway negatively regulates the actin-binding activity of Amot family members through direct phosphorylation.", "corpus_id": 42815617, "score": 0 }, { "doc_id": "212022", "title": "Phosphorylation of Angiomotin by Lats1/2 Kinases Inhibits F-actin Binding, Cell Migration, and Angiogenesis*", "abstract": "Background: Substrates of the Hippo pathway kinases Lats1/2 are largely unknown besides YAP/TAZ. Results: Phosphorylation of angiomotin by Lats1/2 inhibits interaction with F-actin thus impairs cell migration and angiogenesis. Conclusion: AMOTp130 is a physiological and functional substrate of Lats1/2 and the Hippo pathway. Significance: Demonstrating how identification of novel substrates would facilitate understanding the physiology of the Hippo pathway. The Hippo tumor suppressor pathway plays important roles in organ size control through Lats1/2 mediated phosphorylation of the YAP/TAZ transcription co-activators. However, YAP/TAZ independent functions of the Hippo pathway are largely unknown. Here we report a novel role of the Hippo pathway in angiogenesis. Angiomotin p130 isoform (AMOTp130) is phosphorylated on a conserved HXRXXS motif by Lats1/2 downstream of GPCR signaling. Phosphorylation disrupts AMOT interaction with F-actin and correlates with reduced F-actin stress fibers and focal adhesions. Furthermore, phosphorylation of AMOT by Lats1/2 inhibits endothelial cell migration in vitro and angiogenesis in zebrafish embryos in vivo. Thus AMOT is a direct substrate of Lats1/2 mediating functions of the Hippo pathway in endothelial cell migration and angiogenesis.", "corpus_id": 212022, "score": 0 }, { "doc_id": "205263912", "title": "Serum deprivation inhibits the transcriptional co-activator YAP and cell growth via phosphorylation of the 130-kDa isoform of Angiomotin by the LATS1/2 protein kinases", "abstract": "Significance This study defines a unique mechanism controlling the activation of Hippo signaling and consequent inhibition of cell growth. Specifically, serum starvation is found to induce the large tumor suppressor (LATS)1/2 kinases to phosphorylate and thus stabilize the 130 kDa isoform of the membrane-associated polarity protein angiomotin (Amot130). As a consequence, Amot130 recruits the E3 protein-ubiquitin ligase atrophin-1 interacting protein 4. This multiprotein complex then signals the degradation of Yes-associated protein (YAP) and the inhibition of cell growth. These findings significantly modify our current view that YAP phosphorylation by LATS1/2 is sufficient for its inhibition in mammals and thus for growth arrest. Large tumor suppressor (LATS)1/2 protein kinases transmit Hippo signaling in response to intercellular contacts and serum levels to limit cell growth via the inhibition of Yes-associated protein (YAP). Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130. Consistently, the Amot130 (S175A) mutant, which lacks LATS phosphorylation, bound AIP4 poorly under all conditions and showed reduced stability. Amot130 and AIP4 also promoted the ubiquitination and degradation of YAP in response to serum starvation, unlike Amot130 (S175A). Moreover, silencing Amot130 expression blocked LATS1 from inhibiting the expression of connective tissue growth factor, a YAP-regulated gene. Concordant with phosphorylated Amot130 specifically mediating these effects, wild-type Amot130 selectively induced YAP phosphorylation and reduced transcription of connective tissue growth factor in an AIP4-dependent manner versus Amot130 (S175A). Further, Amot130 but not Amot130 (S175A) strongly inhibited the growth of MDA-MB-468 breast cancer cells. The dominant-negative effects of Amot130 (S175A) on YAP signaling also support that phosphorylated Amot130 transduces Hippo signaling. Likewise, Amot130 expression provoked premature growth arrest during mammary cell acini formation, whereas Amot130 (S175A)-expressing cells formed enlarged and poorly differentiated acini. Taken together, the phosphorylation of Amot130 by LATS is found to be a key feature that enables it to inhibit YAP-dependent signaling and cell growth.", "corpus_id": 205263912, "score": 0 }, { "doc_id": "1150861", "title": "Alpha-Catenins Control Cardiomyocyte Proliferation by Regulating Yap Activity", "abstract": "Rationale: Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. Thus, they are unable to effectively replace dying cells in the injured heart. The recent discovery that the transcriptional coactivator Yes-associated protein (Yap) is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators and signaling pathways that control Yap activity in the heart are poorly understood. Objective: To investigate the role of &agr;-catenins in the heart using cardiac-specific &agr;E- and &agr;T-catenin double knockout mice. Methods and Results: We used 2 cardiac-specific Cre transgenes to delete both &agr;E-catenin (Ctnna1) and &agr;T-catenin (Ctnna3) genes either in the perinatal or in the adult heart. Perinatal depletion of &agr;-catenins increased cardiomyocyte number in the postnatal heart. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the &agr;-catenin double knockout hearts. Fetal genes were increased in the &agr;-catenin double knockout hearts indicating a less mature cardiac gene expression profile. Knockdown of &agr;-catenins in neonatal rat cardiomyocytes also resulted in increased proliferation, which could be blocked by knockdown of Yap. Finally, inactivation of &agr;-catenins in the adult heart using an inducible Cre led to increased nuclear Yap and cardiomyocyte proliferation and improved contractility after myocardial infarction. Conclusions: These studies demonstrate that &agr;-catenins are critical regulators of Yap, a transcriptional coactivator essential for cardiomyocyte proliferation. Furthermore, we provide proof of concept that inhibiting &agr;-catenins might be a useful strategy to promote myocardial regeneration after injury.", "corpus_id": 1150861, "score": 0 }, { "doc_id": "1932015", "title": "β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis", "abstract": "Joseph Rosenbluh, Deepak Nijhawan, Andrew G. Cox, Xingnan Li, James T. Neal, Eric J. Schafer, Travis I. Zack, Xiaoxing Wang, Aviad Tsherniak, Anna C. Schinzel, Diane D. Shao, Steven E. Schumacher, Barbara A. Weir, Francisca Vazquez, Glenn S. Cowley, David E. Root, Jill P. Mesirov, Rameen Beroukhim, Calvin J. Kuo, Wolfram Goessling, and William C. Hahn* *Correspondence: william_hahn@dfci.harvard.edu http://dx.doi.org/10.1016/j.cell.2013.03.007", "corpus_id": 1932015, "score": 1 }, { "doc_id": "38691695", "title": "Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis.", "abstract": "We have used an affinity purification method to identify substrates of protein kinase B/Akt. One protein that associates with 14-3-3 in an Akt-dependent manner is shown here to be the Yes-associated protein (YAP), which is phosphorylated by Akt at serine 127, leading to binding to 14-3-3. Akt promotes YAP localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. p73-mediated induction of Bax expression following DNA damage requires YAP function and is attenuated by Akt phosphorylation of YAP. YAP overexpression increases, while YAP depletion decreases, p73-mediated apoptosis following DNA damage, in an Akt inhibitable manner. Akt phosphorylation of YAP may thus suppress the induction of the proapoptotic gene expression response following cellular damage.", "corpus_id": 38691695, "score": 0 }, { "doc_id": "23722711", "title": "Hippo pathway effector Yap promotes cardiac regeneration", "abstract": "The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.", "corpus_id": 23722711, "score": 0 }, { "doc_id": "17012386", "title": "Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy.", "abstract": "Activation of mammalian sterile 20-like kinase 1 (Mst1) by genotoxic compounds is known to stimulate apoptosis in some cell types. The importance of Mst1 in cell death caused by clinically relevant pathologic stimuli is unknown, however. In this study, we show that Mst1 is a prominent myelin basic protein kinase activated by proapoptotic stimuli in cardiac myocytes and that Mst1 causes cardiac myocyte apoptosis in vitro in a kinase activity-dependent manner. In vivo, cardiac-specific overexpression of Mst1 in transgenic mice results in activation of caspases, increased apoptosis, and dilated cardiomyopathy. Surprisingly, however, Mst1 prevents compensatory cardiac myocyte elongation or hypertrophy despite increased wall stress, thereby obscuring the use of the Frank-Starling mechanism, a fundamental mechanism by which the heart maintains cardiac output in response to increased mechanical load at the single myocyte level. Furthermore, Mst1 is activated by ischemia/reperfusion in the mouse heart in vivo. Suppression of endogenous Mst1 by cardiac-specific overexpression of dominant-negative Mst1 in transgenic mice prevents myocyte death by pathologic insults. These results show that Mst1 works as both an essential initiator of apoptosis and an inhibitor of hypertrophy in cardiac myocytes, resulting in a previously unrecognized form of cardiomyopathy.", "corpus_id": 17012386, "score": 0 }, { "doc_id": "90225204", "title": "Regulation of YAP by mTOR and autophagy reveals a therapeutic target of Tuberous Sclerosis Complex", "abstract": "HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Regulation of YAP by mTOR and autophagy reveals a therapeutic target of Tuberous Sclerosis Complex Ning Liang", "corpus_id": 90225204, "score": 0 }, { "doc_id": "32505913", "title": "Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance", "abstract": "Ablation of the kinases Mst1 and Mst2, orthologs of the Drosophila antiproliferative kinase Hippo, from mouse intestinal epithelium caused marked expansion of an undifferentiated stem cell compartment and loss of secretory cells throughout the small and large intestine. Although median survival of mice lacking intestinal Mst1/Mst2 is 13 wk, adenomas of the distal colon are common by this age. Diminished phosphorylation, enhanced abundance, and nuclear localization of the transcriptional coactivator Yes-associated protein 1 (Yap1) is evident in Mst1/Mst2-deficient intestinal epithelium, as is strong activation of β-catenin and Notch signaling. Although biallelic deletion of Yap1 from intestinal epithelium has little effect on intestinal development, inactivation of a single Yap1 allele reduces Yap1 polypeptide abundance to nearly wild-type levels and, despite the continued Yap hypophosphorylation and preferential nuclear localization, normalizes epithelial structure. Thus, supraphysiologic Yap polypeptide levels are necessary to drive intestinal stem cell proliferation. Yap is overexpressed in 68 of 71 human colon cancers and in at least 30 of 36 colon cancer-derived cell lines. In colon-derived cell lines where Yap is overabundant, its depletion strongly reduces β-catenin and Notch signaling and inhibits proliferation and survival. These findings demonstrate that Mst1 and Mst2 actively suppress Yap1 abundance and action in normal intestinal epithelium, an antiproliferative function that frequently is overcome in colon cancer through Yap1 polypeptide overabundance. The dispensability of Yap1 in normal intestinal homeostasis and its potent proliferative and prosurvival actions when overexpressed in colon cancer make it an attractive therapeutic target.", "corpus_id": 32505913, "score": 0 }, { "doc_id": "23076079", "title": "Notch and hippo converge on Cdx2 to specify the trophectoderm lineage in the mouse blastocyst.", "abstract": "The first lineage choice in mammalian embryogenesis is that between the trophectoderm, which gives rise to the trophoblast of the placenta, and the inner cell mass, from which is derived the embryo proper and the yolk sac. The establishment of these lineages is preceded by the inside-versus-outside positioning of cells in the early embryo and stochastic expression of key transcription factors, which is then resolved into lineage-restricted expression. The regulatory inputs that drive this restriction and how they relate to cell position are largely unknown. Here, we show an unsuspected role of Notch signaling in regulating trophectoderm-specific expression of Cdx2 in cooperation with TEAD4. Notch activity is restricted to outer cells and is able to influence positional allocation of blastomeres, mediating preferential localization to the trophectoderm. Our results show that multiple signaling inputs at preimplantation stages specify the first embryonic lineages.", "corpus_id": 23076079, "score": 0 }, { "doc_id": "568228", "title": "Notch Inhibits Yorkie Activity in Drosophila Wing Discs", "abstract": "During development, tissues and organs must coordinate growth and patterning so they reach the right size and shape. During larval stages, a dramatic increase in size and cell number of Drosophila wing imaginal discs is controlled by the action of several signaling pathways. Complex cross-talk between these pathways also pattern these discs to specify different regions with different fates and growth potentials. We show that the Notch signaling pathway is both required and sufficient to inhibit the activity of Yorkie (Yki), the Salvador/Warts/Hippo (SWH) pathway terminal transcription activator, but only in the central regions of the wing disc, where the TEAD factor and Yki partner Scalloped (Sd) is expressed. We show that this cross-talk between the Notch and SWH pathways is mediated, at least in part, by the Notch target and Sd partner Vestigial (Vg). We propose that, by altering the ratios between Yki, Sd and Vg, Notch pathway activation restricts the effects of Yki mediated transcription, therefore contributing to define a zone of low proliferation in the central wing discs.", "corpus_id": 568228, "score": 0 }, { "doc_id": "27701357", "title": "The Yes-associated protein controls the cell density regulation of Hedgehog signaling", "abstract": "The evolutionarily conserved Hedgehog (Hh) signaling pathway is essential for correct embryogenesis and is misregulated in several malignancies. In cell culture, Hh-sensitive cells display a striking dependence on cell density with active Hh signaling requiring cell-to-cell contact. As the Hippo/YAP system is tightly linked to cell density control and contact inhibition, we investigated the cross-talk between the two pathways. Our data reveal that the suppression of Hh signaling in the absence of cellular contacts is independent of primary cilia and is mediated by the YAP oncogene. Overexpression of YAP blocks Hh signaling whereas RNA interference-mediated knockdown of YAP enhances Hh/GLI activity. Despite this negative regulation, Hh signaling promotes YAP activity through post-transcriptional mechanisms, resulting in a negative feedback loop. In vivo, we found strong nuclear YAP immunoreactivity restricted to compartments with low Hh pathway activity in human and mouse pancreatic cancer. Finally, we identified protease-activated receptors (PARs) as molecules being able to override the inverse Hippo/Hh regulation, potentially giving tumors a mechanism to utilize both oncogenic pathways in parallel.Oncogenesis (2014) 3, e112; doi:10.1038/oncsis.2014.27; published online 11 August 2014", "corpus_id": 27701357, "score": 0 }, { "doc_id": "17817607", "title": "JNK phosphorylates Yes-associated protein (YAP) to regulate apoptosis", "abstract": "Yes-associated protein (YAP) regulates DNA damage and chemosensitivity, as well as functioning as a pro-growth, cell size regulator. For both of its roles, regulation by phosphorylation is crucial. We undertook an in vitro screen to identify novel YAP kinases to discover new signaling pathways to better understand YAP's function. We identified JNK1 and JNK2 as robust YAP kinases, as well as mapped multiple sites of phosphorylation. Using inhibitors and siRNA, we showed that JNK specifically phosphorylates endogenous YAP in a number of cell types. We show that YAP protects keratinocytes from UV irradiation but promotes UV-induced apoptosis in a squamous cell carcinoma. We defined the mechanism for this dual role to be YAP's ability to bind and stabilize the pro-proliferative ΔNp63α isoform in a JNK-dependent manner. Our report indicates that an evaluation of the expression of the different isoforms of p63 and p73 is crucial in determining YAP's function.", "corpus_id": 17817607, "score": 0 }, { "doc_id": "11142135", "title": "Control of the hippo pathway by Set7-dependent methylation of Yap.", "abstract": "Methylation of nonhistone proteins is emerging as a regulatory mechanism to control protein function. Set7 (Setd7) is a SET-domain-containing lysine methyltransferase that methylates and alters function of a variety of proteins in vitro, but the in vivo relevance has not been established. We found that Set7 is a modifier of the Hippo pathway. Mice that lack Set7 have a larger progenitor compartment in the intestine, coinciding with increased expression of Yes-associated protein (Yap) target genes. Mechanistically, monomethylation of lysine 494 of Yap is critical for cytoplasmic retention. These results identify a methylation-dependent checkpoint in the Hippo pathway.", "corpus_id": 11142135, "score": 0 }, { "doc_id": "6243458", "title": "Tyrosine phosphorylation controls Runx2‐mediated subnuclear targeting of YAP to repress transcription", "abstract": "Src/Yes tyrosine kinase signaling contributes to the regulation of bone homeostasis and inhibits osteoblast activity. Here we show that the endogenous Yes‐associated protein (YAP), a mediator of Src/Yes signaling, interacts with the native Runx2 protein, an osteoblast‐related transcription factor, and suppresses Runx2 transcriptional activity in a dose‐dependent manner. Runx2, through its PY motif, recruits YAP to subnuclear domains in situ and to the osteocalcin (OC) gene promoter in vivo. Inhibition of Src/Yes kinase blocks tyrosine phosphorylation of YAP and dissociates endogenous Runx2–YAP complexes. Consequently, recruitment of the YAP co‐repressor to subnuclear domains is abrogated and expression of the endogenous OC gene is induced. Our results suggest that Src/Yes signals are integrated through organization of Runx2–YAP transcriptional complexes at subnuclear sites to attenuate skeletal gene expression.", "corpus_id": 6243458, "score": 0 }, { "doc_id": "206975131", "title": "Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage.", "abstract": "Cells undergo apoptosis upon exposure to severe DNA damage stress. Under this condition, p73 is phosphorylated and activated by c-Abl. The transcription coactivator Yap1 binds p73 to generate a complex that escapes p73 proteasomal degradation and recruits p300 to support transcription of proapoptotic genes. However, the mechanism of selective activation of proapoptotic genes by Yap1 remained unclear. In this study, we show that c-Abl directly phosphorylates Yap1 at position Y357 in response to DNA damage. Tyrosine-phosphorylated Yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes. Furthermore, we show that Yap1 switches between p73-mediated proapoptotic and growth arrest target genes based on its phosphorylation state. Thus, our data demonstrate that modification of a transcription coactivator, namely the DNA damage-induced phosphorylation of Yap1 by c-Abl, influences the specificity of target gene activation.", "corpus_id": 206975131, "score": 0 }, { "doc_id": "41628631", "title": "c-Abl antagonizes the YAP oncogenic function", "abstract": "YES-associated protein (YAP) is a central transcription coactivator that functions as an oncogene in a number of experimental systems. However, under DNA damage, YAP activates pro-apoptotic genes in conjunction with p73. This program switching is mediated by c-Abl (Abelson murine leukemia viral oncogene) via phosphorylation of YAP at the Y357 residue (pY357). YAP as an oncogene coactivates the TEAD (transcriptional enhancer activator domain) family transcription factors. Here we asked whether c-Abl regulates the YAP–TEAD functional module. We found that DNA damage, through c-Abl activation, specifically depressed YAP–TEAD-induced transcription. Remarkably, c-Abl counteracts YAP-induced transformation by interfering with the YAP–TEAD transcriptional program. c-Abl induced TEAD1 phosphorylation, but the YAP–TEAD complex remained unaffected. In contrast, TEAD coactivation was compromised by phosphomimetic YAP Y357E mutation but not Y357F, as demonstrated at the level of reporter genes and endogenous TEAD target genes. Furthermore, YAP Y357E also severely compromised the role of YAP in cell transformation, migration, anchorage-independent growth, and epithelial-to-mesenchymal transition (EMT) in human mammary MCF10A cells. These results suggest that YAP pY357 lost TEAD transcription activation function. Our results demonstrate that YAP pY357 inactivates YAP oncogenic function and establish a role for YAP Y357 phosphorylation in cell-fate decision.", "corpus_id": 41628631, "score": 0 }, { "doc_id": "21791196", "title": "PP1 Cooperates with ASPP2 to Dephosphorylate and Activate TAZ*", "abstract": "The Hippo pathway regulates organ size by controlling both cell proliferation and apoptosis. TAZ functions as a transcriptional co-activator downstream of the Hippo pathway and has been implicated in human cancer development. A key step in the Hippo-TAZ pathway is phosphorylation of TAZ by LATS kinase, which leads to TAZ inhibition by both cytoplasmic retention and degradation. However, the mechanism of TAZ dephosphorylation and the responsible phosphatase are unknown. Here, we identified PP1 as a bona fide TAZ phosphatase. PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. Furthermore, ASPP2 facilitates the interaction between TAZ and PP1 to promote TAZ dephosphorylation. As a result, PP1 and ASPP2 increase TAZ-dependent gene expression. This study demonstrates that PP1A and ASPP2 play a critical role in promoting TAZ function by antagonizing the LATS kinase through TAZ dephosphorylation.", "corpus_id": 21791196, "score": 0 }, { "doc_id": "5834665", "title": "PP1A-Mediated Dephosphorylation Positively Regulates YAP2 Activity", "abstract": "Background The Hippo/MST1 signaling pathway plays an important role in the regulation of cell proliferation and apoptosis. As a major downstream target of the Hippo/MST1 pathway, YAP2 (Yes-associated protein 2) functions as a transcriptional cofactor that has been implicated in many biological processes, including organ size control and cancer development. MST1/Lats kinase inhibits YAP2's nuclear accumulation and transcriptional activity through inducing the phosphorylation at serine 127 and the sequential association with 14-3-3 proteins. However, the dephosphorylation of YAP2 is not fully appreciated. Methodology/Principal Findings In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2. Inhibition of PP1 by okadiac acid (OA) increases the phosphorylation at serine 127 and cytoplasmic translocation of YAP2 proteins, thereby mitigating its transcription activity. PP1A expression enhances YAP2's pro-survival capability and YAP2 knockdown sensitizes ovarian cancer cells to cisplatin treatment. Conclusions/Significance Our findings define a novel molecular mechanism that YAP2 is positively regulated by PP1-mediated dephosphorylation in the cell survival.", "corpus_id": 5834665, "score": 0 }, { "doc_id": "6411998", "title": "Structural insights into the YAP and TEAD complex.", "abstract": "The Yes-associated protein (YAP) transcriptional coactivator is a key regulator of organ size and a candidate human oncogene inhibited by the Hippo tumor suppressor pathway. The TEAD family of transcription factors binds directly to and mediates YAP-induced gene expression. Here we report the three-dimensional structure of the YAP (residues 50-171)-TEAD1 (residues 194-411) complex, in which YAP wraps around the globular structure of TEAD1 and forms extensive interactions via three highly conserved interfaces. Interface 3, including YAP residues 86-100, is most critical for complex formation. Our study reveals the biochemical nature of the YAP-TEAD interaction, and provides a basis for pharmacological intervention of YAP-TEAD hyperactivation in human diseases.", "corpus_id": 6411998, "score": 0 }, { "doc_id": "23140563", "title": "TEADs Mediate Nuclear Retention of TAZ to Promote Oncogenic Transformation*", "abstract": "The transcriptional coactivators YAP and TAZ are downstream targets inhibited by the Hippo tumor suppressor pathway. The expression level of TAZ is recently shown to be elevated in invasive breast cancer cells and some primary breast cancers. TAZ is important for breast cancer cell migration, invasion, and tumorigenesis, but the underlying mechanism is not defined. In this study, we show that TAZ interacts with TEAD transcriptional factors. Knockdown of TEADs suppresses TAZ-mediated oncogenic transformation of MCF10A cells. Uncoupling TAZ from Hippo regulation by S89A mutation enhances its transforming ability. Several residues located in the N-terminal region of TAZ are identified to be important for interaction with TEADs, and these same residues are equally important for TAZ to transform MCF10A cells. Mechanistically, TAZ mutants defective in interaction with TEADs fail to accumulate in the nucleus. Live cell imaging of enhanced green fluorescent protein-TAZ and its mutant defective in TEAD interaction suggests that TEAD interaction mediates nuclear retention. These results reveal a novel mechanism for TEADs to regulate nuclear retention and thus the transforming ability of TAZ.", "corpus_id": 23140563, "score": 0 }, { "doc_id": "20931203", "title": "Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.", "abstract": "The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.", "corpus_id": 20931203, "score": 1 }, { "doc_id": "41950172", "title": "TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm.", "abstract": "Mammals express four highly conserved TEAD/TEF transcription factors that bind the same DNA sequence, but serve different functions during development. TEAD-2/TEF-4 protein purified from mouse cells was associated predominantly with a novel TEAD-binding domain at the amino terminus of YAP65, a powerful transcriptional coactivator. YAP65 interacted specifically with the carboxyl terminus of all four TEAD proteins. Both this interaction and sequence-specific DNA binding by TEAD were required for transcriptional activation in mouse cells. Expression of YAP in lymphocytic cells that normally do not support TEAD-dependent transcription (e.g., MPC11) resulted in up to 300-fold induction of TEAD activity. Conversely, TEAD overexpression squelched YAP activity. Therefore, the carboxy-terminal acidic activation domain in YAP is the transcriptional activation domain for TEAD transcription factors. However, whereas TEAD was concentrated in the nucleus, excess YAP65 accumulated in the cytoplasm as a complex with the cytoplasmic localization protein, 14-3-3. Because TEAD-dependent transcription was limited by YAP65, and YAP65 also binds Src/Yes protein tyrosine kinases, we propose that YAP65 regulates TEAD-dependent transcription in response to mitogenic signals.", "corpus_id": 41950172, "score": 0 }, { "doc_id": "24344500", "title": "Connective tissue growth factor autocriny in human hepatocellular carcinoma: Oncogenic role and regulation by epidermal growth factor receptor/yes‐associated protein–mediated activation", "abstract": "The identification of molecular mechanisms involved in the maintenance of the transformed phenotype of hepatocellular carcinoma (HCC) cells is essential for the elucidation of therapeutic strategies. Here, we show that human HCC cells display an autocrine loop mediated by connective tissue growth factor (CTGF) that promotes DNA synthesis and cell survival. Expression of CTGF was stimulated by epidermal growth factor receptor (EGFR) ligands and was dependent on the expression of the transcriptional coactivator, Yes‐associated protein (YAP). We identified elements in the CTGF gene proximal promoter that bound YAP‐enclosing complexes and were responsible for basal and EGFR‐stimulated CTGF expression. We also demonstrate that YAP expression can be up‐regulated through EGFR activation not only in HCC cells, but also in primary human hepatocytes. CTGF contributed to HCC cell dedifferentiation, expression of inflammation‐related genes involved in carcinogenesis, resistance toward doxorubicin, and in vivo HCC cell growth. Importantly, CTGF down‐regulated tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL) receptor 2 expression and was involved in the reduced sensitivity of these cells toward TRAIL‐mediated apoptosis. Conclusion: We have identified autocrine CTGF as a novel determinant of HCC cells' neoplastic behavior. Expression of CTGF can be stimulated through the EGFR‐signaling system in HCC cells in a novel cross‐talk with the oncoprotein YAP. Moreover, to our knowledge, this is the first study that identifies a signaling mechanism triggering YAP gene expression in healthy and transformed liver parenchymal cells. (HEPATOLOGY 2011)", "corpus_id": 24344500, "score": 0 }, { "doc_id": "64521", "title": "The biology of YAP/TAZ: hippo signaling and beyond.", "abstract": "The transcriptional regulators YAP and TAZ are the focus of intense interest given their remarkable biological properties in development, tissue homeostasis and cancer. YAP and TAZ activity is key for the growth of whole organs, for amplification of tissue-specific progenitor cells during tissue renewal and regeneration, and for cell proliferation. In tumors, YAP/TAZ can reprogram cancer cells into cancer stem cells and incite tumor initiation, progression and metastasis. As such, YAP/TAZ are appealing therapeutic targets in cancer and regenerative medicine. Just like the function of YAP/TAZ offers a molecular entry point into the mysteries of tissue biology, their regulation by upstream cues is equally captivating. YAP/TAZ are well known for being the effectors of the Hippo signaling cascade, and mouse mutants in Hippo pathway components display remarkable phenotypes of organ overgrowth, enhanced stem cell content and reduced cellular differentiation. YAP/TAZ are primary sensors of the cell's physical nature, as defined by cell structure, shape and polarity. YAP/TAZ activation also reflects the cell \"social\" behavior, including cell adhesion and the mechanical signals that the cell receives from tissue architecture and surrounding extracellular matrix (ECM). At the same time, YAP/TAZ entertain relationships with morphogenetic signals, such as Wnt growth factors, and are also regulated by Rho, GPCRs and mevalonate metabolism. YAP/TAZ thus appear at the centerpiece of a signaling nexus by which cells take control of their behavior according to their own shape, spatial location and growth factor context.", "corpus_id": 64521, "score": 0 }, { "doc_id": "337623", "title": "Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling", "abstract": "Regulation of organ size is important for development and tissue homeostasis. In Drosophila, Hippo signaling controls organ size by regulating the activity of a TEAD transcription factor, Scalloped, through modulation of its co-activator protein Yki. Here, we show that mouse Tead proteins regulate cell proliferation by mediating Hippo signaling. In NIH3T3 cells, cell density and Hippo signaling regulated the activity of endogenous Tead proteins by modulating nuclear localization of a Yki homolog, Yap1, and the resulting change in Tead activity altered cell proliferation. Tead2-VP16 mimicked Yap1 overexpression, including increased cell proliferation, reduced cell death, promotion of EMT, lack of cell contact inhibition and promotion of tumor formation. Growth-promoting activities of various Yap1 mutants correlated with their Tead-co-activator activities. Tead2-VP16 and Yap1 regulated largely overlapping sets of genes. However, only a few of the Tead/Yap1-regulated genes in NIH3T3 cells were affected in Tead1-/-;Tead2-/- or Yap1-/- embryos. Most of the previously identified Yap1-regulated genes were not affected in NIH3T3 cells or mutant mice. In embryos, levels of nuclear Yap1 and Tead1 varied depending on cell type. Strong nuclear accumulation of Yap1 and Tead1 were seen in myocardium, correlating with requirements of Tead1 for proliferation. However, their distribution did not always correlate with proliferation. Taken together, mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling, but the mechanisms by which Tead/Yap1 regulate cell proliferation differ depending on the cell type, and Tead, Yap1 and Hippo signaling may play multiple roles in mouse embryos.", "corpus_id": 337623, "score": 0 }, { "doc_id": "732540", "title": "Rb inactivation accelerates neoplastic growth and substitutes for recurrent amplification of cIAP1, cIAP2 and Yap1 in sporadic mammary carcinoma associated with p53 deficiency", "abstract": "Genetically defined mouse models offer an important tool to identify critical secondary genetic alterations with relevance to human cancer pathogenesis. We used newly generated MMTV-Cre105Ayn mice to inactivate p53 and/or Rb strictly in the mammary epithelium, and to determine recurrent genomic changes associated with deficiencies of these genes. p53 inactivation led to formation of estrogen receptor-positive raloxifene-responsive mammary carcinomas with features of luminal subtype B. Rb deficiency was insufficient to initiate carcinogenesis but promoted genomic instability and growth rate of neoplasms associated with p53 inactivation. Genome-wide analysis of mammary carcinomas identified a recurrent amplification at chromosome band 9A1, a locus orthologous to human 11q22, which contains protooncogenes cIAP1 (Birc2), cIAP2 (Birc3) and Yap1. It is interesting that this amplicon was preferentially detected in carcinomas carrying wild-type Rb. However, all three genes were overexpressed in carcinomas with p53 and Rb inactivation, likely due to E2F-mediated transactivation, and cooperated in carcinogenesis according to gene knockdown experiments. These findings establish a model of luminal subtype B mammary carcinoma, identify critical role of cIAP1, cIAP2 and Yap1 co-expression in mammary carcinogenesis and provide an explanation for the lack of recurrent amplifications of cIAP1, cIAP2 and Yap1 in some tumors with frequent Rb deficiency, such as mammary carcinoma.", "corpus_id": 732540, "score": 0 }, { "doc_id": "26256854", "title": "Molecular mechanisms underlying RB protein function", "abstract": "Inactivation of the RB protein is one of the most fundamental events in cancer. Coming to a molecular understanding of its function in normal cells and how it impedes cancer development has been challenging. Historically, the ability of RB to regulate the cell cycle placed it in a central role in proliferative control, and research focused on RB regulation of the E2F family of transcription factors. Remarkably, several recent studies have found additional tumour-suppressor functions of RB, including alternative roles in the cell cycle, maintenance of genome stability and apoptosis. These advances and new structural studies are combining to define the multifunctionality of RB.", "corpus_id": 26256854, "score": 0 }, { "doc_id": "5382442", "title": "The retinoblastoma protein and cell cycle control", "abstract": "pRB, the product of the retinoblastoma tumor suppressor gene, operates in the midst of the cell cycle clock apparatus. Its main role is to act as a signal transducer connecting the cell cycle clock with the transcriptional machinery. In this role, pRB allows the clock to control the expression of banks of genes that mediate advance of the cell through a critical phase of its growth cycle. Loss of pRB function deprives the clock and thus the cell of an important mechanism for braking cell proliferation through modulation of gene expression.", "corpus_id": 5382442, "score": 0 }, { "doc_id": "21979191", "title": "Cellular mechanisms of tumour suppression by the retinoblastoma gene", "abstract": "The retinoblastoma (RB) tumour suppressor gene is functionally inactivated in a broad range of paediatric and adult cancers, and a plethora of cellular functions and partners have been identified for the RB protein. Data from human tumours and studies from mouse models indicate that loss of RB function contributes to both cancer initiation and progression. However, we still do not know the identity of the cell types in which RB normally prevents cancer initiation in vivo, and the specific functions of RB that suppress distinct aspects of the tumorigenic process are poorly understood.", "corpus_id": 21979191, "score": 0 }, { "doc_id": "12944121", "title": "Newly identified aspects of tumor suppression by RB", "abstract": "The retinoblastoma (RB) tumor suppressor belongs to a cellular pathway that plays a crucial role in restricting the G1-S transition of the cell cycle in response to a large number of extracellular and intracellular cues. Research in the last decade has highlighted the complexity of regulatory networks that ensure proper cell cycle progression, and has also identified multiple cellular functions beyond cell cycle regulation for RB and its two family members, p107 and p130. Here we review some of the recent evidence pointing to a role of RB as a molecular adaptor at the crossroads of multiple pathways, ensuring cellular homeostasis in different contexts. In particular, we discuss the pro- and anti-tumorigenic roles of RB during the early stages of cancer, as well as the importance of the RB pathway in stem cells and cell fate decisions.", "corpus_id": 12944121, "score": 0 }, { "doc_id": "5902143", "title": "The retinoblastoma tumor suppressor and stem cell biology.", "abstract": "Stem cells play a critical role during embryonic development and in the maintenance of homeostasis in adult individuals. A better understanding of stem cell biology, including embryonic and adult stem cells, will allow the scientific community to better comprehend a number of pathologies and possibly design novel approaches to treat patients with a variety of diseases. The retinoblastoma tumor suppressor RB controls the proliferation, differentiation, and survival of cells, and accumulating evidence points to a central role for RB activity in the biology of stem and progenitor cells. In some contexts, loss of RB function in stem or progenitor cells is a key event in the initiation of cancer and determines the subtype of cancer arising from these pluripotent cells by altering their fate. In other cases, RB inactivation is often not sufficient to initiate cancer but may still lead to some stem cell expansion, raising the possibility that strategies aimed at transiently inactivating RB might provide a novel way to expand functional stem cell populations. Future experiments dedicated to better understanding how RB and the RB pathway control a stem cell's decisions to divide, self-renew, or give rise to differentiated progeny may eventually increase our capacity to control these decisions to enhance regeneration or help prevent cancer development.", "corpus_id": 5902143, "score": 0 }, { "doc_id": "25516683", "title": "Aberrant Regulation of Survivin by the RB/E2F Family of Proteins*", "abstract": "Survivin is a putative oncogene that is aberrantly expressed in cancer cells. It has been hypothesized to play a central role in cancer progression and resistance to therapy in diverse tumor types. Although some of the transcriptional processes regulating its expression have been established, the diversity of genes that may be controlling the levels of its expression in both normal cells as well as in cancer cells has not been fully explored. The most common genetically mutated pathways in human malignancies are the p53 tumor suppressor pathway and the RB/E2F pathway. Both of these pathways, when intact, provide essential checkpoints in the maintenance of normal cell growth and protect the cell from DNA damage. Using non-transformed embryonic fibroblasts, we provide evidence of a molecular link between the regulation of survivin transcription and the RB/E2F family of proteins. We demonstrate that both pRB and p130 can interact with the survivin promoter and can repress survivin transcription. We also show that the E2F activators (E2F1, E2F2, and E2F3) can bind to the survivin promoter and induce survivin transcription. Genetically modified cells that harbor deletions in various members of the RB/E2F family confirm our data from the wild-type cells. Our findings implicate several members of the RB/E2F pathway in an intricate mechanism of survivin gene regulation that, when genetically altered during the process of tumorigenesis, may function within cancer cells to aberrantly alter survivin levels and enhance tumor progression.", "corpus_id": 25516683, "score": 0 }, { "doc_id": "3874173", "title": "Organ size control is dominant over Rb family inactivation to restrict proliferation in vivo.", "abstract": "In mammals, a cell's decision to divide is thought to be under the control of the Rb/E2F pathway. We previously found that inactivation of the Rb family of cell cycle inhibitors (Rb, p107, and p130) in quiescent liver progenitors leads to uncontrolled division and cancer initiation. Here, we show that, in contrast, deletion of the entire Rb gene family in mature hepatocytes is not sufficient for their long-term proliferation. The cell cycle block in Rb family mutant hepatocytes is independent of the Arf/p53/p21 checkpoint but can be abrogated upon decreasing liver size. At the molecular level, we identify YAP, a transcriptional regulator involved in organ size control, as a factor required for the sustained expression of cell cycle genes in hepatocytes. These experiments identify a higher level of regulation of the cell cycle in vivo in which signals regulating organ size are dominant regulators of the core cell cycle machinery.", "corpus_id": 3874173, "score": 1 }, { "doc_id": "27274175", "title": "A YAP/TAZ-Regulated Molecular Signature Is Associated with Oral Squamous Cell Carcinoma", "abstract": "Oral squamous cell carcinoma (OSCC) is a prevalent form of cancer that develops from the epithelium of the oral cavity. OSCC is on the rise worldwide, and death rates associated with the disease are particularly high. Despite progress in understanding the mutational and expression landscape associated with OSCC, advances in deciphering these alterations for the development of therapeutic strategies have been limited. Further insight into the molecular cues that contribute to OSCC is therefore required. Here, we show that the transcriptional regulators YAP (YAP1) and TAZ (WWTR1), which are key effectors of the Hippo pathway, drive protumorigenic signals in OSCC. Regions of premalignant oral tissues exhibit aberrant nuclear YAP accumulation, suggesting that dysregulated YAP activity contributes to the onset of OSCC. Supporting this premise, we determined that nuclear YAP and TAZ activity drives OSCC cell proliferation, survival, and migration in vitro, and is required for OSCC tumor growth and metastasis in vivo. Global gene expression profiles associated with YAP and TAZ knockdown revealed changes in the control of gene expression implicated in protumorigenic signaling, including those required for cell cycle progression and survival. Notably, the transcriptional signature regulated by YAP and TAZ significantly correlates with gene expression changes occurring in human OSCCs identified by The Cancer Genome Atlas (TCGA), emphasizing a central role for YAP and TAZ in OSCC biology. Implications: This study defines a YAP/TAZ-regulated transcriptional program in OSCC and reveals novel roles for nuclear YAP/TAZ activity in the onset and progression of this cancer. Mol Cancer Res; 13(6); 957–68. ©2015 AACR.", "corpus_id": 27274175, "score": 0 }, { "doc_id": "19502937", "title": "Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth", "abstract": "YAP/TAZ are nuclear effectors of the Hippo pathway regulating organ growth and tumorigenesis. Yet, their function as transcriptional regulators remains underinvestigated. By ChIP-seq analyses in breast cancer cells, we discovered that the YAP/TAZ transcriptional response is pervasively mediated by a dual element: TEAD factors, through which YAP/TAZ bind to DNA, co-occupying chromatin with activator protein-1 (AP-1, dimer of JUN and FOS proteins) at composite cis-regulatory elements harbouring both TEAD and AP-1 motifs. YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. This control occurs almost exclusively from distal enhancers that contact target promoters through chromatin looping. YAP/TAZ-induced oncogenic growth is strongly enhanced by gain of AP-1 and severely blunted by its loss. Conversely, AP-1-promoted skin tumorigenesis is prevented in YAP/TAZ conditional knockout mice. This work highlights a new layer of signalling integration, feeding on YAP/TAZ function at the chromatin level.", "corpus_id": 19502937, "score": 0 }, { "doc_id": "4642832", "title": "YAP Regulates S-Phase Entry in Endothelial Cells", "abstract": "The Hippo pathway regulates cell proliferation and apoptosis through the Yes-associated protein (YAP) transcriptional activator. YAP has a well-described role in promoting cell proliferation and survival, but the precise mechanisms and transcriptional targets that underlie these properties are still unclear and likely context-dependent. We found, using siRNA-mediated knockdown, that YAP is required for proliferation in endothelial cells but not HeLa cells. Specifically, YAP is required for S-phase entry and its absence causes cells to accumulate in G1. Microarray analysis suggests that YAP mediates this effect by regulating the transcription of genes involved in the assembly and/or firing of replication origins and homologous recombination of DNA. These findings thus provide insight into the molecular mechanisms by which YAP regulates cell cycle progression.", "corpus_id": 4642832, "score": 0 }, { "doc_id": "38933767", "title": "Cell cycle regulation of the E2F transcription factor involves an interaction with cyclin A", "abstract": "We have examined E2F binding activity in extracts of synchronized NIH 3T3 cells. During the G0 to G1 transition, there is a marked increase in the level of active E2F. Subsequently, there are changes in the nature of E2F-containing complexes. A G1-specific complex increases in abundance, disappears, and is then replaced by another complex as S phase begins. Analysis of extracts of thymidine-blocked cells confirms that the complexes are cell cycle regulated. We also show that the cyclin A protein is a component of the S phase complex. Each complex can be dissociated by the adenovirus E1A 12S product, releasing free E2F. The release of E2F from the cyclin A complex coincides with the stimulation of an E2F-dependent promoter. We suggest that these interactions control the activity of E2F and that disruption of the complexes by E1A contributes to a loss of cellular proliferation control.", "corpus_id": 38933767, "score": 0 }, { "doc_id": "13939733", "title": "Hippo signalling in the G2/M cell cycle phase: lessons learned from the yeast MEN and SIN pathways.", "abstract": "Over the past decade Hippo kinase signalling has been established as an essential tumour suppressor pathway controlling tissue growth in flies and mammals. All members of the Hippo core signalling cassette are conserved from yeast to humans, whereby the yeast analogues of Hippo, Mats and Lats are central components of the mitotic exit network and septation initiation network in budding and fission yeast, respectively. Here, we discuss how far core Hippo signalling components in Drosophila melanogaster and mammals have reported similar mitotic functions as already established for their highly conserved yeast counterparts.", "corpus_id": 13939733, "score": 0 }, { "doc_id": "11641616", "title": "Lats2 Is an Essential Mitotic Regulator Required for the Coordination of Cell Division*", "abstract": "Tumor suppressor Lats2 is a member of the conserved Dbf2 kinase family. It localizes to the centrosome and has been implicated in regulation of the cell cycle and apoptosis. However, the in vivo function of this kinase remains unclear. Here, we show that complete disruption of the gene encoding Lats2 in mice causes developmental defects in the nervous system and embryonic lethality. Furthermore, mutant cells derived from total LATS2-knock-out embryos exhibit mitotic defects including centrosome fragmentation and cytokinesis defects, followed by nuclear enlargement and multinucleation. We show that the Mob1 family, a regulator of mitotic exit, associates with Lats2 to induce its activation. We also show that the complete LATS2-knock-out cells exhibit an acceleration of exit from mitosis and marked down-regulation of critical mitotic regulators. These results suggest that Lats2 plays an essential mitotic role in coordinating accurate cytokinesis completion, governing the stabilization of other mitotic regulators.", "corpus_id": 11641616, "score": 0 }, { "doc_id": "206228525", "title": "A kinase shRNA screen links LATS2 and the pRB tumor suppressor.", "abstract": "pRB-mediated inhibition of cell proliferation is a complex process that depends on the action of many proteins. However, little is known about the specific pathways that cooperate with the Retinoblastoma protein (pRB) and the variables that influence pRB's ability to arrest tumor cells. Here we describe two shRNA screens that identify kinases that are important for pRB to suppress cell proliferation and pRB-mediated induction of senescence markers. The results reveal an unexpected effect of LATS2, a component of the Hippo pathway, on pRB-induced phenotypes. Partial knockdown of LATS2 strongly suppresses some pRB-induced senescence markers. Further analysis shows that LATS2 cooperates with pRB to promote the silencing of E2F target genes, and that reduced levels of LATS2 lead to defects in the assembly of DREAM (DP, RB [retinoblastoma], E2F, and MuvB) repressor complexes at E2F-regulated promoters. Kinase assays show that LATS2 can phosphorylate DYRK1A, and that it enhances the ability of DYRK1A to phosphorylate the DREAM subunit LIN52. Intriguingly, the LATS2 locus is physically linked with RB1 on 13q, and this region frequently displays loss of heterozygosity in human cancers. Our results reveal a functional connection between the pRB and Hippo tumor suppressor pathways, and suggest that low levels of LATS2 may undermine the ability of pRB to induce a permanent cell cycle arrest in tumor cells.", "corpus_id": 206228525, "score": 0 }, { "doc_id": "30187207", "title": "TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin", "abstract": "The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. We previously showed that the pivotal effector of this pathway, YAP, is amplified in tumors and promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. Here, we report that overexpression of TAZ, a paralog of YAP, in human mammary epithelial cells promotes EMT and, in particular, some invasive structures in 3D cultures. TAZ also leads to cell migration and anchorage-independent growth in soft agar. Furthermore, we identified amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, as a target of TAZ. We show that AREG functions in a non-cell-autonomous manner to mediate EGF-independent growth and malignant behavior of mammary epithelial cells. In addition, ablation of TEAD binding completely abolishes the TAZ-induced phenotype. Last, analysis of breast cancer patient samples reveals a positive correlation between TAZ and AREG in vivo. In summary, TAZ-dependent secretion of AREG indicates that activation of the EGFR signaling is an important non-cell-autonomous effector of the Hippo pathway, and TAZ as well as its targets may play significant roles in breast tumorigenesis and metastasis.", "corpus_id": 30187207, "score": 0 }, { "doc_id": "14815358", "title": "Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways", "abstract": "TGF-beta and BMP receptor kinases activate Smad transcription factors by C-terminal phosphorylation. We have identified a subsequent agonist-induced phosphorylation that plays a central dual role in Smad transcriptional activation and turnover. As receptor-activated Smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by CDK8 and CDK9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote Smad transcriptional action, which in the case of Smad1 is mediated by the recruitment of YAP to the phosphorylated linker sites. An effector of the highly conserved Hippo organ size control pathway, YAP supports Smad1-dependent transcription and is required for BMP suppression of neural differentiation of mouse embryonic stem cells. The phosphorylated linker is ultimately recognized by specific ubiquitin ligases, leading to proteasome-mediated turnover of activated Smad proteins. Thus, nuclear CDK8/9 drive a cycle of Smad utilization and disposal that is an integral part of canonical BMP and TGF-beta pathways.", "corpus_id": 14815358, "score": 0 }, { "doc_id": "16232756", "title": "KRAS and YAP1 Converge to Regulate EMT and Tumor Survival", "abstract": "Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling.", "corpus_id": 16232756, "score": 0 }, { "doc_id": "44986558", "title": "The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage.", "abstract": "The transcriptional coactivator Yes-associated protein (YAP) has been shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show that YAP requires the promyelocytic leukemia gene (PML) and nuclear body localization to coactivate p73. YAP imparts selectivity to p73 by promoting the activation of a subset of p53 and/or p73 target promoters. Endogenous p73, YAP, and p300 proteins are concomitantly recruited onto the regulatory regions of the apoptotic target gene p53AIP1 only when cells are exposed to apoptotic conditions. Silencing of YAP by specific siRNA impairs p300 recruitment and reduces histone acetylation on the p53AIP1 target gene, resulting in delayed or reduced apoptosis mediated by p73. We also found that YAP contributes to the DNA damage-induced accumulation of p73 and potentiates the p300-mediated acetylation of p73. Altogether, our findings identify YAP as a key determinant of p73 gene targeting in response to DNA damage.", "corpus_id": 44986558, "score": 0 }, { "doc_id": "29686726", "title": "RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS", "abstract": "Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.", "corpus_id": 29686726, "score": 0 }, { "doc_id": "35189328", "title": "The Hippo signaling pathway in stem cell biology and cancer", "abstract": "The Hippo signaling pathway, consisting of a highly conserved kinase cascade (MST and Lats) and downstream transcription coactivators (YAP and TAZ), plays a key role in tissue homeostasis and organ size control by regulating tissue‐specific stem cells. Moreover, this pathway plays a prominent role in tissue repair and regeneration. Dysregulation of the Hippo pathway is associated with cancer development. Recent studies have revealed a complex network of upstream inputs, including cell density, mechanical sensation, and G‐protein‐coupled receptor (GPCR) signaling, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway in stem cell biology and its potential implications in tissue homeostasis and cancer.", "corpus_id": 35189328, "score": 0 }, { "doc_id": "1958224", "title": "TAZ, a Transcriptional Modulator of Mesenchymal Stem Cell Differentiation", "abstract": "Mesenchymal stem cells (MSCs) are a pluripotent cell type that can differentiate into several distinct lineages. Two key transcription factors, Runx2 and peroxisome proliferator–activated receptor γ (PPARγ), drive MSCs to differentiate into either osteoblasts or adipocytes, respectively. How these two transcription factors are regulated in order to specify these alternate cell fates remains a pivotal question. Here we report that a 14-3-3–binding protein, TAZ (transcriptional coactivator with PDZ-binding motif), coactivates Runx2-dependent gene transcription while repressing PPARγ-dependent gene transcription. By modulating TAZ expression in model cell lines, mouse embryonic fibroblasts, and primary MSCs in culture and in zebrafish in vivo, we observed alterations in osteogenic versus adipogenic potential. These results indicate that TAZ functions as a molecular rheostat that modulates MSC differentiation.", "corpus_id": 1958224, "score": 0 }, { "doc_id": "4421167", "title": "Rb regulates fate choice and lineage commitment in vivo", "abstract": "Mutation of the retinoblastoma gene (RB1) tumour suppressor occurs in one-third of all human tumours and is particularly associated with retinoblastoma and osteosarcoma. Numerous functions have been ascribed to the product of the human RB1 gene, the retinoblastoma protein (pRb). The best known is pRb’s ability to promote cell-cycle exit through inhibition of the E2F transcription factors and the transcriptional repression of genes encoding cell-cycle regulators. In addition, pRb has been shown in vitro to regulate several transcription factors that are master differentiation inducers. Depending on the differentiation factor and cellular context, pRb can either suppress or promote their transcriptional activity. For example, pRb binds to Runx2 and potentiates its ability to promote osteogenic differentiation in vitro. In contrast, pRb acts with E2F to suppress peroxisome proliferator-activated receptor γ subunit (PPAR-γ), the master activator of adipogenesis. Because osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that pRb might play a role in the choice between these two fates. However, so far, there is no evidence for this in vivo. Here we use mouse models to address this hypothesis in mesenchymal tissue development and tumorigenesis. Our data show that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo.", "corpus_id": 4421167, "score": 0 }, { "doc_id": "73484912", "title": "Pax3 and Hippo Signaling Coordinate Melanocyte Gene Expression in Neural Crest.", "abstract": "Loss of Pax3, a developmentally regulated transcription factor expressed in pre-migratory neural crest, results in severe developmental defects and embryonic lethality. Although Pax3 mutations produce profound phenotypes, the intrinsic transcriptional activation exhibited by Pax3 is surprisingly modest. We postulated the existence of transcriptional co-activators that function with Pax3 to mediate developmental functions. A high-throughput screen identified the Hippo effector proteins Taz and Yap65 as Pax3 co-activators. Synergistic co-activation of target genes by Pax3Taz/Yap65 requires DNA binding by Pax3, is Tead-independent, and is regulated by Hippo kinases Mst1 and Lats2. In vivo, Pax3 and Yap65 co-localize in the nucleus of neural crest progenitors in the dorsal neural tube. Neural crest deletion of Taz and Yap65 results in embryonic lethal neural crest defects and decreased expression of the Pax3 target gene, Mitf. These results suggest that Pax3 activity is regulated by the Hippo pathway and that Pax factors are Hippo effectors.", "corpus_id": 73484912, "score": 0 }, { "doc_id": "43278295", "title": "A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.", "abstract": "The T-box transcription factor TBX5 plays essential roles in cardiac and limb development. Various mutations in the TBX5 gene have been identified in patients with Holt-Oram syndrome, which is characterized by congenital defects in the heart and upper extremities. In this study, we identified a WW-domain-containing transcriptional regulator TAZ as a potent TBX5 coactivator. TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF. YAP, a TAZ-related protein with conserved functional domains, also stimulates TBX5-dependent transcription, possibly by forming a heterodimer with TAZ. TBX5 lacks a PY motif, which mediates the association of other proteins with TAZ, and interacts with TAZ through multiple domains including its carboxyl-terminal structure. Truncation mutants of TBX5 identified in patients with Holt-Oram syndrome were markedly impaired in their ability to associate with and be stimulated by TAZ. These findings reveal key roles for TAZ and YAP in the control of TBX5-dependent transcription and suggest the involvement of these coactivators in cardiac and limb development.", "corpus_id": 43278295, "score": 0 }, { "doc_id": "4960329", "title": "Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation", "abstract": "Summary Cell fate acquisition is heavily influenced by direct interactions between master regulators and tissue-specific enhancers. However, it remains unclear how lineage-specifying transcription factors, which are often expressed in both progenitor and mature cell populations, influence cell differentiation. Using in vivo mouse liver development as a model, we identified thousands of enhancers that are bound by the master regulators HNF4A and FOXA2 in a differentiation-dependent manner, subject to chromatin remodeling, and associated with differentially expressed target genes. Enhancers exclusively occupied in the embryo were found to be responsive to developmentally regulated TEAD2 and coactivator YAP1. Our data suggest that Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers. In summary, transcription factor-enhancer interactions are not only tissue specific but also differentiation dependent, which is an important consideration for researchers studying cancer biology or mammalian development and/or using transformed cell lines.", "corpus_id": 4960329, "score": 0 }, { "doc_id": "36310858", "title": "Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma", "abstract": "Without the transcription regulator YAP, KRAS-mutant pancreatic neoplasia cannot progress into invasive cancer. Targeting YAP to Promote the Antitumor Response Pancreatic ductal adenocarcinoma is frequently associated with mutations in KRAS, but targeting RAS proteins is clinically challenging. From studies with genetically engineered mouse models and correlations in human samples, Zhang et al. determined that the protein YAP mediated the transition from pancreatic metaplasia to invasive adenocarcinoma by transcriptionally activating genes induced by KRAS signaling. Deleting Yap in Kras or Kras:Trp53 mutant mouse pancreatic epithelia prevented their proliferation, decreased the expression and secretion of KRAS-regulated proteins that mediate inflammation and migration, and promoted immune cell infiltration in the tumor microenvironment in mice. Because Yap deletion did not affect normal pancreatic development or function, the findings indicate that Yap may be a viable target for KRAS-mutant PDAC. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates and frequently carries oncogenic KRAS mutation. However, KRAS has thus far not been a viable therapeutic target. We found that the abundance of YAP mRNA, which encodes Yes-associated protein (YAP), a protein regulated by the Hippo pathway during tissue development and homeostasis, was increased in human PDAC tissue compared with that in normal pancreatic epithelia. In genetically engineered KrasG12D and KrasG12D:Trp53R172H mouse models, pancreas-specific deletion of Yap halted the progression of early neoplastic lesions to PDAC without affecting normal pancreatic development and endocrine function. Although Yap was dispensable for acinar to ductal metaplasia (ADM), an initial step in the progression to PDAC, Yap was critically required for the proliferation of mutant Kras or Kras:Trp53 neoplastic pancreatic ductal cells in culture and for their growth and progression to invasive PDAC in mice. Yap functioned as a critical transcriptional switch downstream of the oncogenic KRAS–mitogen-activated protein kinase (MAPK) pathway, promoting the expression of genes encoding secretory factors that cumulatively sustained neoplastic proliferation, a tumorigenic stromal response in the tumor microenvironment, and PDAC progression in Kras and Kras:Trp53 mutant pancreas tissue. Together, our findings identified Yap as a critical oncogenic KRAS effector and a promising therapeutic target for PDAC and possibly other types of KRAS-mutant cancers.", "corpus_id": 36310858, "score": 0 }, { "doc_id": "205349612", "title": "The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies", "abstract": "Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.", "corpus_id": 205349612, "score": 0 }, { "doc_id": "11374180", "title": "The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain", "abstract": "The transcriptional coactivator Yes-associated protein (YAP) is a major regulator of organ size and proliferation in vertebrates. As such, YAP can act as an oncogene in several tissue types if its activity is increased aberrantly. Although no activating mutations in the yap1 gene have been identified in human cancer, yap1 is located on the 11q22 amplicon, which is amplified in several human tumors. In addition, mutations or epigenetic silencing of members of the Hippo pathway, which represses YAP function, have been identified in human cancers. Here we demonstrate that, in addition to increasing tumor growth, increased YAP activity is potently prometastatic in breast cancer and melanoma cells. Using a Luminex-based approach to multiplex in vivo assays, we determined that the domain of YAP that interacts with the TEAD/TEF family of transcription factors but not the WW domains or PDZ-binding motif, is essential for YAP-mediated tumor growth and metastasis. We further demonstrate that, through its TEAD-interaction domain, YAP enhances multiple processes known to be important for tumor progression and metastasis, including cellular proliferation, transformation, migration, and invasion. Finally, we found that the metastatic potential of breast cancer and melanoma cells is strongly correlated with increased TEAD transcriptional activity. Together, our results suggest that increased YAP/TEAD activity plays a causal role in cancer progression and metastasis.", "corpus_id": 11374180, "score": 0 }, { "doc_id": "20354279", "title": "Targeting Hippo pathway by specific interruption of YAP‐TEAD interaction using cyclic YAP‐like peptides", "abstract": "Hippo signaling pathway is emerging as a novel target for anticancer therapy because it plays key roles in organ size control and tumorigenesis. As the downstream effectors, Yes‐associated protein (YAP)‐transcriptional enhancer activation domain family member (TEAD) association is essential for YAP‐driven oncogenic activity, while TEAD is largely dispensable for normal tissue growth. We present the design of YAP‐like peptides (17mer) to occupy the interface 3 on TEAD. Introducing cysteines at YAP sites 87 and 96 can induce disulfide formation, as confirmed by crystallography. The engineered peptide significantly improves the potency in disrupting YAP‐TEAD interaction in vitro. To confirm that blocking YAP‐TEAD complex formation by directly targeting on TEAD is a valid approach, we report a significant reduction in tumor growth rate in a hepatocellular carcinoma xenograft model after introducing the dominant‐negative mutation (Y406H) of TEAD1 to abolish YAP‐TEAD interaction. Our results suggest that targeting TEAD is a promising strategy against YAP‐induced oncogenesis.—Zhou, Z., Hu, T., Xu, Z., Lin, Z., Zhang, Z., Feng, T., Zhu, L., Rong, Y., Shen, H., Luk, J. M., Zhang, X., Qin, N. Targeting Hippo pathway by specific interruption of YAP‐TEAD interaction using cyclic YAP‐like peptides. FASEB J. 29, 724‐732 (2015). www.fasebj.org", "corpus_id": 20354279, "score": 0 }, { "doc_id": "40058088", "title": "VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex", "abstract": "Lung cancer is one of the most devastating diseases worldwide with high incidence and mortality. Hippo (Hpo) pathway is a conserved regulator of organ size in both Drosophila and mammals. Emerging evidence has suggested the significance of Hpo pathway in cancer development. In this study, we identify VGLL4 as a novel tumor suppressor in lung carcinogenesis through negatively regulating the formation of YAP-TEAD complex, the core component of Hpo pathway. Our data show that VGLL4 is frequently observed to be lowly expressed in both mouse and human lung cancer specimens. Ectopic expression of VGLL4 significantly suppresses the growth of lung cancer cells in vitro. More importantly, VGLL4 significantly inhibits lung cancer progression in de novo mouse model. We further find that VGLL4 inhibits the activity of the YAP-TEAD transcriptional complex. Our data show that VGLL4 directly competes with YAP in binding to TEADs and executes its growth-inhibitory function through two TDU domains. Collectively, our study demonstrates that VGLL4 is a novel tumor suppressor for lung cancer through negatively regulating the YAP-TEAD complex formation and thus the Hpo pathway.", "corpus_id": 40058088, "score": 0 }, { "doc_id": "6886347", "title": "A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer.", "abstract": "The Hippo pathway has been implicated in suppressing tissue overgrowth and tumor formation by restricting the oncogenic activity of YAP. However, transcriptional regulators that inhibit YAP activity have not been well studied. Here, we uncover clinical importance for VGLL4 in gastric cancer suppression and find that VGLL4 directly competes with YAP for binding TEADs. Importantly, VGLL4's tandem Tondu domains are not only essential but also sufficient for its inhibitory activity toward YAP. A peptide mimicking this function of VGLL4 potently suppressed tumor growth in vitro and in vivo. These findings suggest that disruption of YAP-TEADs interaction by a VGLL4-mimicking peptide may be a promising therapeutic strategy against YAP-driven human cancers.", "corpus_id": 6886347, "score": 0 }, { "doc_id": "4402778", "title": "YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression.", "abstract": "Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach.", "corpus_id": 4402778, "score": 0 }, { "doc_id": "10935041", "title": "Yes-associated protein (YAP) functions as a tumor suppressor in breast", "abstract": "Yes-associated protein (YAP) has been shown to positively regulate p53 family members and to be negatively regulated by the AKT proto-oncogene product in promoting apoptosis. On the basis of this function and its location at 11q22.2, a site of frequent loss of heterozygosity (LOH) in breast cancer, we investigated whether YAP is a tumor suppressor in breast. Examination of tumors by immunohistochemistry demonstrated significant loss of YAP protein. LOH analysis revealed that protein loss correlates with specific deletion of the YAP gene locus. Functionally, short hairpin RNA knockdown of YAP in breast cell lines suppressed anoikis, increased migration and invasiveness, inhibited the response to taxol and enhanced tumor growth in nude mice. This is the first report indicating YAP as a tumor suppressor, revealing its decreased expression in breast cancer as well as demonstrating the functional implications of YAP loss in several aspects of cancer signaling.", "corpus_id": 10935041, "score": 0 }, { "doc_id": "1188189", "title": "A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis.", "abstract": "Despite recent progress, the physiological role of Hippo signaling in mammary gland development and tumorigenesis remains poorly understood. Here we show that the Hippo pathway is functionally dispensable in virgin mammary glands but specifically required during pregnancy. In contrast to many other tissues, hyperactivation of YAP in mammary epithelia does not induce hyperplasia but leads to defects in terminal differentiation. Interestingly, loss of YAP causes no obvious defects in virgin mammary glands but potently suppresses oncogene-induced mammary tumors. The selective requirement for YAP in oncogenic growth highlights the potential of YAP inhibitors as molecular targeted therapies against breast cancers.", "corpus_id": 1188189, "score": 0 }, { "doc_id": "6284558", "title": "YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy", "abstract": "Heart growth is tightly controlled so that the heart reaches a predetermined size. Fetal heart growth occurs through cardiomyocyte proliferation, whereas postnatal heart growth involves primarily physiological cardiomyocyte hypertrophy. The Hippo kinase cascade is an important regulator of organ growth. A major target of this kinase cascade is YAP1, a transcriptional coactivator that is inactivated by Hippo kinase activity. Here, we used both genetic gain and loss of Yap1 function to investigate its role in regulating proliferative and physiologic hypertrophic heart growth. Fetal Yap1 inactivation caused marked, lethal myocardial hypoplasia and decreased cardiomyocyte proliferation, whereas fetal activation of YAP1 stimulated cardiomyocyte proliferation. Enhanced proliferation was particularly dramatic in trabecular cardiomyocytes that normally exit from the cell cycle. Remarkably, YAP1 activation was sufficient to stimulate proliferation of postnatal cardiomyocytes, both in culture and in the intact heart. A dominant negative peptide that blocked YAP1 binding to TEAD transcription factors inhibited YAP1 proliferative activity, indicating that this activity requires YAP1–TEAD interaction. Although Yap1 was a critical regulator of cardiomyocyte proliferation, it did not influence physiological hypertrophic growth of cardiomyocytes, because postnatal Yap1 gain or loss of function did not significantly alter cardiomyocyte size. These studies demonstrate that Yap1 is a crucial regulator of cardiomyocyte proliferation, cardiac morphogenesis, and myocardial trabeculation. Activation of Yap1 in postnatal cardiomyocytes may be a useful strategy to stimulate cardiomyocyte expansion in therapeutic myocardial regeneration.", "corpus_id": 6284558, "score": 0 }, { "doc_id": "16276579", "title": "Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration.", "abstract": "The Hippo signaling pathway has been implicated in mammalian organ size regulation and tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional coactivator Yes-associated protein (YAP), which modulates a proliferative transcriptional program. Recent investigations have demonstrated that while this pathway is activated in quiescent livers, its inhibition leads to liver overgrowth and tumorigenesis. However, the role of the Hippo pathway during the natural process of liver regeneration remains unknown. Here we investigated alterations in the Hippo signaling pathway and YAP activation during liver regeneration using a 70% partial hepatectomy (PH) rat model. Our results indicate an increase in YAP activation by 1 day following PH as demonstrated by increased YAP nuclear localization and increased YAP target gene expression. Investigation of the Hippo pathway revealed a decrease in the activation of core kinases Mst1/2 by 1 day as well as Lats1/2 and its adapter protein Mob1 by 3 days following PH. Evaluation of liver-to-body weight ratios indicated that the liver reaches its near normal size by 7 days following PH, which correlated with a return to baseline YAP nuclear levels and target gene expression. Additionally, when liver size was restored, Mst1/2 kinase activation returned to levels observed in quiescent livers indicating reactivation of the Hippo signaling pathway. These findings illustrate the dynamic changes in the Hippo signaling pathway and YAP activation during liver regeneration, which stabilize when the liver-to-body weight ratio reaches homeostatic levels.", "corpus_id": 16276579, "score": 0 }, { "doc_id": "843818", "title": "Differences in Yes-associated protein and mRNA levels in regenerating liver and hepatocellular carcinoma.", "abstract": "Yes-associated protein (YAP) has been identified as an oncoprotein that regulates organ size by modulating proliferative and apoptotic activities. The aim of this study was to measure YAP gene expression and protein levels during rat liver regeneration and in liver cancer, and to explore possible correlations between YAP levels and cancer cell proliferation following partial hepatectomy. We examined YAP expression in rat regenerating liver using real-time PCR, Western blotting and immunohistochemical methods. YAP mRNA and protein levels were measured in human hepatocellular carcinoma. The results demonstrated that YAP protein levels were markedly increased in the regenerating liver (2.5-3 times), while YAP mRNA levels decreased slightly (1.47-2.17 times) (P=0.017). YAP mRNA and protein levels were both higher in hepatocellular carcinoma than in para-cancerous tissue. In conclusion, liver regeneration alone elevated YAP protein levels without elevating YAP mRNA levels. YAP mRNA and protein levels were both elevated in liver cancer cells.", "corpus_id": 843818, "score": 0 } ]

{ "doc_id": "151265786", "title": "Bias Crime Policing: 'The Graveyard Shift'", "abstract": "Bias crime is crime that is motivated by prejudice or bias towards an attribute of the victim, such as race, religion or sexuality. Police have been criticised for failing to take bias crime seriously, and there is a pressing need to understand the reasons for this failure. This article aims to address this gap by presenting the results of the first empirical study of bias crime policing in the Australian state of New South Wales (NSW). Drawing on interviews with the NSW Police Force (NSWPF), the study found that sustainable reform in this domain has proven elusive. This can be attributed to a number of key challenges including reporting, recording, identification, framing, community engagement and leadership. The lessons that emerge from the findings have important ramifications for all police organisations.", "corpus_id": 151265786 }

[ { "doc_id": "154300703", "title": "The Reconstitution of Law in Local Settings: Agency Discretion, Ambiguity, and a Surplus of Law in the Policing of Hate Crime", "abstract": "An important yet poorly understood function of law enforcement organizations is the role they play in distilling and transmitting the meaning of legal rules to frontline law enforcement officers and their local communities. In this study, we examine how police and sheriff ’s agencies in California collectively make sense of state hate crime laws. To do so, we gathered formal policy documents called ‘‘hate crime general orders’’ from all 397 police and sheriff ’s departments in the state and conducted interviews with law enforcement officials to determine the aggregate patterns of local agencies’ responses to higher law. We also construct a ‘‘genealogy of law’’ to locate the sources of the definitions of hate crime used in agency policies. Despite a common set of state criminal laws, we find significant variation in how hate crime is defined in these documents, which we attribute to the discretion local law enforcement agencies possess, the ambiguity of law, and the surplus of legal definitions of hate crime available in the larger environment to which law enforcement must respond. Some law enforcement agencies take their cue from other agencies, some follow statewide guidelines, and others are oriented toward gaining legitimacy from national professional bodies or groups within their own community. The social mechanisms that produce the observed clustering patterns in terms of approach to hate crime law are mimetic (copying another department), normative (driven by professional standards about training and community social movement pressure), and actuarial (affected by the demands of the crime data collection system). Together these findings paint a picture of policing organizations as mediators between law-on-the-books and law-in-action that are embedded in interorganizational networks with other departments, state and federal agencies, professional bodies, national social movement organizations, and local community groups. The implications of an interorganizational field perspective on law enforcement and implementation are discussed in relation to existing sociolegal research on policing, regulation, and recent neo-institutional scholarship on law.", "corpus_id": 154300703, "score": 1 }, { "doc_id": "151613473", "title": "Ten key developments in modern policing: an Australian perspective", "abstract": "Abstract In this paper we endeavour to isolate the top ten innovations and developments that have occurred in policing in the last thirty years. We consider that each of them brought about a new mindset, pattern or trend into contemporary police practice. We have focused our attention on the last thirty years because it is during this time that we have both maintained a keen academic interest in the field. While we have focused our attention on the way in which each has affected Australian policing, we are cognisant of the fact that many of them had their roots in other settings long before Australian policy-makers adopted or adapted them.", "corpus_id": 151613473, "score": 1 }, { "doc_id": "150906097", "title": "Conflict, Politics and Crime: Aboriginal Communities and the Police", "abstract": "Aboriginal people are grossly over-represented in Australia's courts and prisons. Despite numerous inquiries, State and Federal, and the considerable funds spent trying to understand this phenomenon, nothing has changed. Indigenous people continue to be apprehended, sentenced, incarcerated and to die in prison. One part of this inexorable process is the behaviour of the police. Drawing on research from across Australia, Chris Cunneen focuses on how police and Aboriginal people interact in urban and rural environments. He explores police history and police culture, the nature of Aboriginal offending and the prevalence of over-policing, the use of police discretion, the particular circumstances of Aboriginal youth and Aboriginal women, the experience of community policing and the key police responses to Aboriginal issues. He traces the pressures on both sides of the equation brought by new political demands. In exploring these issues, the author argues that changing the nature of contemporary relations between Aboriginal people and the police is key to altering Aboriginal over-representation in the criminal justice system, and a step towards the advancement of human rights.", "corpus_id": 150906097, "score": 0 }, { "doc_id": "145372252", "title": "Ethnicity and Trust: Perceptions of Police Bias", "abstract": "This study explores trust in police among a university sample of ethnic minority youth in Sydney, Australia, specifically examining the degree to which police are perceived to be biased against respondents' own particular ethnic groups. Results from this university sample replicate those found in previous community studies. By considering more specific questions regarding perceptions of police bias, this study further reveals that young minority groups consider police to be biased against their own ethnic group significantly more than do Caucasian youth. However, both minority youth and the Caucasian majority believe that police target certain ethnic groups, and generally agree on the particular groups that they perceive are targeted by police. These findings imply that perceptions of police bias are not restricted to minorities.", "corpus_id": 145372252, "score": 0 }, { "doc_id": "145124258", "title": "Policing Diversity and Vulnerability in the Post-Macpherson Era: Unintended Consequences and Missed Opportunities", "abstract": "The ripple effects of the Macpherson inquiry were felt by police organizations worldwide. However, the points Macpherson was making were never to be limited to race, ethnicity, or cultural difference. Nonetheless, the policies and practices to emerge since the Macpherson report have taken race and cultural difference as a template for the development of an ever-increasing number of siloed responses to vulnerability in the policing process. In this article, we examine the essential need to depart from the historical and siloed framing of police–race relations. Instead, we argue that policies and practices should respond to vulnerability as a fundamental socio-cultural characteristic of all criminal justice encounters. After much public scrutiny, many vulnerable groups have now become the target of non-negotiable, precautionary protocols for police to abide by, in order to address the disadvantage caused by a variety of attributes (such as age, mental health, language). This siloed approach to diversity and the cultural awareness and quota models that emerged from the Macpherson recommendations are no longer adequate for the increasing differentiation of modern societies. We suggest that Macpherson’s recommendations, despite their success, have left in their wake a series of institutional artefacts that have ossified policing responses to diversity. As a more realistic template to address a wider understanding of diversity, we propose re-centring vulnerability as a ubiquitous characteristic of all criminal justice encounters through the use of Herring and Henderson’s framing of critical diversity (2011).", "corpus_id": 145124258, "score": 0 }, { "doc_id": "153998453", "title": "Policing in a Multicultural Society", "abstract": "Australia in the 1990s is a country of remarkable ethnic and cultural diversity, with more than 100 ethnic groups, speaking 80 immigrant languages and 150 Aboriginal languages (Castles et al. 1988: 25). More than one-quarter of its 17 million people were either born in non-English-speaking countries or the ‘second generation’ of those born in these countries (Jupp 1995). At the 1991 Census 265,459 people, or 1.6 per cent of the total population in Australia, identified themselves as being of Aboriginal or Torres Strait Islander origin (Australian Bureau of Statistics [ABS] 1994a: 5). Australia's ethnic diversity is, however, a relatively recent pheonomenon. At the time of European settlement in 1788, the continent had been inhabited by Aboriginal people for more than 50,000 years. After that the number of Australia's original inhabitants declined dramatically, from nearly one million to about 80,000 by the 1930s, largely as a result of ‘disease, conflict and the disintegration of traditional society’ (Human Rights and Equal Opportunity Commission [HREOC] 1991: 59). By the late 1940s, almost 90 per cent of Australia's population was of British descent. This was achieved through the White Australia Policy which discriminated against the immigration of non-Europeans and provided a system of assisted passage for British immigrants. Since the abandonment of discriminatory policies in the 1970s, however, Australia's population has become increasingly culturally diverse through immigration. By the late 1980s and early 1990s, only 18 per cent of immigrants to Australia were from the United Kingdom and Ireland, compared with 46 per cent in the early 1960s.", "corpus_id": 153998453, "score": 1 }, { "doc_id": "55726009", "title": "Perceptions of Police Legitimacy and Citizen Decisions to Report Hate Crime Incidents in Australia", "abstract": "This article examines the importance of perceptions of police legitimacy in the decision to report hate crime incidents in Australia. It addresses an identified gap in the literature by analysing the 2011-2012 National Security and Preparedness Survey (NSPS) results to not only explore differences between hate crime and non-hate crime reporting but also how individual characteristics and perceptions of legitimacy influence decisions about reporting crime to police. Using the NSPS survey data, we created three Generalised Linear Latent and Mixed Models (Gllamm), which explore the influence of individual characteristics and potential barriers on the decision to report crime/hate crime incidents to police. Our results suggest that hate crimes are less likely to be reported to police in comparison to non-hate crime incidents, and that more positive perceptions of police legitimacy and police cooperation are associated with the victim’s decision to report hate crime victimisation.", "corpus_id": 55726009, "score": 1 }, { "doc_id": "145420906", "title": "A Shared Global Perspective on Hate Crime?", "abstract": "The hate crime concept describes a set of actions that span the worlds of activism, policy, and scholarship and provides the basis for these actors to work together and open up the rule of law to communities that often exist outside its protection. However, there is huge diversity in current approaches across and within these worlds to recording, reporting, legislating against, and researching hate crime, which challenges the notion of a shared and global concept of hate crime. This article offers a framework that helps describe the processes and relationships that generate and refine national and international concepts of hate crime. In so doing, it starts to assess to what extent an internationally coherent approach to understanding and responding to targeted, bigoted violence has been achieved.", "corpus_id": 145420906, "score": 0 }, { "doc_id": "59486709", "title": "A Leap of Faith? Trust in the Police Among Immigrants in England and Wales", "abstract": "It is often assumed that immigrants in countries such as the United Kingdom will report lower levels of trust in the police. Immigrant communities are thought ‘difficult to police’, and minority groups frequently experience problematic relationships with police. Yet, there has been little empirical investigation of this issue in the United Kingdom. In this paper, data from the Crime Survey of England and Wales are used to explore the relationship between immigration and trust in the police. Results suggest that trust is higher among immigrants than among the UK-born population, although there is important variation by time since arrival and experience of policing. Trust in the police is also higher in neighbourhoods that have more immigrants. The paper concludes with some reflection on the nature of trust in the police.", "corpus_id": 59486709, "score": 0 }, { "doc_id": "145406930", "title": "Policing at the margins: fostering trust and cooperation among ethnic minority groups", "abstract": "Over the past few decades, Australia has become less dominated by White-European cultural groups and is increasingly characterized by racial and cultural diversity. This diversity brings many benefits, but it also poses challenges for governance. Authorities such as the police are faced with greater diversity in cultural norms, values, identities, and attitudes toward police and the law. This increase in diversity may therefore have implications for the ability of police to foster trust, obtain compliance, and encourage cooperation among certain groups. Procedural justice has been regarded as central to improving public trust and confidence in authorities. This paper will use survey data to examine the role that procedural justice policing can play in promoting trust and cooperation among ethnic minority groups living in Australia.", "corpus_id": 145406930, "score": 0 }, { "doc_id": "144502725", "title": "Perceptions of group value: how Australian transgender people view policing", "abstract": "In Australia, no one really knows how widespread the Transgender community actually is since transgender people are relatively diffuse and hidden and comprise a ‘hard to get at population’. One recognised form of researching hard-to-reach populations is through online surveys. Online surveys with members of minority groups have significant advantages over other data collection methods, particularly when asking respondents about their perceptions of authoritarian in-groups such as the police. Under the theoretical framework of Social Identity Theory, and the Group-Value Model, an online survey was used to capture transgender peoples' perceptions of the police. This article determines that the gender identities of transgender participants who have had previous contact with police in their professional capacity significantly shapes negative perceptions of treatment quality from police officers.", "corpus_id": 144502725, "score": 0 }, { "doc_id": "143627918", "title": "Fostering cooperation with the police: How do ethnic minorities in Australia respond to procedural justice-based policing?", "abstract": "Public cooperation with police is essential for the control of crime and disorder. Hence, understanding factors that shape public cooperation with the police is important. However, Australian and international studies show that police find it difficult to elicit cooperation from ethnic communities, this made difficult by the fact that ethnic groups display low levels of trust and confidence in the police. This study examines the role that procedural justice plays in fostering minority group perceptions of police legitimacy and their willingness to cooperate with police. Using survey data collected from 1204 Australian citizens, this study tests whether procedurally fair policing can enhance perceptions of police legitimacy and nurture cooperation among ethnic minorities in Australia. Findings reveal that procedural justice predicts views of police legitimacy more so than instrumental factors for both minority and majority group members. The results also suggest that ethnicity moderates the effect of procedural justice on cooperation; specifically, procedural justice is shown to be less effective for nurturing cooperation among ethnic minorities than majority group members. A group identity perspective is used to explain these findings. The findings also have implications for how the police can foster better relationships with ethnically diverse communities.", "corpus_id": 143627918, "score": 1 }, { "doc_id": "147507427", "title": "Justice from within: The relations between a procedurally just organizational climate and police organizational efficiency, endorsement of democratic policing, and officer well-being.", "abstract": "Recent clashes between law enforcement and the public have led to increased attention on policing strategies that build trust and motivate cooperation in communities through the application of fair procedures and decision-making. A growing body of policing research has highlighted that officers commonly report working within police departments that lack procedural fairness and that these intradepartmental dynamics influence officers motivation and behavior on the street. This study builds on this work by examining the influence of a procedurally fair organizational climate on officer’s organizational behavior, commitment to democratic policing, and well-being. Patrol officers and sergeants in a large urban police force completed surveys assessing their perceptions of their department, the communities they police, their views on different policing styles, and their well-being. Results showed that when officers were in a procedurally fair department, they were more likely to trust and feel obligated to obey their supervisors, less likely to be psychologically and emotionally distressed, and less likely to be cynical and mistrustful about the world in general and the communities they police in particular. More importantly, these effects were associated with greater endorsement of democratic forms of policing, increased organizational efficiency, and officer well-being. Taken together these results clearly support the utility of infusing procedural justice into the internal working climate as a means to improve police officer job performance, their well-being, and their relationship with the communities they police.", "corpus_id": 147507427, "score": 1 }, { "doc_id": "147643077", "title": "Ethnic Hate Crime in Australia: Diversity and Change in the Neighbourhood Context", "abstract": "Ecological theories of racially or ethnically motivated hate crime are largely derived from the United States, where racial segregation is highly pronounced. The extent to which these theories explain hate crime in more ethnically integrated countries is presently unclear. We focus on the neighbourhood characteristics influencing self-reported hate crime for 4,396 residents in a city experiencing growing ethnic diversity. We find that the neighbourhood antecedents of hate crime in the Australian context differ from those seen in the United States. While residents speaking a language other than English is a powerful predictor of incidents, neither residential mobility nor increases in in-migration are associated with hate victimization, and neighbourhood place attachment decreases the likelihood of victimization. Our findings suggest that ecological theories of hate crime derived from the United States may be limited in their applicability in multi-ethnic settings.", "corpus_id": 147643077, "score": 0 }, { "doc_id": "150803673", "title": "'Hate crime' and the city", "abstract": "This book, from a leading author in the field, widens understanding of 'hate crime' by demonstrating that many offenders are ordinary people who offend in the context of their everyday lives. Written in a lively and accessible style, the book takes a victim-centred approach to explore and analyse 'hate crime' as a social problem, providing an empirically informed and scholarly perspective. Aimed at academics and students of criminology, sociology, socio-legal studies and social policy, the book draws out the connections between the individual agency of offenders and the background structural context for their actions. The analysis offered adds a new dimension to the debate about criminalising hate in light of concerns about the rise of punitive and expressive justice, scrutinising the balance struck by 'hate crime' laws between the rights of offenders and the rights of victims.", "corpus_id": 150803673, "score": 0 }, { "doc_id": "152059723", "title": "Conceptual divides and practice synergies in law enforcement and public health: some lessons from policing vulnerability in Australia", "abstract": "ABSTRACT The debates about how and whether law enforcement and public health share a policy and practice mandate are perplexing. Frontline practice indicates that this intersection is de rigueur, and that practitioners from both fields see no reason why they cannot work together beneficially. Indeed, police are as much public health interventionists as health practitioners are public safety facilitators. In this article, we identify the conceptual dissonance that continues to frame the debate about law enforcement and public health, and document the practical synergies that exist (and have always existed) in both fields. We suggest that the divide between law enforcement and public health is futile, and that the shared concept of vulnerability in policing, health and law can do much to foster better collaborative practices, policies and shared understandings.", "corpus_id": 152059723, "score": 0 }, { "doc_id": "144137434", "title": "Police occupational culture: classic themes, altered times", "abstract": "Understandings of police culture rely heavily on ethnographies conducted several decades ago. In these classic accounts, authors have identified recurring themes within police dispositions and practices over time and space. There have, however, been important developments within policing contexts, some of which could be expected to transform the cultural ethos that has long underpinned the police identity. This article draws upon ethnographic research conducted in an English police force to explore how much of the classic characteristics of police culture have survived the period of transition. It shows that the underlying world view of officers displays remarkable continuity with older patterns, and argues that police culture endures because the basic pressures associated with the police role have not been removed. In light of this apparent durability of cultural themes, the article calls into question the increasingly accepted view that orthodox conceptions of police culture no longer make any sense.", "corpus_id": 144137434, "score": 0 }, { "doc_id": "143013871", "title": "Self-legitimacy, Police Culture and Support for Democratic Policing in an English Constabulary", "abstract": "When do police officers feel confident in their own authority? What factors influence their sense of their own legitimacy? What is the effect of such ‘self-legitimacy’ on the way they think about policing? This paper addresses these questions using a survey of police officers working in an English constabulary. We find that the most powerful predictor of officers’ confidence in their own authority is identification with their organization, itself something strongly associated with perceptions of the procedural justice of senior management. A greater sense of self-legitimacy is in turn linked to greater commitment to ‘democratic’ modes of policing. Finally, we find that this sense of legitimacy is embedded in a matrix of identities and cultural adaptations within the police organization.", "corpus_id": 143013871, "score": 0 }, { "doc_id": "144855371", "title": "The fourth era of policing: Homeland security", "abstract": "Abstract American policing has been said to have gone through three eras: the political, reform, and community; and consists of four different models of policing: traditional, community policing, problem-oriented and zero-tolerance. With the tragic events of 11 September 2001, and the government's movement toward enhanced domestic security, the author argues that we have entered a new era in American policing and are witnessing the adaptation of a new style of policing, namely Homeland Security. Drawing upon the works of Kelling and Moore (G L Kelling and M H Moore in Perspectives on Policing No 4, Washington DC, National Institute of Justice, 1988; G L Kelling and M H Moore, in J R Greene and S D Mastrofski (eds) Community Policing: Rhetoric or Reality? Praeger, 1991, pp 3–25) and Greene (J R Greene in Criminal Justice 2000: Policies, Processes, and Decisions of the Criminal Justice System Vol 3, 2000), the author advances their work to highlight what this new era and style of policing means for American policing.", "corpus_id": 144855371, "score": 0 }, { "doc_id": "150094503", "title": "Criminal Law as Police Power: Serious Crime, Unsafe Protest and Risks to Public Safety", "abstract": "This article considers the deepening of police power in New South Wales (NSW), Australia, criminal law. It analyses the combined effects of four recent criminal law regimes that not only give the NSW Police Force more powers, but also reflect the significant role of institutional police power and the pre-emptive logic of criminal law. We examine: the introduction of serious crime prevention orders; the introduction of public safety orders; investigative detention powers in relation to terrorist acts; and confiscation, forfeiture and search powers, and trespass offences that target protests. Drawing on the work of ‘police power’ theorists, we argue that these new regimes illustrate the centrality of police power to the criminal law rather than a deviation from a putative, ‘normal’ criminal law.", "corpus_id": 150094503, "score": 0 }, { "doc_id": "142547057", "title": "Qualitative Analysis: Practice and Innovation", "abstract": "Offering a detailed introduction to the practice of data analysis, this book is both user-friendly and theoretically grounded. Drawing on his extensive experience of qualitative research, Douglas Ezzy reviews approaches to data analysis in established research traditions including ethnography, phenomenology and symbolic interactionism, alongside the newer approaches informed by cultural studies and feminism. He explains the difference between inductive, deductive and abductive theory building, provides a guide to computer-assisted analysis and outlines techniques such as journal writing, team meetings and participant reviews. This text is one of the first to treat computer assisted data analysis as an integral part of qualitative research. Exceptionally well written, this is a valuable reference for research students and professional researchers in the social sciences and health.", "corpus_id": 142547057, "score": 0 }, { "doc_id": "147349924", "title": "From Hate to Prejudice: Does the New Terminology of Prejudice Motivated Crime Change Perceptions and Reporting Actions?", "abstract": "Official definitions of hate crime are viewed as overly narrow and unnecessarily exclusive. To enable more inclusive practices, many jurisdictions have embraced alternative terminologies such as bias crime, targeted crime and prejudice motivated crime. In this article, we examine how police agencies in Victoria, Australia, are grappling with incidents and responses to hate crime. Drawing on the accounts of high priority victim groups, we illustrate how victims and victim advocates make sense of new hate crime terminologies and whether these terminologies facilitate hate crime incident reporting. Our findings speak to the importance of shared understanding and vocabularies; however, police responses to prejudice motivated crime incidents and police interactions with victims remain a significant barrier to reporting behaviour.", "corpus_id": 147349924, "score": 0 } ]

{ "doc_id": "13591288", "title": "Pain perception, aversion and fear in fish.", "abstract": "There is now compelling evidence that teleost fish possess similar nociceptive processing systems to those found in terrestrial vertebrates. Noxious stimulation of these nociceptors--specialised pain receptors -in the skin around the snout of fish generates neural activity that can be electrophysiologically recorded, and induces a number of behavioural and physiological changes. To determine whether changes in behaviour are more than simple responses to the noxious stimulation it is necessary to demonstrate that higher order cognitive processes such as mental state or 'affective state' are involved. However, quantifying the 'motivational affected state' of an animal--a concept encompassing not just pain but also fear, hunger, thirst and pleasure - is difficult owing to its subjectivity. Recent empirical work is beginning to test these concepts in fish, and we review a number of these studies and suggest how these general methodologies could be used to further our understanding of fish cognition and the capacity for fish to experience mental states such as fear or suffering.", "corpus_id": 13591288 }

[ { "doc_id": "2428975", "title": "Do fishes have nociceptors? Evidence for the evolution of a vertebrate sensory system", "abstract": "Nociception is the detection of a noxious tissue–damaging stimulus and is sometimes accompanied by a reflex response such as withdrawal. Pain perception, as distinct from nociception, has been demonstrated in birds and mammals but has not been systematically studied in lower vertebrates. We assessed whether a fish possessed cutaneous nociceptors capable of detecting noxious stimuli and whether its behaviour was sufficiently adversely affected by the administration of a noxious stimulus. Electrophysiological recordings from trigeminal nerves identified polymodal nociceptors on the head of the trout with physiological properties similar to those described in higher vertebrates. These receptors responded to mechanical pressure, temperatures in the noxious range (more than 40°C) and 1% acetic acid, a noxious substance. In higher vertebrates nociceptive nerves are either A–delta or C fibres with C fibres being the predominating fibre type. However, in the rainbow trout A–delta fibres were most common, and this offers insights into the evolution of nociceptive systems. Administration of noxious substances to the lips of the trout affected both the physiology and the behaviour of the animal and resulted in a significant increase in opercular beat rate and the time taken to resume feeding, as well as anomalous behaviours. This study provides significant evidence of nociception in teleost fishes and furthermore demonstrates that behaviour and physiology are affected over a prolonged period of time, suggesting discomfort.", "corpus_id": 2428975, "score": 1 }, { "doc_id": "69128306", "title": "Fish and welfare: Do fish have the capacity for pain perception and suffering?", "abstract": "Humans interact with fish in a number of ways and the question of whether fish have the capacity to perceive pain and to suffer has recently attracted considerable attention in both scientific and public fora. Only very recently have neuroanatomical studies revealed that teleost fish possess similar pain-processing receptors to higher vertebrates. Research has also shown that fish neurophysiology and behaviour are altered in response to noxious stimulation. In the light of this evidence and in combination with work illustrating the cognitive capacities of fish, it seems appropriate to respond to a recently published critique (Rose, 2002) in which it is argued that it is not possible for fish to experience fear or pain and that, therefore, they cannot suffer. Whilst we agree with the author that fish are unlikely to perceive pain in the same way that humans do, we believe that currently available evidence indicates that fish have the capacity for pain perception and suffering. As such, it would seem timely to reflect on the implications of fish pain and suffering, and to consider what steps can be taken to ensure the welfare of the fish that we exploit.", "corpus_id": 69128306, "score": 0 }, { "doc_id": "16220451", "title": "The Neurobehavioral Nature of Fishes and the Question of Awareness and Pain", "abstract": "This review examines the neurobehavioral nature of fishes and addresses the question of whether fishes are capable of experiencing pain and suffering. The detrimental effects of anthropomorphic thinking and the importance of an evolutionary perspective for understanding the neurobehavioral differences between fishes and humans are discussed. The differences in central nervous system structure that underlie basic neurobehavioral differences between fishes and humans are described. The literature on the neural basis of consciousness and of pain is reviewed, showing that: (1) behavioral responses to noxious stimuli are separate from the psychological experience of pain, (2) awareness of pain in humans depends on functions of specific regions of cerebral cortex, and (3) fishes lack these essential brain regions or any functional equivalent, making it untenable that they can experience pain. Because the experience of fear, similar to pain, depends on cerebral cortical structures that are absent from fish brains, it is concluded that awareness of fear is impossible for fishes. Although it is implausible that fishes can experience pain or emotions, they display robust, nonconscious, neuroendocrine, and physiological stress responses to noxious stimuli. Thus, avoidance of potentially injurious stress responses is an important issue in considerations about the welfare of fishes.", "corpus_id": 16220451, "score": 0 }, { "doc_id": "27440885", "title": "Balancing animal research with animal well-being: establishment of goals and harmonization of approaches.", "abstract": "A resource is provided for the creation of an institutional program that balances the scientific mission of an institution with the well-being of the animals used in support of the research. The concept of harmonizing scientific goals with animal well-being was first suggested in the early part of the twentieth century and later revitalized in the literature of the 1950s. Harmonization can best be achieved through the promotion of a team initiative. The team should include, at a minimum, the scientist, veterinarian, institutional animal care and use committee, and animal care staff. It is the responsibility of this animal research team to promote and balance the generation of scientifically valid data with animal well-being. The team must strive to minimize or eliminate non-protocol variables that could adversely affect the validity and repeatability of the experimental data. Good experimental design coupled with excellent communication between team members can often minimize or eliminate many variables and result in both better science and animal well-being. To ensure the scientific validity of experimental data, scientists must be aware of the complex nature of the environment in which their animals are maintained. To ensure repeatablity of an experiment, scientists must document and publish both the inanimate and social environments in which their animals are housed. Better documentation of environmental variables and their correlation with experimental results will promote critical knowledge about the relationships between an animal's environment, its well-being, and science.", "corpus_id": 27440885, "score": 0 }, { "doc_id": "27003423", "title": "Nociception in vertebrates: key receptors participating in spinal mechanisms of chronic pain in animals", "abstract": "Our view of vertebrate nociceptive processing is ever changing with the discovery of novel molecules that differentially affect sensory responses to noxious and innocuous stimulation and might be involved specifically in chronic pain states. In order to understand the physiology of nociception and design novel analgesics for intractable chronic pain, it is essential to uncover precisely what changes occur between a normal nociceptive processing state and hypersensitive chronic pain states in the spinal cord following different types of injury. An important area of focus for future work in this area will be the cellular and molecular mechanisms of neuronal plasticity that occur.", "corpus_id": 27003423, "score": 0 }, { "doc_id": "33988768", "title": "Organization of peripheral nerves and spinal roots of the Atlantic stingray, Dasyatis sabina.", "abstract": "1. The sizes and numbers of axons in peripheral nerves and spinal roots were investigated in the stingray, Dasyatis sabina. 2. The axons of the dorsal and ventral roots do not mingle in peripheral nerves of this animal as they do in higher vertebrates. Thus, it was usually possible to split the peripheral nerve into two portions, one containing only dorsal root axons, the other containing only ventral root axons. This feature was useful for the analysis of certain aspects of spinal cord organization. 3. The fact that dorsal and ventral root axons were segregated in peripheral nerves enabled us to demonstrate, without experimental surgery, that the central processes of the dorsal root ganglion cells and the proximal ventral root axons were 10-20% narrower, on the average, than the distal processes of the same dorsal root ganglion cells or the distal parts of the same ventral root axons. 4. The stingray is remarkable in having very few unmyelinated axons in the dorsal roots, ventral roots, or peripheral nerves. This paucity of unmyelinated axons distinguishes the Atlantic stingrays from all other vertebrates whose roots and nerves have been examined for unmyelinated fibers. 5. Similar findings were obtained for one spotted eagle ray (Aetobatus narinari) and two cow-nose rays (Rhinoptera bonasus).", "corpus_id": 33988768, "score": 0 }, { "doc_id": "14807046", "title": "Anatomical and electrophysiological analysis of the trigeminal nerve in a teleost fish, Oncorhynchus \n mykiss\n", "abstract": "The trigeminal nerve in the rainbow trout, Oncorhynchus mykiss, was examined for the presence of A-delta and C fibres. Sections of the three branches of the trigeminal nerve were found to comprise a range of fibre types including A-delta and C fibres. The size range of the cell bodies of the trigeminal ganglion reflected the fibre range since they correlated with the size range of axons in the nerve branches. Electrophysiological recordings of evoked activity from the ganglion confirmed the presence of these fibre types and the proportion of these mirrored the proportion of fibre types in the anatomical analyses. A-beta fibres were most common followed by A-delta fibres, then A-alpha fibres with C fibres being the fewest fibre type found. In higher vertebrates, A-delta and C fibres in the trigeminal nerve convey both somatosensory and nociceptive information to the brain. The evolutionary significance of these results is discussed as well as the potential for nociceptive capability in a lower vertebrate.", "corpus_id": 14807046, "score": 0 }, { "doc_id": "14127825", "title": "Measuring emotional processes in animals: the utility of a cognitive approach", "abstract": "Contemporary researchers regard emotional states as multifaceted, comprising physiological, behavioural, cognitive and subjective components. Subjective, conscious experience of emotion can be inferred from linguistic report in humans, but is inaccessible to direct measurement in non-human animals. However, measurement of other components of emotion is possible, and a variety of methods exist for monitoring emotional processes in animals by measuring behavioural and physiological changes. These are important tools, but they have limitations including difficulties of interpretation and the likelihood that many may be sensitive indicators of emotional arousal but not valence-pleasantness/unpleasantness. Cognitive components of emotion are a largely unexplored source of information about animal emotions, despite the fact that cognition-emotion links have been extensively researched in human cognitive science indicating that cognitive processes-appraisals of stimuli, events and situations-play an important role in the generation of emotional states, and that emotional states influence cognitive functioning by inducing attentional, memory and judgement biases. Building on this research, it is possible to design non-linguistic cognitive measures of animal emotion that may be especially informative in offering new methods for assessing emotional valence (positive as well as negative), discriminating same-valenced emotion of different types, identifying phenotypes with a cognitive predisposition to develop affective disorders, and perhaps shedding light on the issue of conscious emotional experiences in animals.", "corpus_id": 14127825, "score": 1 }, { "doc_id": "26352434", "title": "Deficits in hippocampus-mediated pavlovian conditioning in endogenous hypercortisolism", "abstract": "BACKGROUND\nElevated endogenous levels of corticosteroids cause neural dysfunction and loss, especially within the hippocampus, as well as cognitive impairment in hippocampus-mediated tasks. Because Cushing's syndrome patients suffer from hypercortisolism, they represent a unique opportunity to study the impact of elevated glucocorticoids on cognitive functions. The aim of this study was to examine the performance of Cushing's syndrome patients on trace eyeblink conditioning, a cross-species, hippocampal-mediated test of learning and memory.\n\n\nMETHODS\nEleven Cushing's syndrome patients and 11 healthy control subjects participated in an eyeblink trace conditioning test (1000-msec trace) and a task of declarative memory for words. Salivary cortisol was collected in both the patients and the control subjects, and urinary free cortisol was collected in the patients only.\n\n\nRESULTS\nThe patients exhibited fewer conditional responses and remembered fewer words, compared with the control subjects. Cortisol levels correlated with immediate and delayed declarative memory only. Conditional response correlated with delayed recall after controlling for the magnitude of unconditional response.\n\n\nCONCLUSIONS\nThe integrity of the hippocampus seems to be compromised in Cushing's syndrome patients. Trace eyeblink conditioning might be useful both as a clinical tool to examine changes in hippocampus function in Cushing's disease patients and as a translational tool of research on the impact of chronic exposure of glucocorticoids.", "corpus_id": 26352434, "score": 0 }, { "doc_id": "84043505", "title": "Use of Physiological Telemetry as a Method of Estimating Metabolism of Fish in the Natural Environment", "abstract": "Abstract One of the most difficult components to measure in the energy budgets of natural fish populations is the energy released in metabolism. Telemetry of physiological correlates of metabolism, such as heart rate, can (with calibration) enable direct measurements of metabolism and simultaneous observations of behavior in the natural environment. Heart rate is a good indicator of metabolic rate for northern pike Esox lucius and was used to obtain information on metabolism, activity, and food intake in the natural environment. Mean field metabolic rates were 1.5 times standard metabolic rate. Activity metabolism accounted for 5–10% of total metabolism and was approximately an order of magnitude greater than estimates based on mean swimming speed derived from location tracking. Feeding metabolism was 15–25% of total metabolism. Even when the full metabolic rate calibration is not considered. physiological telemetry can provide useful information on patterns of energy expenditure ofdirect relevance to bio...", "corpus_id": 84043505, "score": 0 }, { "doc_id": "16405663", "title": "The past explains the present: Emotional adaptations and the structure of ancestral environments", "abstract": "Abstract Present conditions and selection pressures are irrelevant to the present design of organisms and do not explain how or why organisms behave adaptively, when they do. To whatever non-chance extent organisms are behaving adaptively, it is 1) because of the operation of underlying adaptations whose present design is the product of selection in the past, and 2) because present conditions resemble past conditions in those specific ways made developmentally and functionally important by the design of those adaptations. All adaptations evolved in response to the repeating elements of past environments, and their structure reflects in detail the recurrent structure of ancestral environments. Even planning mechanisms (such as “consciousness”), which supposedly deal with novel situations, depend on ancestrally shaped categorization processes and are therefore not free of the fast. In fact, the categorization of each new situation into evolutionarily repeating classes involves another kind of adaptation, the emotions, which match specialized modes of organismic operation to evolutionarily recurrent situations. The detailed statistical structure of these iterated systems of events is reflected in the detailed structure of the algorithms that govern emotional state. For this reason, the system of psychological adaptations that comprises each individual meets the present only as a version of the past.", "corpus_id": 16405663, "score": 0 }, { "doc_id": "18478736", "title": "Cognitive ornithology: the evolution of avian intelligence", "abstract": "Comparative psychologists interested in the evolution of intelligence have focused their attention on social primates, whereas birds tend to be used as models of associative learning. However, corvids and parrots, which have forebrains relatively the same size as apes, live in complex social groups and have a long developmental period before becoming independent, have demonstrated ape-like intelligence. Although, ornithologists have documented thousands of hours observing birds in their natural habitat, they have focused their attention on avian behaviour and ecology, rather than intelligence. This review discusses recent studies of avian cognition contrasting two different approaches; the anthropocentric approach and the adaptive specialization approach. It is argued that the most productive method is to combine the two approaches. This is discussed with respects to recent investigations of two supposedly unique aspects of human cognition; episodic memory and theory of mind. In reviewing the evidence for avian intelligence, corvids and parrots appear to be cognitively superior to other birds and in many cases even apes. This suggests that complex cognition has evolved in species with very different brains through a process of convergent evolution rather than shared ancestry, although the notion that birds and mammals may share common neural connectivity patterns is discussed.", "corpus_id": 18478736, "score": 0 }, { "doc_id": "31113845", "title": "Similar antagonism of morphine analgesia by MIF-1 and naloxone in Carassius auratus\n", "abstract": "Prolyl-leucyl-glycinamide (MIF-1), the C-terminal tripeptide of oxytocin, and naloxone were administered intracranially (IC) to goldfish (Carassius auratus) in doses of 0.001, 0.01, 0.1, 1.0 and 10.0 mg/kg and compared to a diluent control group for their ability to reduce the effects of morphine (30 mg/kg IC) in an assay measuring analgesia to electric shock. Threshold levels of pain were determined by the voltage necessary to produce an agitated swimming response (ASR). Both MIF-1 and naloxone were found to significantly reduce the analgesic effects of morphine when compared to the diluent control group. Similar dose-response curves in an apparent sine-wave pattern were noted with both MIF-1 and naloxone when comparisons were made both at 20 minutes after administration of morphine and over the entire 150 minutes of the experiment. The results support the evidence that MIF-1 can act as an opiate antagonist.", "corpus_id": 31113845, "score": 0 }, { "doc_id": "44785832", "title": "Pharmacokinetics of morphine in fish: winter flounder (Pseudopleuronectes americanus) and seawater-acclimated rainbow trout (Oncorhynchus mykiss).", "abstract": "We made a single intraperitoneal (IP) injection of morphine sulfate (40 mg/kg) into winter flounder and seawater acclimated rainbow trout at 10 degrees C and then followed its disposition by measuring the change in plasma morphine concentration for 100 h using a morphine specific ELISA. Disposition also was followed for 6h after a single IV injection of 7.5mg morphine sulfate in winter flounder. Plasma morphine reached a maximum within an hour post-injection IP and then decreased in a bi-exponential fashion with a rapid distribution phase followed by a slower elimination phase. The disposition was slower in flounder than in trout even though the fish were held at the same temperature. For example, plasma clearance was 76 mL h(-)(1) kg(-)(1) in the flounder but was almost twice as much in the trout (153 mL h(-)(1) kg(-)(1)) and mean residence time was 27.9h in the flounder but was 7.0 h in the trout. The present study is the first comprehensive pharmacokinetic analysis for any analgesic in an ectotherm, and our results show that: 1) significant intra-specific variation exists between fishes: and 2) the disposition of morphine in fish is approximately one order of magnitude slower than it is in mammals. These differences may be due in part to mass specific differences in cardiac output.", "corpus_id": 44785832, "score": 0 }, { "doc_id": "14764333", "title": "Investigating fear in domestic rainbow trout, Oncorhynchus mykiss, using an avoidance learning task", "abstract": "The capacity of rainbow trout to experience fear was assessed using an avoidance learning task. Each of 13 fish was placed individually into a two-chambered shuttle tank where it could be subjected to the putative frightening stimulus of a plunging dip net in either chamber. The fish could escape from the stimulus by swimming through a doorway to the other chamber. The fish escaped from the plunging net by swimming through the doorway, some on the first occasion and all after a few exposures. Each fish was then presented with a neutral stimulus of a light that went on 10 s before the net plunged into the water. Over a 5-day period, all fish learned to avoid the plunging net by swimming through the doorway when the light was illuminated. All fish showed evidence of longer-term memory by showing the learned avoidance response on the first occasion they were tested after 7 days of no testing. Whereas the escape responses to the plunging net were immediate and reflexive-like, the avoidance responses to the light going on were delayed a few seconds and more deliberate in nature. This evidence suggests that trout can experience fear and that they can learn to avoid frightening stimuli. It implies that they are sentient animals, more complex than previously thought.", "corpus_id": 14764333, "score": 1 }, { "doc_id": "144625964", "title": "Avoidance learning in goldfish (Carassius auratus) and trout (Oncorhynchus mykiss) and implications for Pain perception", "abstract": "This paper investigates spatially cued behavioural responses of two species of fish to an acute noxious stimulus and demonstrates response elasticity. Typical avoidance responses to a nociceptive stimulus were used to test (1) if fish learn to avoid spatial areas associated with a potentially noxious stimulus, (2) learning and memory improves with increased stimulus intensity and (3) a supposedly innate reflex behavioural responses change depending on the circumstances. Electric shocks with two different intensities, low (2.5 V and 3 V for trout and goldfish, respectively) and high (25 V and 30 V for trout and goldfish, respectively), were administered directly to the skin to stimulate cutaneous nociceptors. Goldfish (n = 8) demonstrated spatially cued shock avoidance and an increase in stimulus voltage, significantly improved shock-avoidance learning and memory. However, trout (n = 8) demonstrated shock-avoidance learning but no significant stimulus discrimination and little information retention. The presence of a conspecific significantly changed this behavioural response to a noxious stimulus. Trout were willing to remain in the vicinity of the conspecific while being subjected to low intensity shock stimuli previously shown to elicit avoidance. Goldfish tended to leave this area yet remain in the mid-tank area, adjacent to the stimulating zone, rather than at the end of the tank. These results suggest that shock avoidance in fish is not purely a reflex action. Fish were prepared to change the supposedly innate avoidance reaction according to a change in circumstances, an important concept in the ongoing debate on pain perception in fish. (c) 2005 Elsevier B.V. All rights reserved.", "corpus_id": 144625964, "score": 1 }, { "doc_id": "142757646", "title": "Through Our Eyes Only?: The Search for Animal Consciousness", "abstract": "Through your eyes only miss Halsey moves her foot bees do it thinking ahead feeling our way balance of evidence.", "corpus_id": 142757646, "score": 0 }, { "doc_id": "86227238", "title": "Poultry welfare: Science or subjectivity?", "abstract": "1. Most people in the developed world agree on what 'animal welfare' is, although it is impossible to give it a precise scientific definition. 2. The argument is made that animal welfare is all to do with the feelings of animals and not the primary needs that these feeling have evolved to protect. 3. Acceptance of subjective feelings as a legitimate subject for scientific investigation has a long and well-established history in science. This acceptance was interrupted by the rise of Behaviorism in the 20th century, but now seems to be re-established. 4. Subjective feelings cannot be studied directly. However, in the animal welfare debate, indirect evidence on feelings is extremely useful, and methods for obtaining this indirect evidence are described. 5. The poultry species are capable of feeling several states of suffering including fear, frustration and pain. A start has been made to elucidate these states and the conditions that cause them, but much remains to be done. Recent evidence suggests that the poultry species may also be capable of experiencing pleasure. 6. It is concluded that, although poultry welfare is all to do with the subjective feelings of the birds, it is possible to be objective and scientific about these feelings. Investigation into poultry welfare, therefore, really is science rather than subjectivity.", "corpus_id": 86227238, "score": 0 }, { "doc_id": "84814729", "title": "Reactions of Juvenile Pacific Salmon to Light", "abstract": "When given a choice between light and dark areas, schools of chum or pink salmon fry remain in the light, sockeye fry prefer the dark and coho fry show no marked preference for either. Newly emerge...", "corpus_id": 84814729, "score": 0 }, { "doc_id": "205028225", "title": "Different types of fear-conditioned behaviour mediated by separate nuclei within amygdala", "abstract": "The amygdala has long been thought to be involved in emotional behaviour, and its role in anxiety and conditioned fear has been highlighted. Individual amygdaloid nuclei have been shown to project to various cortical and subcortical regions implicated in affective processing. Here we show that some of these nuclei have separate roles in distinct mechanisms underlying conditioned fear responses. Rats with lesions of the central nucleus exhibited reduction in the suppression of behaviour elicited by a conditioned fear stimulus, but were simultaneously able to direct their actions to avoid further presentations of this aversive stimulus. In contrast, animals with lesions of the basolateral amygdala were unable to avoid the conditioned aversive stimulus by their choice behaviour, but exhibited normal conditioned suppression to this stimulus. This double dissociation demonstrates that distinct neural systems involving separate amygdaloid nuclei mediate different types of conditioned fear behaviour. We suggest that theories of amygdala function should take into account the roles of discrete amygdala subsystems in controlling different components of integrated emotional responses.", "corpus_id": 205028225, "score": 0 }, { "doc_id": "84831281", "title": "Spatial cognition and its neural basis in teleost fishes", "abstract": "The present review is focused on recent laboratory studies revealing that the spatial behaviour of fishes is as complex and elaborate as described in land vertebrates. In addition, the data presented here indicate that the remarkable richness and plasticity of spatial behaviour in fishes are based on learning and memory mechanisms and cognitive processes that depend on particular brain circuits, possibly homologous to those identified in mammals and birds. For example, there is evidence that the fish hippocampal pallium is essential for processing and encoding complex spatial information to form map-like representations of the environment. In contrast, body-centred orientation strategies or emotional learning are subserved by different cerebral structures, such as the optic tectum, the cerebellum or the amygdalar pallium. These results that suggest a striking similarity in some cognitive processes and their neural basis between fish and land vertebrates are consistent with the possibility that these vertebrate groups share a common basic pattern of brain and behaviour organisation inherited from a common ancestor and conserved through a long history of separate evolution.", "corpus_id": 84831281, "score": 0 }, { "doc_id": "41144358", "title": "The effects of telencephalic pallial lesions on spatial, temporal, and emotional learning in goldfish", "abstract": "In mammals, the pallial amygdala is implicated in emotional learning and memory, whereas the hippocampus is involved in spatial, contextual, or relational memory. This review presents a set of experiments aimed to study the involvement of the dorsomedial and dorsolateral telencephalon of goldfish in spatial and active avoidance learning. Results showed that (1) medial lesions impaired both acquisition and retention of conditioned avoidance response in two-way active avoidance learning experiments with stimuli overlapping (emotional factor) and with an interstimuli gap (temporal and emotional factors), and (2) the medial lesion did not affect spatial learning (spatial, contextual, or relational factors). In contrast, lateral lesions did not impair conditioned avoidance response with stimuli overlapping, but affected conditioned avoidance response with an interstimuli gap and spatial learning. These results support the presence of two differentiated memory systems in teleost fish based on discrete pallial regions: emotional (dorsomedial telencephalon) and spatial/temporal or relational (dorsolateral telencephalon). Furthermore, these functional data support the homology between the medial pallium of the teleost and the pallial amygdala of land vertebrates, and between the teleost lateral pallium and the mammalian hippocampus.", "corpus_id": 41144358, "score": 1 }, { "doc_id": "143392134", "title": "Welfare, Stress, and the Evolution of Feelings", "abstract": "Publisher Summary This chapter discusses the different kinds of feelings and considers the origin and possible function of each feeling. Each of these feelings has a biological role that complements various other anatomical, physiological, and behavioral mechanisms. All have some potential for improving fitness and most are likely to have been the subject of considerable selection pressure, but some aspects of feelings are likely to be just epiphenomena of neural mechanisms. With this view that most aspects of feelings have evolved like other biological mechanisms and that they help significantly in coping and responding, a single view of welfare as the state of an individual as regards its attempts to cope with its environment becomes clearer. Feelings are an important part of the welfare of an individual and should be assessed as well as possible. Other coping procedures and effects of the environment on the individual should also be assessed. An effect on an individual that is adverse in the long term is categorized as stress. Programs for trying to evaluate and improve welfare should combine the use of experiments to assess what is important to the individual by measuring the strengths of preferences, with monitoring studies in which feelings and other aspects of welfare are assessed more directly.", "corpus_id": 143392134, "score": 0 } ]

{ "doc_id": "2996265", "title": "Cortical Responsiveness to Nociceptive Stimuli in Patients with Chronic Disorders of Consciousness: Do C-Fiber Laser Evoked Potentials Have a Role?", "abstract": "It has been shown that the presence of Aδ-fiber laser evoked potentials (Aδ-LEP) in patients suffering from chronic disorders of consciousness (DOC), such as vegetative state (VS) and minimally conscious state (MCS), may be the expression of a residual cortical pain arousal. Interestingly, the study of C-fiber LEP (C-LEP) could be useful in the assessment of cortical pain arousal in the DOC individuals who lack of Aδ-LEP. To this end, we enrolled 38 DOC patients following post-anoxic or post-traumatic brain injury, who met the international criteria for VS and MCS diagnosis. Each subject was clinically evaluated, through the coma recovery scale-revised (CRS-R) and the nociceptive coma scale-revised (NCS-R), and electrophysiologically tested by means of a solid-state laser for Aδ-LEP and C-LEP. VS individuals showed increased latencies and reduced amplitudes of both the Aδ-LEP and C-LEP components in comparison to MCS patients. Although nearly all of the patients had both the LEP components, some VS individuals showed only the C-LEP ones. Notably, such patients had a similar NCS-R score to those having both the LEP components. Hence, we could hypothesize that C-LEP generators may be rearranged or partially spared in order to still guarantee cortical pain arousal when Aδ-LEP generators are damaged. Therefore, the residual presence of C-LEP should be assessed when Aδ-LEP are missing, since a potential pain experience should be still present in some patients, so to properly initiate, or adapt, the most appropriate pain treatment.", "corpus_id": 2996265 }

[ { "doc_id": "25010746", "title": "Pain-related middle-latency somatosensory evoked potentials in the prognosis of post anoxic coma: a preliminary report.", "abstract": "BACKGROUND\nRegarding hypoxic-ischemic encephalopathy, while the bilateral absence of N20/P25 somatosensory evoked potentials (SEPs) is considered to be the best indicator of adverse outcomes, the presence of middle latency evoked potentials (MLCEPs) is associated with a favourable neurological prognosis. The main aim of the present study was to investigate whether painful electrical stimulation might be considered a provocative test in producing MLCEPs and predictor of patient's outcomes after cardiac arrest.\n\n\nMETHODS\nRetrospective pilot study. SEPs with and without pain-related electrical stimulation in both median nerves were recorded in 17 patients with post anoxic coma after cardiac arrest. Glasgow Coma Scale, electroencephalograms, heart rate and blood pressure changes were also recorded at the same time. Three months after cardiac arrest the same measures with inclusion of Glasgow Outcome Scale Extended were also performed only in the remaining patients with severe neurological outcome. No one intervention was made.\n\n\nRESULTS\nPatients who showed MLCEPs had a good outcome, while patients without N20/P25 SEPs but with increases in blood pressure remained in a vegetative state. Patients who did not show N20/P25 SEPs and increase in blood pressure died within one week. Only one patient who showed N20/P25 SEPs was minimally conscious.\n\n\nCONCLUSION\nThese preliminary data suggest that MLCEPs elicited by painful electrical stimulation seem to be a sensitive method to predict the neurological outcome of patients in the acute phase of coma. Blood pressure response might be a prognostic physiological measure of survival in the vegetative state in patients without N20/P25 SEPs.", "corpus_id": 25010746, "score": 0 }, { "doc_id": "14142413", "title": "Cerebral processing of auditory and noxious stimuli in severely brain injured patients: Differences between VS and MCS", "abstract": "We review cerebral processing of auditory and noxious stimuli in minimally conscious state (MCS) and vegetative state (VS) patients. In contrast with limited brain activation found in VS patients, MCS patients show activation similar to controls in response to auditory, emotional and noxious stimuli. Despite an apparent clinical similarity between MCS and VS patients, functional imaging data show striking differences in cortical segregation and integration between these two conditions. However, in the absence of a generally accepted neural correlate of consciousness as measured by functional neuroimaging, clinical assessment remains the gold standard for the evaluation and management of severely brain damaged patients. This research was supported by the Fonds National de la Recherche Scientifique, (FNRS), by the Reine Elisabeth Medical Foundation, by funds of the University of Liège and the Centre Hospitalier Universitaire Sart Tilman, Liège, Belgium, and by a Tom Slick Research Award on Consciousness of the Mind Science Foundation, TX. S. Laureys and P. Maquet are Research Associate and Research Director at the FNRS.", "corpus_id": 14142413, "score": 0 }, { "doc_id": "16891079", "title": "Cortical Processing of Noxious Somatosensory Stimuli in the Persistent Vegetative State", "abstract": "The persistent vegetative state (PVS) is a devastating medical condition characterized by preserved wakefulness contrasting with absent voluntary interaction with the environment. We used positron emission tomography to assess the central processing of noxious somatosensory stimuli in the PVS. Changes in regional cerebral blood flow were measured during high-intensity electrical stimulation of the median nerve compared with rest in 15 nonsedated patients and in 15 healthy controls. Evoked potentials were recorded simultaneously. The stimuli were experienced as highly unpleasant to painful in controls. Brain glucose metabolism was also studied with [(18)F]fluorodeoxyglucose in resting conditions. In PVS patients, overall cerebral metabolism was 40% of normal values. Nevertheless, noxious somatosensory stimulation-activated midbrain, contralateral thalamus, and primary somatosensory cortex in each and every PVS patient, even in the absence of detectable cortical evoked potentials. Secondary somatosensory, bilateral insular, posterior parietal, and anterior cingulate cortices did not show activation in any patient. Moreover, in PVS patients, the activated primary somatosensory cortex was functionally disconnected from secondary somatosensory, bilateral posterior parietal, premotor, polysensory superior temporal, and prefrontal cortices. In conclusion, somatosensory stimulation of PVS patients, at intensities that elicited pain in controls, resulted in increased neuronal activity in primary somatosensory cortex, even if resting brain metabolism was severely impaired. However, this activation of primary cortex seems to be isolated and dissociated from higher-order associative cortices.", "corpus_id": 16891079, "score": 0 }, { "doc_id": "5078012", "title": "Nociceptive laser-evoked brain potentials do not reflect nociceptive-specific neural activity.", "abstract": "Brief radiant laser pulses can be used to activate cutaneous Adelta and C nociceptors selectively and elicit a number of transient brain responses [laser-evoked potentials (LEPs)] in the ongoing EEG. LEPs have been used extensively in the past 30 years to gain knowledge about the cortical mechanisms underlying nociception and pain in humans, by assuming that they reflect at least neural activities uniquely or preferentially involved in processing nociceptive input. Here, by applying a novel blind source separation algorithm (probabilistic independent component analysis) to 124-channel event-related potentials elicited by a random sequence of nociceptive and non-nociceptive somatosensory, auditory, and visual stimuli, we provide compelling evidence that this assumption is incorrect: LEPs do not reflect nociceptive-specific neural activity. Indeed, our results indicate that LEPs can be entirely explained by a combination of multimodal neural activities (i.e., activities also elicited by stimuli of other sensory modalities) and somatosensory-specific, but not nociceptive-specific, neural activities (i.e., activities elicited by both nociceptive and non-nociceptive somatosensory stimuli). Regardless of the sensory modality of the eliciting stimulus, the magnitude of multimodal activities correlated with the subjective rating of saliency, suggesting that these multimodal activities are involved in stimulus-triggered mechanisms of arousal or attentional reorientation.", "corpus_id": 5078012, "score": 1 }, { "doc_id": "45893870", "title": "Brain generators of laser-evoked potentials: from dipoles to functional significance", "abstract": "In this work we review data on cortical generators of laser-evoked potentials (LEPs) in humans, as inferred from dipolar modelling of scalp EEG/MEG results, as well as from intracranial data recorded with subdural grids or intracortical electrodes. The cortical regions most consistently tagged as sources of scalp LERs are the suprasylvian region (parietal operculum, SII) and the anterior cingulate cortex (ACC). Variability in opercular sources across studies appear mainly in the anterior-posterior direction, where sources tend to follow the axis of the Sylvian fissure. As compared with parasylvian activation described in functional pain imaging studies, LEP opercular sources tended to cluster at more superior sites and not to involve the insula. The existence of suprasylvian opercular LEPs has been confirmed by both epicortical (subdural) and intracortical recordings. In dipole-modelling studies, these sources appear to become active less than 150 ms post-stimulus, and remain in action for longer than opercular responses recorded intracortically, thus suggesting that modelled opercular dipoles reflect a \"lumped\" activation of several sources in the suprasylvian region, including both the operculum and the insula. Participation of SI sources to explain LEP scalp distribution remains controversial, but evidence is emerging that both SI and opercular sources may be concomitantly activated by laser pulses, with very similar time courses. Should these data be confirmed, it would suggest that a parallel processing in SI and SII has remained functional in humans for noxious inputs, whereas hierarchical processing from SI toward SII has emerged for other somatosensory sub-modalities. The ACC has been described as a source of LEPs by virtually all EEG studies so far, with activation times roughly corresponding to scalp P2. Activation is generally confined to area 24 in the caudal ACC, and has been confirmed by subdural and intracortical recordings. The inability of most MEG studies to disclose such ACC activity may be due to the radial orientation of ACC currents relative to scalp. ACC dipole sources have been consistently located between the VAC and VPC lines of Talairach's space, near to the cingulate subsections activated by motor tasks involving control of the hand. Together with the fact that scalp activities at this latency are very sensitive to arousal and attention, this supports the hypothesis that laser-evoked ACC activity may underlie orienting reactions tightly coupled with limb withdrawal (or control of withdrawal). With much less consistency than the above-mentioned areas, posterior parietal, medial temporal and anterior insular regions have been occasionally tagged as possible contributors to LEPs. Dipoles ascribed to medial temporal lobe may be in some cases re-interpreted as being located at or near the insular cortex. This would make sense as the insular region has been shown to respond to thermal pain stimuli in both functional imaging and intracranial EEG studies.", "corpus_id": 45893870, "score": 0 }, { "doc_id": "207448180", "title": "Pain in prolonged disorders of consciousness: Laser evoked potentials findings in patients with vegetative and minimally conscious states", "abstract": "Abstract Introduction: Pain perception is currently an open question in patients suffering from prolonged disorders of consciousness. The aim of the present study was to examine nociceptive specific laser evoked responses (LEPs) in view of long-latency evoked potentials by non-painful electrical stimuli (SEPs) and auditory mismatch negativity (MM). Methods: Three vegetative state (VS), four minimal Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, stimulating the dorsum of the right hand by noxious laser and innocuous electrical stimulus, according to normal controls subjective rating. An auditory paradigm for MM was also employed. Results: The MM was present in all patients. The LEP vertex complex was recognizable in all cases, with a significant latency increase of both N2 and P2 which displayed changes of topographic representation. Late SEPs were absent in all patients except in one MCS case, who showed a significant N2 and P2 latency increase. Discussion: The results may suggest that high relevant stimuli may be processed even in patients with severe brain damage. Larger series and multimodal approaches may contribute to confirm that cortical arousal toward pain salience may be a primary function for life persistence.", "corpus_id": 207448180, "score": 1 }, { "doc_id": "15553435", "title": "Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state", "abstract": "Aims: Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient visual, acoustic, somatosensory electric non-nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation. Methods: Five Vegetative State (VS), 4 Minimally Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 s. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2) vertex complex in the 500 ms post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R) and Coma Recovery Scale (CRS-R) for clinical evaluation of pain perception and consciousness impairment. Results: The laser evoked potentials (LEPs) were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. Discussion: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the degree of cognitive and motor behavior recovery. This underlines the importance of considering the potential experience of pain also in patients in vegetative state and to appropriately assess a possible treatment also in those patients.", "corpus_id": 15553435, "score": 1 }, { "doc_id": "14351291", "title": "Determinants of laser-evoked EEG responses: pain perception or stimulus saliency?", "abstract": "Although laser-evoked electroencephalographic (EEG) responses are increasingly used to investigate nociceptive pathways, their functional significance remains unclear. The reproducible observation of a robust correlation between the intensity of pain perception and the magnitude of the laser-evoked N1, N2, and P2 responses has led some investigators to consider these responses a direct correlate of the neural activity responsible for pain intensity coding in the human cortex. Here, we provide compelling evidence to the contrary. By delivering trains of three identical laser pulses at four different energies, we explored the modulation exerted by the temporal expectancy of the stimulus on the relationship between intensity of pain perception and magnitude of the following laser-evoked brain responses: the phase-locked N1, N2, and P2 waves, and the non-phase-locked laser-induced synchronization (ERS) and desynchronization (ERD). We showed that increasing the temporal expectancy of the stimulus through stimulus repetition at a constant interstimulus interval 1) significantly reduces the magnitudes of the laser-evoked N1, N2, P2, and ERS; and 2) disrupts the relationship between the intensity of pain perception and the magnitude of these responses. Taken together, our results indicate that laser-evoked EEG responses are not determined by the perception of pain per se, but are mainly determined by the saliency of the eliciting nociceptive stimulus (i.e., its ability to capture attention). Therefore laser-evoked EEG responses represent an indirect readout of the function of the nociceptive system.", "corpus_id": 14351291, "score": 0 }, { "doc_id": "9304986", "title": "Evidence of a specific spinal pathway for the sense of warmth in humans.", "abstract": "While research on human sensory processing shows that warm input is conveyed from the periphery by specific, unmyelinated primary sensory neurons, its pathways in the central nervous system (CNS) remain unclear. To gain physiological information on the spinal pathways that convey warmth or nociceptive sensations, in 15 healthy subjects, we studied the cerebral evoked responses and reaction times in response to laser stimuli selectively exciting Adelta nociceptors or C warmth receptors at different levels along the spine. To minimize the conduction distance along the primary sensory neuron, we directed CO(2)-laser pulses to the skin overlying the vertebral spinous processes. Using brain source analysis of the evoked responses with high-resolution electroencephalography and a realistic model of the head based on individual magnetic resonance imaging scans, we also studied the cortical areas involved in the cerebral processing of warm and nociceptive inputs. The activation of C warmth receptors evoked cerebral potentials with a main positive component peaking at 470-540 ms, i.e., a latency clearly longer than that of the corresponding wave yielded by Adelta nociceptive input (290-320 ms). Spinal neurons activated by the warm input had a slower conduction velocity (2.5 m/s) than the nociceptive spinal neurons (11.9 m/s). Brain source analysis of the cerebral responses evoked by the Adelta input yielded a very strong fit for one single generator in the mid portion of the cingulate gyrus; the warmth-related responses were best explained by three generators, one within the cingulate and two in the right and left opercular-insular cortices. Our results support the existence of slow-conducting second-order neurons specific for the sense of warmth.", "corpus_id": 9304986, "score": 1 }, { "doc_id": "21683711", "title": "Are the processes reflected by late and ultra-late laser evoked potentials specific of nociception?", "abstract": "Publisher Summary This chapter reviews different hypotheses and their consequences regarding the functional significance of both late and ultra-late laser-evoked brain potentials (LEPs). An alternate hypothesis is presented, challenging the nociceptive specificity that is often ascribed to LEPs. Activation of Aδ- and C-fiber nociceptors produces a sensation of first pain and second pain without necessarily evoking late and ultra-late LEP responses. This observation indicates that the processes underlying LEPs may not be directly related to the perception of nociceptive input. Occurrence and amplitude of LEPs seem strongly conditioned by the salience of the evoking afferent input, suggesting that LEPs reflect processes related to mechanisms of involuntary attentional capture. The morphological, topographical, and behavioral similarities between N2 and P2 LEP components and the late endogenous vertex potentials that can be evoked by any kind of sensory stimulation suggests that these “vertex” components reflect nonspecific processes common to all sensory modalities.", "corpus_id": 21683711, "score": 0 }, { "doc_id": "2691014", "title": "Novelty is not enough: laser-evoked potentials are determined by stimulus saliency, not absolute novelty.", "abstract": "Event-related potentials (ERPs) elicited by transient nociceptive stimuli in humans are largely sensitive to bottom-up novelty induced, for example, by changes in stimulus attributes (e.g., modality or spatial location) within a stream of repeated stimuli. Here we aimed 1) to test the contribution of a selective change of the intensity of a repeated stimulus in determining the magnitude of nociceptive ERPs, and 2) to dissect the effect of this change of intensity in terms of \"novelty\" and \"saliency\" (an increase of stimulus intensity is more salient than a decrease of stimulus intensity). Nociceptive ERPs were elicited by trains of three consecutive laser stimuli (S1-S2-S3) delivered to the hand dorsum at a constant 1-s interstimulus interval. Three, equally spaced intensities were used: low (L), medium (M), and high (H). While the intensities of S1 and S2 were always identical (L, M, or H), the intensity of S3 was either identical (e.g., HHH) or different (e.g., MMH) from the intensity of S1 and S2. Introducing a selective change in stimulus intensity elicited significantly larger N1 and N2 waves of the S3-ERP but only when the change consisted in an increase in stimulus intensity. This observation indicates that nociceptive ERPs do not simply reflect processes involved in the detection of novelty but, instead, are mainly determined by stimulus saliency.", "corpus_id": 2691014, "score": 0 }, { "doc_id": "44426002", "title": "Scalp topography of ultralate (C-fibres) evoked potentials following thulium YAG laser stimuli to tiny skin surface areas in humans", "abstract": "AIM\nTo investigate (1) the scalp topography of ultralate laser evoked potentials (LEPs) related to C-fibre activation, which can directly be obtained by thulium YAG (Tm YAG) laser stimulation of tiny skin surface areas (about 0.23 mm(2)) and (2) the influence of the performance of a motor task on ultralate LEPs.\n\n\nMETHODS\nLaser stimuli were applied to the dorsum of the left hand. LEPs were recorded with 58 scalp electrodes from 9 healthy subjects in two different conditions, with and without a reaction time (RT) task (press a button upon detection).\n\n\nRESULTS\nOn high resolution electroenchephalogram recordings, ultralate LEPs were characterized by a broad positive component (peak latency: 1133+/-91 ms) with maximum amplitude about the vertex. Moreover, the performance of a RT task had no influence on latency, amplitude and topographical patterns of two maps chosen at the positive peak latency in ultralate LEPs. Nevertheless, a negative inflexion (latency 1300 ms) appeared after the positive component in the task condition possibly reflecting movement-related potentials.\n\n\nCONCLUSION\nTm YAG laser stimulation of tiny skin surface areas allows recording the dynamic scalp topography of ultralate (C-fibres) LEPs, with or without the performance of a RT task.", "corpus_id": 44426002, "score": 0 }, { "doc_id": "22249783", "title": "Attention-related modifications of ultra-late CO2 laser evoked potentials to human trigeminal nerve stimulation", "abstract": "Our study aimed at investigating the scalp topography of ultra-late CO(2) laser evoked potentials (LEPs), which are related to C fiber activation, and at exploring the effect of attention deviation on ultra-late LEPs. Brain responses to non-painful CO(2) laser stimuli were recorded in ten healthy subjects in three different conditions: (i) neutral condition in which subjects did not have any task; (ii) distraction condition in which subjects were asked to perform a mathematical task; and (iii) attention condition in which subjects had to count the number of stimuli. In all subjects, also A fiber-related late LEPs were recorded after painful CO(2) laser stimulation. The ultra-late LEPs in attention condition included an earlier negative potential (ultra-late N1) in the contralateral temporal region and a simultaneous frontal positive response (ultra-late P1). Later, a vertex biphasic component (ultra-late N2a and ultra-late P2) was identifiable. The vertex ultra-late LEP amplitude was significantly decreased in both neutral and distraction condition. Ultra-late LEPs showed a longer latency than late LEPs, but the scalp distributions of both ultra-late and late LEPs were very similar, thus suggesting that the same cerebral areas may be involved in their generation. Since attention deviations have a strong effect on ultra-late LEP amplitude, the subject's attention should be addressed to CO(2) laser stimuli when ultra-late LEPs are used for clinical purposes.", "corpus_id": 22249783, "score": 0 }, { "doc_id": "105489", "title": "Stimulus novelty, and not neural refractoriness, explains the repetition suppression of laser-evoked potentials.", "abstract": "Brief radiant laser pulses selectively activate skin nociceptors and elicit transient brain responses (laser-evoked potentials [LEPs]). When LEPs are elicited by pairs of stimuli (S1-S2) delivered at different interstimulus intervals (ISIs), the S2-LEP is strongly reduced at short ISIs (250 ms) and progressively recovers at longer ISIs (2,000 ms). This finding has been interpreted in terms of order of arrival of nociceptive volleys and refractoriness of neural generators of LEPs. However, an alternative explanation is the modulation of another experimental factor: the novelty of the eliciting stimulus. To test this alternative hypothesis, we recorded LEPs elicited by pairs of nociceptive stimuli delivered at four ISIs (250, 500, 1,000, 2,000 ms), using two different conditions. In the constant condition, the ISI was identical across the trials of each block, whereas in the variable condition, the ISI was varied randomly across trials and single-stimulus trials were intermixed with paired trials. Therefore the time of occurrence of S2 was both less novel and more predictable in the constant than in the variable condition. In the constant condition, we observed a significant ISI-dependent suppression of the biphasic negative-positive wave (N2-P2) complex of the S2-LEP. In contrast, in the variable condition, the S2-LEP was completely unaffected by stimulus repetition. The pain ratings elicited by S2 were not different in the two conditions. These results indicate that the repetition-suppression of the S2-LEP is not due to refractoriness in nociceptive afferent pathways, but to a modulation of novelty and/or temporal predictability of the eliciting stimulus. This provides further support to the notion that stimulus saliency constitutes a crucial determinant of LEP magnitude and that a significant fraction of the brain activity time-locked to a brief and transient sensory stimulus is not directly related to the quality and the intensity of the corresponding sensation, but to bottom-up attentional processes.", "corpus_id": 105489, "score": 0 }, { "doc_id": "11350308", "title": "Recommendations for the clinical use of somatosensory-evoked potentials", "abstract": "The International Federation of Clinical Neurophysiology (IFCN) is in the process of updating its Recommendations for clinical practice published in 1999. These new recommendations dedicated to somatosensory-evoked potentials (SEPs) update the methodological aspects and general clinical applications of standard SEPs, and introduce new sections dedicated to the anatomical-functional organization of the somatosensory system and to special clinical applications, such as intraoperative monitoring, recordings in the intensive care unit, pain-related evoked potentials, and trigeminal and pudendal SEPs. Standard SEPs have gained an established role in the health system, and the special clinical applications we describe here are drawing increasing interest. However, to prove clinically useful each of them requires a dedicated knowledge, both technical and pathophysiological. In this article we give technical advice, report normative values, and discuss clinical applications.", "corpus_id": 11350308, "score": 0 }, { "doc_id": "24466809", "title": "Coma Recovery Scale-Revised: evidentiary support for hierarchical grading of level of consciousness.", "abstract": "OBJECTIVE\nTo investigate the neurobehavioral pattern of recovery of consciousness as reflected by performance on the subscales of the Coma Recovery Scale-Revised (CRS-R).\n\n\nDESIGN\nRetrospective item response theory (IRT) and factor analysis.\n\n\nSETTING\nInpatient rehabilitation facilities.\n\n\nPARTICIPANTS\nRehabilitation inpatients (N=180) with posttraumatic disturbance in consciousness who participated in a double-blinded, randomized, controlled drug trial.\n\n\nINTERVENTIONS\nNot applicable.\n\n\nMAIN OUTCOME MEASURES\nScores on CRS-R subscales.\n\n\nRESULTS\nThe CRS-R was found to fit factor analytic models adhering to the assumptions of unidimensionality and monotonicity. In addition, subscales were mutually independent based on residual correlations. Nonparametric IRT reaffirmed the finding of monotonicity. A highly constrained confirmatory factor analysis model, which imposed equal factor loadings on all items, was found to fit the data well and was used to estimate a 1-parameter IRT model.\n\n\nCONCLUSIONS\nThis study provides evidence of the unidimensionality of the CRS-R and supports the hierarchical structure of the CRS-R subscales, suggesting that it is an effective tool for establishing diagnosis and monitoring recovery of consciousness after severe traumatic brain injury.", "corpus_id": 24466809, "score": 0 }, { "doc_id": "6986367", "title": "A sensitive scale to assess nociceptive pain in patients with disorders of consciousness", "abstract": "Objective To determine the sensitivity of the Nociception Coma Scale (NCS), the first scale developed to assess nociceptive pain in vegetative state and minimally conscious state patients, in comparing behavioural changes in response to noxious versus non-noxious stimulation. Methods The NCS was administered to assess patients' responses in three conditions: (1) baseline (observation of spontaneous behaviours), (2) non-noxious/tactile stimulation (taps on the patient's shoulder), and (3) noxious stimulation (pressure on the nail bed). Results We included 64 patients (27 vegetative state and 37 minimally conscious state; age range 20–82 years; 22 traumatic brain injury; 21 in the acute stage). The NCS total scores and subscores (motor, verbal and facial) were higher for the noxious versus the non-noxious stimulation conditions. We did not observe a difference between the non-noxious and the noxious stimulation conditions for the visual subscale. We also found a NCS cut-off value of 4 differentiating the patients receiving a noxious stimulation from patients receiving a non-noxious stimulation. The exclusion of the visual subscale increased the cut-off sensitivity (from 46% to 73%; specificity of 97% and accuracy of 85%). Conclusion We propose a new version of the NCS excluding the visual subscale, the NCS-R, which constitutes a highly sensitive tool to assess responses to nociceptive pain in severely brain injured patients.", "corpus_id": 6986367, "score": 0 }, { "doc_id": "32830772", "title": "The JFK coma recovery scale—revised", "abstract": "The JFK Coma Recovery Scale (CRS) was developed to help characterise and monitor patients functioning at Rancho Levels I–IV and has been used widely in both clinical and research settings within the US and Europe. The CRS was recently revised to address a number of concerns emanating from our own clinical experience with the scale, feedback from users and researchers as well as the results of Rasch analyses. Additionally, the CRS did not include all of the behavioural criteria necessary to diagnose the minimally conscious state (MCS), thereby limiting diagnostic utility. The revised JFK Coma Recovery Scale (CRS-R) includes addition of new items, merging of items found to be statistically similar, deletion or modification of items showing poor fit with the scale's underlying construct, renaming of items, more stringent scoring criteria, and quantification of elicited behaviours to improve accuracy of rating. Psychometric properties of the CRS-R appear to meet standards for measurement and evaluation tools for use in clinical and research settings, and diagnostic application suggests that the scale is capable of discriminating patients in the minimally conscious state from those in the vegetative state. Individuals interested in obtaining a copy of the JFK CRS-R and administration and scoring procedures are referred to the authors.", "corpus_id": 32830772, "score": 0 }, { "doc_id": "10448329", "title": "Direct isolation of ultra-late (C-fibre) evoked brain potentials by CO2 laser stimulation of tiny cutaneous surface areas in man", "abstract": "In this study, it is reported that CO2 laser heat stimulation of tiny skin surface area (0.15 mm2) provides a unique method to directly and selectively activate C-fibre as assessed by the ultra-late brain potentials (peak latencies: N810, P996) evoked consistently across a set of stimulus energy levels. On a larger surface area (15.5 mm2), low energy stimulation also resulted in minute ultra-late potential, while higher intensities induced only late potentials related to A-delta fibre activity (peak latencies: N247, P394). The selective activation of C afferent sensory terminals in the skin by stimulation of tiny surface area is explained by their relative high density and lower activation threshold.", "corpus_id": 10448329, "score": 1 }, { "doc_id": "18486576", "title": "Clinical usefulness of laser-evoked potentials", "abstract": "In contrast to the function of the visual or auditory pathways which are electrophysiologically accessible by visual or auditory evoked potentials, the somatosensory pathway cannot be investigated as a whole by conventional somatosensory evoked potentials (SEP), because these only reflect function of large fibers, dorsal columns, medial lemniscus and their thalamo-cortical projections mediating sensations like touch and vibration. The other half of the somatosensory system, signaling temperature and pain perception, uses a different set of afferents and different central pathways, the function of which is accessible by laser-evoked potentials (LEPs). LEP can document lesions of the spinothalamic tract and (lateral) brainstem and of thalamo-cortical projections conveying thermo-nociceptive signals. In the peripheral nerve, LEP can help distinguish between large and small fiber neuropathies. The rapid heating of the skin by infrared laser pulses can easily be applied to non-glabrous skin in any dermatome. In recent years, many clinical studies have demonstrated that LEP can supply evidence for establishing clinical diagnoses when deficits of the nociceptive system are present. This review outlines principles and recording techniques for LEP in patients and compiles typical LEP findings in patients with lesions due to different diseases at various levels of the nociceptive pathways. Limitations for the use of LEP are pointed out, too, like the uncertainty of lesion location along these pathways and the fact that LEP can reliably show correlates of reduced nociceptive function but only rarely of enhanced transmission (like in hyperalgesia).", "corpus_id": 18486576, "score": 0 }, { "doc_id": "11386865", "title": "Statistically robust measurement of evoked response onset latencies", "abstract": "Onset latencies of evoked responses are useful for determining delays in sensory pathways and for indicating spread of activity between brain areas, therefore inferring causality. Previous studies have applied several different methods and parameters for detecting onsets, mainly utilizing thresholds based on the mean and standard deviation (SD) of the pre-stimulus \"baseline\" time window, or using t-tests of group data to determine when the response first differs significantly from the baseline. However, these methods are not statistically robust, have low power when the baseline data are not normally distributed, and are heavily influenced by outliers in the baseline. Here, we examine using a modified boxplot method known as the \"median rule\" for determining onset latencies. This rule makes no assumptions about the baseline distribution, is resistant to outliers, and can be applied to individual level data therefore allowing intersubject and interregional comparisons. We first show with simulations that the median rule is significantly less sensitive to outliers in the baseline than the SD method. We then use simulations to demonstrate the effect of skewness on onset latencies. Finally, we use magnetoencephalography (MEG) to show that the median rule can be easily applied to real data and gives reasonable results. In most situations the different methods give similar results, which enhances comparability across studies, but in data sets with a high noise level there is a clear advantage to using a statistically robust method. In conclusion, the median rule is an excellent method for estimating onset latencies in evoked responses.", "corpus_id": 11386865, "score": 0 }, { "doc_id": "2032474", "title": "NeuPSIG guidelines on neuropathic pain assessment", "abstract": "&NA; This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes. Measurement of trigeminal reflexes mediated by A‐beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser‐evoked potentials is useful for assessing function of the A‐delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction. The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended.", "corpus_id": 2032474, "score": 0 }, { "doc_id": "129177", "title": "Unmyelinated trigeminal pathways as assessed by laser stimuli in humans.", "abstract": "Laser pulses excite superficial free nerve endings innervated by small-myelinated (Adelta) and unmyelinated (C) fibres. Whereas laser-evoked scalp potentials (LEPs) are now reliably used to assess function of the Adelta-fibre nociceptive pathways in patients with peripheral or central lesions, the selective activation of C-fibre receptors and recording of the related brain potentials remain difficult. To investigate trigeminal C-fibre function, we directed laser pulses to the facial skin and studied sensory perception and scalp evoked potentials related to Adelta- or C-fibre activation in healthy humans and patients--one having a bilateral facial palsy, two a trigeminal neuropathy, and two a Wallenberg syndrome. We also measured afferent conduction velocity and, with source analysis, studied the brain generators. Whereas laser pulses of low intensity and small irradiated area elicited pinprick sensations and standard Adelta-LEPs, laser pulses of very-low intensity and large irradiated area elicited warmth sensations and scalp potentials with a latency compatible with C-fibre conduction (negative wave 280 ms, positive wave 380 ms); the estimated conduction velocity was 1.2 m/s. The main waves of the scalp potentials originated from the anterior cingulate gyrus; they were preceded by activity in the opercular region and followed by activity in the insular region. The patient with bilateral facial palsy, who had absent trigeminal-facial reflexes, had normal Adelta- and C-related scalp potentials; the patients with trigeminal neuropathy, characterized by loss of myelinated and sparing of unmyelinated fibres, had absent Adelta- but normal C-related potentials; and the patients with Wallenberg syndrome had absent Adelta- and C-related potentials. We conclude that laser pulses with appropriate characteristics evoke brain potentials related to the selective activation of trigeminal nociceptive Adelta or thermal C fibres. The trigeminal territory yields rewarding LEP findings owing to the high density of thermal receptors and, because the short conduction distance, minimizes the problem of signal dispersion along slow-conducting unmyelinated afferents. The opercular-insular region and the cingulate gyrus are involved in the processing of C-fibre trigeminal inputs. The method we describe may prove useful in patients with lesions affecting the trigeminal thermal pain pathways.", "corpus_id": 129177, "score": 1 }, { "doc_id": "207307532", "title": "Pathophysiology of pain in postherpetic neuralgia: A clinical and neurophysiological study", "abstract": "Abstract Postherpetic neuralgia is an exceptionally drug‐resistant neuropathic pain. To investigate the pathophysiological mechanisms underlying postherpetic neuralgia we clinically investigated sensory disturbances, pains and itching, with an 11‐point numerical rating scale in 41 patients with ophthalmic postherpetic neuralgia. In all the patients we recorded the blink reflex, mediated by non‐nociceptive myelinated Aβ‐fibers, and trigeminal laser evoked potentials (LEPs) related to nociceptive myelinated Aδ‐ and unmyelinated C‐fiber activation. We also sought possible correlations between clinical sensory disturbances and neurophysiological data. Neurophysiological testing yielded significantly abnormal responses on the affected side compared with the normal side (P < 0.001). The blink reflex delay correlated with the intensity of paroxysmal pain, whereas the Aδ‐ and C‐LEP amplitude reduction correlated with the intensity of constant pain (P < 0.01). Allodynia correlated with none of the neurophysiological data. Our study shows that postherpetic neuralgia impairs all sensory fiber groups. The neurophysiological‐clinical correlations suggest that constant pain arises from a marked loss of nociceptive afferents, whereas paroxysmal pain is related to Aβ‐fiber demyelination. These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia.", "corpus_id": 207307532, "score": 0 }, { "doc_id": "23490880", "title": "CO2 laser radiant heat pulses activate C nociceptors in man", "abstract": "Cerebral potentials evoked by noxious CO2 laser stimuli in man have been referred to nociceptive Aδ units. This paper shows 1) that ultra short (5–50 ms) high power (≤ 50 W) CO2 laser skin stimuli are able to activate nociceptive C units in man, and 2) that these C nociceptors have to be assumed to terminate in the very superficial skin layer (≤300 μm depth).", "corpus_id": 23490880, "score": 0 }, { "doc_id": "7476970", "title": "Clinical evaluation criteria for the assessment of impaired pain sensitivity by thulium-laser evoked potentials", "abstract": "OBJECTIVES\nCortical potentials evoked by carbon dioxide laser pulses have been applied in clinical practice to study nociceptive pathways for several years. In this study, we evaluate the properties of an infrared laser (thulium-YAG) with a penetration depth in the skin that matches the intracutaneous depth of nociceptors.\n\n\nMETHODS\nTemperature measurements and modelling showed that the thulium laser generates painful intracutaneous temperatures with less surface heating than the carbon dioxide laser and with no side effects (up to 600 mJ pulse energy). To develop clinical evaluation criteria, laser-evoked potentials (LEPs) were recorded from 3 midline positions (Fz, Cz, Pz) versus linked earlobes in 23 healthy subjects. Within a session, two skin areas were studied twice in a balanced sequence using randomized interstimulus intervals and two intensities in randomized order.\n\n\nRESULTS\nAfter hand and foot stimulation with 540 mJ pulses, all subjects showed reproducible biphasic vertex potential, consisting of a negativity (hand: 210 ms, foot: 250 ms) and a positivity (hand: 330 ms, foot: 380 ms). Mean habituation of the vertex potential amplitude across runs was 25% (hand) or 16% (foot); due to the balanced sequence it did not affect the other comparisons. Following foot stimulation, peak latencies were significantly longer (by 40-50 ms) and amplitudes were significantly smaller than following hand stimulation (22.5+/-6.7 vs. 30.3+/-10.9 microV, mean+/-SD). Using 2. 5 standard deviations from the mean as a cut-off, absolute normative values were determined for peak latencies and amplitudes. In addition, relative normative values were determined for paired comparisons (hand-hand, foot-foot, hand-foot).\n\n\nCONCLUSIONS\nThe thulium-YAG laser is a useful tool for assessment of impaired pain sensitivity. Representative case reports illustrate that unlike for early SEP components, the most frequent LEP abnormalities were amplitude differences.", "corpus_id": 7476970, "score": 0 }, { "doc_id": "43024160", "title": "How do we selectively activate skin nociceptors with a high power infrared laser? Physiology and biophysics of laser stimulation", "abstract": "This review presents and discusses the leading arguments justifying the use of high power laser stimulators to explore the nociceptive system. To grasp the particularity of such stimulators, fundamentals concerning the interaction of low-energy radiation with the skin will be recalled and focused on the optimal match between the wavelength of the emitting source and the thermophysical properties of the skin. This knowledge shall allow us to discuss critical characteristics of laser stimulators. Study of the cutaneous spectrum of receptors showed that laser stimulators allow the selective activation of A(delta) and C-fiber nociceptors. We will present different methods, which increase the selectivity of the laser stimulation, restricting the activation to isolated C-fiber nociceptors. These methods open new perspectives in the study of the cerebral processing of signals ascending through A(delta) and/or C nociceptors and should contribute to a better understanding of their central interaction and integration in normal and pathological states.", "corpus_id": 43024160, "score": 0 }, { "doc_id": "10255143", "title": "Evoked potentials to nociceptive stimuli delivered by CO2 or Nd:YAP lasers", "abstract": "OBJECTIVE\nThis study compares the amplitude, latency, morphology, scalp topography and intracranial generators of laser-evoked potentials (LEPs) to CO(2) and Nd:YAP laser stimuli.\n\n\nMETHODS\nLEPs were assessed in 11 healthy subjects (6 men, mean age 39+/-10 years) using a 32-channel acquisition system. Laser stimuli were delivered on the dorsum of both hands (intensity slightly above pain threshold), and permitted to obtain lateralised (N1) and vertex components (N2-P2) with similar scalp distribution for both types of lasers.\n\n\nRESULTS\nThe N1-YAP had similar latencies but significantly higher amplitudes relative to N1-CO(2). The N2-P2 complex showed earlier latencies, higher amplitudes (N2) and more synchronised responses when using Nd:YAP stimulation. The distribution of intracranial generators assessed with source localization analyses (sLORETA) was similar for Nd:YAP and CO(2) lasers. The insular, opercular, and primary sensorimotor cortices were active during the N1 time-window, whereas the anterior midcingulate, supplementary motor areas and mid-anterior insulae were active concomitant to the N2-P2 complex.\n\n\nCONCLUSIONS\nEarlier latencies and larger amplitudes recorded when using Nd:YAP pulses suggest a more synchronized nociceptive afferent volley with this type of laser.\n\n\nSIGNIFICANCE\nThis, together with its handy utilization due to optic fibre transmission, may favour the use of Nd:YAP lasers in clinical settings.", "corpus_id": 10255143, "score": 0 }, { "doc_id": "19065693", "title": "Aδ nociceptor response to laser stimuli: selective effect of stimulus duration on skin temperature, brain potentials and pain perception", "abstract": "OBJECTIVE\nTo disclose a possible effect of duration of pulsed laser heat stimuli on Adelta nociceptor responses, skin temperature profiles, brain evoked potentials and pain perception.\n\n\nMETHODS\nWe used a laser stimulator which works in the millisecond range and allows us to change the duration of the pulse while keeping the total energy of the stimulus constant. In 10 healthy volunteers, we measured the intensity of perceived pain with a 0-10 scale and the latency and amplitude of the early N1 and late N2 components of the scalp potentials evoked by laser pulses of equal energy and three different stimulus durations (2, 10, and 20 ms). Using a specifically developed pyrometer with a temporal resolution lower than 1 ms we also measured stimulus-induced changes of skin temperature.\n\n\nRESULTS\nStimulus duration significantly influenced temperature rise times, pain perception, and brain potentials. Shorter stimulus durations yielded steeper slopes in the skin temperature profiles and higher pain ratings, shortened the latency of the N1 and N2 components, and increased the amplitude of N1.\n\n\nCONCLUSIONS AND SIGNIFICANCE\nThe shorter stimulus duration shortens receptor activation times and yields a more synchronous afferent volley, thus providing a stronger spatial-temporal summation at central synapses that enhances intensity of first pain and brain potentials. This may prove useful in clinical applications.", "corpus_id": 19065693, "score": 0 }, { "doc_id": "13933573", "title": "Human Brain Responses to Concomitant Stimulation of Aδ and C Nociceptors", "abstract": "Intense radiant heat pulses concomitantly activate Aδ- and C-fiber skin nociceptors, and elicit a typical double sensation: an initial Aδ-related pricking pain is followed by a C-related prolonged burning sensation. It has been repeatedly reported that C-fiber laser-evoked potentials (C-LEPs) become detectable only when the concomitant activation of Aδ-fibers is avoided or reduced. Given that the saliency of the eliciting stimulus is a major determinant of LEPs, one explanation for these observations is that the saliency of the C-input is smaller than that of the preceding Aδ-input. However, even if the saliency of the C-input is reduced because of the preceding Aδ-input, a C-LEP should still be visible even when preceded by an Aδ-LEP response. Here we tested this hypothesis by applying advanced signal processing techniques (peak alignment and time-frequency decomposition) to electroencephalographic data collected in two experiments conducted in 34 and 96 healthy participants. We show that, when using optimal stimulus parameters (delivering >80 stimuli within a small skin territory), C-LEPs can be reliably detected in most participants. Importantly, C-LEPs are observed even when preceded by Aδ-LEPs, both in average waveforms and single trials. By providing quantitative information about several response properties of C-LEPs (latency jitter, stimulus-response and perception–response functions, dependency on stimulus repetitions and stimulated area), these results define optimal parameters to record C-LEPs simply and reliably. These findings have important clinical implications for assessing small-fiber function in neuropathies and neuropathic pain.", "corpus_id": 13933573, "score": 0 }, { "doc_id": "44267261", "title": "Laser-evoked potential abnormalities in central pain patients: the influence of spontaneous and provoked pain.", "abstract": "We recorded laser-evoked cortical potentials (LEPs) in 54 consecutive patients presenting with unilateral neuropathic central pain (n = 42) or with lateralized pain of non-organic origin (n = 12). A number of cases in each group had superimposed hyperalgesia or allodynia. In patients with central pain, LEPs were significantly attenuated after stimulation over the painful territory, relative to stimulation of the homologous normal territory. LEP attenuation concerned not only patients with decreased pain/heat sensation, but also those with allodynia or hyperalgesia to laser pulses. In contrast, LEPs were never attenuated in patients with non-organic forms of pain, in whom LEPs could even be enhanced to stimulation of the painful territory. Increased responses in non-organic pain were a reminder of the cognitive modulation observed in normal subjects who direct attention to a laser stimulus. Enhanced LEPs never accompanied truly neuropathic hyperalgesia or allodynia. In central pain patients with exclusively spontaneous pain, LEP attenuation was more pronounced than that observed in those with allodynia and hyperalgesia. Patients with allodynia also presented occasionally ultra-late responses (>700 ms) to stimulation of the painful side. The hypothesis that such responses may reflect activation of a slow conducting 'medial' pain system is discussed. We conclude that, as currently recorded, LEPs essentially reflect the activity of a 'lateral' pain system subserved at the periphery by rapidly conducting A-delta fibres. They are useful to document the sensorial deficits (deafferentation) leading to neuropathic pain syndromes. Conversely, in the case of deafferentation, they fail to index adequately the affective aspects of pain sensation. On practical grounds, chronic pain coupled with reduced LEPs substantiates the diagnosis of neuropathic pain, whereas the finding of normal or enhanced LEPs to stimulation of a painful territory suggests the integrity of pain pathways, and does not support a neuropathic pathophysiology. In neuropathic cases, partial LEP preservation might increase the probability of developing provoked pain (allodynia/hyperalgesia). The possible predictive value of this phenomenon, when observed before the development of pain, remains to be demonstrated. In selected contexts (pain sine materia, non-organic anaesthesia), normal or enhanced LEPs may support a psychogenic participation in the syndrome.", "corpus_id": 44267261, "score": 0 }, { "doc_id": "27403210", "title": "The medial pain system, cingulate cortex, and parallel processing of nociceptive information.", "abstract": "Nociceptive information in the cerebral cortex is thought to be processed according to discriminative properties, including localization and intensity, and affective associations. Stimulus localization is assessed mainly in somatosensory and posterior parietal cortices, while affective responses are processed in limbic regions. It has been known for four decades that ablations of anterior cingulated cortex (ACC) and its underlying white matter, the cingulum bundle, reduce or abolish affective responses to noxious stimuli, while sensory localization remains intact. Cingulate cortex forms a cingulum around the genual, dorsal, and splenial parts of the corpus callosum. The human cingulate sulci can form single or double parallel patterns that make averaging across cases difficult in functional imaging studies. The multiple sulcal patterns are related in turn to different depths with the single cingulated sulcus having the greatest depth of more than 1.5 cm. In order to expedite conversations about cingulate cortex, the cingulated gyrus is routinely divided into four regions that have unique cytoarchitectures, connections, and functions. The four regions and associated areas are as follows: perigenual areas 25, 24, and 32; midcingulate areas 24’ and 32’; posterior areas 23 and 31; retrosplenial areas 29 and 30. Since early distinctions between anterior and posterior cingulated cortices are not adequate for either structural or functional studies, the designation of a midcingulate region provides a simple regional designation to avoid such concepts as a posterior anterior cingulate cortex.", "corpus_id": 27403210, "score": 0 }, { "doc_id": "15189194", "title": "Limbic hyperconnectivity in the vegetative state", "abstract": "Objective: To investigate functional connectivity between the default mode network (DMN) and other networks in disorders of consciousness. Methods: We analyzed MRI data from 11 patients in a vegetative state and 7 patients in a minimally conscious state along with age- and sex-matched healthy control subjects. MRI data analysis included nonlinear spatial normalization to compensate for disease-related anatomical distortions. We studied brain connectivity data from resting-state MRI temporal series, combining noninferential (independent component analysis) and inferential (seed-based general linear model) methods. Results: In DMN hypoconnectivity conditions, a patient's DMN functional connectivity shifts and paradoxically increases in limbic structures, including the orbitofrontal cortex, insula, hypothalamus, and the ventral tegmental area. Conclusions: Concurrently with DMN hypoconnectivity, we report limbic hyperconnectivity in patients in vegetative and minimally conscious states. This hyperconnectivity may reflect the persistent engagement of residual neural activity in self-reinforcing neural loops, which, in turn, could disrupt normal patterns of connectivity.", "corpus_id": 15189194, "score": 0 }, { "doc_id": "40481239", "title": "Functional plasticity in primate somatosensory thalamus following chronic lesion of the ventral lateral spinal cord", "abstract": "The long-term consequences of thoracic spinothalamic tract lesion on the physiological properties of neurons in the ventral posterior lateral nucleus of the thalamus in monkeys were assessed. Neurons responding to both compressive and phasic brush stimuli (multireceptive neurons), but not brush-specific (low-threshold) neurons, in the partially deafferented thalamus showed increased spontaneous activity, increased responses evoked by cutaneous stimuli and larger mean receptive field size than the same types of cells in the thalamus with intact innervation. The spike train properties of both the spontaneous and evoked discharges of cells were also altered so that there was an increased incidence of spike-bursts in cells of deafferented thalamus. These changes were widespread in the thalamus, and included cells in both the fully innervated forelimb representation and the partially denervated hindlimb representation ipsilateral to the lesion. The spontaneous and evoked spike trains in the ipsilateral thalamus also show increased frequency of both spike-burst and non-burst events compared to the intact thalamus. These results indicate that chronic spinothalamic tract lesion produces widespread changes in the physiological properties of a discrete cell population of the thalamus.The findings in this study indicate that the thalamic processing of somatosensory information conveyed by the lemniscal system is altered by transection of the spinothalamic tract. This change in sensory processing in the thalamus would result in altered cortical processing of innocuous somatosensory inputs following deafferentation and so possibly contribute to the generation of the central pain syndrome.", "corpus_id": 40481239, "score": 0 }, { "doc_id": "36998895", "title": "Hyperalgesia with reduced laser evoked potentials in neuropathic pain", "abstract": "Nociceptive evoked potentials to laser stimuli (LEPs) are able to detect lesions of pain and temperature pathways at peripheral, spinal and supraspinal levels. It is commonly accepted that LEP attenuation correlates with the loss of pain and temperature sensations, while pathological heat-pain hypersensitivity has been associated with increased LEP amplitude. Here we present two patients in whom increased pain sensation (hyperalgesia) to laser stimuli was, on the contrary, associated to delayed, desynchronized and attenuated LEPs. Both patients experienced increased unpleasantness and affective reactions to laser, associated to poor ability to localize the stimulus. In both cases the results may be explained by an overactivation of the 'medial pain system', in one patient due to deafferentation of cortical sensory areas by a capsular lesion, and in the other to imbalance between A-delta and C fiber excitation due to peripheral nerve injury. Our results suggest that LEPs, as currently recorded, reflect the activity of a 'lateral' pain system subserved by rapidly conducting fibers. They may therefore, assess the sensory and cognitive dimensions of pain, but may not index adequately the affective-emotional aspects of pain sensation conveyed by the 'medial' pain system. The dissociation between pain sensation and cortical EPs deserve to be added to the current semiology of LEPs, as the presence of abnormal pain to laser on the background of reduced LEPs substantiates the neuropathic nature of the pain.", "corpus_id": 36998895, "score": 0 }, { "doc_id": "25048533", "title": "C- and A delta-fiber components of heat-evoked cerebral potentials in healthy human subjects.", "abstract": "Feedback-controlled laser heat was used to stimulate the hairy skin of the hand dorsum and forearm, and heat-evoked cerebral potentials were recorded at midline (Fz, Cz, Pz) and temporal (T3, T4) scalp positions. Based on data from primary afferent electrophysiology a stimulus level (40 degrees C) was chosen, which is above C-fiber heat threshold, but clearly below A delta-nociceptor heat threshold in order to excite selectively C-fibers without concomitant excitation of A delta-fibers. Feedback-controlled stepped heat stimuli to 40 degrees C elicited ultralate laser evoked potentials (LEPs) at the vertex in a high proportion of experiments (90%). Estimates of conduction velocity calculated from latency shifts between the hand and forearm sites of ultralate LEPs (2.4 m/s) and of reaction times (2.8 m/s) confirmed mediation of ultralate potentials by unmyelinated nerve fibers (nociceptors and/or warm fibers). The ultralate LEP could be differentiated from resolution of contingent negative variation (CNV), an endogenous potential related to expectation and response preparation, by its scalp topography. Strong heat stimuli of 48 degrees C, which is suprathreshold for most A delta- and C-fiber nociceptors, elicited the well-known late LEPs mediated by nociceptive Adelta-fibers confirming previous studies. The LEP waveform to strong heat stimuli also contained an ultralate component reminiscent of an ultralate LEP following the late LEP. Ultralate and late LEP had identical scalp topography. In conclusion, the method of temperature-controlled laser heat stimuli allows the selective and reliable examination of A delta- and C-fiber-mediated afferent pathways and the related cortical processing without the complication of dissociating A-fiber nerve blocks.", "corpus_id": 25048533, "score": 0 } ]

{ "doc_id": "379164", "title": "Multilocus coalescent analyses reveal the demographic history and speciation patterns of mouse lemur sister species", "abstract": "BackgroundDebate continues as to whether allopatric speciation or peripatric speciation through a founder effect is the predominant force driving evolution in vertebrates. The mouse lemurs of Madagascar are a system in which evolution has generated a large number of species over a relatively recent time frame. Here, we examine speciation patterns in a pair of sister species of mouse lemur, Microcebus murinus and M. griseorufus. These two species have ranges that are disparately proportioned in size, with M. murinus showing a much more extensive range that marginally overlaps that of M. griseorufus. Given that these two species are sister taxa, the asymmetric but overlapping geographic ranges are consistent with a model of peripatric speciation. To test this hypothesis, we analyze DNA sequence data from four molecular markers using coalescent methods. If the peripatric speciation model is supported, we predict substantially greater genetic diversity in M. murinus, relative to M. griseorufus. Further, we expect a larger effective population size in M. murinus and in the common ancestor of the two species than in M. griseorufus, with a concomitant decrease in gene tree/species tree incongruence in the latter and weak signs of demographic expansion in M. murinus.ResultsOur results reject a model of peripatric divergence. Coalescent effective population size estimates were similar for both extant species and larger than that estimated for their most recent common ancestor. Gene tree results show similar levels of incomplete lineage sorting within species with respect to the species tree, and locus-specific estimates of genetic diversity are concordant for both species. Multilocus demographic analyses suggest range expansions for M. murinus, with this species also experiencing more recent population declines over the past 160 thousand years.ConclusionsResults suggest that speciation occurred in allopatry from a common ancestor narrowly distributed throughout southwest Madagascar, with subsequent range expansion for M. murinus. Population decline in M. murinus is likely related to patterns of climate change in Madagascar throughout the Pleistocene, potentially exacerbated by continual anthropogenic perturbation. Genome-level data are needed to quantify the role of niche specialization and adaptation in shaping the current ranges of these species.", "corpus_id": 379164 }

[ { "doc_id": "18148765", "title": "Multilocus Methods for Estimating Population Sizes, Migration Rates and Divergence Time, With Applications to the Divergence of Drosophila pseudoobscura and D. persimilis", "abstract": "The genetic study of diverging, closely related populations is required for basic questions on demography and speciation, as well as for biodiversity and conservation research. However, it is often unclear whether divergence is due simply to separation or whether populations have also experienced gene flow. These questions can be addressed with a full model of population separation with gene flow, by applying a Markov chain Monte Carlo method for estimating the posterior probability distribution of model parameters. We have generalized this method and made it applicable to data from multiple unlinked loci. These loci can vary in their modes of inheritance, and inheritance scalars can be implemented either as constants or as parameters to be estimated. By treating inheritance scalars as parameters it is also possible to address variation among loci in the impact via linkage of recurrent selective sweeps or background selection. These methods are applied to a large multilocus data set from Drosophila pseudoobscura and D. persimilis. The species are estimated to have diverged ∼500,000 years ago. Several loci have nonzero estimates of gene flow since the initial separation of the species, with considerable variation in gene flow estimates among loci, in both directions between the species.", "corpus_id": 18148765, "score": 0 }, { "doc_id": "3212668", "title": "Isolation with migration models for more than two populations.", "abstract": "A method for studying the divergence of multiple closely related populations is described and assessed. The approach of Hey and Nielsen (2007, Integration within the Felsenstein equation for improved Markov chain Monte Carlo methods in population genetics. Proc Natl Acad Sci USA. 104:2785-2790) for fitting an isolation-with-migration model was extended to the case of multiple populations with a known phylogeny. Analysis of simulated data sets reveals the kinds of history that are accessible with a multipopulation analysis. Necessarily, processes associated with older time periods in a phylogeny are more difficult to estimate; and histories with high levels of gene flow are particularly difficult with more than two populations. However, for histories with modest levels of gene flow, or for very large data sets, it is possible to study large complex divergence problems that involve multiple closely related populations or species.", "corpus_id": 3212668, "score": 0 }, { "doc_id": "3607228", "title": "The divergence of chimpanzee species and subspecies as revealed in multipopulation isolation-with-migration analyses.", "abstract": "The divergence of bonobos and three subspecies of the common chimpanzee was examined under a multipopulation isolation-with-migration (IM) model with data from 73 loci drawn from the literature. A benefit of having a full multipopulation model, relative to conducting multiple pairwise analyses between sampled populations, is that a full model can reveal historical gene flow involving ancestral populations. An example of this was found in which gene flow is indicated between the western common chimpanzee subspecies and the ancestor of the central and the eastern common chimpanzee subspecies. The results of a full analysis on all four populations are strongly consistent with analyses on pairs of populations and generally similar to results from previous studies. The basal split between bonobos and common chimpanzees was estimated at 0.93 Ma (0.68-1.54 Ma, 95% highest posterior density interval), with the split among the ancestor of three common chimpanzee populations at 0.46 Ma (0.35-0.65), and the most recent split between central and eastern common chimpanzee populations at 0.093 Ma (0.041-0.157). Population size estimates mostly fell in the range from 5,000 to 10,000 individuals. The exceptions are the size of the ancestor of the common chimpanzee and the bonobo, at 17,000 (8,000-28,000) individuals, and the central common chimpanzee and its immediate ancestor with the eastern common chimpanzee, which have effective size estimates at 27,000 (16,000-44,000) and 32,000 (19,000-54,000) individuals, respectively.", "corpus_id": 3607228, "score": 0 }, { "doc_id": "17332403", "title": "PERSPECTIVE: GENE DIVERGENCE, POPULATION DIVERGENCE, AND THE VARIANCE IN COALESCENCE TIME IN PHYLOGEOGRAPHIC STUDIES", "abstract": "Molecular methods as applied to the biogeography of single species (phylogeography) or multiple codistributed species (comparative phylogeography) have been productively and extensively used to elucidate common historical features in the diversification of the Earth's biota. However, only recently have methods for estimating population divergence times or their confidence limits while taking into account the critical effects of genetic polymorphism in ancestral species become available, and earlier methods for doing so are underutilized. We review models that address the crucial distinction between the gene divergence, the parameter that is typically recovered in molecular phylogeographic studies, and the population divergence, which is in most cases the parameter of interest and will almost always postdate the gene divergence. Assuming that population sizes of ancestral species are distributed similarly to those of extant species, we show that phylogeographic studies in vertebrates suggest that divergence of alleles in ancestral species can comprise from less than 10% to over 50% of the total divergence between sister species, suggesting that the problem of ancestral polymorphism in dating population divergence can be substantial. The variance in the number of substitutions (among loci for a given species or among species for a given gene) resulting from the stochastic nature of DNA change is generally smaller than the variance due to substitutions along allelic lines whose coalescence times vary due to genetic drift in the ancestral population. Whereas the former variance can be reduced by further DNA sequencing at a single locus, the latter cannot. Contrary to phylogeographic intuition, dating population divergence times when allelic lines have achieved reciprocal monophyly is in some ways more challenging than when allelic lines have not achieved monophyly, because in the former case critical data on ancestral population size provided by residual ancestral polymorphism is lost. In the former case differences in coalescence time between species pairs can in principle be explained entirely by differences in ancestral population size without resorting to explanations involving differences in divergence time. Furthermore, the confidence limits on population divergence times are severely underestimated when those for number of substitutions per site in the DNA sequences examined are used as a proxy. This uncertainty highlights the importance of multilocus data in estimating population divergence times; multilocus data can in principle distinguish differences in coalescence time (T) resulting from differences in population divergence time and differences in T due to differences in ancestral population sizes and will reduce the confidence limits on the estimates.", "corpus_id": 17332403, "score": 0 }, { "doc_id": "8227854", "title": "Estimating effective population size from samples of sequences: inefficiency of pairwise and segregating sites as compared to phylogenetic estimates.", "abstract": "It is known that under neutral mutation at a known mutation rate a sample of nucleotide sequences, within which there is assumed to be no recombination, allows estimation of the effective size of an isolated population. This paper investigates the case of very long sequences, where each pair of sequences allows a precise estimate of the divergence time of those two gene copies. The average divergence time of all pairs of copies estimates twice the effective population number and an estimate can also be derived from the number of segregating sites. One can alternatively estimate the genealogy of the copies. This paper shows how a maximum likelihood estimate of the effective population number can be derived from such a genealogical tree. The pairwise and the segregating sites estimates are shown to be much less efficient than this maximum likelihood estimate, and this is verified by computer simulation. The result implies that there is much to gain by explicitly taking the tree structure of these genealogies into account.", "corpus_id": 8227854, "score": 0 }, { "doc_id": "1304011", "title": "Estimating effective population size and mutation rate from sequence data using Metropolis-Hastings sampling.", "abstract": "We present a new way to make a maximum likelihood estimate of the parameter 4N mu (effective population size times mutation rate per site, or theta) based on a population sample of molecular sequences. We use a Metropolis-Hastings Markov chain Monte Carlo method to sample genealogies in proportion to the product of their likelihood with respect to the data and their prior probability with respect to a coalescent distribution. A specific value of theta must be chosen to generate the coalescent distribution, but the resulting trees can be used to evaluate the likelihood at other values of theta, generating a likelihood curve. This procedure concentrates sampling on those genealogies that contribute most of the likelihood, allowing estimation of meaningful likelihood curves based on relatively small samples. The method can potentially be extended to cases involving varying population size, recombination, and migration.", "corpus_id": 1304011, "score": 0 }, { "doc_id": "15404558", "title": "Maximum-likelihood estimation of migration rates and effective population numbers in two populations using a coalescent approach.", "abstract": "A new method for the estimation of migration rates and effective population sizes is described. It uses a maximum-likelihood framework based on coalescence theory. The parameters are estimated by Metropolis-Hastings importance sampling. In a two-population model this method estimates four parameters: the effective population size and the immigration rate for each population relative to the mutation rate. Summarizing over loci can be done by assuming either that the mutation rate is the same for all loci or that the mutation rates are gamma distributed among loci but the same for all sites of a locus. The estimates are as good as or better than those from an optimized FST-based measure. The program is available on the World Wide Web at http://evolution.genetics. washington.edu/lamarc.html/.", "corpus_id": 15404558, "score": 0 }, { "doc_id": "2078799", "title": "Bayesian species delimitation using multilocus sequence data", "abstract": "In the absence of recent admixture between species, bipartitions of individuals in gene trees that are shared across loci can potentially be used to infer the presence of two or more species. This approach to species delimitation via molecular sequence data has been constrained by the fact that genealogies for individual loci are often poorly resolved and that ancestral lineage sorting, hybridization, and other population genetic processes can lead to discordant gene trees. Here we use a Bayesian modeling approach to generate the posterior probabilities of species assignments taking account of uncertainties due to unknown gene trees and the ancestral coalescent process. For tractability, we rely on a user-specified guide tree to avoid integrating over all possible species delimitations. The statistical performance of the method is examined using simulations, and the method is illustrated by analyzing sequence data from rotifers, fence lizards, and human populations.", "corpus_id": 2078799, "score": 1 }, { "doc_id": "23581676", "title": "Statistical phylogeography.", "abstract": "While studies of phylogeography and speciation in the past have largely focused on the documentation or detection of significant patterns of population genetic structure, the emerging field of statistical phylogeography aims to infer the history and processes underlying that structure, and to provide objective, rather than ad hoc explanations. Methods for parameter estimation are now commonly used to make inferences about demographic past. Although these approaches are well developed statistically, they typically pay little attention to geographical history. In contrast, methods that seek to reconstruct phylogeographic history are able to consider many alternative geographical scenarios, but are primarily nonstatistical, making inferences about particular biological processes without explicit reference to stochastically derived expectations. We advocate the merging of these two traditions so that statistical phylogeographic methods can provide an accurate representation of the past, consider a diverse array of processes, and yet yield a statistical estimate of that history. We discuss various conceptual issues associated with statistical phylogeographic inferences, considering especially the stochasticity of population genetic processes and assessing the confidence of phylogeographic conclusions. To this end, we present some empirical examples that utilize a statistical phylogeographic approach, and then by contrasting results from a coalescent-based approach to those from Templeton's nested cladistic analysis (NCA), we illustrate the importance of assessing error. Because NCA does not assess error in its inferences about historical processes or contemporary gene flow, we performed a small-scale study using simulated data to examine how our conclusions might be affected by such unconsidered errors. NCA did not identify the processes used to simulate the data, confusing among deterministic processes and the stochastic sorting of gene lineages. There is as yet insufficient justification of NCA's ability to accurately infer or distinguish among alternative processes. We close with a discussion of some unresolved problems of current statistical phylogeographic methods to propose areas in need of future development.", "corpus_id": 23581676, "score": 0 }, { "doc_id": "18665436", "title": "SPECIATIONAL HISTORY OF AUSTRALIAN GRASS FINCHES (POEPHILA) INFERRED FROM THIRTY GENE TREES*", "abstract": "Abstract Multilocus genealogical approaches are still uncommon in phylogeography and historical demography, fields which have been dominated by microsatellite markers and mitochondrial DNA, particularly for vertebrates. Using 30 newly developed anonymous nuclear loci, we estimated population divergence times and ancestral population sizes of three closely related species of Australian grass finches (Poephila) distributed across two barriers in northern Australia. We verified that substitution rates were generally constant both among lineages and among loci, and that intralocus recombination was uncommon in our dataset, thereby satisfying two assumptions of our multilocus analysis. The reconstructed gene trees exhibited all three possible tree topologies and displayed considerable variation in coalescent times, yet this information provided the raw data for maximum likelihood and Bayesian estimation of population divergence times and ancestral population sizes. Estimates of these parameters were in close agreement with each other regardless of statistical approach and our Bayesian estimates were robust to prior assumptions. Our results suggest that black-throated finches (Poephila cincta) diverged from long-tailed finches (P. acuticauda and P. hecki) across the Carpentarian Barrier in northeastern Australia around 0.6 million years ago (mya), and that P. acuticauda diverged from P. hecki across the Kimberley Plateau–Arnhem Land Barrier in northwestern Australia approximately 0.3 mya. Bayesian 95% credibility intervals around these estimates strongly support Pleistocene timing for both speciation events, despite the fact that many gene divergences across the Carpentarian region clearly predated the Pleistocene. Estimates of ancestral effective population sizes for the basal ancestor and long-tailed finch ancestor were large (about 521,000 and about 384,000, respectively). Although the errors around the population size parameter estimates are considerable, they are the first for birds taking into account multiple sources of variance.", "corpus_id": 18665436, "score": 0 }, { "doc_id": "16499648", "title": "Working at the interface of phylogenetics and population genetics: a biogeographical analysis of Triaenops spp. (Chiroptera: Hipposideridae)", "abstract": "New applications of genetic data to questions of historical biogeography have revolutionized our understanding of how organisms have come to occupy their present distributions. Phylogenetic methods in combination with divergence time estimation can reveal biogeographical centres of origin, differentiate between hypotheses of vicariance and dispersal, and reveal the directionality of dispersal events. Despite their power, however, phylogenetic methods can sometimes yield patterns that are compatible with multiple, equally well‐supported biogeographical hypotheses. In such cases, additional approaches must be integrated to differentiate among conflicting dispersal hypotheses. Here, we use a synthetic approach that draws upon the analytical strengths of coalescent and population genetic methods to augment phylogenetic analyses in order to assess the biogeographical history of Madagascar's Triaenops bats (Chiroptera: Hipposideridae). Phylogenetic analyses of mitochondrial DNA sequence data for Malagasy and east African Triaenops reveal a pattern that equally supports two competing hypotheses. While the phylogeny cannot determine whether Africa or Madagascar was the centre of origin for the species investigated, it serves as the essential backbone for the application of coalescent and population genetic methods. From the application of these methods, we conclude that a hypothesis of two independent but unidirectional dispersal events from Africa to Madagascar is best supported by the data.", "corpus_id": 16499648, "score": 0 }, { "doc_id": "5888652", "title": "Genomic consequences of multiple speciation processes in a stick insect", "abstract": "Diverse geographical modes and mechanisms of speciation are known, and individual speciation genes have now been identified. Despite this progress, genome-wide outcomes of different evolutionary processes during speciation are less understood. Here, we integrate ecological and spatial information, mating trials, transplantation data and analysis of 86 130 single nucleotide polymorphisms (SNPs) in eight populations (28 pairwise comparisons) of Timema cristinae stick insects to test the effects of different factors on genomic divergence in a system undergoing ecological speciation. We find patterns consistent with effects of numerous factors, including geographical distance, gene flow, divergence in host plant use and climate, and selection against maladaptive hybridization (i.e. reinforcement). For example, the number of highly differentiated ‘outlier loci’, allele-frequency clines and the overall distribution of genomic differentiation were recognizably affected by these factors. Although host use has strong effects on phenotypic divergence and reproductive isolation, its effects on genomic divergence were subtler and other factors had pronounced effects. The results demonstrate how genomic data can provide new insights into speciation and how genomic divergence can be complex, yet predictable. Future work could adopt experimental, mapping and functional approaches to directly test which genetic regions are affected by selection and determine their physical location in the genome.", "corpus_id": 5888652, "score": 0 }, { "doc_id": "3245997", "title": "Divergent selection and heterogeneous genomic divergence", "abstract": "Levels of genetic differentiation between populations can be highly variable across the genome, with divergent selection contributing to such heterogeneous genomic divergence. For example, loci under divergent selection and those tightly physically linked to them may exhibit stronger differentiation than neutral regions with weak or no linkage to such loci. Divergent selection can also increase genome‐wide neutral differentiation by reducing gene flow (e.g. by causing ecological speciation), thus promoting divergence via the stochastic effects of genetic drift. These consequences of divergent selection are being reported in recently accumulating studies that identify: (i) ‘outlier loci’ with higher levels of divergence than expected under neutrality, and (ii) a positive association between the degree of adaptive phenotypic divergence and levels of molecular genetic differentiation across population pairs [‘isolation by adaptation’ (IBA)]. The latter pattern arises because as adaptive divergence increases, gene flow is reduced (thereby promoting drift) and genetic hitchhiking increased. Here, we review and integrate these previously disconnected concepts and literatures. We find that studies generally report 5–10% of loci to be outliers. These selected regions were often dispersed across the genome, commonly exhibited replicated divergence across different population pairs, and could sometimes be associated with specific ecological variables. IBA was not infrequently observed, even at neutral loci putatively unlinked to those under divergent selection. Overall, we conclude that divergent selection makes diverse contributions to heterogeneous genomic divergence. Nonetheless, the number, size, and distribution of genomic regions affected by selection varied substantially among studies, leading us to discuss the potential role of divergent selection in the growth of regions of differentiation (i.e. genomic islands of divergence), a topic in need of future investigation.", "corpus_id": 3245997, "score": 0 }, { "doc_id": "11830469", "title": "PERIPATRIC SPECIATION DRIVES DIVERSIFICATION AND DISTRIBUTIONAL PATTERN OF REEF HERMIT CRABS (DECAPODA: DIOGENIDAE: CALCINUS)", "abstract": "The diversity on coral reefs has long captivated observers. We examine the mechanisms of speciation, role of ecology in speciation, and patterns of species distribution in a typical reef‐associated clade—the diverse and colorful Calcinus hermit crabs—to address the origin of tropical marine diversity. We sequenced COI, 16S, and H3 gene regions for ∼90% of 56 putative species, including nine undescribed, “cryptic” taxa, and mapped their distributions. Speciation in Calcinus is largely peripatric at remote locations. Allopatric species pairs are younger than sympatric ones, and molecular clock analyses suggest that >2 million years are needed for secondary sympatry. Substantial niche conservatism is evident within clades, as well as a few major ecological shifts between sister species. Color patterns follow species boundaries and evolve rapidly, suggesting a role in species recognition. Most species prefer and several are restricted to oceanic areas, suggesting great dispersal abilities and giving rise to an ocean‐centric diversity pattern. Calcinus diversity patterns are atypical in that the diversity peaks in the west‐central oceanic Pacific rather than in the Indo‐Malayan “diversity center.” Calcinus speciation patterns do not match well‐worn models put forth to explain the origin of Indo‐West Pacific diversity, but underscore the complexity of marine diversification.", "corpus_id": 11830469, "score": 0 }, { "doc_id": "44554158", "title": "Evolution of coral reef fish Thalassoma spp. (Labridae). 1. Molecular phylogeny and biogeography", "abstract": "Wrasses in the genus Thalassoma comprise 27 recognized species that occur predominantly on coral reefs and subtropical rocky reefs worldwide. The phylogenetic relationships for 26 species were examined based on two mitochondrial genes (cytochrome b and 16S rRNA) and one nuclear intron (the first intron of the ribosomal protein S7). Two closely related species, the bird-wrasses (Gomphosus varius Lacepède, 1801 and G. caerulaeus Lacepède, 1801), were also included in the analysis. These species grouped within the genus Thalassoma. Thalassoma newtoni (Osório, 1891) from Sao Tome, which is generally synonymized with the Atlantic/Mediterranean Thalassoma pavo (Linnaeus, 1758) appears to be a valid species. Using a molecular clock, the genus was estimated to have originally diverged 8–13 million years ago, with Thalassoma ballieui (Vaillant and Sauvage, 1875) from Hawaii and Thalassoma septemfasciata Scott, 1959 from Western Australia as the ancestral species. Approximately 5–10 million years ago, a sudden burst of speciation resulted in seven clades, which were resolved with the sequence data. The terminal Tethyan event and the closing of the Isthmus of Panama were probably the major historical factors shaping the evolution of species in the genus Thalassoma. These data on the spatio-temporal pattern of speciation in the Indo-Pacific indicate that peripheral species have been generated at various times throughout the history of the genus, and that none of the widespread species are relatively young. Thus, there is no clear support for centrifugal (youngest at the periphery) versus centripetal (oldest at the periphery) modes of generation of species, two theories which have been used to account for geographic gradients in species diversity.", "corpus_id": 44554158, "score": 0 }, { "doc_id": "19940411", "title": "Gene Trees in Species Trees", "abstract": "Exploration of the relationship between gene trees and their containing species trees leads to consideration of how to reconstruct species trees from gene trees and of the concept of phylogeny as a cloud of gene histories. When gene copies are sampled from various species, the gene tree relating these copies might disagree with the species phylogeny. This discord can arise from horizontal transfer (including hybridization), lineage sorting, and gene duplication and ex- tinction. Lineage sorting could also be called deep coalescence, the failure of ancestral copies to coalesce (looking backwards in time) into a common ancestral copy until deeper than previous speciation events. These events depend on various factors; for instance, deep coalescence is more likely if the branches of the species tree are short (in generations) and wide (in population size). A similar dependence on process is found in historical biogeography and host-parasite relation- ships. Each of the processes of discord could yield a different parsimony criterion for reconstruct- ing the species tree from a set of gene trees: with horizontal transfer, choose the species tree that minimizes the number of transfer events; with deep coalescence, choose the tree minimizing the number of extra gene lineages that had to coexist along species lineages; with gene duplication, choose the tree minimizing duplication and/or extinction events. Maximum likelihood methods for reconstructing the species tree are also possible because coalescence theory provides the prob- ability that a particular gene tree would occur given a species tree (with branch lengths and widths specified). In considering these issues, one is provoked to reconsider precisely what is phylogeny. Perhaps it is misleading to view some gene trees as agreeing and other gene trees as disagreeing with the species tree; rather, all of the gene trees are part of the species tree, which can be visualized like a fuzzy statistical distribution, a cloud of gene histories. Alternatively, phylogeny might be (and has been) viewed not as a history of what happened, genetically, but as a history of what could have happened, i.e., a history of changes in the probabilities of inter- breeding. (Biogeography; coalescence; coevolution; evolution; gene duplication; gene genealogy; gene trees; horizontal transfer; hybridization; lineage sorting; parsimony; phylogeny; species con- cepts; species trees; tree reconciliation.)", "corpus_id": 19940411, "score": 0 }, { "doc_id": "5260411", "title": "DNA Barcoding: Promise and Pitfalls", "abstract": "In this issue of PLoS Biology, Hebert et al. (2004) have set out to test the resolution and performance of “DNA barcoding,” using a single mtDNA gene, cytochrome c oxidase I (COI), for a sample of North American birds. Before turning to details of this study, it is useful as context to consider the following questions: What is DNA barcoding, and what does it promise? What is new about it? Why is it controversial? What are the potential pitfalls?", "corpus_id": 5260411, "score": 0 }, { "doc_id": "10397429", "title": "Recent trends in molecular phylogenetic analysis: where to next?", "abstract": "The acquisition of large multilocus sequence data is providing researchers with an unprecedented amount of information to resolve difficult phylogenetic problems. With these large quantities of data comes the increasing challenge regarding the best methods of analysis. We review the current trends in molecular phylogenetic analysis, focusing specifically on the topics of multiple sequence alignment and methods of tree reconstruction. We suggest that traditional methods are inadequate for these highly heterogeneous data sets and that researchers employ newer more sophisticated search algorithms in their analyses. If we are to best extract the information present in these data sets, a sound understanding of basic phylogenetic principles combined with modern methodological techniques are necessary.", "corpus_id": 10397429, "score": 0 }, { "doc_id": "17860060", "title": "Two New Species of Mouse Lemurs (Cheirogaleidae: Microcebus) from Eastern Madagascar", "abstract": "The number of newly discovered Malagasy vertebrate taxa has multiplied in recent years, emphasizing the importance of complete taxon sampling for phylogenetics, biogeography, functional ecology, and conservation biology, especially in such a biodiversity hotspot. In particular, the diversity of extant lemurs is much higher than previously thought, and we have yet to comprehend fully the full extent of lemuriform biodiversity. A recent genetic analysis of mtDNA and nDNA sequence data in Malagasy mouse lemurs revealed the existence of several novel mtDNA clades based on new field sampling. These geographically defined and previously unrecognized mtDNA clades corresponded precisely to patterns of population structure revealed in the analysis of the nDNA data, thus confirming their evolutionary divergence from other mouse lemur clades. Two of these independently evolving lineages correspond to specimens that were collected by us in the Marolambo and Manantantely/Ivorona regions. Here we summarize the genetic evidence and report on the morphometric and external characteristics of these animals, formally describing them as new species. This report thus brings the number of currently recognized and described mouse lemur species to 20. The forests in which these mouse lemurs were discovered have been heavily degraded in the past decade, prompting the classification of one of the new species as Endangered by the IUCN, even before its formal description. As with several other newly described lemur species, immediate field studies and appropriate conservation actions are therefore urgent.", "corpus_id": 17860060, "score": 0 }, { "doc_id": "55164896", "title": "MORPHOLOGY, BEHAVIOUR AND MOLECULAR EVOLUTION OF GIANT MOUSE LEMURS (MIRZA SPP.) GRAY, 1870, WITH DESCRIPTION OF A NEW SPECIES.", "abstract": "Giant mouse lemurs (genus Mirza) are small nocturnal primates endemic to Madagascar, of which a single species (M. coquereli) is currently recognized. It is distributed along Madagascar’s west coast, with a gap of several hundred kilometres between two presumed subpopulations. Previous studies in the field and in captivity indicated substantial differences in several aspects of the biology of these two subpopulations. We therefore collected morphometric, genetic and behavioural data from populations representing the southern and northern end of their range to examine these differences in more detail. We obtained standard morphometric field measurements and DNA samples from a total of 74 adult males and females at Kirindy (central western Madagascar) and Ambato (northwestern Madagascar) and compared their social organisation. We also studied a total of 9 Mirza specimens housed at the Rijksmuseum van Natuurlijke Historie Leiden (The Netherlands). Our morphometric analyses revealed that the two Mirza populations differed significantly in 12 out of 13 measures, with the northern Mirza sporting smaller values in all traits except testes volume. Northern Mirza spent the day in nests with 2-8 (mean 4.1) individuals, whereas Mirza in the south virtually always slept alone. Moreover, reproduction in the northern population occurred several months earlier than in the south. We also sequenced the complete mitochondrial cytochrome b (cyt b) gene from several specimens and found that (1) the two populations differed by 3.33-3.51 %, which is similar to genetic distances observed among several closely related species of mouse lemurs (Microcebus), (2) DNA extracted from tissue on skulls collected in 1868/1870 yielded partial cyt b sequences that aligned perfectly with the northern and southern population samples, respectively, and (3) Microcebus from Andasibe clearly differed genetically from all other known mouse lemur species, indicating a separate species status for this population. Based on the combination of morphological, behavioural and genetic differences between Mirza from Kirindy and Ambato we conclude that they should be separated at the species level. Because M. coquereli was described based on a specimen from the southern population, we describe the northern Mirza as a species new to science.", "corpus_id": 55164896, "score": 0 }, { "doc_id": "56920", "title": "Revision of the Mouse Lemurs (Microcebus) of Eastern Madagascar", "abstract": "Phylogenetic analysis of ca. 4500 base pairs of mitochondrial DNA sequence data reveals further genetic diversity in mouse lemurs (Microcebus) on the eastern and western coasts of Madagascar. Molecular data and phylogenetic analyses revise the previously monotypic species of eastern Madagascar, Microcebus rufus, with the description of 3 new species. Three additional Microcebus species are proposed in eastern Madagascar, along with another Microcebus species in western Madagascar. Correlating the molecular data with previously generated sequence data, we present a tentative pattern of distribution along the east coast. We show that the general distribution of Microcebus is based on a traditional eastern/western division. The preliminary model appears strongly influenced by both rivers and altitudinal differences acting independently as barriers.", "corpus_id": 56920, "score": 0 }, { "doc_id": "8473176", "title": "First indications of a highland specialist among mouse lemurs (Microcebus spp.) and evidence for a new mouse lemur species from eastern Madagascar", "abstract": "The factors that limit the distribution of the highly diverse lemur fauna of Madagascar are still debated. We visited an understudied region of eastern Madagascar, a lowland rainforest site (Sahafina, 29–230 m a.s.l.) close to the Mantadia National Park, in order to conduct a survey and collect further distributional data on mouse lemurs. We captured, measured, photographed, and sampled mouse lemurs from the Sahafina forest, performed standard phylogenetic methods based on three mitochondrial DNA genes, and conducted morphometric comparisons in order to clarify their phylogenetic position and taxonomic status. The mouse lemurs from the Sahafina forest could not be assigned to any of the known mouse lemur species and were highly divergent in all molecular analyses from all previously described species. Since they also differed morphometrically from their sister species and from their geographic neighbors, we propose species status and include a species description at the end. This study suggests that M. lehilahytsara may be the first highland specialist among all mouse lemurs. The distribution of the newly described mouse lemur is not fully known, but seems to be rather restricted and highly fragmented, which raises serious conservation concerns.", "corpus_id": 8473176, "score": 0 }, { "doc_id": "30615967", "title": "Adaptive radiation and behaviour of the Malagasy lemurs.", "abstract": "The systematic distribution of behavioural characters in lemurs can be analysed using the same techniques as for anatomical characters, without considering physiological mechanisms. Behaviour and structure are usually interdependent (functional morphology), so it follows that behavioural features probably evolve hand-in-hand with morphology. Behavioural and morphological characters generally exhibit the same patterns of systematic distribution, though it is not yet clear whether evolution typically operates through selection of inherited behaviour patterns, or through indirect canalization of behaviour which is dependent upon particular structures. The extant Malagasy lemurs and their recent subfossil relatives must be considered together as an integrated lemur fauna, which has undergone great reduction over the last few thousand years. The lemurs appear to form a natural group with the Afro-Asian loris/bush-baby group, certain Miocene lorisoids from East Africa ('Progalago group') and the Eocene Adapinae (Northern Europe) and Notharctinae (North America). This natural group can be referred to as the Strepsirhini. Simpson's classification (1945) implies that these Strepsirhines are closely related to the Tupaiidae (tree-shrews), and to the fossil Anagalidae and Plesiadapidae. Inclusion of these groups in the Order Primates is regarded here as superfluous, and discussion is restricted to the Strepsirhini, as defined above. It is suggested that the Malagasy lemurs and the Afro-Asian bush-babies and lorises had a common origin in Africa (lemur/loris stock), and that this ancestral stock had an earlier common origin with the Adapinae and Notharctinae of the Northern continents. The geographical distribution of the lemurs within Madagascar is examined, and seven basic zones of species distribution are identified. Each of these zones has distinctive climatic and vegetational characteristics which can be expressed on a 'climagramme' incorporating Emberger's pluviothermic quotient. Major physical barriers can be recognized along all of the boundaries between the present distribution zones. A model is suggested, in which climatically and physically demarcated zones of this kind can operate as agents for geographical isolation and speciation. Occasional emigration from zone to zone could produce a dynamic situation in which ecological competition between closely related species would favour a pattern of adaptive radiation with individual species becoming increasingly specialized for distinct ecological niches. In order to discuss the origin of the ancestors of the Malagasy lemurs, the relationship between Madagascar and other land-masses is examined. Although most authors agree that emigration from Africa has provided the main basis for biological invasion of Madagascar, there has been some controversy about the pattern of spatial relationships between Madagascar and Africa over time. Some authors (notably Simpson (1943) and Millot (1952)) have favoured a 'stable continents' hypothesis, and this has led to a concentration of interest on the Northern continents as the seat of Primate evolution. One outcome of this has been the suggestion that lemurs and lorises are separately derived from Northern European Adapinae. New geophysical evidence indicates that the 'stable continents' hypothesis is virtually untenable, and that continental drift theory provides the only coherent explanation of terrestrial evolution. This shifts the emphasis on Primate evolution to the Southern continents (notably Africa), and it seems likely that the lemurs and lorises had a common ancestry in Africa during the early Tertiary (for which no fossil evidence is available). One further consequence of drift theory is the observation that the Mozambique Channel has probably increased in width throughout the Tertiary, and that emigration of mammals to Madagascar from Africa has become increasingly improbable. Having established that Madagascar was probably invaded by a very small number of ancestral lemur species, which subsequently underwent adaptive radiation within the island, the systematic distribution of behavioural characters among living forms is examined. Attention is given to annual and daily patterns of activity, nesting patterns, diet (and some correlated dental features), locomotion (and some skeletal features), reproduction and social behaviour. In each case, it is shown that the Mouse Lemur group (Cheirogaleinae) and the Indri group (Indriidae) are internally cohesive in their characteristic behaviour patterns. The True Lemur group (Lemurinae) exhibits a wide range of behavioural adaptation, which is paralleled by equivalent morphological diversity. Behaviourally, the Aye-aye (Daubentonia) is as distinct as it is in morphological terms. By a process of induction, it is established that the behaviour of the ancestral lemurs was probably quite similar to that now exhibited by some Cheirogaleinae (particularly Microcebus), although living species in this group exhibit a number of probable specializations away from the ancestral condition. This conclusion is not surprising, since the Cheirogaleinae are also the least specialized of the lemurs in morphological terms. However, it is significant that the same ancestral pattern can be deduced for the loris/bush-baby group. Thus, the common ancestor of the Southern Strepsirhini (lemurs + lorises) was probably a small omnivorous form feeding primarily on insects, fruit and sap. The sap would have been gathered with the 'tooth-scraper' in the lower anterior dentition. There was probably a weakly developed spatial system of social organization, with central males of a population nucleus having access to females (a small number to each male), and peripheral males living on the fringe of each population. Competition between males would have provided a basis for selective mating and migration of peripheral males between population nuclei would have ensured exogamy. Extension of Walker's (1967) exemplary study of prosimian locomotion shows that the ancestral lemur/loris probably exhibited hindlimb dominated locomotion based on a grasping function of the extremities (primarily developed in the pes). The ancestral lemur/loris was probably nest-living, giving birth to - and caring for - a small number of well-developed infants after a relatively long period of gestation. There is some evidence that this ancestral form was nocturnal in habits, and it seems likely that the ancestral species which invaded Madagascar would have had a well-developed seasonal pattern of activity. Arboreal adaptation, the attachment to a nest, the small body size, and the ability to survive an adverse period of poor food supply (e.g. on the basis of fat reserves) would have fitted the early lemurs for a period of chance emigration across the Mozambique Channel on natural rafts of vegetation. Such rafts could have been formed from trees and other vegetation torn from forests lining rivers (e.g. the River Zambesi) on the east coast of Africa. Since the common ancestor of the lemurs and lorises was not very far removed from the ancestral Primate stock, many of the characters listed above must have been to some extent developed in the earliest Primates. This provides further evidence for the hypothesis that tree-shrews, anagalids and plesiadapids are quite separately derived from the ancestral Eutherian mammal stock, and that these three groups have no specific relationship to the Order Primates.", "corpus_id": 30615967, "score": 0 }, { "doc_id": "54958144", "title": "Population Genetic Analysis of Myzopoda (Chiroptera: Myzopodidae) in Madagascar", "abstract": "Abstract The chiropteran family Myzopodidae is endemic to Madagascar and is characterized by several unique morphologies, such as sessile adhesive discs on the thumb and sole. A new species, Myzopoda schliemanni, was recently described from western Madagascar that is morphologically distinct and geographically disjunct from the eastern species, M. aurita, the only other member of this family. Geographic variation within Myzopoda has only recently been studied at the morphological level and has never been addressed at the genetic level. We used a combination of phylogenetic, coalescent, and population genetic analyses to characterize the speciation history of Myzopoda and to clarify current and former patterns of gene flow within and between Myzopoda. Mitochondrial DNA sequences were used to determine whether genetic data support the morphologically distinct species M. schliemanni, to infer the distribution of the common ancestor of extant Myzopoda, to estimate effective population sizes (Ne) and levels of migration between species, and to determine patterns of population structure within species. Phylogenetic and network analyses revealed the existence of 4 well-supported clades in Myzopoda, but could not resolve relationships among those clades. Divergent haplotypes within species may result from either recent gene flow between the 2 species or more likely from incomplete lineage sorting. Multiple coalescent-based methodologies produced concordant estimates of Ne for Myzopoda, but conflicting signals for migration between the species, probably reflecting differences in the underlying models used by the methods. We found significant genetic structure within M. aurita, but no correlation with geography. This pattern may result from recent gene flow facilitated by expansion of Ravenala stands, an important day-roost tree for Myzopoda, associated with anthropogenic deforestation and the opening up of new habitat for members of this genus.", "corpus_id": 54958144, "score": 0 }, { "doc_id": "23067362", "title": "Biogeographic Evolution of Madagascar's Microendemic Biota", "abstract": "The endemic species richness on Madagascar, relative to landmass area, is unparalleled in the world. Many organisms on the island have restricted geographical ranges. A comprehensive hypothesis explaining the evolution of this microendemism has yet to be developed. Using an analysis of watersheds in the context of Quaternary climatic shifts, we provide a new mechanistic model to explain the process of explosive speciation on the island. River catchments with sources at relatively low elevations were zones of isolation and hence led to the speciation of locally endemic taxa, whereas those at higher elevations were zones of retreat and dispersion and hence contain proportionately lower levels of microendemism. These results provide a framework for biogeographic and phylogeographic studies, as well as a basis for prioritizing conservation actions of the remaining natural forest habitats on the island.", "corpus_id": 23067362, "score": 0 }, { "doc_id": "13031974", "title": "Testing species-level diversification hypotheses in Madagascar: the case of microendemic Brookesia leaf chameleons.", "abstract": "Madagascar's flora and fauna are remarkable both for their diversity and supraspecific endemism. Moreover, many taxa contain large numbers of species with limited distributions. Several hypotheses have been proposed to explain this high level of microendemism, including 1) riverine barrier, 2) mountain refuge, and 3) watershed contraction hypotheses, the latter 2 of which center on fragmentation due to climatic shifts associated with Pliocene/Pleistocene glaciations. The Malagasy leaf chameleon genus Brookesia is a speciose group with a high proportion of microendemic taxa, thus making it an excellent candidate to test these vicariance scenarios. We used mitochondrial and nuclear sequence data to construct a Brookesia phylogeny, and temporal concordance with Pliocene/Pleistocene speciation scenarios was tested by estimating divergence dates using a relaxed-clock Bayesian method. We strongly reject a role for Pliocene/Pleistocene climatic fluctuations in species-level diversification of Brookesia. We also used simulations to test the spatial predictions of the watershed contraction model in a phylogenetic context, independent of its temporal component, and found no statistical support for this model. The riverine barrier model is likewise a qualitatively poor fit to our data, but some relationships support a more ancient mountain refuge effect. We assessed support for the 3 hypotheses in a nonphylogenetic context by examining altitude and species richness and found a significant positive correlation between these variables. This is consistent with a mountain refuge effect but does not support the watershed contraction or riverine barrier models. Finally, we find repeated higher level east-west divergence patterns 1) between the 2 sister clades comprising the Brookesia minima group and 2) within the clade of larger leaf chameleons, which shows a basal divergence between western and eastern/northern sister clades. Our results highlight the central role of phylogeny in any meaningful tests of species-level diversification theories.", "corpus_id": 13031974, "score": 0 }, { "doc_id": "27927363", "title": "Madagascar as a model region of species diversification.", "abstract": "Tropical biotas provide excellent settings in which to explore mechanisms of evolutionary diversification, yet these processes remain poorly understood. Pioneering work on biodiversity patterns and diversification processes in other tropical regions has recently been complemented by studies in Madagascar. Here we review diversity models and diversification mechanisms proposed for the fauna of this island and the perspectives for testing them. Madagascar has a diverse biota that has evolved in isolation, and is characterised by regionally pronounced and locally steep environmental gradients, common patterns of microendemism across taxa and numerous evolutionary radiations. These characteristics establish Madagascar as a promising system for the study of pattern and process in species diversification.", "corpus_id": 27927363, "score": 0 }, { "doc_id": "6405023", "title": "Remarkable species diversity in Malagasy mouse lemurs (primates, Microcebus).", "abstract": "Phylogenetic analysis of mtDNA sequence data confirms the observation that species diversity in the world's smallest living primate (genus Microcebus) has been greatly underestimated. The description of three species new to science, and the resurrection of two others from synonymy, has been justified on morphological grounds and is supported by evidence of reproductive isolation in sympatry. This taxonomic revision doubles the number of recognized mouse lemur species. The molecular data and phylogenetic analyses presented here verify the revision and add a historical framework for understanding mouse lemur species diversity. Phylogenetic analysis revises established hypotheses of ecogeographic constraint for the maintenance of species boundaries in these endemic Malagasy primates. Mouse lemur clades also show conspicuous patterns of regional endemism, thereby emphasizing the threat of local deforestation to Madagascar's unique biodiversity.", "corpus_id": 6405023, "score": 0 }, { "doc_id": "87664506", "title": "Mouse Lemur Phylogeography Revises a Model of Ecogeographic Constraint in Madagascar", "abstract": "Mouse lemurs (genus Microcebus) are small nocturnal primates that are ubiquitously distributed throughout Madagascar. Until the past decade or so, it was believed that there were only two species, one that occupied the eastern regions of Madagascar (M. rufus) and one that occupied the western regions of Madagascar (M. murinus). Intensive field studies, accompanied by genetic analysis, have revealed that the two species taxonomy vastly underestimates the actual species diversity, however, with eight species now recognized. There are numerous indicators that even the eight species taxonomy is an insufficient representation of their actual evolutionary diversity. Our chapter reviews some of the evidence both for the presently acknowledged species diversity, and clarifies the evidence for supposing that there are other species yet to be identified. Primarily, the chapter focuses on the unexpected phylogeographic patterns revealed by mitochondrial DNA analysis. These data show that mouse lemur species do not form western and eastern clades, as ecogeographic evidence might suggest. Rather, there appears to be a historical separation of species into northern and southern clades. We emphasize the point, however, that this latter pattern is based on incomplete species and geographic sampling. Only complete sampling of populations from all regions of Madagascar will reveal the true historical patterns of mouse lemur evolution.", "corpus_id": 87664506, "score": 0 }, { "doc_id": "25840084", "title": "The ever-increasing diversity in mouse lemurs: three new species in north and northwestern Madagascar.", "abstract": "Mouse lemurs (Microcebus spp.) are the world's smallest primates and endemic to Madagascar. Several recent taxonomic revisions resulted in an extraordinary increase of recognized species. What still was considered as being two species at the beginning of the 20th century is currently recognized as 12 taxa. Based on fur coloration pattern, they can be divided into grayish and reddish forms. Two major models have been proposed to explain the extensive speciation events in the Malagasy fauna. The best known suggests that major rivers and mountains combine to act as effective barriers to gene flow and thereby facilitate allopatric speciation processes. A more recent model used an analysis of watersheds in the context of Quaternary climatic shifts to explain the process of explosive speciation on the island. We tested these two models by covering the areas between all major rivers (n=8) in northwestern and northern Madagascar. Mouse lemurs were systematically caught, sampled and morphometrically characterized in 25 sites (with 2-49 individuals per site and species). A complete phylogeny was constructed on the basis of the sequences of three mitochondrial loci (in total 1296 bp). The phylogenetic data revealed a previously unknown biodiversity with three new mouse lemur species among the reddish forms, each having a very small distribution, i.e., being restricted to only one Inter-River-System (IRS). Morphometric analyses underlined their distinctiveness and a brief formal species description is provided. In contrast to the reddish forms, grayish forms have a very low species diversity coupled with broad distributions that cover more than one IRS. These differences among the species are discussed as outcome of divergent colonization scenarios. Elements of both biogeographic models are combined in a new hypothesis that aims to explain the speciation process leading to the present distribution of mouse lemurs in Madagascar.", "corpus_id": 25840084, "score": 0 }, { "doc_id": "22919924", "title": "Molecular Evidence of Reproductive Isolation in Sympatric Sibling Species of Mouse Lemurs", "abstract": "Recent morphological and molecular phylogenetic studies of mouse lemurs (Microcebus) living in the western and southern regions of Madagascar have shown that specific diversity had been considerably underestimated. In large part, this underestimate was due to the lack of sufficient specimens from given localities to assess properly the level of phenotypic variation within and between populations. The accurate delineation of specific boundaries has no doubt been confounded by the diminutive size, nocturnal habits, and subtle morphological variation characteristic of mouse lemurs, which can make field identification of individuals problematic. We illustrate the use of molecular phylogenetic analysis to reveal reproductive isolation in two sympatric mouse lemur species, Microcebus murinus and M. griseorufus. Their documentation in the Berenty Private Reserve in the extreme south of Madagascar verifies the historically-broad distribution of Microcebus griseorufus, a species recently resurrected from synonomy.", "corpus_id": 22919924, "score": 1 }, { "doc_id": "205361394", "title": "Hybridization between mouse lemurs in an ecological transition zone in southern Madagascar", "abstract": "Hybrid zones in ecotones can be useful model systems for the study of evolutionary processes that shape the distribution and discreteness of species. Such studies could be important for an improved understanding of the complex biogeography of Madagascar, which is renowned for its outstanding degree of small‐scale endemism. Certain forest remnants in central Madagascar indicate that transitional corridors across the island could have connected microendemics in different forest types in the past. Evolutionary processes in such corridors are difficult to study because most of these corridors have disappeared due to deforestation in central Madagascar. We studied a hybrid zone in one of the few remaining ecotonal corridors between dry and humid forests in Madagascar, which connects two species of mouse lemurs, Microcebus griseorufus in dry spiny forest and Microcebus murinus in humid littoral forest. We sampled 162 mouse lemurs at nine sites across this boundary. Morphometric analyses revealed intermediate morphotypes of many individuals in transitional habitat. Bayesian clustering of microsatellite genotypes and assignment tests yielded evidence for a mixed ancestry of mouse lemurs in the ecotone, where we also observed significant linkage disequilibria and heterozygote deficiency. In contrast to these observations, mitochondrial haplotypes displayed a sharply delimited boundary at the eastern edge of spiny forest, which was noncoincident with the signals from microsatellite data. Among several alternative scenarios, we propose asymmetric nuclear introgression due to male‐biased dispersal, divergent environmental selection, and an expansion of dry spiny forest in the course of aridification as a probable explanation of our observations.", "corpus_id": 205361394, "score": 0 }, { "doc_id": "896721", "title": "Hybridization of mouse lemurs: different patterns under different ecological conditions", "abstract": "BackgroundSeveral mechanistic models aim to explain the diversification of the multitude of endemic species on Madagascar. The island's biogeographic history probably offered numerous opportunities for secondary contact and subsequent hybridization. Existing diversification models do not consider a possible role of these processes. One key question for a better understanding of their potential importance is how they are influenced by different environmental settings. Here, we characterized a contact zone between two species of mouse lemurs, Microcebus griseorufus and M. murinus, in dry spiny bush and mesic gallery forest that border each other sharply without intermediate habitats between them. We performed population genetic analyses based on mtDNA sequences and nine nuclear microsatellites and compared the results to a known hybrid zone of the same species in a nearby wide gradient from dry spiny bush over transitional forest to humid littoral forest.ResultsIn the spiny-gallery system, Microcebus griseorufus is restricted to the spiny bush; Microcebus murinus occurs in gallery forest and locally invades the dryer habitat of its congener. We found evidence for bidirectional introgressive hybridization, which is closely linked to increased spatial overlap within the spiny bush. Within 159 individuals, we observed 18 hybrids with mitochondrial haplotypes of both species. Analyses of simulated microsatellite data indicate that we identified hybrids with great accuracy and that we probably underestimated their true number. We discuss short-term climatic fluctuations as potential trigger for the dynamic of invasion and subsequent hybridization. In the gradient hybrid zone in turn, long-term aridification could have favored unidirectional nuclear introgression from Microcebus griseorufus into M. murinus in transitional forest.ConclusionsMadagascar's southeastern transitional zone harbors two very different hybrid zones of mouse lemurs in different environmental settings. This sheds light on the multitude of opportunities for the formation of hybrid zones and indicates an important influence of environmental factors on secondary contact and hybridization. Our findings suggest that hybridization could enhance the adaptability of mouse lemurs without necessarily leading to a loss of distinctiveness. They point to a potential role of hybridization in Madagascar's diversification history that requires further investigation.", "corpus_id": 896721, "score": 0 }, { "doc_id": "19541472", "title": "Origins, Diversity and Relationships of Lemurs", "abstract": "AbstractI review new evidence on origins and adaptive radiation of Malagasy lemurs, a remarkably diverse group containing 13% of living primate species. The number of recognized lemur species has increased significantly, partly due to research revealing specific subdivisions within known populations but mainly because of discovery of new populations through fieldwork. Some species feared to be extinct have also been rediscovered. Specific numbers have increased particularly in small-bodied, cryptic genera for which continued research will surely reveal even more species.Adaptative radiation of lemurs has been essentially confined to Madagascar. The high density of lemur species on that island, associated with very small geographical ranges, has major implications both for their evolutionary divergence and for conservation. Reconstructions of phylogenetic relationships among primates have been considerably enhanced by DNA sequence data. Sufficient data are now available from both nuclear and mitochondrial sequences to examine relationships among and within the major groups of living primates. Most studies have confirmed that lemurs constitute a monophyletic sister-group of the lorisiform clade and all exclude a specific relationship between cheirogaleids and lorisiforms repeatedly inferred from morphological evidence. However, some analyses indicate that the aye-aye may have branched away before the divergence between other lemurs and lorisiforms. DNA sequence analyses have also yielded a broad consensus for relationships between Eulemur, Hapalemur, Lemur and Varecia: Varecia branched away first, while Lemur is more closely related to Hapalemur than to Eulemur.\nAs debate about phylogenetic relationships among lemurs and other primates seems to have been settled in favor of lemur monophyly (possibly excluding the aye-aye), only a single invasion of Madagascar is required; but it must still be explained how ancestral lemurs could have migrated there at an appropriate time. Separation between Madagascar and Africa was apparently complete by about 120 Ma, too far in the past for direct overland migration. A recent hypothesis suggested that uplifted land in the Mozambique Channel assisted colonization of Madagascar 26-45 Ma, seemingly agreeing with an estimated date of about 40 Ma for divergence of lemurs from other primates. However, mounting evidence suggests that divergence occurred significantly earlier. Because the earliest known fossil representatives of several modern orders of placental mammals (including primates) are dated no earlier than the early Tertiary, it is widely accepted that their divergence took place after the Cretaceous/Tertiary mass extinction. Yet the known fossil record can only yield minimum divergence times; if sampling is poor and/or biased there may be a considerable discrepancy between minimum and actual dates. There is, for example, virtually no known fossil record for lemurs in Madagascar and the earliest known representatives are subfossil lemurs, so in this case a direct reading of the fossil record would indicate that the lemurs first originated just a few thousand years ago! Examination of underestimation of times of origin because of poor sampling in the fossil record has confirmed previous suggestions that primates originated considerably earlier than generally believed. Several recent phylogenetic reconstructions based on DNA sequence data and using calibration dates derived from groups other than primates provide independent support for this inference. Overall, it now seems that primates originated at around 90 Ma rather than the 55 Ma indicated by direct reading of the known fossil record. Hence, colonization of Madagascar by lemurs would have taken place at about 80 Ma, double the date usually accepted, and should be interpreted in terms of contemporary continental relationships.", "corpus_id": 19541472, "score": 0 }, { "doc_id": "10858188", "title": "Multiple nuclear loci reveal patterns of incomplete lineage sorting and complex species history within western mouse lemurs (Microcebus).", "abstract": "Mouse lemurs (genus Microcebus) are nocturnal primates endemic to the island of Madagascar. Until recently, they were classified as two species, one from eastern and one from western Madagascar. Previously published analyses of morphometric and mitochondrial DNA data show strong support for the recognition of more than eight species, however. Here, we test the eight-species hypothesis with DNA data derived from four independently segregating nuclear loci. We find many areas of congruence between the mitochondrial and nuclear data, but incomplete lineage sorting and low mutation rates limit the phylogenetic resolution of the nuclear data. Even so, the nuclear loci unanimously find evidence for three deeply diverged lineages within the mouse lemur radiation: one that is congruent with the mtDNA \"southern clade\", another that is congruent with the mtDNA \"northern clade\", and one monospecific branch comprised of the species Microcebus ravelobensis. The latter result in particular emphasizes the need for careful biological study of this species.", "corpus_id": 10858188, "score": 1 }, { "doc_id": "656177", "title": "Delimiting Species without Nuclear Monophyly in Madagascar's Mouse Lemurs", "abstract": "Background Speciation begins when populations become genetically separated through a substantial reduction in gene flow, and it is at this point that a genetically cohesive set of populations attain the sole property of species: the independent evolution of a population-level lineage. The comprehensive delimitation of species within biodiversity hotspots, regardless of their level of divergence, is important for understanding the factors that drive the diversification of biota and for identifying them as targets for conservation. However, delimiting recently diverged species is challenging due to insufficient time for the differential evolution of characters—including morphological differences, reproductive isolation, and gene tree monophyly—that are typically used as evidence for separately evolving lineages. Methodology In this study, we assembled multiple lines of evidence from the analysis of mtDNA and nDNA sequence data for the delimitation of a high diversity of cryptically diverged population-level mouse lemur lineages across the island of Madagascar. Our study uses a multi-faceted approach that applies phylogenetic, population genetic, and genealogical analysis for recognizing lineage diversity and presents the most thoroughly sampled species delimitation of mouse lemur ever performed. Conclusions The resolution of a large number of geographically defined clades in the mtDNA gene tree provides strong initial evidence for recognizing a high diversity of population-level lineages in mouse lemurs. We find additional support for lineage recognition in the striking concordance between mtDNA clades and patterns of nuclear population structure. Lineages identified using these two sources of evidence also exhibit patterns of population divergence according to genealogical exclusivity estimates. Mouse lemur lineage diversity is reflected in both a geographically fine-scaled pattern of population divergence within established and geographically widespread taxa, as well as newly resolved patterns of micro-endemism revealed through expanded field sampling into previously poorly and well-sampled regions.", "corpus_id": 656177, "score": 1 }, { "doc_id": "18124980", "title": "Incongruence between genetic and morphological diversity in Microcebus griseorufus of Beza Mahafaly", "abstract": "BackgroundThe past decade has seen a remarkable increase in the number of recognized mouse lemur species (genus Microcebus). As recently as 1994, only two species of mouse lemur were recognized according to the rules of zoological nomenclature. That number has now climbed to as many as fifteen proposed species. Indeed, increases in recognized species diversity have also characterized other nocturnal primates – galagos, sportive lemurs, and tarsiers. Presumably, the movement relates more to a previous lack of information than it does to any recent proclivity for taxonomic splitting. Due to their nocturnal habits, one can hypothesize that mouse lemurs will show only minimal variation in pelage coloration as such variation should be inconsequential for the purposes of mate and/or species recognition. Even so, current species descriptions for nocturnal strepsirrhines place a good deal of emphasis on relatively fine distinctions in pelage coloration.ResultsHere, we report results from a multi-year study of mouse lemur populations from Beza Mahafaly in southern Madagascar. On the basis of morphological and pelage variation, we initially hypothesized the presence of up to three species of mouse lemurs occurring sympatrically at this locality, one of which appeared to be undescribed. Genetic analysis reveals definitively, however, that all three color morphs belong to a single recognized species, Microcebus griseorufus. Indeed, in some cases, the three color morphs can be characterized by identical mitochondrial haplotypes.ConclusionGiven these results, we conclude that investigators should always proceed with caution when using a single data source to identify novel species. A synthetic approach that combines morphological, genetic, geographic, and ecological data is most likely to reveal the true nature of species diversity.", "corpus_id": 18124980, "score": 0 }, { "doc_id": "18367182", "title": "Geneious Basic: An integrated and extendable desktop software platform for the organization and analysis of sequence data", "abstract": "Summary: The two main functions of bioinformatics are the organization and analysis of biological data using computational resources. Geneious Basic has been designed to be an easy-to-use and flexible desktop software application framework for the organization and analysis of biological data, with a focus on molecular sequences and related data types. It integrates numerous industry-standard discovery analysis tools, with interactive visualizations to generate publication-ready images. One key contribution to researchers in the life sciences is the Geneious public application programming interface (API) that affords the ability to leverage the existing framework of the Geneious Basic software platform for virtually unlimited extension and customization. The result is an increase in the speed and quality of development of computation tools for the life sciences, due to the functionality and graphical user interface available to the developer through the public API. Geneious Basic represents an ideal platform for the bioinformatics community to leverage existing components and to integrate their own specific requirements for the discovery, analysis and visualization of biological data. Availability and implementation: Binaries and public API freely available for download at http://www.geneious.com/basic, implemented in Java and supported on Linux, Apple OSX and MS Windows. The software is also available from the Bio-Linux package repository at http://nebc.nerc.ac.uk/news/geneiousonbl. Contact: peter@biomatters.com", "corpus_id": 18367182, "score": 0 }, { "doc_id": "10960997", "title": "MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform.", "abstract": "A multiple sequence alignment program, MAFFT, has been developed. The CPU time is drastically reduced as compared with existing methods. MAFFT includes two novel techniques. (i) Homo logous regions are rapidly identified by the fast Fourier transform (FFT), in which an amino acid sequence is converted to a sequence composed of volume and polarity values of each amino acid residue. (ii) We propose a simplified scoring system that performs well for reducing CPU time and increasing the accuracy of alignments even for sequences having large insertions or extensions as well as distantly related sequences of similar length. Two different heuristics, the progressive method (FFT-NS-2) and the iterative refinement method (FFT-NS-i), are implemented in MAFFT. The performances of FFT-NS-2 and FFT-NS-i were compared with other methods by computer simulations and benchmark tests; the CPU time of FFT-NS-2 is drastically reduced as compared with CLUSTALW with comparable accuracy. FFT-NS-i is over 100 times faster than T-COFFEE, when the number of input sequences exceeds 60, without sacrificing the accuracy.", "corpus_id": 10960997, "score": 0 }, { "doc_id": "12474926", "title": "RDP3: a flexible and fast computer program for analyzing recombination", "abstract": "Summary: RDP3 is a new version of the RDP program for characterizing recombination events in DNA-sequence alignments. Among other novelties, this version includes four new recombination analysis methods (3SEQ, VISRD, PHYLRO and LDHAT), new tests for recombination hot-spots, a range of matrix methods for visualizing over-all patterns of recombination within datasets and recombination-aware ancestral sequence reconstruction. Complementary to a high degree of analysis flow automation, RDP3 also has a highly interactive and detailed graphical user interface that enables more focused hands-on cross-checking of results with a wide variety of newly implemented phylogenetic tree construction and matrix-based recombination signal visualization methods. The new RDP3 can accommodate large datasets and is capable of analyzing alignments ranging in size from 1000×10 kilobase sequences to 20×2 megabase sequences within 48 h on a desktop PC. Availability: RDP3 is available for free from its web site http://darwin.uvigo.es/rdp/rdp.html Contact: darrenpatrickmartin@gmail.com Supplementary information: The RDP3 program manual contains detailed descriptions of the various methods it implements and a step-by-step guide describing how best to use these.", "corpus_id": 12474926, "score": 0 }, { "doc_id": "30694158", "title": "Possible emergence of new geminiviruses by frequent recombination.", "abstract": "Although exchange of genetic information by recombination plays a role in the evolution of viruses, the extent to which it generates diversity is not clear. We analyzed genomes of geminiviruses for recombination using a new statistical procedure developed to detect gene conversions. Geminiviruses (family, Geminiviridae) are a group of plant viruses characterized by a genome of circular single-stranded DNA (approximately 2700 nucleotides in length) encapsidated in twinned quasi-isometric particles. Complete nucleotide sequences of geminiviruses were aligned, and recombination events were detected by searching pairs of viruses for sequences that are significantly more similar than expected based on random distribution of polymorphic sites. The analyses revealed that recombination is very frequent and occurs between species and within and across genera. Tests identified 420 statistically significant recombinant fragments distributed across the genome. The results suggest that recombination is a significant contributor to geminivirus evolution. The high rate of recombination may be contributing to the recent emergence of new geminivirus diseases.", "corpus_id": 30694158, "score": 0 }, { "doc_id": "5111557", "title": "Analyzing the mosaic structure of genes", "abstract": "SummarySome genes in prokaryotes consist of a mosaic of regions derived from different ancestors by horizontal gene transfer. A method is described for demonstrating the statistical significance of such mosaic structure and for locating the crossover points separating different regions.", "corpus_id": 5111557, "score": 0 }, { "doc_id": "15343045", "title": "RDP: detection of recombination amongst aligned sequences", "abstract": "SUMMARY\nRecombination Detection Program (RDP) is a program that applies a pairwise scanning approach to the detection of recombination amongst a group of aligned DNA sequences. The software runs under Windows95 and combines highly automated screening of large numbers of sequences with a highly interactive interface for examining the results of the analyses.", "corpus_id": 15343045, "score": 0 }, { "doc_id": "60509238", "title": "DnaSP v5: A software for comprehensive analysis of DNA polymorphism data", "abstract": "Motivation: DnaSP is a software package for a comprehensive analysis of DNA polymorphism data. Version 5 implements a number of new features and analytical methods allowing extensive DNA polymorphism analyses on large datasets. Among other features, the newly implemented methods allow for: (i) analyses on multiple data files; (ii) haplotype phasing; (iii) analyses on insertion/deletion polymorphism data; (iv) visualizing sliding window results integrated with available genome annotations in the UCSC browser. Availability: Freely available to academic users from: http://www.ub.edu/dnasp Contact: jrozas@ub.edu", "corpus_id": 60509238, "score": 0 }, { "doc_id": "13724742", "title": "Development and application of a phylogenomic toolkit: resolving the evolutionary history of Madagascar's lemurs.", "abstract": "Lemurs and the other strepsirrhine primates are of great interest to the primate genomics community due to their phylogenetic placement as the sister lineage to all other primates. Previous attempts to resolve the phylogeny of lemurs employed limited mitochondrial or small nuclear data sets, with many relationships poorly supported or entirely unresolved. We used genomic resources to develop 11 novel markers from nine chromosomes, representing approximately 9 kb of nuclear sequence data. In combination with previously published nuclear and mitochondrial loci, this yields a data set of more than 16 kb and adds approximately 275 kb of DNA sequence to current databases. Our phylogenetic analyses confirm hypotheses of lemuriform monophyly and provide robust resolution of the phylogenetic relationships among the five lemuriform families. We verify that the genus Daubentonia is the sister lineage to all other lemurs. The Cheirogaleidae and Lepilemuridae are sister taxa and together form the sister lineage to the Indriidae; this clade is the sister lineage to the Lemuridae. Divergence time estimates indicate that lemurs are an ancient group, with their initial diversification occurring around the Cretaceous-Tertiary boundary. Given the power of this data set to resolve branches in a notoriously problematic area of primate phylogeny, we anticipate that our phylogenomic toolkit will be of value to other studies of primate phylogeny and diversification. Moreover, the methods applied will be broadly applicable to other taxonomic groups where phylogenetic relationships have been notoriously difficult to resolve.", "corpus_id": 13724742, "score": 0 }, { "doc_id": "297799", "title": "Delimiting species without monophyletic gene trees.", "abstract": "Genetic data are frequently used to delimit species, where species status is determined on the basis of an exclusivity criterium, such as reciprocal monophyly. Not only are there numerous empirical examples of incongruence between the boundaries inferred from such data compared to other sources like morphology -- especially with recently derived species, but population genetic theory also clearly shows that an inevitable bias in species status results because genetic thresholds do not explicitly take into account how the timing of speciation influences patterns of genetic differentiation. This study represents a fundamental shift in how genetic data might be used to delimit species. Rather than equating gene trees with a species tree or basing species status on some genetic threshold, the relationship between the gene trees and the species history is modeled probabilistically. Here we show that the same theory that is used to calculate the probability of reciprocal monophyly can also be used to delimit species despite widespread incomplete lineage sorting. The results from a preliminary simulation study suggest that very recently derived species can be accurately identified long before the requisite time for reciprocal monophyly to be achieved following speciation. The study also indicates the importance of sampling, both with regards to loci and individuals. Withstanding a thorough investigation into the conditions under which the coalescent-based approach will be effective, namely how the timing of divergence relative to the effective population size of species affects accurate species delimitation, the results are nevertheless consistent with other recent studies (aimed at inferring species relationships), showing that despite the lack of monophyletic gene trees, a signal of species divergence persists and can be extracted. Using an explicit model-based approach also avoids two primary problems with species delimitation that result when genetic thresholds are applied with genetic data -- the inherent biases in species detection arising from when and how speciation occurred, and failure to take into account the high stochastic variance of genetic processes. Both the utility and sensitivities of the coalescent-based approach outlined here are discussed; most notably, a model-based approach is essential for determining whether incompletely sorted gene lineages are (or are not) consistent with separate species lineages, and such inferences require accurate model parameterization (i.e., a range of realistic effective population sizes relative to potential times of divergence for the purported species). It is the goal (and motivation of this study) that genetic data might be used effectively as a source of complementation to other sources of data for diagnosing species, as opposed to the exclusion of other evidence for species delimitation, which will require an explicit consideration of the effects of the temporal dynamic of lineage splitting on genetic data.", "corpus_id": 297799, "score": 0 }, { "doc_id": "7040691", "title": "Bayesian inference of population size history from multiple loci", "abstract": "BackgroundEffective population size (Ne) is related to genetic variability and is a basic parameter in many models of population genetics. A number of methods for inferring current and past population sizes from genetic data have been developed since JFC Kingman introduced the n-coalescent in 1982. Here we present the Extended Bayesian Skyline Plot, a non-parametric Bayesian Markov chain Monte Carlo algorithm that extends a previous coalescent-based method in several ways, including the ability to analyze multiple loci.ResultsThrough extensive simulations we show the accuracy and limitations of inferring population size as a function of the amount of data, including recovering information about evolutionary bottlenecks. We also analyzed two real data sets to demonstrate the behavior of the new method; a single gene Hepatitis C virus data set sampled from Egypt and a 10 locus Drosophila ananassae data set representing 16 different populations.ConclusionThe results demonstrate the essential role of multiple loci in recovering population size dynamics. Multi-locus data from a small number of individuals can precisely recover past bottlenecks in population size which can not be characterized by analysis of a single locus. We also demonstrate that sequence data quality is important because even moderate levels of sequencing errors result in a considerable decrease in estimation accuracy for realistic levels of population genetic variability.", "corpus_id": 7040691, "score": 0 }, { "doc_id": "2522419", "title": "Bayesian Phylogenetics with BEAUti and the BEAST 1.7", "abstract": "Computational evolutionary biology, statistical phylogenetics and coalescent-based population genetics are becoming increasingly central to the analysis and understanding of molecular sequence data. We present the Bayesian Evolutionary Analysis by Sampling Trees (BEAST) software package version 1.7, which implements a family of Markov chain Monte Carlo (MCMC) algorithms for Bayesian phylogenetic inference, divergence time dating, coalescent analysis, phylogeography and related molecular evolutionary analyses. This package includes an enhanced graphical user interface program called Bayesian Evolutionary Analysis Utility (BEAUti) that enables access to advanced models for molecular sequence and phenotypic trait evolution that were previously available to developers only. The package also provides new tools for visualizing and summarizing multispecies coalescent and phylogeographic analyses. BEAUti and BEAST 1.7 are open source under the GNU lesser general public license and available at http://beast-mcmc.googlecode.com and http://beast.bio.ed.ac.uk", "corpus_id": 2522419, "score": 0 }, { "doc_id": "26387069", "title": "jModelTest 2: more models, new heuristics and parallel computing", "abstract": "jModelTest 2: more models, new heuristics and parallel computing Diego Darriba, Guillermo L. Taboada, Ramón Doallo and David Posada Supplementary Table 1. New features in jModelTest 2 Supplementary Table 2. Model selection accuracy Supplementary Table 3. Mean square errors for model averaged estimates Supplementary Note 1. Hill-climbing hierarchical clustering algorithm Supplementary Note 2. Heuristic filtering Supplementary Note 3. Simulations from prior distributions Supplementary Note 4. Speed-up benchmark on real and simulated datasets", "corpus_id": 26387069, "score": 0 }, { "doc_id": "14963272", "title": "Divergence dates for Malagasy lemurs estimated from multiple gene loci: geological and evolutionary context", "abstract": "The lemurs of Madagascar are a unique radiation of primates that show an extraordinary diversity of lifestyles, morphologies and behaviours. However, very little is known about the relative antiquity of lemuriform clades due to the lack of terrestrial fossils for the Tertiary of Madagascar. Here, we employ a Bayesian method to estimate divergence dates within the lemuriform radiation using several unlinked gene loci and multiple fossil calibrations outside the lemuriform clade. Two mitochondrial genes (cytochrome oxidase II and cytochrome b), two nuclear introns (transthyretin intron 1 and von Willebrand factor gene intron 11) and one nuclear exon (interphotoreceptor retinoid binding protein, exon 1) are used in separate and combined analyses. The genes differ in taxon sampling and evolutionary characteristics but produce congruent date estimates. Credibility intervals narrow considerably in combined analyses relative to separate analyses due to the increased amount of data. We also test the relative effects of multiple vs. single calibration points, finding that, when only single calibration points are employed, divergence dates are systematically underestimated. For the mitochondrial DNA data set, we investigate the effects of sampling density within the mouse lemur radiation (genus Microcebus). When only two representative species are included, estimated dates throughout the phylogeny are more recent than with the complete‐species sample, with basal nodes less affected than recent nodes. The difference appears to be due to the manner in which priors on node ages are constructed in the two analyses. In nearly all analyses, the age of the lemuriform clade is estimated to be approximately 62–65 Ma, with initial radiation of mouse lemurs and true lemurs (genus Eulemur) occurring approximately 8–12 Ma. The antiquity of the mouse lemur radiation is surprising given the near uniform morphology among species. Moreover, the observation that mouse lemurs and true lemurs are of similar ages suggests discrepancies in rates of morphological, behavioural and physiological evolution in the two clades, particularly with regard to characteristics of sexual signalling. These differences appear to correlate with the nocturnal vs. diurnal lifestyles, respectively, of these two primate groups.", "corpus_id": 14963272, "score": 0 }, { "doc_id": "1021017", "title": "Bayesian Inference of Species Trees from Multilocus Data", "abstract": "Until recently, it has been common practice for a phylogenetic analysis to use a single gene sequence from a single individual organism as a proxy for an entire species. With technological advances, it is now becoming more common to collect data sets containing multiple gene loci and multiple individuals per species. These data sets often reveal the need to directly model intraspecies polymorphism and incomplete lineage sorting in phylogenetic estimation procedures. For a single species, coalescent theory is widely used in contemporary population genetics to model intraspecific gene trees. Here, we present a Bayesian Markov chain Monte Carlo method for the multispecies coalescent. Our method coestimates multiple gene trees embedded in a shared species tree along with the effective population size of both extant and ancestral species. The inference is made possible by multilocus data from multiple individuals per species. Using a multiindividual data set and a series of simulations of rapid species radiations, we demonstrate the efficacy of our new method. These simulations give some insight into the behavior of the method as a function of sampled individuals, sampled loci, and sequence length. Finally, we compare our new method to both an existing method (BEST 2.2) with similar goals and the supermatrix (concatenation) method. We demonstrate that both BEST and our method have much better estimation accuracy for species tree topology than concatenation, and our method outperforms BEST in divergence time and population size estimation.", "corpus_id": 1021017, "score": 0 }, { "doc_id": "57864", "title": "Relaxed Phylogenetics and Dating with Confidence", "abstract": "In phylogenetics, the unrooted model of phylogeny and the strict molecular clock model are two extremes of a continuum. Despite their dominance in phylogenetic inference, it is evident that both are biologically unrealistic and that the real evolutionary process lies between these two extremes. Fortunately, intermediate models employing relaxed molecular clocks have been described. These models open the gate to a new field of “relaxed phylogenetics.” Here we introduce a new approach to performing relaxed phylogenetic analysis. We describe how it can be used to estimate phylogenies and divergence times in the face of uncertainty in evolutionary rates and calibration times. Our approach also provides a means for measuring the clocklikeness of datasets and comparing this measure between different genes and phylogenies. We find no significant rate autocorrelation among branches in three large datasets, suggesting that autocorrelated models are not necessarily suitable for these data. In addition, we place these datasets on the continuum of clocklikeness between a strict molecular clock and the alternative unrooted extreme. Finally, we present analyses of 102 bacterial, 106 yeast, 61 plant, 99 metazoan, and 500 primate alignments. From these we conclude that our method is phylogenetically more accurate and precise than the traditional unrooted model while adding the ability to infer a timescale to evolution.", "corpus_id": 57864, "score": 0 }, { "doc_id": "13864758", "title": "RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models", "abstract": "UNLABELLED\nRAxML-VI-HPC (randomized axelerated maximum likelihood for high performance computing) is a sequential and parallel program for inference of large phylogenies with maximum likelihood (ML). Low-level technical optimizations, a modification of the search algorithm, and the use of the GTR+CAT approximation as replacement for GTR+Gamma yield a program that is between 2.7 and 52 times faster than the previous version of RAxML. A large-scale performance comparison with GARLI, PHYML, IQPNNI and MrBayes on real data containing 1000 up to 6722 taxa shows that RAxML requires at least 5.6 times less main memory and yields better trees in similar times than the best competing program (GARLI) on datasets up to 2500 taxa. On datasets > or =4000 taxa it also runs 2-3 times faster than GARLI. RAxML has been parallelized with MPI to conduct parallel multiple bootstraps and inferences on distinct starting trees. The program has been used to compute ML trees on two of the largest alignments to date containing 25,057 (1463 bp) and 2182 (51,089 bp) taxa, respectively.\n\n\nAVAILABILITY\nicwww.epfl.ch/~stamatak", "corpus_id": 13864758, "score": 0 }, { "doc_id": "531861", "title": "Speciation in little: the role of range and body size in the diversification of Malagasy mantellid frogs", "abstract": "BackgroundThe rate and mode of lineage diversification might be shaped by clade-specific traits. In Madagascar, many groups of organisms are characterized by tiny distribution ranges and small body sizes, and this high degree of microendemism and miniaturization parallels a high species diversity in some of these groups. We here investigate the geographic patterns characterizing the radiation of the frog family Mantellidae that is virtually endemic to Madagascar. We integrate a newly reconstructed near-complete species-level timetree of the Mantellidae with georeferenced distribution records and maximum male body size data to infer the influence of these life-history traits on each other and on mantellid diversification.ResultsWe reconstructed a molecular phylogeny based on nuclear and mitochondrial DNA for 257 species and candidate species of the mantellid frog radiation. Based on this phylogeny we identified 53 well-supported pairs of sister species that we used for phylogenetic comparative analyses, along with whole tree-based phylogenetic comparative methods. Sister species within the Mantellidae diverged at 0.2-14.4 million years ago and more recently diverged sister species had geographical range centroids more proximate to each other, independently of their current sympatric or allopatric occurrence. The largest number of sister species pairs had non-overlapping ranges, but several examples of young microendemic sister species occurring in full sympatry suggest the possibility of non-allopatric speciation. Range sizes of species included in the sister species comparisons increased with evolutionary age, as did range size differences between sister species, which rejects peripatric speciation. For the majority of mantellid sister species and the whole mantellid radiation, range and body sizes were associated with each other and small body sizes were linked to higher mitochondrial nucleotide substitution rates and higher clade diversity. In contrast, small range sizes were unexpectedly associated with a slow-down of mitochondrial substitution rates.ConclusionsBased on these results we define a testable hypothesis under which small body sizes result in limited dispersal capabilities and low physiological tolerances, causing smaller and more strongly fragmented ranges. This can be thought to facilitate reproductive isolation and thus favor speciation. Contrary to the expectation of the faster speciation of such microendemic phenotype species, we only found small body sizes of mantellid frogs to be linked to higher diversification and substitution rates, but not small range sizes. A joint analysis of various species-rich regional anuran radiations might provide enough species with all combinations of range and body sizes for a more conclusive test of this hypothesis.", "corpus_id": 531861, "score": 0 }, { "doc_id": "2421915", "title": "Signals of recent spatial expansions in the grey mouse lemur (Microcebus murinus)", "abstract": "BackgroundPleistocene events have shaped the phylogeography of many taxa worldwide. Their genetic signatures in tropical species have been much less explored than in those living in temperate regions. We analysed the genetic structure of a Malagasy primate species, a mouse lemur with a wide distribution (M. murinus), in order to investigate such phylogeographic processes on a large tropical island. We also evaluated the effects of anthropogenic pressures (fragmentation/deforestation) and natural features (geographic distance, rivers) on genetic structure in order to complement our understanding of past and present processes of genetic differentiation.ResultsThe analysis of the mitochondrial D-loop sequences of 195 samples from 15 study sites (10 from a continuous forest and five from isolated forest fragments) from two adjacent Inter-River-Systems (IRSs) revealed that forest fragmentation and the river restrict gene flow, thereby leading to an increased genetic differentiation between populations beyond the effect of isolation-by-distance. Demographic simulations detected signals of two successive spatial expansions that could be preliminarily dated to the late Pleistocene and early Holocene. The haplotype network revealed geographic structure and showed deep molecular divergences within and between the IRSs that would be congruent with a two-step colonization scenario.ConclusionsThis study supports the hypothesis of a relatively recent spatial expansion of the grey mouse lemur in northwestern Madagascar, which may also explain why this taxon, in contrast to its congeners, has not yet undergone allopatric speciation in the studied area and possibly across its presently wide range.", "corpus_id": 2421915, "score": 0 }, { "doc_id": "85628531", "title": "Latitude drives diversification in Madagascar's endemic dry forest rodent Eliurus myoxinus (subfamily Nesomyinae)", "abstract": "Numerous hypotheses have been proposed for the historical processes governing the rich endemism of Madagas- car's biodiversity. The 'watershed model' suggests that drier climates in the recent geological past have resulted in the contraction of forests around major watersheds, thereby defining areas of endemism. We test whether this hypothesis explains phylogeographical patterns in a dry forest-dependent rodent, Eliurus myoxinus, an endemic species widely distributed through western Madagascar. We sequenced the mitochondrial cytochrome b locus and nuclear introns of the β-fibrinogen and the growth hormone receptor genes for E. myoxinus. Using a parametric bootstrapping approach, we tested whether the mitochondrial gene tree data fit expectations of local differentiation given the watershed model. We additionally estimated population differentiation and historical demographic parameters, and reconstructed the spatial history of E. myoxinus to highlight spatial and temporal patterns of differentiation. The data do not support the watershed model as a clear explanation for the genetic patterns of diversity within extant E. myoxinus populations. We find striking patterns of latitudinal genetic structure within western Madagascar, and indicate possible roles for environmental and ecological gradients along this axis in generating phylogeographical diversity. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2013, 110, 500-517.", "corpus_id": 85628531, "score": 0 }, { "doc_id": "26180579", "title": "A chronology for late prehistoric Madagascar.", "abstract": "A database has been assembled with 278 age determinations for Madagascar. Materials 14C dated include pretreated sediments and plant macrofossils from cores and excavations throughout the island, and bones, teeth, or eggshells of most of the extinct megafaunal taxa, including the giant lemurs, hippopotami, and ratites. Additional measurements come from uranium-series dates on speleothems and thermoluminescence dating of pottery. Changes documented include late Pleistocene climatic events and, in the late Holocene, the apparently human-caused transformation of the environment. Multiple lines of evidence point to the earliest human presence at ca. 2300 14C yr BP (350 cal yr BC). A decline in megafauna, inferred from a drastic decrease in spores of the coprophilous fungus Sporormiella spp. in sediments at 1720+/-40 14C yr BP (230-410 cal yr AD), is followed by large increases in charcoal particles in sediment cores, beginning in the SW part of the island, and spreading to other coasts and the interior over the next millennium. The record of human occupation is initially sparse, but shows large human populations throughout the island by the beginning of the Second Millennium AD. Dating of the \"subfossil\" megafauna, including pygmy hippos, elephant birds, giant tortoises, and large lemurs, demonstrates that most if not all the extinct taxa were still present on the island when humans arrived. Many taxa overlapped chronologically with humans for a millennium or more. The extinct lemurs Hadropithecus stenognathus, Pachylemur insignis, Mesopropithecus pithecoides, and Daubentonia robusta, and the elephant birds Aepyornis spp. and Mullerornis spp., were still present near the end of the First Millennium AD. Palaeopropithecus ingens, Megaladapis edwardsi, and Archaeolemur sp. (cf. edwardsi) may have survived until the middle of the Second Millennium A.D. One specimen of Hippopotamus of unknown provenance dates to the period of European colonization.", "corpus_id": 26180579, "score": 1 }, { "doc_id": "126423239", "title": "Rates, Patterns, and Processes of Landscape Transformation and Extinction in Madagascar", "abstract": "Inferring cause and effect from the fossil record is not a wholly satisfying enterprise. The evidence is stale. Many useful details are missing, perhaps never to be found. Sequential events may be collapsed together, inverted, or mixed with evidence from other times. Few relevant parameters can be measured directly. Paleoecologists must forge ahead despite these obstacles, however, as extinction and environmental change are subjects too important to ignore.", "corpus_id": 126423239, "score": 0 }, { "doc_id": "23268852", "title": "Distribution and Morphological Variation of Microcebus spp. Along an Environmental Gradient in Southeastern Madagascar", "abstract": "The lemurs of Madagascar are known for their extraordinary levels of speciation. However, the mechanisms and environmental conditions that led to this diversity remain obscure. We used 3 species of Microcebus (M. griseorufus, M. murinus, M. rufus) occurring along an environmental gradient as a model to investigate 1) how the different species are distributed in relation to variation in environmental conditions and ecotones; 2) whether or not the morphology of a given species varies in relation to environmental conditions; and 3) whether or not there is evidence for morphological character displacement to reduce congeneric competition in sympatry vs. allopatry. The 3 species of Microcebus show clear associations with specific habitat types. Distributions overlap at ecotones. Nevertheless, the ecotone between dry spiny and gallery forest represents a species boundary between Microcebus griseorufus and M. murinus while the ecotone between dry spiny forest and evergreen humid forest represents the species boundary between M. murinus and M. rufus. Different ambient conditions are not reflected in changes in body measurements of Microcebus murinus living in different vegetation formations. There is no indication for character displacement in sympatry vs. allopatry. Thus, differences in body mass or other morphological characteristics do not contribute to species separation between Microcebus griseorufus and M. murinus. The results confirm the importance of ecotones as species boundaries as a condition postulated for the radiation of lemur and other species on Madagascar. They also demonstrate different habitat affinities of seemingly very similar lemur species and thus illustrate our very limited understanding of the actual selection pressures, adaptations of lemurs to their environments, and their possible response to interspecific competition.", "corpus_id": 23268852, "score": 0 }, { "doc_id": "12592868", "title": "Habitat Separation of Sympatric Microcebus spp. in the Dry Spiny Forest of South-Eastern Madagascar", "abstract": "We investigated whether or not habitat structure contributes to the separation of two sister species of lemurs and their hybrids. For this, we studied Microcebusmurinus and M. griseorufus along a continuous vegetation gradient where populations of the two species occur in sympatry or in allopatry. In allopatry, the two species are generalists without any sign of microhabitat selectivity. In sympatry, both species differed significantly and discriminated against certain habitat structures: M. murinus was found in microhabitats with larger trees than average while M. griseorufus utilized microhabitats with smaller trees. Hybrids between the two species did not show any significant discrimination for or against microhabitat structure and did not differ in their habitat utilization from either parent species. Both species can go into torpor and hibernation. M. griseorufus is seen more frequently during the cool dry season than M. murinus. We assume that M. murinus goes into extended torpor or hibernation more frequently than M. griseorufus. We interpret the different occurrence of large-sized trees in microhabitats of M. murinus as a prerequisite for M. murinus to be able to spend extended periods of time in tree holes that are isolated and allow hibernation at reduced temperature levels.", "corpus_id": 12592868, "score": 0 }, { "doc_id": "51738785", "title": "Patterns of species change in anthropogenically disturbed forests of Madagascar", "abstract": "Five main conclusions arise from this review of the responses of species to anthropogenic disturbance in Madagascar: First, species’ reactions to anthropogenic disturbance are generally negative, but remain poorly known. Our knowledge is patchy among and within higher taxonomic groups; we are still largely gathering case studies. Second, taxonomic groups vary considerably in which proximate factors are most important. Third, several groups show differing responses within different ecoregions. Whether these differences are consistent across groups requires further testing. Fourth, related species often have divergent reactions to disturbance, even within lower taxonomic groupings (families or genera). Thus, we cannot rely on phylogenetic relatedness or even ecological similarity to infer similarity in responses. Finally, disturbance typically reduces species diversity (especially of native and/or endemic species), but also causes species turnover, typically with forest specialists replaced by grassland generalists, and endemics replaced by non-endemics (including invasives). Given these knowledge gaps, we stress the urgency of applied studies that assess species’ ecology, behaviour and health across disturbance gradients, including purely anthropogenic landscapes. Remaining natural vegetation and protected areas will be unable to preserve Madagascar’s biodiversity under the impact of climatic change; we must understand responses of plants and animals to disturbance in order to create buffer zones and corridors combining secondary, degraded and natural habitats.", "corpus_id": 51738785, "score": 0 } ]

{ "doc_id": "132949369", "title": "Nonbreeder birds at colonies display qualitatively similar seasonal mass change patterns as breeders", "abstract": "Abstract The difficulty in studying nonbreeding birds means that little is known about them or their resource requirements, despite forming a large and significant component of a population. One way to assess food requirements is to examine changes in body mass, because it indicates the amount of food acquired. In terms of body mass changes, our expectation is that nonbreeders will either (a) be in poorer condition than the breeders which potentially explains why they do not breed or (b) remain at a stable higher mass as they are unconstrained by the physiological costs associated with rearing chicks. Here, we interrogate body mass datasets of breeding and nonbreeding birds of two penguin species to assess these predictions and determine whether differences in mass exist between these two groups throughout the breeding season. The first dataset is from a wild Adélie penguin population, where bird mass was recorded automatically and breeding status determined from a resighting program. A second population of captive gentoo penguins were weighed regularly each breeding season. We demonstrate that although there were times in each year when breeders were heavier than their nonbreeding counterparts for both populations, the mass changes showed qualitatively similar patterns throughout the breeding season irrespective of breeding status. Heavier breeders at times during the breeding season are not unexpected but the overall similar pattern of mass change irrespective of breeding status is in contrast to expectations. It appears that breeding status per se and the constraints that breeding places on birds are not the only driver of changes in mass throughout the breeding season and, although not explicitly studied here, the role of hormones in driving changes in appetite could be key to explain these results. These results present a significant step toward understanding food requirements of nonbreeders in avian populations.", "corpus_id": 132949369 }

[ { "doc_id": "87708004", "title": "Modelling Annual Changes in Numbers of Breeding Fulmars, Fulmarus glacialis, at a Colony in Orkney", "abstract": "(1) During a long-term study of breeding fulmars in Orkney, the number of birds breeding each year has increased on average, but with some considerable variations between years. (2) In a species with deferred maturity, low fidelity to natal colony and which is faithful to both mate and nest site, the factors causing changes in breeding numbers are likely to be annual survival of established breeders and annual recruitment of new breeders. (3) Recruitment could not be measured directly, but an index was determined, based upon the number of unringed breeding birds. However, in the observed data there were some occasions in which not all of the unringed birds breeding in one year necessarily bred the following year. There is some evidence to suggest that this may be due to intermittent breeding and/or emigration, probably involving inexperienced breeders. (4) A new index of 'recruitment', which could be negative, was calculated from the observed data. A model was developed to simulate breeding population size over a series of years, using observed annual values of survival and 'recruitment' as input parameters. (5) Simulations from the model were realistic in terms of variation between years and correlations between variables. (6) The model was therefore run using particular observed values for both 'recruitment' and survival. It was found that 'recruitment' had a much greater effect upon the population size than did survival of breeding adults. (7) The model was then used to predict the size of the breeding population one year in advance, with reasonable accuracy. (8) The simulations highlight the need for further information about the behaviour and movements of potential breeding recruits.", "corpus_id": 87708004, "score": 0 }, { "doc_id": "73607888", "title": "ON COLONY SIZE , BREEDING SUCCESS , RECRUITMENT AND INTER-COLONY DISPERSAL IN A TASMANIAN COLONY OF SHORT-TAILED SHEARWATERS PUFFINUS TENUIROSTRIS OVER A 30-YEAR PERIOD", "abstract": "SERVENTY, D.L. and P.J. CURRY 1984. Observations on colony size, breeding success, recruitment and intercolony dispersal in a Tasmanian colony of Short-tailed Shearwaters Puffinus tenurrostrrs over a 30-year period. Emu 84: 71-79. A programme to mark a small colony of Short-tailed Shearwaters, by means of monel leg-bands, was begun on Fisher Island during 1947-50 as part of a comprehensive study. Banding of all adults and their young has colitinued every year since (to 1980). The numbsrf breeding bu r rowsoc_cup ied~~h year declined steadily during the first 25 years of the study, at the end of which numbers had been reduced by 71%. More recently, numbers have begun to increase again. No change has occurred in the relative sizes of three sub-colonies existing within the island. Annual rates of breeding success were usually lower than those reported from other less-studiedcolcGn?es and have tenTeZT03eeZher relatilvilyhigh (> 55%) or else poor (< 40%). Some chicks were raised every year; on average, the smallest sub-colony was as successful as the largest. Nearly all breeding failures occurred before the chick-rearing stage and few successfully hatched chicks failed to fledge. No banded young were recaptured at the colony before age two and most not until three years and upwards. Age at first breeding for both sexes ranged from five to at least ten years. Forty-one per cent of chicks banded over 20 consecutive seasons were subsequently recovered alive on their natal island but only 35% of these were recruited as breeders. Losses of immatures and young adults through emigration were offset by an annual recruitment of unbanded immigrants, most of which could not have been bred on the island. After 30 years, the proportion of Fisherbred breeders in the colony was stable at 41-46%. Band recoveries confirmed inter-colony dispersal by young adults. Fisher-bred birds found in nearby colonies were encountered mainly in the nearest breeding area on the closest neighbouring island. Repeated disturbance of the colony during the course of the study is thought to have contributed to the decline of the colony, due to increased burrow desertion, decreased breeding success and decreased recruitment of young adults.", "corpus_id": 73607888, "score": 0 }, { "doc_id": "1037122", "title": "Long-term population studies of seabirds.", "abstract": "Long-term studies of seabirds, some now 30-40 years old, have begun to reveal significant age-related changes in the survival and reproduction o f these long-lived animals. Evidence for density-dependent regulation of seabird numbers, however, remains sparse whereas unpredictable, disastrous breeding years may be an important influence. Critical evaluation will require better data on (1) the extent of movements of seabirds between colonies, (2) the characteristics of those individuals that contribute disproportionately to the next generation, and (3) the importance of year and/or cohort effects on population processes.", "corpus_id": 1037122, "score": 0 }, { "doc_id": "86570386", "title": "Age and the timing of breeding in a long‐lived bird: a role for stress hormones?", "abstract": "Summary \n1. Young birds often reproduce later in the season than older ones, with poorer breeding success, but the proximate mechanisms involved in such a pattern remain poorly studied, especially in long-lived species. One possible mechanism is the endocrine stress response which is accompanied by the release of corticosterone. Elevated corticosterone levels can trigger physiological and behavioural responses that may delay or even suppress reproduction. \n \n2. We tested the hypothesis that the delayed timing of breeding of young birds may be related to a greater susceptibility to stress compared with older ones during the pre-laying period of the breeding season. For this purpose, known-age (7–44 years old) pre-laying snow petrels, Pagodroma nivea, were monitored for baseline and acute stress-induced corticosterone levels. We examined whether baseline and stress-induced corticosterone levels were related to age, and whether they could influence the decision to breed and egg-laying date. \n \n3. Young snow petrels were more likely to skip the breeding season and to breed later than middle-aged birds. In addition, the oldest birds bred later than middle-aged ones, suggesting a possible senescence on laying dates. Baseline corticosterone levels were independent of age but young and very old birds were more sensitive to stress than middle-aged ones. However, there was no effect of stress-induced corticosterone levels on breeding decision and egg-laying date. Elevated baseline corticosterone levels during the pre-laying period were associated with a higher probability of skipping breeding in females and a delayed timing of egg-laying in both sexes. \n \n4. These results suggest that the greater susceptibility of young breeders to stress was not the functional mechanism explaining their delayed timing of breeding. Baseline corticosterone levels, although independent of age, appear to be a more likely mediator of breeding decision and egg-laying date. In long-lived birds, the relationship between age and timing of breeding may be rather indirect, as other age-related factors such as breeding experience or foraging skills may have a deeper impact on baseline corticosterone than age per se.", "corpus_id": 86570386, "score": 1 }, { "doc_id": "88013377", "title": "Reproductive endocrinology and mechanisms of breeding inhibition in cooperatively breeding Florida Scrub Jays Aphelocoma C. coerulescens)", "abstract": "Although the ecological and evolutionary bases of cooperative breeding have received close scrutiny, few studies have explored the physiological mechanisms responsible for delayed breeding by helpers. We chose the Florida Scrub Jay, Aphelocoma c. coerulescens, to determine whether breeders and nonbreeders have different hormone profiles during the reproductive season. We found that male nonbreeders had significantly lower testosterone levels and higher progesterone levels than did male breeders. Nonbreeder and breeder males had similar plasma levels of corticosterone. Elevated plasma levels of progesterone in nonbreeder males may interfere with the reproductive activity at the behavioral or physiological level. Alternatively, progesterone may enable these nonbreeding males to express parental behavior in the absence of a parent/offspring relationship, but the occurrence of the highest levels of progesterone during nest building and egg laying supports the former interpretation. In females, we found that nonbreeders had significantly lower levels of estradiol and corticosterone than breeders. The low levels of primary sex steroid hormones in male and female nonbreeders may physiologically and behaviorally inhibit reproductive activity and suggest hat these individuals are reproductively incompetent. The absence of high levels of corticosterone in nonbreeders suggests that this reproductive inhibition is not due to glucocorticoid-mediated stress imposed by dominant breeders.", "corpus_id": 88013377, "score": 1 }, { "doc_id": "86551100", "title": "Intermittent Breeding of the Fulmar (Fulmarus glacialis (L.)), with some General Observations on Non‐Breeding in Sea‐Birds", "abstract": "Summary. \n \n1 \n There is a large non-breeding population of Fulmars and other Pro-cellariiform birds, which suggests that they do not breed annually. \n \n2 \n In non-breeding Fulmars obtained in northern Labrador in July it was found that the length of the middle claws varied from 16.0 to 10.6 mm., due to wear. As pelagic birds can only wear down their claws when breeding, this observation strongly suggests a non-breeding population of mixed age-groups. \n \n3 \n Ovaries from four representative non-breeding females were sectioned, and histological confirmation obtained of the relation of claw-length to age. Resorbed remnants of ovulated follicles prove that all these birds had bred in one or many previous years, and thus that their reproduction is intermittent. \n \n4 \n A case of follicular atresia accompanied by the extrusion of yolk into the stroma is figured. \n \n5 \n When breeding is inhibited in the Fulmar and certain other birds the annual (post-nuptial) moult occurs prematurely. A short discussion is given of other effects of inhibited breeding in marine birds.", "corpus_id": 86551100, "score": 0 }, { "doc_id": "87588505", "title": "Non-breeders as a buffer against environmental stress : declines in numbers of great skuas on Foula, Shetland, and prediction of future recruitment", "abstract": "1. The number of breeding great skuas Catharacta skua on Foula, Shetland, was determined by counting apparently occupied territories (AOTs) during the 1988 and 1990 breeding seasons (2400 and 2340 AOTs, respectively, representing 20% of the northern hemisphere population). 2. A decrease in the availability of the preferred food, sandeels Ammodytes marines, has been accompanied by a slight fall in AOTs, a considerable increase in foraging effort of breeding adults and a 75% fall in breeding success, indicating that food shortage has put the population under stress. 3. Two methods are presented which allow the number of non-breeding great skuas frequenting Foula to be estimated, based on studies of individually colourringed birds. Totals of 3303 (SE = 243) and 4013 (SE = 479) non-breeding great skuas were estimated to frequent Foula in the 1989 and 1990 breeding seasons, respectively. These totals are far greater than indicated by individual counts, due to each bird staying in the colony an average of only 16-21 days. 4. Both the number of breeders and the peak number of non-breeders have declined since 1977, although the peak number of non-breeders decreased much more (non-breeders by 80%, breeders by 21.5%). The rapid decrease in numbers of non-breeders appears to be due to increased recruitment as a consequence of a reduction in adult survival rate, since age at first breeding and breeding success did not change before 1987. 5. Because breeding success since 1987 has been only 25% of the previous average, we predict that the dramatic reduction in the number of non-breeders at Foula since the mid-1970s will soon be followed by a rapid reduction in recruitment, and a further and much faster drop in breeding numbers, over the next few years. 6. This study supports the suggestion of Porter & Coulson (1987) that numbers of non-breeders at seabird colonies may provide an early and sensitive indication of environmental changes having adverse effects on the population, since non-breeders act as a buffer to such stress.", "corpus_id": 87588505, "score": 0 }, { "doc_id": "53629328", "title": "Large-scale population assessment informs conservation management for seabirds in Antarctica and the Southern Ocean: A case study of Adélie penguins", "abstract": "Abstract Antarctica and the Southern Ocean are increasingly affected by fisheries, climate change and human presence. Antarctic seabirds are vulnerable to all these threats because they depend on terrestrial and marine environments to breed and forage. We assess the current distribution and total abundance of Adelie penguins in East Antarctica and find there are 3.5 (95% CI 2.9–4.2) million individuals of breeding age along the East Antarctic coastline and 5.9 (4.2–7.7) million individuals foraging in the adjacent ocean after the breeding season. One third of the breeding population numbering over 1 million individuals breed within 10 km of research stations, highlighting the potential for human activities to impact Adelie penguin populations despite their current high abundance. The 16 Antarctic Specially Protected Areas currently designated in East Antarctica offer protection to breeding populations close to stations in four of six regional populations. The East Antarctic breeding population consumes an average of 193 500 tonnes of krill and 18 800 tonnes of fish during a breeding season, with consumption peaking at the end of the breeding season. These findings can inform future conservation management decisions in the terrestrial environment under the Protocol on Environmental Protection to develop a systematic network of protected areas, and in the marine environment under the Convention for the Conservation of Antarctic Marine Living Resources to allow the consumption needs of Adelie penguins to be taken into account when setting fishery catch limits. Extending this work to other penguin, flying seabird, seal and whale species is a priority for conservation management in Antarctica and the Southern Ocean.", "corpus_id": 53629328, "score": 0 }, { "doc_id": "205318019", "title": "Recruitment and survival of immature seabirds in relation to oil spills and climate variability.", "abstract": "1. In long-lived animals with delayed maturity, the non-breeding component of the population may play an important role in buffering the effects of stochastic mortality. Populations of colonial seabirds often consist of more than 50% non-breeders, yet because they spend much of their early life at sea, we understand little about their impact on the demographic process. 2. Using multistate capture-mark-recapture techniques, we analyse a long-term data set of individually identifiable common guillemots, Uria aalge Pont., to assess factors influencing their immature survival and two-stage recruitment process. 3. Analysis of the distribution of ringed common guillemots during the non-breeding season, separated by age classes, revealed that all age classes were potentially at risk from four major oil spills. However, the youngest age class (0-3 years) were far more widely spread than birds 4-6 years old, which were more widely spread than birds aged 6 and over. Therefore the chance of encountering an oil spill was age-dependent. 4. A 2-year compound survival estimate for juvenile guillemots was weakly negatively correlated with winter sea-surface temperature, but was not influenced by oil spills. Non-breeder survival did not vary significantly over time. 5. In years following four oil spills, juvenile recruitment was almost double the value in non-oil-spill years. Recent work from Skomer Island showed a doubling of adult mortality associated with major oil spills, which probably reduced competition at the breeding colony, allowing increased immature recruitment to compensate for these losses. We discuss the implications of compensatory recruitment for assessing the impact of oil pollution incidents.", "corpus_id": 205318019, "score": 0 }, { "doc_id": "46821668", "title": "Energyscapes and prey fields shape a North Atlantic seabird wintering hotspot under climate change", "abstract": "There is an urgent need for a better understanding of animal migratory ecology under the influence of climate change. Most current analyses require long-term monitoring of populations on the move, and shorter-term approaches are needed. Here, we analysed the ecological drivers of seabird migration within the framework of the energyscape concept, which we defined as the variations in the energy requirements of an organism across geographical space as a function of environmental conditions. We compared the winter location of seabirds with their modelled energy requirements and prey fields throughout the North Atlantic. Across six winters, we tracked the migration of 94 little auks (Alle alle), a key sentinel Arctic species, between their East Greenland breeding site and wintering areas off Newfoundland. Winter energyscapes were modelled with Niche Mapper™, a mechanistic tool which takes into account local climate and bird ecophysiology. Subsequently, we used a resource selection function to explain seabird distributions through modelled energyscapes and winter surface distribution of one of their main prey, Calanus finmarchicus. Finally, future energyscapes were calculated according to IPCC climate change scenarios. We found that little auks targeted areas with high prey densities and moderately elevated energyscapes. Predicted energyscapes for 2050 and 2095 showed a decrease in winter energy requirements under the high emission scenario, which may be beneficial if prey availability is maintained. Overall, our study demonstrates the great potential of the energyscape concept for the study of animal spatial ecology, in particular in the context of global change.", "corpus_id": 46821668, "score": 0 }, { "doc_id": "54923494", "title": "Modelling population dynamics of seabirds: importance of the effects of climate fluctuations on breeding proportions", "abstract": "Environmental factors and their interactions are likely to have shaped specific breeding and survival strategies in top predators. Understanding how climatic factors affect populations requires detailed investigation of the demographic parameters and population modelling. Here, we focus on the modelling of a southern fulmar population over a 39 year period in Terre Adelie, Antarctica, using Leslie matrix models to understand from a prospective and retrospective point of view, how vital rates and their variations, affect the cyclic population dynamics. The elasticity of population growth rate to adult survival was very high (0.95), as predicted by a slow–fast continuum in avian life histories. However, adult survival varied little between years (mean±SD: 0.92±0.07), and could not explain the strong fluctuations observed in the number of breeders and chicks. The high temporal fluctuations of the proportion of breeders (0.57±0.22) and breeding success (0.70±0.14) had the strongest impact on population dynamics, despite their weak elasticities (0.05). Before the 1980s, population fluctuations were mainly explained by a direct impact of sea-ice extent (SIE) anomalies during summer (by a threshold effect) on the proportion of breeders. After 1980s, 3 years periodic population fluctuations were best predicted by 3 years cyclic variations in the proportion of breeders. SIE showed a marked change of periodicity during the 1980s, and SIE during winter fluctuated with a 3 years periodicity during 1980–1995. The marked change in population dynamics, through a change of the variations of the proportion of breeders, may be explained in the light of a regime shift that probably occurred around the 1980s, and which affected the sea ice environment, the availability of prey, and thus the demographic parameters and population dynamics of southern fulmars.", "corpus_id": 54923494, "score": 0 }, { "doc_id": "84923897", "title": "Colony attendance and censusing of Black Guillemots Cepphus grylle in Shetland", "abstract": "The diurnal rhythm of colony attendance by Black Guillemots varied seasonally. No tidal effects were detected but in April attendance was lower when winds exceeded force 4. Numbers were most stable during 05.00–08.00 GMT in the pre-breeding period. Counts at this time and in winds of force 4 or less provide the best estimate of adult populations. Between late March and mid-May, counts of adults associated with breeding habitat account for most birds occupying suitable nest sites and censuses in northern Britain should be conducted in this period. As the proportion of non-breeding adults varies between colonies, no universal correction factor can be used to estimate the number of breeding attempts from counts of birds. Counts aimed at detecting maximum attendance provide greater accuracy than single counts made by flushing all birds on to the sea but take longer. Monitoring units should be stretches o-f coastline that include a number of colonies of different sizes.", "corpus_id": 84923897, "score": 0 }, { "doc_id": "127779324", "title": "Adélie and Chinstrap Penguins: Their Potential as Monitors of the Southern Ocean Marine Ecosystem", "abstract": "Analysis of annual variability in the parameters recommended by CCAMLR for ecosystem monitoring revealed considerable variation among the parameters for which we have sufficient data to make an assessment. Interpretation of the observed variability was greatly enhanced when several parameters were considered simultaneously. In concert, the parameters should be useful for assessing perturbations in the Antarctic ecosystem. The choice of Adelie and chinstrap penguins as key indicator species seems an excellent one, given their very different responses to the highly variable conditions in the Antarctic Peninsula region, their species-specific breeding patterns, and the asynchrony between their respective breeding seasons. If a time series of data becomes available, it may be possible to differentiate between fishery-induced and natural perturbations in the ecosystem.", "corpus_id": 127779324, "score": 1 }, { "doc_id": "16178456", "title": "Thermodynamic modelling predicts energetic bottleneck for seabirds wintering in the northwest Atlantic", "abstract": "SUMMARY Studying the energetics of marine top predators such as seabirds is essential to understand processes underlying adult winter survival and its impact on population dynamics. Winter survival is believed to be the single most important life-history trait in long-lived species but its determinants are largely unknown. Seabirds are inaccessible during this season, so conventional metabolic studies are extremely challenging and new approaches are needed. This paper describes and uses a state-of-the-art mechanistic model, Niche Mapper™, to predict energy expenditure and food requirements of the two main seabird species wintering in the northwest Atlantic. We found that energy demand increased throughout the winter phase in both species. Across this period, mean estimated daily energy requirements were 1306 kJ day–1 for Brünnich's guillemots (Uria lomvia) and 430 kJ day–1 for little auks (Alle alle) wintering off Greenland and Newfoundland. Mean estimated daily food requirements were 547 g wet food day–1 for Brünnich's guillemots, and 289 g wet food day–1 for little auks. For both species and both wintering sites, our model predicts a sharp increase in energy expenditure between November and December, primarily driven by climatic factors such as air temperature and wind speed. These findings strongly suggest the existence of an energetic bottleneck for North Atlantic seabirds towards the end of the year, a challenging energetic phase which might explain recurrent events of winter mass-mortality, so called `seabird winter wrecks'. Our study therefore emphasizes the relevance of thermodynamics/biophysical modelling for investigating the energy balance of wintering marine top predators and its interplay with survival and population dynamics in the context of global change.", "corpus_id": 16178456, "score": 0 }, { "doc_id": "84331250", "title": "FIELD METABOLIC RATE AND FOOD REQUIREMENT SCALING IN MAMMALS AND BIRDS", "abstract": "Field metabolic rates (FMRs or HF), all measured using doubly labeled water, of 23 species of eutherian mammals, 13 species of marsupial mammals, and 25 species of birds were summarized and analyzed allometrically (log10-1og10 regressions). FMR is strong- ly correlated with body mass in each of these groups. FMR scales differently than does basal or standard metabolic rate in eutherians (FMR slope = 0.81) and marsupials (FMR slope = 0.58), but not in birds (FMR slope = 0.64 overall, but 0.75 in passerines and 0.75 in all other birds). Medium-sized (240-5 50 g) eutherians, marsupials, and birds have similar FMRs, and these are - 17 times as high as FMRs of like-sized ectothermic vertebrates such as iguanid lizards. For endothermic vertebrates, the energy cost of surviving in nature is enormous compared with that for ectotherms. Within the eutherians, marsupials, or birds, FMR scales differently for the following subgroups: rodents, passerine birds, her- bivorous eutherians, herbivorous marsupials, desert eutherians, desert birds, and seabirds. Equations are given for use in predicting daily and annual FMR and food requirement of a species of terrestrial vertebrate, given its body mass.", "corpus_id": 84331250, "score": 0 }, { "doc_id": "88192227", "title": "Daily body-mass loss and nitrogen excretion during molting fast of Macaroni Penguins", "abstract": "SHORT, L. L. 1972. Hybridization, taxonomy and avian evolution. Ann. Mo. Bot. Gard. 59:447-453. TAYLOR, A. L., AND E. D. FORSMAN. 1976. Recent range extensions of the Barred Owl in western North America, including the first records for Oregon. Condor 78:560-561. U.S. FISH AND WILDLIFE SERVICE. 1990. Determination of threatened status for the Northern Spotted Owl, Final rule. U.S. Federal Register 55(123): 26114-26194. Voous, K. H. 1989. Owls of the Northern Hemisphere. MIT Press, Cambridge, Massachusetts.", "corpus_id": 88192227, "score": 0 }, { "doc_id": "5623588", "title": "Refeeding signal in fasting-incubating king penguins: changes in behavior and egg temperature.", "abstract": "This study is directed toward understanding the process of feeding stimulation (\"refeeding signal\") that has been suggested to operate below a body mass threshold or critical metabolic status in spontaneously fasting birds. Behavior and egg temperature (T(egg)) were continuously monitored by video monitoring and biotelemetry, respectively, in fasting-incubating king penguins kept in a pen to prevent relief by the partner until spontaneous egg abandonment. Penned birds fasted 10 days more and lost 1.2 kg more than birds relieved normally by their partner, abandoning the egg about 1 wk after reaching a critical body mass. Definitive egg abandonment was preceded by transitory abandonments of progressively increasing duration during which time the birds went further and further away from their egg. There were marked interindividual differences but on average transitory abandonments began 36 +/- 5 h before the definitive abandonment and were paralleled by resumption of display songs signaling the readiness of the bird to depart for feeding. T(egg) was maintained at around 35.7 degrees C during normal incubation but significantly decreased the last 2 days before egg abandonment. These changes are interpreted as reflecting a stimulation to refeed at a threshold body mass corresponding to a critical fat store depletion. Thus the fasting-incubating king penguin appears to be an interesting animal model for understanding the long-term metabolic control of feeding behavior in relation to energy status.", "corpus_id": 5623588, "score": 0 }, { "doc_id": "4381796", "title": "Behavioral changes in fasting emperor penguins: evidence for a \"refeeding signal\" linked to a metabolic shift.", "abstract": "This study examines the relationships between metabolic status and behavior in spontaneously fasting birds in the context of long-term regulation of body mass and feeding. Locomotor activity, escape behavior, display songs, body mass, and metabolic and endocrine status of captive male emperor penguins were recorded during a breeding fast. We also examined whether body mass at the end of the fast affected further survival. The major part of the fast ( phase II) was characterized by the maintenance of a very low level of locomotor activity, with almost no attempt to escape, by an almost constant rate of body mass loss, and by steady plasma levels of uric acid, β-hydroxybutyrate, and corticosterone. This indicates behavioral and metabolic adjustments directed toward sparing energy and body protein. Below a body mass of ∼24 kg ( phase III), spontaneous locomotor activity and attempts to escape increased by up to 8- and 15-fold, respectively, and display songs were resumed. This probably reflected an increase in the drive to refeed. Simultaneously, daily body mass loss and plasma levels of uric acid and corticosterone increased, whereas plasma levels of β-hydroxybutyrate decreased. Some experimental birds were seen again in following years. These findings suggest that at a threshold of body mass, a metabolic and endocrine shift, possibly related to a limited availability of fat stores, acts as a \"refeeding signal\" that improves the survival of penguins to fasting.", "corpus_id": 4381796, "score": 0 }, { "doc_id": "4426019", "title": "Thermal strategies of king penguins during prolonged fasting in water", "abstract": "ABSTRACT Most animals experience periods of unfavourable conditions, challenging their daily energy balance. During breeding, king penguins fast voluntarily for up to 1.5 months in the colony, after which they replenish their energy stores at sea. However, at sea, birds might encounter periods of low foraging profitability, forcing them to draw from previously stored energy (e.g. subcutaneous fat). Accessing peripheral fat stores requires perfusion, increasing heat loss and thermoregulatory costs. Hence, how these birds balance the conflicting demands of nutritional needs and thermoregulation is unclear. We investigated the physiological responses of king penguins to fasting in cold water by: (1) monitoring tissue temperatures, as a proxy of tissue perfusion, at four distinct sites (deep and peripheral); and (2) recording their oxygen consumption rate while birds floated inside a water tank. Despite frequent oscillations, temperatures of all tissues often reached near-normothermic levels, indicating that birds maintained perfusion to peripheral tissues throughout their fasting period in water. The oxygen consumption rate of birds increased with fasting duration in water, while it was also higher when the flank tissue was warmer, indicating greater perfusion. Hence, fasting king penguins in water maintained peripheral perfusion, despite the associated greater heat loss and, therefore, thermoregulatory costs, probably to access subcutaneous fat stores. Hence, the observed normothermia in peripheral tissues of king penguins at sea, upon completion of a foraging bout, is likely explained by their nutritional needs: depositing free fatty acids (FFA) in subcutaneous tissues after profitable foraging or mobilizing FFA to fuel metabolism when foraging success was insufficient. Summary: Maintenance of near-normothermic temperatures in peripheral tissues of king penguins when fasting in cold water suggests maintained perfusion, presumably to mobilize free fatty acids from subcutaneous adipose tissue.", "corpus_id": 4426019, "score": 0 }, { "doc_id": "54764932", "title": "Environmental conditions and life history constraints determine foraging range in breeding Adélie penguins", "abstract": "Foraging movements of Adelie penguins are constrained both by environmental con- ditions (e.g. sea ice cover) and life history factors (e.g. regular offspring provisioning). We describe within season changes in foraging range, trip duration and body condition of Adelie penguins nest- ing at Bechervaise Island, East Antarctica, in the context of these constraints. Penguins were satellite tracked over multiple seasons during the incubation, guard, creche and pre-moult phases of their annual cycle. They ranged farthest during incubation when sea ice was extensive and shortest dur- ing the guard stage when chicks were small and sea ice limited in extent. Prior to their annual moult the birds foraged hundreds of kilometres to the west and east of their breeding sites. A recurrent polynya facilitated access to the sea early in the season when ice cover was extensive. Kernel analy- ses showed that penguins foraged most intensively close to the colony, along submarine canyons and at the continental shelf break. Increases in foraging range, as the chick rearing period progressed, were consistent with changing energy requirements of adults and chicks and likely intraspecific competition. Whilst provisioning their offspring, penguins adopted a variable combination of time minimising and food maximising foraging behaviour in which choice of foraging rule was determined largely by adult body condition.", "corpus_id": 54764932, "score": 1 }, { "doc_id": "83593073", "title": "Measurements and seasonal changes in weight of guillemots Uria aalge at a breeding colony", "abstract": "We caught, weighed and measured Guillemots at a colony before and during the breeding season, and when they returned to the colony in October following the main moult of the year. Their sex and breeding status were assessed by detailed observations. Males were heaviest in the prelaying period and lightest when they had young. Lost weight was regained by the autumn. Females showed a similar pattern but the changes were less marked. Adults showed a significant decline in weight with increasing age of the chick. Nonbreeding birds had similar wing lengths to adults but were lighter in weight. We could detect no effect of weight in the prebreeding period on whether or not birds bred, when the egg was laid or breeding success.", "corpus_id": 83593073, "score": 1 }, { "doc_id": "15750878", "title": "Physiological Condition and Reproductive Consequences in Adélie Penguins1", "abstract": "Abstract Animals must make “decisions” (e.g., when or whether to breed, the effort to put into a breeding episode) by integrating physiological, environmental and social inputs. This integration can be studied only in a field context. In Adélie penguins (Pygoscelis adeliae) reproduction is constrained by foraging ecology, mode of transport, and the extreme latitude at which they live. The decision whether to breed in a given year is influenced by body conditions. Adélie penguins must fast for several weeks during the early reproductive stages and use stored fat for metabolic energy. Females that return to the colony, but do not breed, are 10–12% lighter than females that do breed. Birds that are relatively low in body mass tend to have lower reproductive success than heavier birds, and an individual's reproductive success is positively correlated with the body fat stores it had on arrival. After eggs are laid, parents alternate in attending the nest. Nest failure occurs if one parent does not make a timely return and its fasting partner must eventually leave. During normal-length fasts plasma corticosterone and glucose levels do not change. Blood β-hydroxybutyrate levels gradually increase during the fast while uric acid levels remain low, but in birds with the longest fasts (>∼50 days), ketone levels may fall and uric acid levels increase, indicative of a switch from using fat to using body proteins for metabolism. In incubating males, hematocrit and hemoglobin concentrations also increase, suggesting dehydration can accompany energy stress during the breeding fast.", "corpus_id": 15750878, "score": 1 }, { "doc_id": "411545", "title": "To breed or not to breed: a seabird's response to extreme climatic events", "abstract": "Intermittent breeding is an important life-history strategy that has rarely been quantified in the wild and for which drivers remain unclear. It may be the result of a trade-off between survival and reproduction, with individuals skipping breeding when breeding conditions are below a certain threshold. Heterogeneity in individual quality can also lead to heterogeneity in intermittent breeding. We modelled survival, recruitment and breeding probability of the red-footed booby (Sula sula), using a 19 year mark–recapture dataset involving more than 11 000 birds. We showed that skipping breeding was more likely in El-Niño years, correlated with an increase in the local sea surface temperature, supporting the hypothesis that it may be partly an adaptive strategy of birds to face the trade-off between survival and reproduction owing to environmental constraints. We also showed that the age-specific probability of first breeding attempt was synchronized among different age-classes and higher in El-Niño years. This result suggested that pre-breeders may benefit from lowered competition with experienced breeders in years of high skipping probabilities.", "corpus_id": 411545, "score": 0 }, { "doc_id": "42916254", "title": "How partnerships end in guillemots Uria aalge: chance events, adaptive change, or forced divorce?", "abstract": "Divorce in socially monogamous species can result from different mechanisms, for example, chance events, active desertion of the partner, or the intrusion of a third individual ousting the partner. We compared the predictions associated with such mechanisms with data from common guillemots (Uria aalge) breeding on the Isle of May, Scotland. The data cover the years 1982--2005 and show a yearly divorce rate of 10.2%. In most divorces (86%), one of the original partners moved to another breeding site, whereas the other bird stayed and bred with a new partner. On average, movers had a significantly lower breeding success after divorce, stayers were largely unaffected, whereas the incoming birds benefited significantly from the change. This pattern fits best the predictions of the \"forced-divorce\" hypothesis, suggesting that many divorces were caused by incoming birds rather than the original partners or chance events. Although we are unable to document the precise behavioral sequence that led to divorces, our interpretation is supported by observations of frequent fights over breeding-site ownership. Our data also indicate within-population diversity of divorce mechanisms: some divorces were apparently accidental, others desertion of partners and sites if the latter were of low quality. Our study finally illustrates that a negative correlation between breeding success and probability of divorce (which our data show) need not indicate the adaptiveness of divorce for the original partners. Because such a connection has often been made, adaptive divorce may in general be less common than usually assumed. Copyright 2007, Oxford University Press.", "corpus_id": 42916254, "score": 0 }, { "doc_id": "21934158", "title": "Working less to gain more: when breeding quality relates to foraging efficiency.", "abstract": "In animal populations, a minority of individuals consistently achieves the highest breeding success and therefore contributes the most recruits to future generations. On average, foraging performance is important in determining breeding success at the population level, but evidence is scarce to show that more successful breeders (better breeders) forage differently than less successful ones (poorer breeders). To test this hypothesis, we used a 10-year, three-colony, individual-based longitudinal data set on breeding success and foraging parameters of a long-lived bird, the Adélie Penguin, Pygoscelis adeliae. Better breeders foraged more efficiently than poorer breeders under harsh environmental conditions and when offspring needs were higher, therefore gaining higher net energy profit to be allocated to reproduction and survival. These results imply that adverse \"extrinsic\" conditions might select breeding individuals on the basis of their foraging ability. Adélie Penguins show sufficient phenotypic plasticity that at least a portion of the population is capable of surviving and successfully reproducing despite extreme variability in their physical and biological environment, variability that is likely to be associated with climate change and, ultimately, with the species' evolution. This study is the first to demonstrate the importance of \"extrinsic\" conditions (in terms of environmental conditions and offspring needs) on the relationship between foraging behavior and individual quality.", "corpus_id": 21934158, "score": 0 }, { "doc_id": "83755661", "title": "THE TIMING OF BIRDS‘ BREEDING SEASONS", "abstract": "Summary \nExamination of survival rdtes of nestlings and fledglings of some species show that there is a strong tendency for those young which are hatched earliest in the season to have the greatest chance of surviving to breed. Since natural selection so strongly favours parents who leave many surviving young, the question arises as to why other birds breed later than the date at which they could most successfully raise their young. \n \nIt is suggested that the food supply for the breeding females immediately prior to the breeding season may limit their ability to form eggs and the females may thus not be able to lay at the time which would result in young being in the nest at the best time for raising them, but as soon after this time as the female is able to produce her eggs. Not all species are likely to be prevented, by food shortage, from breeding at the best time for raising young and the groups of birds most likely to be affected are discussed.", "corpus_id": 83755661, "score": 0 }, { "doc_id": "19490597", "title": "Effects of age and reproductive status on individual foraging site fidelity in a long-lived marine predator", "abstract": "Individual foraging specializations, where individuals use a small component of the population niche width, are widespread in nature with important ecological and evolutionary implications. In long-lived animals, foraging ability develops with age, but we know little about the ontogeny of individuality in foraging. Here we use precision global positioning system (GPS) loggers to examine how individual foraging site fidelity (IFSF), a common component of foraging specialization, varies between breeders, failed breeders and immatures in a long-lived marine predator—the northern gannet Morus bassanus. Breeders (aged 5+) showed strong IFSF: they had similar routes and were faithful to distal points during successive trips. However, centrally placed immatures (aged 2–3) were far more exploratory and lacked route or foraging site fidelity. Failed breeders were intermediate: some with strong fidelity, others being more exploratory. Individual foraging specializations were previously thought to arise as a function of heritable phenotypic differences or via social transmission. Our results instead suggest a third alternative—in long-lived species foraging sites are learned during exploratory behaviours early in life, which become canalized with age and experience, and refined where possible—the exploration-refinement foraging hypothesis. We speculate similar patterns may be present in other long-lived species and moreover that long periods of immaturity may be a consequence of such memory-based individual foraging strategies.", "corpus_id": 19490597, "score": 0 }, { "doc_id": "35461302", "title": "The biochemistry of natural fasting at its limits", "abstract": "There are several groups of animals that are adapted for extremely long duration fasting as part of their reproductive cycle. Penguins, bears and seals routinely fast without food or water for months at time. However, they do not ‘starve’, as the biochemical implications of starving are very different from those of successful fasting. There are distinct biochemical adaptations in lipid, carbohydrate and especially protein metabolism that allow these animals to survive. It appears, at least for penguins and seals, that the duration of the fast may be limited by changes that occur in biochemical regulation near the end of the fast. In all of these species, the biochemistry of fasting and the ecological and behavioral demands of their breeding cycles are closely interrelated.", "corpus_id": 35461302, "score": 0 }, { "doc_id": "89125347", "title": "How to molt while fasting in the cold: the metabolic and hormonal adaptations of Emperor and King penguins", "abstract": "Like other penguin species, molting Emperor Aptenodytes forsteri and King A. patagonica penguins remain ashore and fast for several weeks during which their entire plumage is simultaneously renewed. Molt therefore involves the use of endogenous lipid reserves and body protein to meet the nutrient requirements not only for new feather synthesis, but also for the increase in energy expenditure associated with the decrease in thermal insulation. This energetic and metabolic stress results in a 45% decrease in body mass and in a 50% loss of body protein. There is no evidence that metabolic hormones such as glucagon, insulin and corticosterone play a major role in the control of metabolic events specifically related to molt. In contrast, the marked increase in circulating thyroxine at the onset of new feather synthesis in adult Emperor and King penguins, and in Emperor Penguin chicks, suggests that this hormone triggers molt by stimulating the development of the new plumage. On the other hand, triiodothyronine could intervene in the control of energy metabolism in situations of acute cold exposure, as during the loss of old feathers in the antarctic adult Emperor Penguins.", "corpus_id": 89125347, "score": 0 }, { "doc_id": "92183093", "title": "Fit is fat: winter body mass of Atlantic Puffins Fratercula arctica", "abstract": "ABSTRACT Capsule: Atlantic Puffins Fratercula arctica from Scottish and Norwegian populations were significantly heavier in winter than when rearing chicks. Aims: To compare body masses of Atlantic Puffins on their wintering grounds off the Faroe Islands with those of birds rearing chicks at colonies in Scotland and Norway. Methods: We took standardized measurements of wing length and body mass of Atlantic Puffins during the summer chick-rearing period and on the wintering grounds near the Faroe Islands. These measurements were used to estimate seasonal changes in body mass for the two breeding populations. In three cases data were available for individuals weighed both at the colony and on the wintering grounds. Results: On average, Atlantic Puffins breeding in Scotland and Norway increased their body mass by 20–30% between the chick-rearing period and winter. The very limited individual level data accorded well with the population level estimates. Conclusions: Our results provide the first estimates of the order of magnitude in mass change between two key life history stages in this species. They indicate that gains in body mass between chick-rearing and winter are at least double the decline in mass previously recorded between incubation and chick-rearing. Given the Atlantic Puffin’s deteriorating conservation status, improved information on seasonal changes in body condition should help determine the underlying causes of die-offs in major wreck incidents such as those reported in recent years.", "corpus_id": 92183093, "score": 1 }, { "doc_id": "86544244", "title": "Fat or lean: adjustment of endogenous energy stores to predictable and unpredictable changes in allostatic load", "abstract": "Summary\r\nThe ability to store energy endogenously is an important ecological mechanism that allows animals to buffer predictable and unpredictable variation in allostatic load. The secretion of glucocorticoids, which reflects changes in allostatic load, is suggested to play a major role in the adjustment of endogenous stores to these varying conditions.\r\nAlthough crucially important, the relationship between allostatic load and energy stores remains largely unexplored. Two contrasting hypotheses describe how stores may be adjusted: animals may use low allostatic loads to increase stores to a maximum possible (‘fat and fit’), or they can attain a lean physique due to fitness advantages of a low body mass (‘lean and fit’).\r\nWe compiled observational and experimental data available for a long-lived seabird to examine the relationship between glucocorticoids and stored energy at two life history stages (incubation and chick-rearing). Data were collected across multiple years and colonies in the North Pacific, thereby reflecting the wide range of environmental conditions birds' encounter in the marine environment. During experimental manipulations, allostatic load was minimized by supplementing food to free-living birds.\r\nWe found that the relationship between allostatic load and energy stores was clearly curvilinear at both life history stages. Observational data suggested that energy stores remained relatively stable under low allostatic load and decreased under high loads. Experimental data showed that birds did not maximize energy stores under favourable conditions but maintained energy stores below a physiologically attainable level.\r\nEnergy stores remained consistently lower during chick-rearing compared to incubation across the wide range of variations in allostatic load suggesting that stage-specific trade-offs limit the accumulation of energy during favourable environmental conditions. Secretion of glucocorticoids did not appear to mediate this shift in energy stores between the life history stages.\r\nOverall, results of this study support the ‘lean and fit’ hypothesis. We conclude that increased energy stores may not necessarily reflect better environmental conditions experienced by individuals or predict their higher fitness. A major advantage of adopting a lean physique when environmental conditions allow may be the avoidance of additional energetic costs for moving a heavy body. In breeding seabirds, this advantage may be more important during chick-rearing. In the focal species, the secretion of glucocorticoids might be involved in regulation of energy stores within a life history stage but does not appear to mediate an adaptive shift in energy stores between the incubating and chick-rearing stages of reproduction.", "corpus_id": 86544244, "score": 1 }, { "doc_id": "55621332", "title": "GEOGRAPHIC STRUCTURE OF ADÉLIE PENGUIN POPULATIONS: OVERLAP IN COLONY-SPECIFIC FORAGING AREAS", "abstract": "In an investigation of the factors leading to geographic structuring among Adelie Penguin (Pygoscelis adeliae) populations, we studied the size and overlap of colony- specific foraging areas within an isolated cluster of colonies. The study area, in the south- western Ross Sea, included one large and three smaller colonies, ranging in size from 3900 to 135 000 nesting pairs, clustered on Ross and Beaufort Islands. We used triangulation of radio signals from transmitters attached to breeding penguins to determine foraging loca- tions and to define colony-specific foraging areas during the chick-provisioning period of four breeding seasons, 1997-2000. Colony populations (nesting pairs) were determined using aerial photography just after egg-laying; reproductive success was estimated by com- paring ground counts of chicks fledged to the number of breeding pairs apparent in aerial photos. Foraging-trip duration, meal size, and adult body mass were estimated using RFID (radio frequency identification) tags and an automated reader and weighbridge. Chick growth was assessed by weekly weighing. We related the following variables to colony size: foraging distance, area, and duration; reproductive success; chick meal size and growth rate; and seasonal variation in adult body mass. We found that penguins foraged closest to their respective colonies, particularly at the smaller colonies. However, as the season pro- gressed, foraging distance, duration, and area increased noticeably, especially at the largest colony. The foraging areas of the smaller colonies overlapped broadly, but very little foraging area overlap existed between the large colony and the smaller colonies, even though the foraging area of the large colony was well within range of the smaller colonies. Instead, the foraging areas of the smaller colonies shifted as that of the large colony grew. Colony size was not related to chick meal size, chick growth, or parental body mass. This differed from the year previous to the study, when foraging trips of the large colony were very long, parents lost mass, and chick meals were smaller. In light of existing data on prey abundance in neritic waters in Antarctica suggesting that krill are relatively evenly distributed and in high abundance in the Southern Ross Sea, we conclude that penguins depleted or changed the availability of their prey, that the degree of alteration was a function of colony size, and that the large colony affected the location (and perhaps ultimately the size) of foraging areas for the smaller colonies. It appears, therefore, that foraging dynamics play a role in the geographic structuring of colonies in this species.", "corpus_id": 55621332, "score": 0 }, { "doc_id": "83696479", "title": "Ashmole's halo : direct evidence for prey depletion by a seabird", "abstract": "Fish population densities were measured at various instances from 2 large colonies of double-crested cormorants Phalacrocorax auritus to test the hypothesis that seabirds deplete prey close to their colonies. Fish densities were significantly lower in bays used by cormorants for feeding than in those outside their foraging range. Our findings provide direct evidence for prey depletion, and support Ashmole's (1963)hypothesis that seabird populations are limited by food supplies during the breeding \nseason. \n).", "corpus_id": 83696479, "score": 0 }, { "doc_id": "86903696", "title": "Reproductive consequences of environment-driven variation in Adélie penguin breeding phenology", "abstract": "Adelie penguins Pygoscelis adeliae exhibit phenological variability across their geo- graphic range due to fixed and variable forcing factors acting differentially on populations. Shifts in breeding phenology can be indicative of environmental change when cues for breeding ini - tiation are tightly linked with environmental conditions. Adelie penguins on opposite sides of Antarctica display contrasting trends in clutch initiation dates, with different explanations of underlying causes. To make comparisons possible with a third significant Adelie penguin popula- tion region, we examined temporal trends and driving factors of breeding phenology at Becher- vaise Island in East Antarctica. We have extended existing knowledge by examining how pheno- logical dates are related throughout a breeding season, as well as the reproductive consequences of phenological variation. In contrast to other sites, we saw no evidence at this site of shifts towards early or delayed arrival or clutch initiation. Arrival, clutch initiation dates and the length of the incubation period had different environmental forcing factors, which explained up to 36% of the temporal variability. Penguins had a reduced courtship and egg-lay period when their arrival was delayed, and this led to later clutch initiation, later parent departure for foraging trips and later chick hatch. The phenological variations recorded here were not detrimental to chick-rearing. In particular, a delay in the start of breeding activities did not result in poor reproductive success. This indicates the importance of other factors for chick survival. Inter-annual pheno logical vari- ability at this location is compared with that at other locations to further develop the colony latitude-breeding phenology relationship for Adelie penguins.", "corpus_id": 86903696, "score": 0 }, { "doc_id": "43908349", "title": "Statistical Computing: An Introduction to Data Analysis Using S-PLUS", "abstract": "First, a clariŽ cation: This book is not about traditional statistical computing topics, such as random number generation, approximation of probability distribution functions, least squares computations, and so forth. The book’s subtitle reveals what it is about: “An Introduction to Data Analysis using S-PLUS.” Crawley’s intention, as stated in the Preface, is to provide “both an introduction to and a reference manual for statistics and computing.” (The commercial package S-PLUS appears in the subtitle, but the Preface notes the availability of the freeware R system, which can be obtained at www.r-project.org. The author states that all the examples in the book will also work in R. Based on my experience with the two packages, some code tweaking may be required when using R, but you cannot beat the price.) My Ž rst reaction when I began to peruse this book was “wow”: More than 750 pages, covering a vast range of topics in statistical modeling. Roughly speaking, the Ž rst third of the book covers material suitable for a Ž rst course in statistics, the middle third covers basic applied linear models (regression and analysis of variance), and the Ž nal third covers a number of advanced statistical modeling methods, including generalized linear models, tree-based models, nonparametric smoothing, survival analysis, time series, mixed-effects models, and spatial statistics. There is a certain logic to the sequencing of topics in the text, but Crawley has made some nonstandard (one might even say quirky) decisions. For instance, power calculations are discussed three chapters before the classical hypothesis testing procedures are introduced. The early chapter on basic graphical techniques includes displays of tree-based models but excludes probability plotting. The formal introduction of probability distributions is quite thorough, but does not appear until Chapter 26, two-thirds of the way through the book. A number of examples involve the use of procedures that are not formally introduced until much later in the book. (Including more cross-referencing when this happens would make the book more effective as a self-study guide.) On balance, I can recommend this book for the intended audience, as long as they understand what they are in for. It contains a wealth of sage advice about the process of designing studies, analyzing data, and Ž tting statistical models and could become a treasured reference. However, the style is fairly terse and fast-paced, and neophytes may Ž nd it somewhat overwhelming. In the Preface, Crawley says “Learning S-PLUS will not be easy, but you won’t regret making the effort.” The same can be said for reading this book.", "corpus_id": 43908349, "score": 0 }, { "doc_id": "61891765", "title": "Least-Squares Means: The R Package lsmeans", "abstract": "Least-squares means are predictions from a linear model, or averages thereof. They are useful in the analysis of experimental data for summarizing the effects of factors, and for testing linear contrasts among predictions. The lsmeans package (Lenth 2016) provides a simple way of obtaining least-squares means and contrasts thereof. It supports many models fitted by R (R Core Team 2015) core packages (as well as a few key contributed ones) that fit linear or mixed models, and provides a simple way of extending it to cover more model classes.", "corpus_id": 61891765, "score": 0 }, { "doc_id": "3912443", "title": "Energetic Physiology Mediates Individual Optimization of Breeding Phenology in a Migratory Arctic Seabird", "abstract": "The influence of variation in individual state on key reproductive decisions impacting fitness is well appreciated in evolutionary ecology. Rowe et al. (1994) developed a condition-dependent individual optimization model predicting that three key factors impact the ability of migratory female birds to individually optimize breeding phenology to maximize fitness in seasonal environments: arrival condition, arrival date, and ability to gain in condition on the breeding grounds. While empirical studies have confirmed that greater arrival body mass and earlier arrival dates result in earlier laying, no study has assessed whether individual variation in energetic management of condition gain effects this key fitness-related decision. Using an 8-year data set from over 350 prebreeding female Arctic common eiders (Somateria mollissima), we tested this component of the model by examining whether individual variation in two physiological traits influencing energetic management (plasma triglycerides: physiological fattening rate; baseline corticosterone: energetic demand) predicted individual variation in breeding phenology after controlling for arrival date and body mass. As predicted by the optimization model, individuals with higher fattening rates and lower energetic demand had the earliest breeding phenology (shortest delays between arrival and laying; earliest laying dates). Our results are the first to empirically determine that individual flexibility in prebreeding energetic management influences key fitness-related reproductive decisions, suggesting that individuals have the capacity to optimally manage reproductive investment.", "corpus_id": 3912443, "score": 1 }, { "doc_id": "205777525", "title": "Corticosterone and foraging behavior in a diving seabird: the Adélie penguin, Pygoscelis adeliae.", "abstract": "Because hormones mediate physiological or behavioral responses to intrinsic or extrinsic stimuli, they can help us understand how animals adapt their foraging decisions to energetic demands of reproduction. Thus, the hormone corticosterone deserves specific attention because of its influence on metabolism, food intake and locomotor activities. We examined the relationships between baseline corticosterone levels and foraging behavior or mass gain at sea in a diving seabird, the Adélie penguin, Pygoscelis adeliae. Data were obtained from free-ranging penguins during the brooding period (Adélie Land, Antarctica) by using satellite transmitters and time-depth-recorders. The birds were weighed and blood sampled before and after a foraging trip (pre-trip and post-trip corticosterone levels, respectively). Penguins with elevated pre-trip corticosterone levels spent less time at sea and stayed closer to the colony than penguins with low pre-trip corticosterone levels. These short trips were associated with a higher foraging effort in terms of diving activity and a lower mass gain at sea than long trips. According to previous studies conducted on seabird species, these results suggest that penguins with elevated pre-trip corticosterone levels might maximize the rate of energy delivery to the chicks at the expense of their body reserves. Moreover, in all birds, corticosterone levels were lower post-foraging than pre-foraging. This decrease could result from either the restoration of body reserves during the foraging trip or from a break in activity at the end of the foraging trip. This study demonstrates for the first time in a diving predator the close relationships linking foraging behavior and baseline corticosterone levels. We suggest that slight elevations in pre-trip corticosterone levels could play a major role in breeding effort by facilitating foraging activity in breeding seabirds.", "corpus_id": 205777525, "score": 0 }, { "doc_id": "4783719", "title": "Ghrelin affects stopover decisions and food intake in a long-distance migrant", "abstract": "Significance Twice a year, billions of birds migrate across continents. Along their route, most species spend considerable time at stopover sites to replenish their fuel stores. What physiological signals tell them when they are ready to continue their journey? Ghrelin is a recently discovered hormone involved in appetite regulation. We found that ghrelin concentrations correlated positively with fat stores of wild garden warblers. Further, birds injected with ghrelin decreased their food intake and increased their drive to continue migration. Hence, our study shows that hormones regulating food intake and energy stores control migratory behavior. This is a previously unknown role for a hormonal system shared by birds and mammals, whose disruption causes eating disorders and obesity. Billions of birds migrate long distances to either reach breeding areas or to spend the winter at more benign places. On migration, most passerines frequently stop over to rest and replenish their fuel reserves. To date, we know little regarding how they decide that they are ready to continue their journey. What physiological signals tell a bird’s brain that its fuel reserves are sufficient to resume migration? A network of hormones regulates food intake and body mass in vertebrates, including the recently discovered peptide hormone, ghrelin. Here, we show that ghrelin reflects body condition and influences migratory behavior of wild birds. We measured ghrelin levels of wild garden warblers (Sylvia borin) captured at a stopover site. Further, we manipulated blood concentrations of ghrelin to test its effects on food intake and migratory restlessness. We found that acylated ghrelin concentrations of garden warblers with larger fat scores were higher than those of birds without fat stores. Further, injections of unacylated ghrelin decreased food intake and increased migratory restlessness. These results represent experimental evidence that appetite-regulating hormones control migratory behavior. Our study lays a milestone in migration physiology because it provides the missing link between ecologically dependent factors such as condition and timing of migration. In addition, it offers insights in the regulation of the hormonal system controlling food intake and energy stores in vertebrates, whose disruption causes eating disorders and obesity.", "corpus_id": 4783719, "score": 0 }, { "doc_id": "17849861", "title": "Exogenous corticosterone mimics a late fasting stage in captive Adelie penguins (Pygoscelis adeliae).", "abstract": "Fasting is part of penguin's breeding constraints. During prolonged fasting, three metabolic phases occur successively. Below a threshold in body reserves, birds enter phase III (PIII), which is characterized by hormonal and metabolic shifts. These changes are concomitant with egg abandonment in the wild and increased locomotor activity in captivity. Because corticosterone (CORT) enhances foraging activity, we investigated the variations of endogenous CORT, and the effects of exogenous CORT on the behavioral, hormonal, and metabolic responses of failed breeder Adélie penguins. Untreated and treated captive male birds were regularly weighed and sampled for blood while fasting, and locomotor activity was recorded daily. Treated birds were implanted with various doses of CORT during phase II. Untreated penguins entering PIII had increased CORT (3.5-fold) and uric acid (4-fold; reflecting protein catabolism) levels, concomitantly with a rise in locomotor activity (2-fold), while prolactin (involved in parental care in birds) levels declined by 33%. In CORT-treated birds, an inverted-U relationship was obtained between CORT levels and locomotor activity. The greatest increase in locomotor activity was observed in birds implanted with a high dose of CORT (C100), locomotor activity showing a 2.5-fold increase, 4 days after implantation to a level similar to that of birds in PIII. Moreover, uric acid levels increased three-fold in C100-birds, while prolactin levels declined by 30%. The experimentally induced rise in CORT levels mimicked metabolic, hormonal, and behavioral changes, characterizing late fasting, thus supporting a role for this hormone in the enhanced drive for refeeding occurring in long-term fasting birds.", "corpus_id": 17849861, "score": 0 }, { "doc_id": "2038560", "title": "Elevated corticosterone levels decrease reproductive output of chick-rearing Adélie penguins but do not affect chick mass at fledging", "abstract": "Stress hormones allow animals to adjust their physiology and behaviour to predictable and unpredictable changes in the environment. We investigated the effects of an increase in stress hormone levels on the breeding effort and the reproductive ouput of chick-rearing male Adélie penguins.", "corpus_id": 2038560, "score": 0 }, { "doc_id": "30576212", "title": "Sea ice cover and its influence on Adélie Penguin reproductive performance.", "abstract": "The relationship between Adélie Penguins (Pygoscelis adeliae) and ice is well established, with sea ice influencing penguin populations through a variety of processes operating at different spatial and temporal scales. To further explain the relationship between sea ice and Adélie Penguin reproductive performance, we investigated the relative importance of various measures of sea ice cover on breeding success at Béchervaise Island, East Antarctica. Our results show a clear distinction in the response of penguins to different types of ice, as well as to the timing of the presence of sea ice. Nearshore sea ice, which is composed primarily of fast ice during the guard stage of the breeding season, had an overwhelmingly strong and negative impact on penguin reproductive performance. The influence of winter and offshore guard-stage ice was only evident in conjunction with nearshore ice. Predicting Adélie Penguin population growth in relation to changes in the sea ice environment may be complicated because penguin-ice interactions vary according to the type of sea ice present, the season in which it is present, and the processes contributing to population growth that are influenced by sea ice.", "corpus_id": 30576212, "score": 0 }, { "doc_id": "7584865", "title": "Climate change and Southern Ocean ecosystems I: how changes in physical habitats directly affect marine biota.", "abstract": "Antarctic and Southern Ocean (ASO) marine ecosystems have been changing for at least the last 30 years, including in response to increasing ocean temperatures and changes in the extent and seasonality of sea ice; the magnitude and direction of these changes differ between regions around Antarctica that could see populations of the same species changing differently in different regions. This article reviews current and expected changes in ASO physical habitats in response to climate change. It then reviews how these changes may impact the autecology of marine biota of this polar region: microbes, zooplankton, salps, Antarctic krill, fish, cephalopods, marine mammals, seabirds, and benthos. The general prognosis for ASO marine habitats is for an overall warming and freshening, strengthening of westerly winds, with a potential pole-ward movement of those winds and the frontal systems, and an increase in ocean eddy activity. Many habitat parameters will have regionally specific changes, particularly relating to sea ice characteristics and seasonal dynamics. Lower trophic levels are expected to move south as the ocean conditions in which they are currently found move pole-ward. For Antarctic krill and finfish, the latitudinal breadth of their range will depend on their tolerance of warming oceans and changes to productivity. Ocean acidification is a concern not only for calcifying organisms but also for crustaceans such as Antarctic krill; it is also likely to be the most important change in benthic habitats over the coming century. For marine mammals and birds, the expected changes primarily relate to their flexibility in moving to alternative locations for food and the energetic cost of longer or more complex foraging trips for those that are bound to breeding colonies. Few species are sufficiently well studied to make comprehensive species-specific vulnerability assessments possible. Priorities for future work are discussed.", "corpus_id": 7584865, "score": 0 } ]

{ "doc_id": "36689687", "title": "Adapting APSIM to model the physiology and genetics of complex adaptive traits in field crops.", "abstract": "Progress in molecular plant breeding is limited by the ability to predict plant phenotype based on its genotype, especially for complex adaptive traits. Suitably constructed crop growth and development models have the potential to bridge this predictability gap. A generic cereal crop growth and development model is outlined here. It is designed to exhibit reliable predictive skill at the crop level while also introducing sufficient physiological rigour for complex phenotypic responses to become emergent properties of the model dynamics. The approach quantifies capture and use of radiation, water, and nitrogen within a framework that predicts the realized growth of major organs based on their potential and whether the supply of carbohydrate and nitrogen can satisfy that potential. The model builds on existing approaches within the APSIM software platform. Experiments on diverse genotypes of sorghum that underpin the development and testing of the adapted crop model are detailed. Genotypes differing in height were found to differ in biomass partitioning among organs and a tall hybrid had significantly increased radiation use efficiency: a novel finding in sorghum. Introducing these genetic effects associated with plant height into the model generated emergent simulated phenotypic differences in green leaf area retention during grain filling via effects associated with nitrogen dynamics. The relevance to plant breeding of this capability in complex trait dissection and simulation is discussed.", "corpus_id": 36689687 }

[ { "doc_id": "84796520", "title": "Gene-to-phenotype models and complex trait genetics", "abstract": "The premise that is explored in this paper is that in some cases, in order to make progress in the design of molecular breeding strategies for complex traits, we will need a theoretical framework for quantitative genetics that is grounded in the concept of gene-networks. We seek to develop a gene-to-phenotype (G→P) modelling framework for quantitative genetics that explicitly deals with the context-dependent gene effects that are attributed to genes functioning within networks, i.e. epistasis, gene × environment interactions, and pleiotropy. The E(NK) model is discussed as a starting point for building such a theoretical framework for complex trait genetics. Applying this framework to a combination of theoretical and empirical G→P models, we find that although many of the context-dependent effects of genetic variation on phenotypic variation can reduce the rate of genetic progress from breeding, it is possible to design molecular breeding strategies for complex traits that on average will outperform phenotypic selection. However, to realise these potential advantages, empirical G→P models of the traits will need to take into consideration the context-dependent effects that are a consequence of epistasis, gene × environment interactions, and pleiotropy. Some promising G→P modelling directions are discussed.", "corpus_id": 84796520, "score": 0 }, { "doc_id": "83321734", "title": "Scale and Complexity in Plant Systems Research : Gene-Plant-Crop Relations", "abstract": "Preface: Genetics of plant performance: from molecular analysis to modeling: 1. Genetic and molecular analysis of growth responses to environmental factors using Arabidopsis thaliana natural Variation M. Reymond et al.- 2. From QTLs to genes controlling root traits in maize R. Tuberosa and S. Salvi.- 3. Multi-trait multi-environment QTL modelling for drought stress adaptation in maize M. Malosetti et al .- 4. Accounting for variability in the detection and use of markers for simple and complex traits S.C. Chapman et al.- 5. An integrated systems approach to crop improvement G.L. Hammer and D.R. Jordan.- 6. Crop systems biology: an approach to connect functional genomics with crop modeling X. Yin and P.C. Struik.- Modelling genotype x environment interactions: 7. A modelling approach to genotype x environment interaction:genetic analysis of the response of maize growth to environmental conditions W. Sadok et al.- 8. Modelling genotype x environment x management interactions to improve yield, water use efficiency and grain protein in wheat S. Asseng and N.C. Turner.- 9. Physiological processes to understand genotype x environment interactions in maize silking dynamics L. Borras, M.E. Westgate and J.P. Astini.- 10. Modelling the genetic basis of response curves underlying genotype x environment interaction F.A. van Eeuwijk, M. Malosetti and M.P. Boer.- Physiology and genetics of crop adaptation: 11. Physiological interventions in breeding for adaptation to abiotic stress M.P. Reynolds and R.M. Trethowan.- 12. Physiological traits for improving wheat yield under a wide range of conditions G.A. Slafer and J.L. Araus.- 13. Is plant growth driven by sink regulation? Implications for crop models, phenotyping approaches and ideotypes M. Dingkuhn et al.- 14. Yield improvement associated with Lr19 translocation in wheat: which plant attributes are modified? D.J. Miralles, E. Resnicoff and R. Carretero.- Physiology and modelling of crop adaptation: 15.Simulation analysis of physiological traits to improve yield, nitrogen use efficiency and grain protein concentration in wheat P. Martre et al.- 16. An architectural approach to investigate maize response to low temperature K. Chenu et al.- 17. Tillering in spring wheat: a 3D virtual plant-modelling study J.B. Evers and J. Vos.- 18. Use of crop growth models to evaluate physiological traits in genotypes of horticultural crops E. Heuvelink et al.- Diversity, resource use and crop performance: 19. Role of root clusters in phosphorus acquisition and increasing biological diversity in agriculture H. Lambers and M.W. Shane.- 20. Prospects for genetic improvement to increase lowland rice yields with less water and nitrogen S. Peng and B.A.M. Bouman.- 21. Exploiting diversity to manage weeds in agro-ecosystems L. Bastiaans et al.- Outlook and dialogue: 22. When can intelligent design of crops by humans outperform natural selection? R.F. Denison.- 23. Integrated assessment of agricultural systems at multiple scales M.K. van Ittersum and J. Wery.- 24. A dialogue on interdisciplinary collaboration to bridge the gap between plant genomics and crop sciences P.C. Struik et al.- List of reviewers", "corpus_id": 83321734, "score": 0 }, { "doc_id": "5082074", "title": "Virtual plants: modelling as a tool for the genomics of tolerance to water deficit.", "abstract": "Modelling can simulate the responses of virtual plants carrying diverse combinations of alleles under different scenarios of abiotic stress. The main difficulty is mathematically expressing the genetic variability of responses to environmental conditions. Modelling via gene regulatory networks is not feasible for such complex systems, but plants can be modelled using response curves to environmental conditions that are 'meta mechanisms' at plant level. Each genotype is represented by a set of response parameters that are valid under a wide range of conditions. Transgenesis of one function experimentally affected one response parameter only. Transgenic plants or plants carrying any combination of quantitative trait loci might therefore be simulated and tested under different climatic scenarios, before genetic manipulations are performed.", "corpus_id": 5082074, "score": 1 }, { "doc_id": "32693208", "title": "Role of crop physiology in predicting gene-to-phenotype relationships.", "abstract": "Robust crop physiological modelling could become an essential tool in explaining crop behaviour using insights from functional genomics. Current crop models can predict crop performance over a range of environmental conditions. Recently, quantitative trait loci (QTL) information has been incorporated into crop models, which has shown the potential for narrowing genotype–phenotype gaps and for applying QTL-based models to the analysis of genotype-by-environment interactions. For further progress, the model structure must be upgraded to allow more physiological feedback features to be incorporated. Model input parameters should be designed to be grounded potentially in gene-level understanding. Integration of crop modelling into genetic and genomic research should enhance the future position of crop physiology in ‘plant breeding by design'.", "corpus_id": 32693208, "score": 0 }, { "doc_id": "1676171", "title": "Models for navigating biological complexity in breeding improved crop plants.", "abstract": "Progress in breeding higher-yielding crop plants would be greatly accelerated if the phenotypic consequences of making changes to the genetic makeup of an organism could be reliably predicted. Developing a predictive capacity that scales from genotype to phenotype is impeded by biological complexities associated with genetic controls, environmental effects and interactions among plant growth and development processes. Plant modelling can help navigate a path through this complexity. Here we profile modelling approaches for complex traits at gene network, organ and whole plant levels. Each provides a means to link phenotypic consequence to changes in genomic regions via stable associations with model coefficients. A unifying feature of the models is the relatively coarse level of granularity they use to capture system dynamics. Much of the fine detail is not directly required. Robust coarse-grained models might be the tool needed to integrate phenotypic and molecular approaches to plant breeding.", "corpus_id": 1676171, "score": 0 }, { "doc_id": "107848685", "title": "Modelling Crop Improvement in a G×E×M Framework via Gene–Trait–Phenotype Relationships", "abstract": "This chapter introduces fundamental concepts of modeling natural systems using a G×E×M framework and discusses the prospects for an integrated approach for improving crop performance that tackles the G×E×M interactions holistically. It outlines general principles of modeling biophysical systems, including a description of fundamental components of crop models. It describes G×E×M systems and introduces gene-to-phenotype (GP) models and concepts of adaptation landscapes as applied to plant breeding. The chapter discusses the application of the framework by studying genetic improvement of maize in the US Corn Belt. It reviews and summarizes theoretical developments toward a framework that integrates quantitative genetics, breeding simulation, and modeling of physiological traits and dynamic GP relations. Such a framework is intended to enable breeders and agronomists to project trajectories in the G×E×M space into the future and gain insights on the consequences of manipulating genomes to the creation of improved crops for target management and environments.", "corpus_id": 107848685, "score": 1 }, { "doc_id": "84571176", "title": "Trait physiology and crop modelling as a framework to link phenotypic complexity to underlying genetic systems", "abstract": "New tools derived from advances in molecular biology have not been widely adopted in plant breeding for complex traits because of the inability to connect information at gene level to the phenotype in a manner that is useful for selection. In this study, we explored whether physiological dissection and integrative modelling of complex traits could link phenotype complexity to underlying genetic systems in a way that enhanced the power of molecular breeding strategies. A crop and breeding system simulation study on sorghum, which involved variation in 4 key adaptive traits-phenology, osmotic adjustment, transpiration efficiency, stay-green-and a broad range of production environments in north-eastern Australia, was used. The full matrix of simulated phenotypes, which consisted of 547 location-season combinations and 4235 genotypic expression states, was analysed for genetic and environmental effects. The analysis was conducted in stages assuming gradually increased understanding of gene-to-phenotype relationships, which would arise from physiological dissection and modelling. It was found that environmental characterisation and physiological knowledge helped to explain and unravel gene and environment context dependencies in the data. Based on the analyses of gene effects, a range of marker-assisted selection breeding strategies was simulated. It was shown that the inclusion of knowledge resulting from trait physiology and modelling generated an enhanced rate of yield advance over cycles of selection. This occurred because the knowledge associated with component trait physiology and extrapolation to the target population of environments by modelling removed confounding effects associated with environment and gene context dependencies for the markers used. Developing and implementing this gene-to-phenotype capability in crop improvement requires enhanced attention to phenotyping, ecophysiological modelling, and validation studies to test the stability of candidate genetic regions.", "corpus_id": 84571176, "score": 0 }, { "doc_id": "25597384", "title": "Short-term responses of leaf growth rate to water deficit scale up to whole-plant and crop levels: an integrated modelling approach in maize.", "abstract": "Physiological and genetic studies of leaf growth often focus on short-term responses, leaving a gap to whole-plant models that predict biomass accumulation, transpiration and yield at crop scale. To bridge this gap, we developed a model that combines an existing model of leaf 6 expansion in response to short-term environmental variations with a model coordinating the development of all leaves of a plant. The latter was based on: (1) rates of leaf initiation, appearance and end of elongation measured in field experiments; and (2) the hypothesis of an independence of the growth between leaves. The resulting whole-plant leaf model was integrated into the generic crop model APSIM which provided dynamic feedback of environmental conditions to the leaf model and allowed simulation of crop growth at canopy level. The model was tested in 12 field situations with contrasting temperature, evaporative demand and soil water status. In observed and simulated data, high evaporative demand reduced leaf area at the whole-plant level, and short water deficits affected only leaves developing during the stress, either visible or still hidden in the whorl. The model adequately simulated whole-plant profiles of leaf area with a single set of parameters that applied to the same hybrid in all experiments. It was also suitable to predict biomass accumulation and yield of a similar hybrid grown in different conditions. This model extends to field conditions existing knowledge of the environmental controls of leaf elongation, and can be used to simulate how their genetic controls flow through to yield.", "corpus_id": 25597384, "score": 1 }, { "doc_id": "20248675", "title": "Applying modelling experiences from the past to shape crop systems biology: the need to converge crop physiology and functional genomics.", "abstract": "Functional genomics has been driven greatly by emerging experimental technologies. Its development as a scientific discipline will be enhanced by systems biology, which generates novel, quantitative hypotheses via modelling. However, in order to better assist crop improvement, the impact of developing functional genomics needs to be assessed at the crop level, given a projected diminishing effect of genetic alteration on phenotypes from the molecule to crop levels. This review illustrates a recently proposed research field, crop systems biology, which is located at the crossroads of crop physiology and functional genomics, and intends to promote communications between the two. Past experiences with modelling whole-crop physiology indicate that the layered structure of biological systems should be taken into account. Moreover, modelling not only plays a role in data synthesis and quantitative prediction, but certainly also in heuristics and system design. These roles of modelling can be applied to crop systems biology to enhance its contribution to our understanding of complex crop phenotypes and subsequently to crop improvement. The success of crop systems biology needs commitments from scientists along the entire knowledge chain of plant biology, from molecule or gene to crop and agro-ecosystem.", "corpus_id": 20248675, "score": 0 }, { "doc_id": "17848114", "title": "The GP problem: Quantifying gene-to-phenotype relationships", "abstract": "In this paper we refer to the gene-to-phenotype modeling challenge as the GP problem. Integrating information across levels of organization within a genotype-environment system is a major challenge in computational biology. However, resolving the GP problem is a fundamental requirement if we are to understand and predict phenotypes given knowledge of the genome and model dynamic properties of biological systems. Organisms are consequences of this integration, and it is a major property of biological systems that underlies the responses we observe. We discuss the E(NK) model as a framework for investigation of the GP problem and the prediction of system properties at different levels of organization. We apply this quantitative framework to an investigation of the processes involved in genetic improvement of plants for agriculture. In our analysis, N genes determine the genetic variation for a set of traits that are responsible for plant adaptation to E environment-types within a target population of environments. The N genes can interact in epistatic NK gene-networks through the way that they influence plant growth and development processes within a dynamic crop growth model. We use a sorghum crop growth model, available within the APSIM agricultural production systems simulation model, to integrate the gene-environment interactions that occur during growth and development and to predict genotype-to-phenotype relationships for a given E(NK) model. Directional selection is then applied to the population of genotypes, based on their predicted phenotypes, to simulate the dynamic aspects of genetic improvement by a plant-breeding program. The outcomes of the simulated breeding are evaluated across cycles of selection in terms of the changes in allele frequencies for the N genes and the genotypic and phenotypic values of the populations of genotypes.", "corpus_id": 17848114, "score": 0 }, { "doc_id": "12069162", "title": "Integrated physiological and agronomic modelling of N capture and use within the plant.", "abstract": "Today farmers have several constraints to take into account in managing their crops: (i) competitiveness: productivity must be maintained or increased whereas inputs must be decreased, (ii) the environmental consequences of cultural practices: pesticide and fertilizer use must be decreased, and (iii) product quality must be improved and nitrogen nutrition is an important factor in harvest quality. These new constraints sometimes conflict: maximum yield is often obtained with large amounts of N, increasing the risks of N leaching. The determination of rates and dates for nitrogen application must become more precise in this context. Tools are required for the forecasting of crop requirements, the diagnosis of N deficiencies during the crop cycle and breeding of new adapted varieties. Models and diagnosis indicators have been developed to meet these needs, but those relating to nitrogen are often based on empirical relationships. Moreover, the available models and indicators often fail to account for cultivar-specific responses. The improvement of agronomic tools and the breeding of new varieties adapted to new cropping systems should be based on a thorough understanding of the key metabolic processes involved, and the relative contributions of these processes to yield determination in conditions of fluctuating N supply. For both purposes, more information is required about plant and crop N economy. In this paper, the way in which N absorption and use within the plant and crop, plant responses to deficiencies and excesses of nitrogen are taken into account in major agronomic models is described first. The level of sophistication of the modules comprising these models depends on operational objectives. Secondly, the ways in which the most recent molecular plant physiology findings can, and indeed should, be integrated into models at the crop and crop cycle levels are described. The potential value of this approach for improving current agronomic models and diagnostic tools, and for breeding more efficient varieties is also discussed.", "corpus_id": 12069162, "score": 0 }, { "doc_id": "83675763", "title": "Modelling protein content and composition in relation to crop nitrogen dynamics for wheat", "abstract": "Abstract Protein concentration and composition are key components of the end-use value for wheat (Triticum aestivum L.) grain. Although the qualitative composition of the grain is genetically determined, the quantitative composition is significantly modified by growing conditions, and there are important management × genotype × environment interactions. We recently reported a model of grain N accumulation and partitioning for wheat grain. The main assumptions made in this model are: (1) the accumulation of structural/metabolic proteins (albumins-globulins and amphiphils) is sink-driven and is a function of temperature; (2) the accumulation of storage proteins (gliadins and glutenins) is supply limited; (3) on the one hand the allocation of structural/metabolic proteins between albumin-globulin and amphiphilic protein fractions and on the other hand the allocation of storage protein between gliadin and glutenin fractions during grain growth is constant. A modified version of this grain model has been coupled with a revised version of the wheat simulation model Sirius99, allowing us to analyze the interactions between the vegetative sources and the reproductive sinks for N at the crop level. The main modifications to Sirius99 concerned the post-anthesis N uptake and remobilisation. After anthesis, the potential rate of crop N uptake was assumed to decrease linearly with accumulated thermal time, and the actual rate of N uptake was limited by the capacity of the stem to store accumulated N. During grain filling the daily rate of N transfer to grain was calculated daily according to the current crop N-status. The coupled model (SiriusQuality1) simulated dynamics of total grain N and of the different grain protein fractions reasonably well. At maturity, measured total grain N ranged from 0.56 to 1.32 mg N grain−1, and the observed and simulated total grain N were well correlated (r2 = 0.82, slope = 1.08) with a mean error of prediction of 0.11 mg N grain−1. The simulated kinetics of crop N accumulation and stem N were closer to the observations with SiriusQuality1 than with Sirius99, in particular during the reproductive stage. At maturity, simulated and observed quantities of albumins-globulins were poorly correlated (r2 = 0.02). Over the 18 experimental cases studied here, the quantity of storage proteins varied more than three-fold, and the observed and simulated quantities of gliadins and glutenins were well correlated (r2 = 0.79 and 0.72, respectively). The simulations of total N and storage proteins accumulation provided by SiriusQuality1 confirmed that accumulation of grain N is overall source- rather than sink-regulated, at least under non-luxury N conditions. SiriusQuality1 provides a simple mechanistic framework that explains environmental effects on grain protein concentration and composition. The next step is to incorporate genetically related model parameters that will portray genotypic differences in protein concentration and composition.", "corpus_id": 83675763, "score": 0 }, { "doc_id": "85820723", "title": "A process-based model to simulate nitrogen distribution in wheat (Triticum aestivum) during grain-filling.", "abstract": "Nitrogen (N) distribution among plant organs plays a major role in crop production and, in general, plant fitness to the environment. In the present study, a process-based model simulating N distribution within a wheat (Triticum aestivum L.) culm during grain filling was developed using a functional-structural approach. A model of turnover of the photosynthetic apparatus was used to describe the fluxes between a common pool of mobile N and each leaf lamina. Grain N accumulation within a time-step was modelled as the minimum between the quantity calculated by a potential function and the N available in the common pool. Nitrogen dynamics in the other organs (i.e. stem, chaff, root N uptake and remobilisation) were accounted for by forced variables. Using a unique set of six parameters, the model was able to simulate the observed N kinetics of each lamina and of the grains under a wide range of crop N supplies and for three cultivars. The time-course of the vertical gradient of lamina N during grain filling was realistically simulated as an emerging property of the local processes defined at the lamina scale. The model described in the present study offers new insight into the interactions between N metabolism, plant architecture and productivity.", "corpus_id": 85820723, "score": 0 }, { "doc_id": "153525555", "title": "Infusing the use of seasonal climate forecasting into crop management practice in North East Australia using discussion support software", "abstract": "Seasonal climate forecasting offers potential for improving management of crop production risks in the cropping systems of NE Australia. But how is this capability best connected to management practice? Over the past decade, we have pursued participative systems approaches involving simulation-aided discussion with advisers and decision-makers. This has led to the development of discussion support software as a key vehicle for facilitating infusion of forecasting capability into practice. In this paper, we set out the basis of our approach, its implementation and preliminary evaluation. We outline the development of the discussion support software Whopper Cropper, which was designed for, and in close consultation with, public and private advisers. Whopper Cropper consists of a database of simulation output and a graphical user interface to generate analyses of risks associated with crop management options. The charts produced provide conversation pieces for advisers to use with their farmer clients in relation to the significant decisions they face. An example application, detail of the software development process and an initial survey of user needs are presented. We suggest that discussion support software is about moving beyond traditional notions of supply-driven decision support systems. Discussion support software is largely demand-driven and can compliment participatory action research programs by providing cost-effective general delivery of simulation-aided discussions about relevant management actions. The critical role of farm management advisers and dialogue among key players is highlighted. We argue that the", "corpus_id": 153525555, "score": 0 }, { "doc_id": "2967482", "title": "Simulating the Yield Impacts of Organ-Level Quantitative Trait Loci Associated With Drought Response in Maize: A “Gene-to-Phenotype” Modeling Approach", "abstract": "Under drought, substantial genotype–environment (G × E) interactions impede breeding progress for yield. Identifying genetic controls associated with yield response is confounded by poor genetic correlations across testing environments. Part of this problem is related to our inability to account for the interplay of genetic controls, physiological traits, and environmental conditions throughout the crop cycle. We propose a modeling approach to bridge this “gene-to-phenotype” gap. For maize under drought, we simulated the impact of quantitative trait loci (QTL) controlling two key processes (leaf and silk elongation) that influence crop growth, water use, and grain yield. Substantial G × E interaction for yield was simulated for hypothetical recombinant inbred lines (RILs) across different seasonal patterns of drought. QTL that accelerated leaf elongation caused an increase in crop leaf area and yield in well-watered or preflowering water deficit conditions, but a reduction in yield under terminal stresses (as such “leafy” genotypes prematurely exhausted the water supply). The QTL impact on yield was substantially enhanced by including pleiotropic effects of these QTL on silk elongation and on consequent grain set. The simulations obtained illustrated the difficulty of interpreting the genetic control of yield for genotypes influenced only by the additive effects of QTL associated with leaf and silk growth. The results highlight the potential of integrative simulation modeling for gene-to-phenotype prediction and for exploiting G × E interactions for complex traits such as drought tolerance.", "corpus_id": 2967482, "score": 0 }, { "doc_id": "7666871", "title": "QTL analysis and QTL-based prediction of flowering phenology in recombinant inbred lines of barley.", "abstract": "Combining ecophysiological modelling and genetic mapping has increasingly received attention from researchers who wish to predict complex plant or crop traits under diverse environmental conditions. The potential for using this combined approach to predict flowering time of individual genotypes in a recombinant inbred line (RIL) population of spring barley (Hordeum vulgare L.) was examined. An ecophysiological phenology model predicts preflowering duration as affected by temperature and photoperiod, based on the following four input traits: f(o) (the minimum number of days to flowering at the optimum temperature and photoperiod), theta1 and theta2 (the development stages for the start and the end of the photoperiod-sensitive phase, respectively), and delta (the photoperiod sensitivity). The model-input trait values were obtained from a photoperiod-controlled greenhouse experiment. Assuming additivity of QTL effects, a multiple QTL model was fitted for the model-input traits using composite interval mapping. Four to seven QTL were identified for each trait. Each trait had at least one QTL specific to that trait alone. Other QTL were shared by two or all traits. Values of the model-input traits predicted for the RILs from the QTL model were fed back into the ecophysiological model. This QTL-based ecophysiological model was subsequently used to predict preflowering duration (d) for eight field trial environments. The model accounted for 72% of the observed variation among 94 RILs and 94% of the variation among the two parents across the eight environments, when observations in different environments were pooled. However, due to the low percentage (34-41%) of phenotypic variation accounted for by the identified QTL for three model-input traits (theta1, theta2 and delta), the QTL-based model accounted for somewhat less variation among the RILs than the model using original phenotypic input trait values. Nevertheless, days to flowering as predicted from the QTL-based ecophysiological model were highly correlated with days to flowering as predicted from QTL-models per environment for days to flowering per se. The ecophysiological phenology model was thus capable of extrapolating (QTL) information from one environment to another.", "corpus_id": 7666871, "score": 0 }, { "doc_id": "83589013", "title": "A Gene‐Based Model to Simulate Soybean Development and Yield Responses to Environment", "abstract": "Realizing the potential of agricultural genomics into practical applications requires quantitative predictions for complex traits and different genotypes and environmental conditions. The objective of this study was to develop and test a procedure for quantitative prediction of phenotypes as a function of environment and specific genetic loci in soybean [Glycine max (L.) Merrill]. We combined the ecophysiological model CROPGRO-Soybean with linear models that predict cultivar-specific parameters as functions of E loci. The procedure involved three steps: (i) a field experiment was conducted in Florida in 2001 to obtain phenotypic data for a set of near-isogenic lines (NILs) with known genotypes at six E loci; (ii) we used these data to estimate cultivar-specific parameters for CROPGRO-Soybean, minimizing root mean square error (RMSE) between observed and simulated values; (iii) these parameters were then expressed as linear functions of the (known) E loci. CROPGRO-Soybean predicted various phenological stages for the same NILs grown in 2002 in Florida with a RMSE of about 5 d using the E loci-derived parameters. A second evaluation of the approach used phenotypic data from cultivar trials conducted in Illinois. Cultivars were genotyped at the E loci using microsatellites. The model predicted time to maturity in the Illinois variety trials with RMSE around 7.5 d; it also explained 75% of the time-to-maturity variance and 54% of the yield variance. Our results suggest that gene-based approaches can effectively use agricultural genomics data for cultivar performance prediction. This technology may have multiple uses in plant breeding.", "corpus_id": 83589013, "score": 0 }, { "doc_id": "22959718", "title": "Crop model based QTL analysis across environments and QTL based estimation of time to floral induction and flowering in Brassica oleracea", "abstract": "Studying quantitative traits is complicated due to genotype by environment interactions. One strategy to overcome these difficulties is to combine quantitative trait loci (QTL) and ecophysiological models, e.g. by identifying QTLs for the response curves of adaptive traits to influential environmental factors. A B. oleracea DH-population segregating for time to flowering was cultivated at different temperature regimes. Composite interval mapping was carried out on the three parameters of a model describing time to flowering as a function of temperature, i.e. on the intercept and slope of the response of time to floral induction to temperature and on the duration from transition to flowering. The additive effects of QTLs detected for the parameters have been used to estimate time to floral induction and flowering in the B. oleracea DH-population. The combined QTL and crop model explained 66% of the phenotypic variation for time to floral induction and 56% of the phenotypic variation for time to flowering. Estimation of time to floral induction and flowering based on environment specific QTLs explained 61 and 41% of the phenotypic variation. Results suggest that flowering time can be predicted effectively by coupling QTL and crop models and that using crop modelling tools for QTL analysis increases the power of QTL detection.", "corpus_id": 22959718, "score": 0 }, { "doc_id": "5033930", "title": "Linking physiological and genetic analyses of the control of leaf growth under changing environmental conditions", "abstract": "Decrease in leaf growth rate under water deficit can be seen as an adaptive process. The analysis of its genetic variability is therefore important in the context of drought tolerance. Several mechanisms are widely believed to drive the reduction in leaf growth rate under water deficit, namely leaf carbon balance, incomplete turgor maintenance, and decrease in cell wall plasticity or in cell division rate, with contributions from hormones such as abscisic acid or ethylene. Each of these mechanisms is still controversial, and involves several families of genes. It is argued that gene regulatory networks are not feasible for modelling such complex systems. Leaf growth can be modelled via response curves to environmental conditions, which are considered as ‘meta-mechanisms’ at a higher degree of organisation. Response curves of leaf elongation rate to meristem temperature, atmospheric vapour pressure deficit, and soil water status were established in recombinant inbred lines (RILs) of maize in experiments carried out in the field and in the greenhouse. A quantitative trait locus (QTL) analysis was conducted on the slopes of these responses. Each parameter of the ecophysiological model could then be computed as the sum of QTL effects, allowing calculation of parameters of new RILs, either virtual or existing. Leaf elongation rates of new RILS were simulated and were similar to measurements in a growth chamber experiment. This opens the way to the simulation of virtual genotypes, known only by their alleles, in any climatic scenario. Each genotype is therefore represented by a set of response parameters, valid in a large range of conditions and deduced from the alleles at QTLs.", "corpus_id": 5033930, "score": 0 }, { "doc_id": "21597384", "title": "Leaf growth rate per unit thermal time follows QTL-dependent daily patterns in hundreds of maize lines under naturally fluctuating conditions.", "abstract": "We have analysed daily patterns of leaf elongation rate (LER) in large data sets with 318 genotypes placed in naturally fluctuating temperature and evaporative demand, and examined the effect of targeted alleles on these patterns. The method consisted, firstly, in expressing elongation rate per unit thermal time, so it became temperature independent; secondly, in a joint analysis of diurnal fluctuations of elongation rate and of micrometeorological conditions in several experiments, and finally, in a comparison of daily patterns between groups of genotypes possessing targeted alleles. (1) Conditions for using thermal time at a time step of 15 min were first tested successfully in 318 recombinant inbred lines (RILs) of three mapping populations. (2) An analysis of 1989 time courses revealed a robust daily pattern of LER per unit thermal time (LERth) over several experiments. LERth was constant during the night and was reproducible (for a given RIL) over up to 10 consecutive nights in different experiments. It declined rapidly during the early morning, closely following the daily pattern of transpiration rate. (3) Groups of RILs carrying alleles conferring a high response to temperature had markedly higher night-time plateau of LER than those with low responses. Groups of RILs with high response to evaporative demand had rapid decreases in elongation rate at the transition between night and day, while this decrease was slower in groups of RILs with low response. These results open the way for using kinetics of responses to environmental stimuli as a phenotyping tool in genetic analyses.", "corpus_id": 21597384, "score": 0 }, { "doc_id": "84156330", "title": "Evaluation of a Crop Simulation Model that Incorporates Gene Action", "abstract": "Crop simulation models are receiving increasing use in agricultural research. However, applications to plant breeding have been limited, in part due to the restricted capabilities of models to represent genetic differences. A gene-based simulation model, GeneGro, has been developed that integrates action of seven genes into a common bean (Phaseolus vulgaris L.) model. The genes for physiological traits identified in the model include Ppd, Hr, Fin, Fd, Ssz-1, Ssz-2, and Ssz-3. Evaluation of GeneGro was performed by comparison of measured field data vs. simulated data, and through a sensitivity analysis of the model. The experimental data set for model comparison was comprised of 14 field trials conducted in Canada, the USA, Mexico, and Colombia, representing 213 treatment combinations and including 39 cultivars. GeneGro explained 75% of variation in days to flower, 68% in days to maturity, and 39% in seed mass, but only 11% of variation in seed yield. Most of the variation in simulated seed yield was accounted for by the model when mean effects of site and cultivars were removed through regression analysis. This suggests that the poor simulation of seed yield was partially due to errors in simulating differences among sites rather than from simulating the response of genotypes to sites. Seed yield simulations were made for 96 genotypes that represented all expected phenotypic combinations of the seven genes included in the model. Simulations were conducted using historical weather data from Fargo, ND; Madero, Mexico; and Palmira, Colombia. GeneGro predicted that photoperiod sensitivity, conferred by Ppd and Hr, would result in zero seed yields at Fargo, a slight seed yield increase at Madero, and no effect at Palmira. Testing effects of maturity on seed yield, the genotypes fin and Fd resulted in lower seed yields due to shorter growth cycles, in agreement with field trials. The predicted effects of the three genes related to seed size varied among the sites. These results support the use of genetic information to represent cultivar differences in simulation models. They also emphasize the need for a better understanding of the physiological genetics of traits such as phenology, seed size, and growth habit.", "corpus_id": 84156330, "score": 0 }, { "doc_id": "11308294", "title": "Crop modeling, QTL mapping, and their complementary role in plant breeding", "abstract": "Received for publication May 1, 2001. Crop modelers and geneticists have developed a vision of their roles in plant breeding from their own perspective. However, to improve breeding efficiency, interdisciplinary collaboration becomes increasingly important. The objective of this paper is to explore opportunities for collaboration between modelers and geneticists in ideotype breeding for high crop yield. The advent of molecular markers enables variation of a complex trait to be dissected into the effects of quantitative trait loci (QTL) and assists the transfer of these QTL into desired cultivars or lines. A recent study in which QTL information was linked to crop modeling has shown that QTL analysis removes part of random errors of measured model input parameters and that QTL information can successfully be coupled with crop models to replace measured parameters. The QTL-based modeling overcomes the limitations in designing ideotypes by using models that ignore the inheritance of model input traits. On the other hand, crop modeling can potentially be a powerful tool to resolve genotype x environment interactions and to dissect yield into characters that might be under simpler genetic control. Based on the complementary aspects of crop modeling and QTL mapping, we propose an approach that integrates marker-assisted selection into model-based ideotype framework to support breeding for high crop yield. For this approach to be effective, there is a need to develop crop models that are capable of predicting yield differences among genotypes in a population under various environmental conditions.", "corpus_id": 11308294, "score": 0 }, { "doc_id": "11960979", "title": "An overview of APSIM, a model designed for farming systems simulation", "abstract": "The Agricultural Production Systems Simulator (APSIM) is a modular modelling framework that has been developed by the Agricultural Production Systems Research Unit in Australia. APSIM was developed to simulate biophysical process in farming systems, in particular where there is interest in the economic and ecological outcomes of management practice in the face of climatic risk. The paper outlines APSIM's structure and provides details of the concepts behind the different plant, soil and management modules. These modules include a diverse range of crops, pastures and trees, soil processes including water balance, N and P transformations, soil pH, erosion and a full range of management controls. Reports of APSIM testing in a diverse range of systems and environments are summarised. An example of model performance in a long-term cropping systems trial is provided. APSIM has been used in a broad range of applications, including support for on-farm decision making, farming systems design for production or resource management objectives, assessment of the value of seasonal climate forecasting, analysis of supply chain issues in agribusiness activities, development of waste management guidelines, risk assessment for government policy making and as a guide to research and education activity. An extensive citation list for these model testing and application studies is provided.", "corpus_id": 11960979, "score": 0 }, { "doc_id": "85418047", "title": "Development of a generic crop model template in the cropping system model APSIM", "abstract": "The Agricultural Production Systems slMulator, APSIM, is a cropping system modelling environment that simulates the dynamics of soil-plant-management interactions within a single crop or a cropping system. Adaptation of previously developed crop models has resulted in multiple crop modules in APSIM, which have low scientific transparency and code efficiency. A generic crop model template (GCROP) has been developed to capture unifying physiological principles across crops (plant types) and to provide modular and efficient code for crop modelling. It comprises a standard crop interface to the APSIM engine, a generic crop model structure, a crop process library, and well-structured crop parameter files. The process library contains the major science underpinning the crop models and incorporates generic routines based on physiological principles for growth and development processes that are common across crops. It allows APSIM to simulate different crops using the same set of computer code. The generic model structure and parameter files provide an easy way to test, modify, exchange and compare modelling approaches at process level without necessitating changes in the code. The standard interface generalises the model inputs and outputs, and utilises a standard protocol to communicate with other APSIM modules through the APSIM engine. The crop template serves as a convenient means to test new insights and compare approaches to component modelling, while maintaining a focus on predictive capability. This paper describes and discusses the scientific basis, the design, implementation and future development of the crop template in APSIM. On this basis, we argue that the combination of good software engineering with sound crop science can enhance the rate of advance in crop modelling. Crown Copyright (C) 2002 Published by Elsevier Science B.V. All rights reserved.", "corpus_id": 85418047, "score": 0 }, { "doc_id": "88389608", "title": "Physiological Determinants of Crop Growth.", "abstract": "Physiological determinants of crop growth , Physiological determinants of crop growth , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی", "corpus_id": 88389608, "score": 0 }, { "doc_id": "92672466", "title": "How do crops manipulate water supply and demand?", "abstract": "The supply of water provided by the root system of a crop stand is defined in terms of the rate at which water is extracted by a root front moving downwards with a constant velocity, the available water per unit soil volume, and a time constant that is inversely proportional to root density. The demand for water, often identified with a potential transpiration rate, is defined in terms of a maximum crop growth rate multiplied by the conservative ratio of transpiration to dry-matter production. From experimental evidence, supported by theory, this ratio is proportional to the mean saturation vapour-pressure deficit. As hypothesized, the root front accelerates during seedling establishment to keep demand and supply in balance. Once a maximum root velocity is reached ( ca. 2-4 cm d-1) transpiration is limited by water supply, except when the soil behind the root front is wetted by rain or irrigation, when it is limited by demand. Irrigation amounts and timing can both be estimated from this scheme.", "corpus_id": 92672466, "score": 0 }, { "doc_id": "153505453", "title": "Roots and drought resistance", "abstract": "Passioura, J.B., 1983. Roots and drought resistance. Agric. Water Manage., 7: 265–280. \n \nThe influence of roots on the yield of water-limited crops is analysed with the help of the identity: \n \nyield = water used × water-use efficiency × harvest index \n \nDespite being severely water-stressed, many droughted crops leave substantial amounts of apparently available water in the subsoil at maturity. The factors influencing this amount are outlined, particularly those concerning the morphology of the root system. Prospects for improving yield by extracting the residual water are discussed. \n \nBecause roots are difficult to harvest, water-use efficiency is usually defined as above-ground-biomass/water-used. It follows that the more assimilate a plant transfers to its roots the lower will be its water-use efficiency. There is presumably an optimal root/ shoot ratio (in terms of water relations) at which above-ground biomass is maximal for a given water supply. This ratio appears to exceed the optimum in many cases. \n \nFor a given biomass, the yield of a grain crop depends in part on the pattern of water use during the season, because harvest index is often related to the proportion of the total water supply that is used after anthesis. For crops relying on a limited supply of stored water, a high axial resistance to flow in the roots may ensure that water in the subsoil is not used so quickly that too little remains at anthesis for the plants to set and fill an adequate number of grains. A breeding program aimed at changing this resistance in wheat roots is described. \n \nFinally, the principles are discussed on which physiological research can be useful in improving drought resistance. The need to dissect water-limited yield into largely independent components is emphasised, for such a dissection greatly improves the focus of the research.", "corpus_id": 153505453, "score": 0 }, { "doc_id": "86659965", "title": "Water and nitrogen limitations in soybean grain production I. Model development", "abstract": "A simple, phenomenological model was developed to describe the carbon, nitrogen, and water budgets of a soybean (Glycine max (L.) Merr) crop from emergence to maturity. Daily meteorological data input to the model were minimum temperature, maximum temperature, solar radiation, and precipitation. Leaves were grown to give a linear function of mean daily temperature. From the calculated leaf area index the daily intercepted solar radiation by the crop was determined. Daily carbon accumulation was calculated as a linear function of intercepted radiation. The daily nitrogen accumulation rate was calculated as a linear function of vegetative biomass. Leaf growth, carbon accumulation and symbiotic-nitrogen fixation rates were all made sensitive to the amount of soil water. Experimental data were collected to develop the empirical relationships between these three physiological processes and the amount of transpirable soil water. These data showed nitrogen fixation rates to be more sensitive to soil dehydration than either leaf growth or leaf gas exchange. Preliminary tests showed that model predictions compared favorably with field observations. An analysis of the model's behavior showed that crop yield was most sensitive to those variables influencing the interception of solar radiation and its conversion to biomass.", "corpus_id": 86659965, "score": 0 }, { "doc_id": "84054935", "title": "Development and evaluation of a sorghum model based on CERES-Maize in a semi-arid tropical environment", "abstract": "Birch, C.J., Carberry, P.S., Muchow, R.C., McCown, R.L. and Hargreaves, J.N.G., 1990. Development and evaluation of a sorghum model based on CERES-Maize in a semi-arid tropical environment. Field Crops Res., 24: 87-104. This paper reports on the development and evaluation of a grain sorghum model (CERESSorghum ( SAT ) ) for use in the semi-arid tropics. The model was developed from a version of CERESMaize, previously adapted for use in this climatic zone. Functions for phenology, leaf growth, leaf senescence, assimilate accumulation and grain growth were modified using a small subset of sorghum data and validated against a much larger field-data set. When tested with cultivar De Kalb DK55 at Katherine, Northern Territory, the model successfully predicted grain-yield with a root mean square deviation of 0.972 to ha- ~ over a range of sowing dates and water regimes resulting in observed yields ranging from 1.56 to 6.28 t ha -~. Deviations of predicted from observed yields were no greater than those of maize predictions by the parent model. Prediction of components of yield and biomass were also satisfactory. Calibration required 28 changes to the CERES-Maize(SAT) model, of which 15 were changes to coefficients in equations rather than substantial changes to the model. Because of the ease of conversion and the time-use efficiency found in these analyses, the techniques used in this paper could have application where locally calibrated models are required.", "corpus_id": 84054935, "score": 0 }, { "doc_id": "84580710", "title": "A model to assess nitrogen limitations on the growth and yield of spring wheat", "abstract": "Under many conditions the availability of soil nitrogen imposes an important constraint on wheat (Triticum aestivum L.) yields. In this paper a simple, mechanistic model of spring-wheat growth and yield was proposed to account for nitrogen uptake and use by the crop. A soil nitrogen balance was developed so that crop nitrogen uptake was restrained when the available mineral nitrogen in the soil was exhausted. The crop nitrogen uptake rate was calculated as a function of cumulative thermal units. Leaf area development and maintenance, radiation-use efficiency, and stem growth were assumed to depend on accumulated nitrogen. Seed growth resulted in nitrogen transfer from leaves and stems to the seeds. The model was compared against data collected in nine years of experimentation at Gilat, Israel. Good agreement between observed and simulated yields was obtained for varying nitrogen fertilizer treatments (r2=0.94) and levels of soil nitrogen following fallow (r2=0.93).", "corpus_id": 84580710, "score": 0 }, { "doc_id": "86567868", "title": "A sunflower simulation model: I. Model development", "abstract": "In dryland farming systems, opportunities to improve sunflower (Helianthus annuus L.) yields are mostly associated with management decisions made at planting. Dynamic crop simulation models can assist in making such decisions. This study reports the structure of QSUN, a simple and mechanistic crop model for sunflower, and how it accounts for the dynamic interaction of the crop with the soil and aerial environment. The model incorporates several recent approaches to simulation of crop growth in dryland conditions. QSUN estimates growth, development, and yield of a sunflower crop. Daily inputs of temperature and photoperiod drive a phenology submodel to predict stages of emergence, bud visibility, 50% anthesis, and maturity [...]", "corpus_id": 86567868, "score": 0 }, { "doc_id": "84858520", "title": "Assessing climatic risk to sorghum production in water-limited subtropical environments. I.Development and testing of a simulation model", "abstract": "Abstract Sorghum ( Sorghum bicolor (L.) Moench.) is one of the major summer crops grown in the subtropics. The high rainfall variability and limited planting opportunities in these regions make crop production risky. A robust crop simulation model can assist farmer decision-making via simulation analyses to quantify production risks. Accordingly, we developed a simple, yet mechanistic crop simulation model for sorghum for use in assessing climatic risk to production in water-limited environments. The model simulates grain yield, biomass accumulation, crop leaf area, phenology and soil water balance. The model uses a daily time-step and readily available weather and soil information and assumes no nutrient limitation. The model was tested on numerous data ( n =38) from experiments spanning a broad range of environments in the semi-arid tropics and subtropics. Potential limitations in the model were identified and examined in a novel testing procedure by using combinations of predicted and observed data in various modules of the model. The model performed satisfactorily, accounting for 94% and 64% of the variation in total biomass and grain yield, respectively. The difference in outcome for biomass and yield was caused by limitations in predicting harvest index. The concepts involved, and the limitations encountered, developing a crop model to be simple but consistent with the biophysical rigour required for application to such a diverse range of environments, are discussed.", "corpus_id": 84858520, "score": 1 }, { "doc_id": "205110481", "title": "Modelling genotypic and environmental control of leaf area dynamics in grain sorghum. I. Whole plant level", "abstract": "Abstract Leaf area dynamics are controlled by genotypic and environmental influences. In this series of papers, general models of leaf area dynamics of uniculm and tillering sorghum ( Sorghum bicolor (L.) Moench) at the whole plant and individual leaf levels were developed to examine and quantify both genotypic and environmental controls. Green leaf area was modelled by examining leaf area production and senescence separately. Data from field experiments involving broad ranges of hybrids and environments were collated and analysed. Crops were grown with adequate water and nutrient supply. In this paper, a general framework to model leaf area production at the whole plant level is presented. Accumulation of total plant leaf area (TPLA) (without losses due to senescence) was simulated using a logistic function of thermal time (TT) from emergence and it increased to its maximum value (TPLA max ) shortly before flowering. To calculate TT, base optimum and maximum temperatures of 11, 30 and 42° C respectively were derived by examining the effect of temperature on rate of appearance of fully expanded leaves. Hence, TT incorporated the major effect exerted on TPLA by temperature. Most remaining genotypic and environmental variation in TPLA was related to variation in TPLA max . Values of TPLA max were predicted from total leaf number on the main culm (TLN) and fertile tiller number per plant (FTN) by allowing for a curvilinear increase in TPLA max with TLN and a sequential decrease in total leaf area produced by successive surviving tillers relative to that on the main culm. The potential genotypic and environmental controls on TPLA, introduced via factors affecting TLN and FTN, were considered. Frr seven hybrids grown in eight environments (locations and times of planting), this simple general model accounted for 93% of observed variation in TPLA with time, with a root mean square deviation of 664 cm 2 for observed values of TPLA ranging from 161 to 11 302 cm 2 .", "corpus_id": 205110481, "score": 0 }, { "doc_id": "84154227", "title": "Modelling genotypic and environmental control of leaf area dynamics in grain sorghum. II. Individual leaf level", "abstract": "Carberry, P.S., Muchow, R.C. and Hammer, G.L., 1993. Modelling genotypic and environmental control of leaf area dynamics in grain sorghum. II. Individual leaf level. Field Crops Res., 33:311328. Development of leaf area on tiller axes of grain sorghum (Sorghum bicolor (L.) Moench) has previously either been ignored or treated with over-simplifications in crop simulation models. This paper describes a framework to simulate total leaf area of tillering sorghums based on the prediction of the appearance and expansion of individual leaves. Data were collated from experiments on grain sorghum hybrids grown at locations ranging in latitude from 39 ° 11 'N to 27°33'S. A leaf area model was developed which simulated axes within plants independently, such that the production and expansion of individual leaves were simulated on the main culm and each developing tiller. The model simulates total leaf area per plant (TPLA) (without losses due to senescence) using functions to predict: (i) the appearance of successive axes on plants as a function of thermal time from emergence; (ii) a constant rate of mature leaf production per axis per unit of thermal time; (iii) the profile of mature leaf areas for leaves on each axis as a function of total number of leaves produced per axis; and (iv) the leaf area contribution of immature leaves at any time as equivalent to that for a constant number of mature leaves. For seven sorghum hybrids grown at three locations, a general model simulated TPLA over time, accounting for 90% of observed variation with a root mean square deviation of 905 cm 2 for observed values of TPLA ranging from 161 cm 2 to 10584 cm 2.", "corpus_id": 84154227, "score": 0 }, { "doc_id": "84347401", "title": "Genotype-by-Environment Interaction in Grain Sorghum. II. Effects of Temperature and Photoperiod on Ontogeny", "abstract": "(…) Development rate of all hybrids exhibited a curvilinear response to temperature in both phases. Old and new hybrids differed in their temperature responses in GS1 but were similar in GS2. New hybrids had slower rates of development at all temperatures, but the difference was greater at higher temperature (>25 o C). All hybrids had similar short-day photoperiodic response in GS1, with a critical photoperiod 13.2 h. The models were tested on a separate data set covering a similar broad range of environments and performed well", "corpus_id": 84347401, "score": 0 }, { "doc_id": "85888789", "title": "Effect of Heat and Drought Stress on Sorghum ( Sorghum Bicolor ). I. Panicle Development and Leaf Appearance", "abstract": "Seven sorghum lines, flowering from 50 to 87 days after sowing, were subjected to early drought stress, late stress, and both early and late stress in the field during the dry season in India. Panicle initiation was delayed by 2–25 days and flowering by 1–59 days by the drought stress treatments, the greatest effect being in the treatment subjected to both early and late stress. Stress increased the period between panicle initiation and flowering by retarding the rate of panicle development; when stress was severe panicle development stopped. Upon relief of stress following irrigation, panicle development resumed at rates comparable to those in a fully irrigated control. The rate of leaf appearance was affected in a similar manner to panicle development soon after water was withheld. Rate of leaf appearance and panicle development decreased as pre-dawn leaf water potential decreased and ceased at water potentials of −0.55 and −0.7 MPa, respectively", "corpus_id": 85888789, "score": 0 }, { "doc_id": "84898108", "title": "Functional dynamics of the nitrogen balance of sorghum: I. N demand of vegetative plant parts", "abstract": "Stay-green, an important trait for grain yield of sorghum grown under water limitation, has been associated with a high leaf nitrogen content at the start of grain filling. This study quantifies the N demand of leaves and stems and explores effects of N stress on the N balance of vegetative plant parts of three sorghum hybrids differing in potential crop height. The hybrids were grown under well-watered conditions at three levels of N supply. Vertical profiles of biomass and N% of leaves and stems, together with leaf size and number, and specific leaf nitrogen (SLN), were measured at regular intervals. The hybrids had similar minimum but different critical and maximum SLN, associated with differences in leaf size and N partitioning, the latter associated with differences in plant height. N demand of expanding new leaves was represented by critical SLN, and structural stem N demand by minimum stem N%. The fraction of N partitioned to leaf blades increased under N stress. A framework for N dynamics of leaves and stems is developed that captures effects of N stress and genotype on N partitioning and on critical and maximum SLN.", "corpus_id": 84898108, "score": 1 }, { "doc_id": "83567185", "title": "Nitrogen Response of Leaf Photosynthesis and Canopy Radiation Use Efficiency in Field-Grown Maize and Sorghum", "abstract": "The grain yielding capability of maize (Zea mays L.) and sorghum [Sorghum bicolor (L.) Moench] is dependent on the capacity of the crop to assimilate CO 2 . Carbon dioxide assimilation can be measured directly at the leaf level (C A ) and indirectly at the canopy levels by determining radiation use efficiency (RUE). Since leaf N content per unit leaf area (LN) was expected to influence both of these measures of CO 2 assimilation, the primary objective of this study was to obtain field data on C A and RUE in response to differing LN induced by varying the amount of applied N fertilizer [...]", "corpus_id": 83567185, "score": 0 }, { "doc_id": "96779604", "title": "Potential yield and water-use efficiency benefits in sorghum from limited maximum transpiration rate.", "abstract": "Limitations on maximum transpiration rates, which are commonly observed as midday stomatal closure, have been observed even under well-watered conditions. Such limitations may be caused by restricted hydraulic conductance in the plant or by limited supply of water to the plant from uptake by the roots. This behaviour would have the consequences of limiting photosynthetic rate, increasing transpiration efficiency, and conserving soil water. A key question is whether the conservation of water will be rewarded by sustained growth during seed fill and increased grain yield. This simulation analysis was undertaken to examine consequences on sorghum yield over several years when maximum transpiration rate was imposed in a model. Yields were simulated at four locations in the sorghum-growing area of Australia for 115 seasons at each location. Mean yield was increased slightly (5-7%) by setting maximum transpiration rate at 0.4 mm h-1. However, the yield increase was mainly in the dry, low-yielding years in which growers may be more economically vulnerable. In years with yield less than ∼450 g m-2, the maximum transpiration rate trait resulted in yield increases of 9-13%. At higher yield levels, decreased yields were simulated. The yield responses to restricted maximum transpiration rate were associated with an increase in efficiency of water use. This arose because transpiration was reduced at times of the day when atmospheric demand was greatest. Depending on the risk attitude of growers, incorporation of a maximum transpiration rate trait in sorghum cultivars could be desirable to increase yields in dry years and improve water use efficiency and crop yield stability.", "corpus_id": 96779604, "score": 0 }, { "doc_id": "84392510", "title": "Can Changes in Canopy and/or Root System Architecture Explain Historical Maize Yield Trends in the U.S. Corn Belt?", "abstract": "Continuous increase in the yield of maize (Zea mays L.) in the U.S. Corn Be-It has involved an interaction with plant density. A number of contributing traits and mechanisms have been suggested. In this Study we used a modeling approach to examine whether changes in canopy and/or root system architecture might explain the observed trends. A maize crop model was generalized so that changes in canopy and root system architecture could be examined. A layered, diurnal canopy photosynthesis model was introduced to predict consequences of change in canopy architecture. A two-dimensional root exploration model was introduced to predict consequences of change in root system architecture. Field experiments were conducted to derive model parameters for the base hybrid (Pioneer 3394). Simulation studies for various canopy and root system architectures were undertaken for a range of sites, soils, and densities. Simulated responses to density compared well with those found in field experiments. The analysis indicated that (i) change in root system architecture and water capture had a direct effect on biomass accumulation and historical yield trends; and (ii) change in canopy architecture had little direct effect but likely had important indirect effects via leaf area retention and partitioning of carbohydrate to the ear, The study provided plausible explarations and identified testable hypotheses for future research and crop improvement effort.", "corpus_id": 84392510, "score": 0 }, { "doc_id": "53344991", "title": "Transpiration-use efficiency of barley", "abstract": "Transpiration-use efficiency, the ratio of biomass (Y) produced per unit of water transpired (T) by a crop, depends on crop characteristics and on the environment in which crops develop. Transpiration-use efficiency has been described as Y/T = kc/Da, where kc is a crop dependent constant and Da is the daytime air vapor pressure deficit. Our objectives were to determine Y/T and kc of barley grown in Pullman, WA, and to analyze the variation in Y/T and kc of barley (Hordeum vulgare L.) and wheat (Triticum aestivum L.) reported in the literature. Transpiration and biomass accumulation of barley crops were measured in the years 2000 and 2001. The coefficient kc was estimated as the slope of the regression between cumulative values of biomass and T/Da .I t ranged from 6.6 � 0.4 to 6.9 � 0.2 Pa. These figures are greater than 5.8 Pa obtained by applying equations developed by Tanner and Sinclair [Tanner, C.B., Sinclair, T.R., 1983. Efficient water use in crop production: research or re-search. In: Taylor, H.M., et al. (Eds.), Limitations to Efficient Water Use in Crop Production. ASA, Madison, WI, pp. 1‐27]. Data on kc reported in the literature, although scarce, ranged from 3.0 to 5.9 Pa for barley, and from 2.8 to 6.7 Pa for wheat, with the lower values occurring at low Da (<1 kPa). This variability seems to associate with the response of the internal (leaf) to external (bulk air) CO2 concentration ratio (ci/ca) to changes of the leaf-to-air vapor pressure deficit (Dl), suggesting that kc rather than a constant could be a function of Dl. The evaluation of more field data on kc, the field validation of the response of ci/ca to Dl, and testing this approach for different species and cultivars is needed to improve the understanding of the Y/T determination at the canopy level. # 2005 Elsevier B.V. All rights reserved.", "corpus_id": 53344991, "score": 0 }, { "doc_id": "86686287", "title": "On the extent of genetic variation for transpiration efficiency in sorghum", "abstract": "A glasshouse study examined 49 diverse sorghum lines for variation in transpiration efficiency. Three of the 49 lines grown were Sorghum spp, native to Australia; one was the major weed Johnson grass (Sorghum halepense), and the remaining 45 lines were cultivars of Sorghum bicolor. All plants were grown under non-limiting water and nutrient conditions using a semi-automatic pot watering system designed to facilitate accurate measurement of water use. Plants were harvested 56-58 days after sowing and dry weights of plant parts were determined. Transpiration efficiency differed significantly among cultivars. The 3 Australian native sorghums had much lower transpiration efficiency than the other 46 cultivars, which ranged from 7.7 to 6.0 g/kg. For the 46 diverse cultivars, the ratio of range in transpiration efficiency to its l.s.d. was 2.0, which was similar to that found among more adapted cultivars in a previous study. This is a significant finding as it suggests that there is likely to be little pay-off from pursuing screening of unadapted material for increased variation in transpiration efficiency. It is necessary, however, also to examine absolute levels of transpiration efficiency to determine whether increased levels have been found. The cultivar with greatest transpiration efficiency in this study (IS9710) had a value 9% greater (P < 0.05) than the accepted standard for adapted sorghum cultivars. The potential impact of such an increase in transpiration efficiency warrants continued effort to capture it. Transpiration efficiency has been related theoretically and experimentally to the degree of carbon isotope discrimination in leaf tissue in sorghum, which thus offers a relatively simple selection index. In this study, the variation in transpiration efficiency was not related simply to carbon isotope discrimination. Significant associations of transpiration efficiency with ash content and indices of photosynthetic capacity were found. However, the associations were not strong. These results suggest that a simple screening technique could not be based on any of the measures or indices analysed in this study. A better understanding of the physiological basis of the observed genetic differences in transpiration efficiency may assist in developing reliable selection indices. It was concluded that the potential value of the improvement in transpiration efficiency over the accepted standard and the degree of genetic variation found warrant further study on this subject. It was suggested that screening for genetic variation under water-limiting conditions may provide useful insights and should be pursued.", "corpus_id": 86686287, "score": 0 }, { "doc_id": "84333373", "title": "Water extraction by grain sorghum in a sub-humid environment. I. Analysis of the water extraction pattern", "abstract": "Abstract Under water-limiting conditions, water extraction by a dryland crop is limited by the depth of the root system, and by the rate and degree of water extraction. The water extraction pattern of 6 crops of grain sorghum under continous soil drying in a sub-humid sub-tropical environment was analysed in terms of two components: the rate of descent of the extraction front down the soil profile (extraction front velocity), and the time required to extract 90% of the extractable water from each depth after the extraction front arrived (1/kl90). Extractable water content (θa), at each depth, was defined as the difference between the stable water content (θ) at the start of extraction and the lower asymptote of the exponential decay curve of θ versus time (lower limit). The crops varied in genotype, level of evaporative demand, degree of tillering, and plant population density, and were grown on the same soil type over two seasons. The aim of the study was to test the stability of the extraction front velocity, θa and of 1/kl90 under different agronomic and environmental conditions, to assess their usefulness for modelling water extraction of sorghum. Extraction front velocity varied little among the 6 crops with an overall average of 3.43 cm day−1. The extraction front of crops that were grown under long, terminal drying cycles continued to descend until early grain-filling, reaching a maximum depth of 190 cm. The value of 1/kl90 in the upper 100 cm of the profile varied considerably across crops. It is shown that this variation can be explained by variation in root length density and level of evaporative demand. For crops exposed to a long, terminal drying cycle, the actual water extracted below 150 cm depth was less than θa in the soil layers above 150 cm. This was due to both a lower θa below 150 cm, associated with low root length density, and also insufficient time between the arrival of the extraction front and maturity, for the crop to extract all the water above the lower limit.", "corpus_id": 84333373, "score": 0 }, { "doc_id": "85165236", "title": "Developing guidelines for replanting grain sorghum: II. Improved methods of simulating caryopsis weight and tiller number", "abstract": "Enhancing the yield prediction accuracy of SORKAM, a growth model for sorghum [Sorghum bicolor (L.) Moench], requires improving the simulation of grain growth and the relationship between tiller number and minimum temperature. A new grain growth equation, developed from 1990 data collected at Manhattan, KS, relates grainfilling rate to the rate of change of plant dry matter per caryopsis during the effective filling period. Additional functions are specified for the lag and leveling-off phases of caryopsis growth, resulting in a new submodel, which was tested against data from Kansas and two Australian sites. The tiller number calculation was revised using three years of Manhattan data. After incorporating the new submodels, SORKAM outputs were compared with observed yields and yield components in three Kansas regions. The R 2 values for yield increased from 0.27, 0.46, and 0.79 to 0.76, 0.69, and 0.90 for eastern, central, and western Kansas, respectively. Caryopsis weight comparisons showed that the revised model accounted for 48 to 72% of observed variability, up from 15 to 57% for the original model. Tiller number predictions also improved, although modestly.", "corpus_id": 85165236, "score": 0 }, { "doc_id": "86519511", "title": "REVIEW Towards an explanation of crop nitrogen demand based on the optimization of leaf nitrogen per unit leaf area", "abstract": "An area of plant science that is still uncertain is precisely what determines plants' demand for nitrogen (N), that is the amount of N they need to take up from the soil to meet their requirements for potential growth and synthesis of new tissue. A robust and unequivocal physiological basis from which to determine N demand is lacking. Yet N dominates plant nutrition. No nutrient is needed in larger quantities and, in most environments, no nutrient is in such limiting supply. Knowledge of the factors governing N demand is essential to predict the needs of crops under a wide range of field situations, so that growers can be given more reliable fertilizer recommendations (Greenwood 1982; van Keulen et al . 1989). This is important, not just for economic reasons, but because of the risks to the environment that can arise from the over-application of N fertilizers, in particular the problem of nitrate leaching (Addiscott et al . 1991).", "corpus_id": 86519511, "score": 0 }, { "doc_id": "84797935", "title": "Leaf Nitrogen, Photosynthesis, and Crop Radiation Use Efficiency: A Review", "abstract": "Three crop species were considered: solybean (Glycine max [L.] Merr.), rice (Oryza sativa L.), and maize (Zea mays L.). A relationship was developed predicting crop radiation use efficiency (biomass accumulated per unit solar radiation intercepted) for each of the crops as a function of both leaf CO 2 assimilation rate and leaf N content. At the leaf CO 2 assimilation rates typical of a species, the radiation use efficiency was predicted to be about 1.2 g MJ -1 for soybean, 1.4 g MJ -1 for rice, and 1.7 g MJ -1 for maize", "corpus_id": 84797935, "score": 0 }, { "doc_id": "23582014", "title": "Patterns of light and nitrogen distribution in relation to whole canopy carbon gain in C3 and C4 mono- and dicotyledonous species", "abstract": "An analytical model was used to describe the optimal nitrogen distribution. From this model, it was hypothesized that the non-uniformity of the nitrogen distribution increases with the canopy extinction rate for light and the total amount of free nitrogen in the canopy, and that it is independent of the slope of the relation between light saturated photosynthesis (Pm) and leaf nitrogen content (nL). These hypotheses were tested experimentally for plants with inherently different architectures and different photosynthetic modes. A garden experiment was carried out with a C3 monocot [rice, Oryza sativa (L.)], a C3 dicot [soybean, Glycine max (L.) Merr] a C4 monocot [sorghum, Sorghum bicolor (L.) Moensch] and a C4 dicot [amarantus, Amaranthus cruentus (L.)]. Leaf photosynthetic characteristics as well as light and nitrogen distribution in the canopies of dense stands of these species were measured. The dicot stands were found to have higher extinction coefficients for light than the monocot stands. Dicots also had more non-uniform N distribution patterns. The main difference between the C3 and C4 species was that the C4 species were found to have a greater slope value of the leaf-level Pm—nL relation. Patterns of N distribution were similar in stands of the C3 and C4 species. In general, these experimental results were in accordance with the model predictions, in that the pattern of nitrogen allocation in the canopy is mainly determined by the extinction coefficient for light and the total amount of free nitrogen.", "corpus_id": 23582014, "score": 0 }, { "doc_id": "84162988", "title": "Functional dynamics of the nitrogen balance of sorghum. II. Grain filling period.", "abstract": "Maintenance of green leaf area during grain filling can increase grain yield of sorghum grown under terminal water limitation. This 'stay-green' trait has been related to the nitrogen (N) supply-demand balance during grain filling. This study quantifies the N demand of grain and N translocation rates from leaves and stem and explores effects of genotype and N stress on onset and rate of leaf senescence during the grain filling period. Three hybrids differing in potential height were grown at three levels of N supply under well-watered conditions. Vertical profiles of biomass, leaf area, and N% of leaves, stem and grain were measured at regular intervals. Weekly SPAD chlorophyll readings on main shoot leaves were correlated with observed specific leaf nitrogen (SLN) to derive seasonal patterns of leaf N content. For all hybrids, individual grain N demand was sink determined and was initially met through N translocation from the stem and rachis. Only if this was insufficient did leaf N translocation occur. Maximum N translocation rates from leaves and stem were dependent on their N status. However, the supply of N at canopy scale was also related to the amount of leaf area senescing at any one time. This supply-demand framework for N dynamics explained effects of N stress and genotype on the onset and rate of leaf senescence.", "corpus_id": 84162988, "score": 1 }, { "doc_id": "153968710", "title": "APSIM's water and nitrogen modules and simulation of the dynamics of water and nitrogen in fallow systems", "abstract": "Abstract APSIM (Agricultural Production Systems Simulator) is a software system which provides a flexible structure for the simulation of climatic and soil management effects on growth of crops in farming systems and changes in the soil resource. The focus of this paper is the predictive performance of APSIM for simulation of soil water and nitrate nitrogen in contrasting soils (vertisols and alfisols) and environments. The three APSIM modules that determine the dynamics of water, carbon, and nitrogen in the soil system (viz. SOILWAT, SOILN and RESIDUE v.1) are described in terms of the processes represented, with particular emphasis on aspects of their coding that differ from their precursors in CERES and PERFECT. The most fundamental change is in SOILN, which now provides a formal balance of both carbon and nitrogen in the soil and includes a labile soil organic matter pool that decomposes more rapidly than the bulk of the soil organic matter. Model performance, in terms of prediction of soil water and nitrate, is evaluated during fallows, thereby avoiding complications arising from water use and nitrogen uptake by a crop. One data set is from a long-term experiment on a vertisol in southeast Queensland which studied two tillage treatments (conventional and zero tillage) in combination with fertiliser nitrogen inputs for the growth of wheat; soil water and nitrate were measured twice each year (pre-planting and post-harvest). The second comes from experiments at Katherine, Northern Territory, where legume leys growing on alfisols were chemically killed and ensuing changes in soil water and nitrate were measured during a single season. For both datasets, the predictive ability of the model was satisfactory for water and nitrate, in terms of both the total amounts in the whole profile and their distribution with depth. Since neither of these datasets included measurements of the runoff component of the water balance, this aspect of model performance was evaluated, and shown to be generally good, using data from a third source where runoff had been measured from contour bay catchments.", "corpus_id": 153968710, "score": 0 }, { "doc_id": "86814330", "title": "Effect of nitrogen supply on the comparative productivity of maize and sorghum in a semi-arid tropical environment II. Radiation interception and biomass accumulation", "abstract": "Abstract Differences in biomass accumulation due to variable nitrogen supply in maize and sorghum grown under irrigation in the semi-arid tropics were associated with differences in both radiation interception and the efficiency with which intercepted radiation was used to produce dry matter. Radiation-use efficiency was more responsive to N supply than was radiation interception. Radiation-use efficiency increased with higher rates of applied N; maximum radiation-use efficiency was greater in maize than in sorghum; and radiation-use efficiency declined during grain filling in maize more than in sorghum. These differences were explained in terms of specific leaf N. A linear relationship, which was similar for both species, was fitted between radiation-use efficiency and specific leaf N. It is concluded that radiation-use efficiency may not be as stable across environments as was previously thought, but rather depends on the balance of leaf growth, N uptake and allocation to leaves, and N mobilization from leaves to grain.", "corpus_id": 86814330, "score": 0 }, { "doc_id": "41708799", "title": "From dwarves to giants? Plant height manipulation for biomass yield.", "abstract": "The increasing demand for lignocellulosic biomass for the production of biofuels provides value to vegetative plant tissue and leads to a paradigm shift for optimizing plant architecture in bioenergy crops. Plant height (PHT) is among the most important biomass yield components and is the focus of this review, with emphasis on the energy grasses maize (Zea mays) and sorghum (Sorghum bicolor). We discuss the scientific advances in the identification of PHT quantitative trait loci (QTLs) and the understanding of pathways and genes controlling PHT, especially gibberellins and brassinosteroids. We consider pleiotropic effects of QTLs or genes affecting PHT on other agronomically important traits and, finally, we discuss strategies for applying this knowledge to the improvement of dual-purpose or dedicated bioenergy crops.", "corpus_id": 41708799, "score": 0 }, { "doc_id": "36883734", "title": "Maize Radiation Use Efficiency under Optimal Growth Conditions", "abstract": "Accurate measurement of crop growth and radiation use efficiency (RUE) under optimal growth conditions is required to predict plant dry matter accumulation and grain yield near the genetic growth potential. Research was conducted to quantify the biomass and leaf area index (LAI) accumulation, extinction coefficient, and RUE of maize (Zea mays L.) under conditions of optimal growth. Maize was grown in two environments over five growing seasons (1998-2002). Total aboveground biomass at maturity ranged from 2257 g m -2 in 1998 to 2916 g m -2 in 2001; values that are considerably greater than the biomass achieved in most previous studies on RUE in maize. Peak LAI ranged from 4.8 to 7.8. Maize extinction coefficients during vegetative growth (k) were within the range of recently published values (0.49 ± 0.03), with no clear pattern of differences in k among years. Seasonal changes in interception of photosynthetically active radiation (PAR) were similar across all but one year. Estimates of RUE were obtained using the short-interval crop growth rate method and the cumulative biomass and absorbed PAR (APAR) method. Values of RUE obtained using the two methods were 3.74 (±0.20) g MJ -1 APAR and 3.84 (±0.08) g MJ -1 APAR, respectively, and did not vary among years. This compares to a published mean RUE for maize of 3.3 g MJ -1 of intercepted PAR (Mitchell et al., 1998). Moreover, RUE did not decline during grain filling. Differences in biomass accumulation among years were attributed in part to differences in observed radiation interception, which varied primarily due to differences in LAI. Maize simulation models that rely on RUE for biomass accumulation should use an RUE of 3.8 g MJ -1 APAR for predicting optimum yields without growth limitations.", "corpus_id": 36883734, "score": 0 }, { "doc_id": "84909123", "title": "Heterosis for Leaf CO2 Exchange Rate during the Grain‐Filling Period in Maize", "abstract": "Heterosis for grain yield in maize (Zea mays L.) manifests itself through its effects on the components of grain yield, dry matter accumulation at maturity, harvest index, and its effects on physiological processes underlying these components, such as leaf CO 2 exchange rate (CER). The objectives of this study were (i) to quantify the pattern of leaf CER throughout the grain-filling period in maize hybrids and their parental inbred lines, and (ii) to determine the mode of inheritance of leaf CER during the grain-filling period. Studies were performed with 12 F 1 hybrids and their seven inbred parents grown hydroponically in the field at the Cambridge Research Station, ON, Canada, in 2002. Data were recorded on leaf CER from silking to maturity, and grain yield, aboveground dry matter, and root dry matter at maturity. Mean leaf CER of hybrids was not different from that of their parental inbred lines at silking. However, significant differences became apparent 2 wk after silking and became increasingly larger as plants advanced toward maturity. In general, leaf CER differed among inbred lines but did not differ among hybrids. Combining ability analysis showed that predominantly additive genetic effects influence the expression of leaf CER late in the season. Finally, the maintenance of leaf CER throughout a plant's life cycle, rather than potential leaf CER, is positively associated with dry matter accumulation during the grain-filling period and grain yield.", "corpus_id": 84909123, "score": 0 }, { "doc_id": "83669642", "title": "Ecophysiological traits in maize hybrids and their parental inbred lines: Phenotyping of responses to contrasting nitrogen supply levels", "abstract": "Abstract Maize ( Zea mays L.) breeding based primarily on final grain yield has been successful in improving this trait since the introduction of hybrids. Contrarily, understanding of the variation in ecophysiological processes responsible of this improvement is limited, especially between parental inbred lines and their hybrids. This limitation may hinder future progress in genetic gain, especially in environments where heritability estimation is reduced because grain yield is severely affected by abiotic stresses. The objective of this study was to analyze the genotypic variation between inbred lines and derived hybrids in the physiological determinants of maize grain yield at the crop level, and how differences among hybrids and parental inbreds may effect contrasting responses to N stress. Special emphasis was given to biomass production and partitioning during the critical period for kernel number determination. Phenotyping included the evaluation of 26 morpho-physiological attributes for 6 maize inbred lines and 12 derived hybrids, cropped in the field at contrasting N supply levels (N 0 : no N added; N 400 : 400 kg N ha −1 applied as urea) during three growing seasons. Tested genotypes differed in the response to reduce N supply for most measured traits. Grain yield was always larger for hybrids than for inbreds, but N deficiency affected the former more than the latter (average reduction in grain yield of 40% for hybrids and of 24% for inbreds). We also found (i) a common pattern across genotypes and N levels for the response of kernel number per plant to plant growth rate during the critical period, (ii) a reduced apical ear reproductive capacity (i.e., kernel set per unit of ear growth rate) of inbreds as compared to hybrids, (iii) similar RUE during the critical period and N absorption at maturity at low N levels for both groups of genotypes, but enhanced RUE and N absorption of hybrids at high N supply levels, and (iv) an improved N utilization efficiency of hybrids across all levels of N supply. Results are indicative of a more efficient use of absorbed N by hybrids than by parental inbreds. Larger grain yield of hybrids than of inbreds at N 0 was associated to (i) enhanced dry matter accumulation due to improved light interception during the life cycle and (ii) enhanced biomass partitioning to the grain.", "corpus_id": 83669642, "score": 0 }, { "doc_id": "28797384", "title": "Loss of an MDR Transporter in Compact Stalks of Maize br2 and Sorghum dw3 Mutants", "abstract": "Agriculturally advantageous reduction in plant height is usually achieved by blocking the action or production of gibberellins. Here, we describe a different dwarfing mechanism found in maize brachytic2 (br2) mutants characterized by compact lower stalk internodes. The height reduction in these plants results from the loss of a P-glycoprotein that modulates polar auxin transport in the maize stalk. The sorghum ortholog of br2 is dwarf3 (dw3), an unstable mutant of long-standing commercial interest and concern. A direct duplication within the dw3 gene is responsible for its mutant nature and also for its instability, because it facilitates unequal crossing-over at the locus.", "corpus_id": 28797384, "score": 0 }, { "doc_id": "84272493", "title": "Developing guidelines for replanting grain sorghum: I. Validation and sensitivity analysis of the SORKAM sorghum growth model", "abstract": "Sorghum [Sorghum bicolor (L.) Moench] producers often have difficulty determining when plant stands are low enough to merit replanting. Our objective was to use SORKAM, a sorghum growth model, to develop guidelines for replanting grain sorghum. A necessary first step is validation of the model over an extensive range of management and environmental factors. Validation was accomplished using 19 field data sets representing 11 yr and six Kansas locations. Several nonparametric tests were used to compare observed and simulated yields, yield components, and phenological dates. In addition, sensitivities of yield and yield components were determined in response to yearly climate, planting date, plant population, and maturity class changes. Model sensitivities were compared with sensitivities calculated from field data. While phenological predictions were adequate, SORKAM could capture only 27 to 79% of grain yield variability at the locations tested. Yield predictions from different plant populations within a planting date were particularly inaccurate. The validation and sensitivity analyses showed that the poor yield predictions were the result of improper computation of tiller number and faulty partitioning of biomass to caryopsis weight. Partitioning errors translocated enough assimilate from culm to grain to make yields essentially constant across populations within a planting date. To use SORKAM to generate replant guidelines, improvements must be made in modeling the relationships among yield components and the source-sink relationship that determines caryopsis weight.", "corpus_id": 84272493, "score": 0 }, { "doc_id": "84159288", "title": "Determination of grain number in sorghum", "abstract": "Grain number is an important component of grain yield in sorghum. Research in wheat and maize has indicated a dependency of grain number on the crop or panicle growth rate around anthesis (CGRa and PGRa respectively), but little quantitative information is available for sorghum. The aim of this paper was firstly to quantify the effect of CGRa and PGRa on grain number and secondly, to identify other parameters that could be used as substitutes for PGRa. Analyses included data from a number of experiments, covering a range in nitrogen and drought treatments and including both tall (single dwarf) and short (triple dwarf) hybrids. CGRa and SGRa (stem growth rate) were calculated from the derivative of a curvilinear function fitted to experimental data, and PGRa was obtained by subtraction of SGRa from CGRa. Results indicated a linear relationship between grain number and CGRa, but the slope differed for tall and short hybrids. This was due to a difference in the proportion of dry matter allocated to the reproductive organs around anthesis (Pr), as PGRa was closely related to grain number, irrespective of crop height. Since panicle dry mass at maturity (excluding grain) was closely correlated with reproductive biomass shortly after anthesis, this indicator represents an integration of panicle growth during the critical period for yield determination in sorghum (i.e. flag leaf until start of grain filling). Panicle biomass at maturity (excluding grain) was thus also linearly related to grain number, and the relationship was independent of crop height and of the timing, severity, or type of stress. Our results indicate that panicle mass at maturity could provide an alternative to PGRa for the estimation of grain number.", "corpus_id": 84159288, "score": 0 }, { "doc_id": "81641426", "title": "Radiation Use Efficiency", "abstract": "Publisher Summary This chapter reviews the various aspects of radiation use efficiency (RUE). Topics that are covered include theoretical analyses, experimental determination and measures, and sources of variability. Crop growth rate (dm/dt) could be readily estimated from successive harvests through the growing season. The studies that examined theoretically the nature of RUE will be reviewed. These theoretical studies help to give a background and framework for evaluating potential sources of variation in experimental measures of RUE. Specifically, theoretical studies help to identify variations in the environment and crops that might influence RUE. The various experimental measures of RUE are also discussed. RUE was calculated based on differing leaf photosynthetic rates of various crop species and varying levels of solar radiation. The chapter compares RUE reported for various species and experiments. The focus is particularly on data collected under optimum, usually control conditions, to compare observations on potential RUE from each study. The collection of a baseline of potential RUE data could serve as a useful reference in developing a realistic perspective on the upper limits of RUE that might be reasonably expected for individual crop species.", "corpus_id": 81641426, "score": 0 }, { "doc_id": "85327309", "title": "Simulating Seed Number in Grain Sorghum from Increases in Plant Dry Weight", "abstract": "Simulation of seed number for crop models is important in identifying cultural practices, which enhance yield stability. Field and crop simulation studies examined the relationship between dry weight accumulation and seed number per plant to potentially improve the capability of the grain sorghum [Sorghum bicolor (L.) Moench] model, SORKAM, to simulate seed number. The best estimates of seed numbers were obtained from plant dry weight accumulated during the 360 growing degree day intervals encompassing panicle branch-spikelet formation (PBSI) and panicle elongation through anthesis (EA(I)). Comparison of observed vs. simulated seed numbers using SORKAM's original equations accounted for 57% of the variation in seed number, but it underestimated high seed numbers. Accumulated plant dry weight for the PBSI and EA(I) intervals accounted for 49 and 64% of the variation in seed number, respectively. Simulation of seed numbers improved when the more sensitive water stress coefficient (for leaf area, WATCO(Ie)) was applied to the interval (PBSI or EA(I)) experiencing the highest water stress while the less sensitive water stress coefficient (for dry weight, WATCO(dw)) was applied to the interval experiencing the lowest water stress. The slope from the regression of observed on simulated seed numbers was 0.80 (r(2) = 0.57) for SORKAM with the WATCO(Ie) switch compared with 0.59 (r(2) = 0.57) in the original SORKAM model. Hence, the timing and recovery of water stress during the panicle development period was important in estimating seed number of sorghum.", "corpus_id": 85327309, "score": 0 }, { "doc_id": "83543607", "title": "Reproductive partitioning and seed set efficiency in soybean, sunflower and maize", "abstract": "Abstract Seed number per plant (SNP) can be modelled as a function of plant growth rate during the critical period for seed set (PGR C ), the proportion of plant growth partitioned to reproductive organs ( P R ) and the minimum assimilate requirement per seed ( λ ). In comparison to PGR C , less attention has been given to P R and λ . In this paper, we analysed reproductive partitioning and λ in three species of contrasting reproductive strategies, soybean ( Glycine max L. Merrill), sunflower ( Helianthus annuus L.) and maize ( Zea mays L.). To study plant-to-plant variation and to characterise stability of the variables analysed, we focused on individual plants grown under a wide range of plant densities. In soybean and sunflower, reproductive partitioning comprised about 50% of shoot growth, was fairly stable in a wide range of plant growth, and only decreased in a few, very small plants. In comparison, reproductive partitioning in non-prolific maize showed an optimum, was generally below 50% and exhibited a strong variation and instability at plant growth rates ≅2 g/day. Among species, stability of reproductive partitioning correlated inversely with a PGR C threshold for reproductive growth and positively with reproductive plasticity at high PGR C . Consideration of reproductive partitioning improved estimation of seed number, particularly in maize, a species prone to barrenness. Seed number as a function of reproductive growth was adequately described through linear (soybean) and hyperbolic models with x -intercepts (sunflower and maize). Seed set efficiency in terms of seed number per unit of reproductive growth (Ef) was constant only in soybean. In sunflower and maize, Ef increased with decreasing reproductive growth and became highly variable and unstable when reproductive growth was close to the threshold for seed set. In maize, such threshold was higher than in soybean and sunflower possibly as a consequence of a higher minimum combined demand for assimilate, resulting from a higher λ and number of simultaneously developing sinks. Inclusion of parameters assessing (i) stability in reproductive partitioning at low plant growth rates, and (ii) the minimum assimilate requirement per seed might improve seed number estimation.", "corpus_id": 83543607, "score": 0 }, { "doc_id": "86195858", "title": "Floret development in near isogenic wheat lines differing in plant height", "abstract": "Abstract The effects of Rht1 and Rht2 alleles on the dynamics of floret development in isogenic lines (dwarf, DD; semi-dwarf, SD and standard height, SH) of spring wheat were investigated. Studies were conducted on wheat grown in the field in each of 4 years and where water and nutrients were non-limiting. The number of grains per spike was significantly greater in the lines with Rht alleles than in the SH lines. Grain number for each line was such that DD>SD>SH. Grains per spike varied with the number of grains per spikelet rather than number of spikelets per spike. Grains per spikelet in turn varied with the number of fertile florets at anthesis. Florets were considered fertile when male and female reproductive organs had developed green anthers and bifidum stigma, respectively. The dwarfing genes had no effect on the percentage of fertile florets setting grain. Increased number of fertile florets per spikelet due to the presence of Rht1 and Rht2 alleles in the genome was a consequence of the higher number of relatively distal primordia, to progress to the stage of fertile floret at anthesis in the DD and SD than in the SH lines. This ability to allow that a greater proportion of distal florets maintain a normal rate of development was related to the fact that Rht alleles produced a more favourable assimilate partitioning to the spike during the pre-anthesis period associated with the reduction in stem growth imposed by Rht alleles. This allowed a higher proportion of the later-initiated floret primordia to produce fertile florets at anthesis.", "corpus_id": 86195858, "score": 0 }, { "doc_id": "85177643", "title": "Environmental and genetic control of morphogenesis in crops: towards models simulating phenotypic plasticity", "abstract": "As molecular biologists are realising the importance of physiology in understanding functional genomics of quantitative traits, and as physiologists are realising the formidable prospects for improving their phenotypic models with information on the underlying gene networks, researchers worldwide are working on linked physiological-genetic models. These efforts are in their early methodological stage despite, or because of, the availability of many different types of models, the problem being to bring together the different ways that scientists see the plant. This paper describes some current efforts to adapt phenotype models to the objective of simulating gene-phene processes at the plant or crop scale. Particular emphasis is given to the models' capacity to simulate genotype x environment interaction and the resulting phenotypic plasticity, assuming that this permits the defining of model parameters that are closer to specific gene action. Three different types of approaches are presented: (1) a generic, mathematical-architectural model called GREENLAB that simulates resource-modulated morphogenesis; (2) an ecophysiological model of peach tree fruit development and filling, parameterised for a mapping population to evaluate the potential of plugging quantitative trait locus (QTL) effects into the model; and (3) the new model Ecomeristem that constructs plant architecture and its phenotypic plasticity from meristem behaviour, the principal hypothesis being that resource limitations and stresses feed back on the meristems. This latter choice is based on the fact that gene expression happens to a large extent in the meristems. The model is evaluated on the basis of preliminary studies on vegetative-stage rice. The different modelling concepts are critically discussed with respect to their ability to simulate phenotypic plasticity and to operate with parameters that approximate specific gene action, particularly in the area of morphogenesis.", "corpus_id": 85177643, "score": 0 }, { "doc_id": "21684809", "title": "Dry Matter Partitioning in Tomato: Validation of a Dynamic Simulation Model", "abstract": "Abstract A model for dynamic simulation of dry matter distribution between reproductive and vegetative plant parts and the distribution among individual fruit trusses in glasshouse tomato, is validated. The model is part of the crop growth model TOMSIM and is based on the hypothesis that dry matter distribution is regulated by the sink strengths of the plant organs, quantified by their potential growth rates, i.e. the growth rates at non-limiting assimilate supply. Within the plant, individual fruit trusses are distinguished and sink strength of a truss is described as a function of its development stage. Truss development rate is a function of temperature only. The same potential growth curve, proportional to the number of fruits per truss, is adopted for all trusses. In a simple version of the model, vegetative plant parts are lumped together as one sink with a constant sink strength. In a more detailed version, vegetative sink strength is calculated as the sum of sink strengths of vegetative units (three leaves and stem internodes between two trusses). The model was validated for six glasshouse experiments, covering effects of planting date, plant density, number of fruits per truss (pruning at anthesis), truss removal (every second truss removed at anthesis), single- and double-shoot plants and a temperature experiment conducted in climate rooms at 17, 20 or 23 °C. Daily increase in above-ground dry weight, average daily temperatures and number of set fruits per truss were inputs to the model. Both the simple and the more detailed model showed good agreement between measured and simulated fraction of dry matter partitioned into the fruits over time. For the simple version of the model, the slope of the lines relating simulated to measured fraction partitioned into the fruits (16 data sets), varied between 0.92 and 1.11, on average it was 1.04, implying 4% over-estimation for this fraction. For the detailed model these numbers were slightly better: 0.89, 1.08 and 1.01, respectively. The temperature experiment revealed no important direct influence of temperature on the ratio between generative and vegetative sink strength. Simulated truss growth curves showed reasonable agreement with the measurements, although both models over-estimated (17% on average) final dry weight of the lower trusses (truss 1 –3) on a plant. Modelling dry matter partitioning based on sink strengths of organs is promising, as it is a general, dynamic and flexible approach, showing good agreement between measurements and simulation for a range of conditions. Applicability of the model is, however, still limited as long as the number of fruits per truss (flower and /or fruit abortion) is not simulated, as this is a major feedback mechanism in plant growth.", "corpus_id": 21684809, "score": 0 }, { "doc_id": "15224811", "title": "Integrating simulation of architectural development and source-sink behaviour of peach trees by incorporating Markov chains and physiological organ function submodels into L-PEACH.", "abstract": "L-PEACH is an L-system-based functional-structural model for simulating architectural growth and carbohydrate partitioning among individual organs in peach (Prunus persica (L.) Batsch) trees. The original model provided a prototype for how tree architecture and carbon economy could be integrated, but did not simulate peach tree architecture realistically. Moreover, evaluation of the functional characteristics of the individual organs and the whole tree remained a largely open issue. In the present study, we incorporated Markovian models into L-PEACH to improve the architecture of the simulated trees. The model was also calibrated to grams of carbohydrate, and tools for systematically displaying quantitative outputs and evaluating the behaviour of the model were developed. The use of the Markovian model concept to model tree architecture in L-PEACH reproduced tree behaviour and responses to management practices visually similar to trees in commercial orchards. The new architectural model along with several improvements in the carbohydrate-partitioning algorithms derived from the model evaluation significantly improved the results related to carbon allocation, such as organ growth, carbohydrate assimilation, reserve dynamics and maintenance respiration. The model results are now consistent within the modelled tree structure and are in general agreement with observations of peach trees growing under field conditions.", "corpus_id": 15224811, "score": 0 }, { "doc_id": "11022297", "title": "Quantitative genetics and functional-structural plant growth models: simulation of quantitative trait loci detection for model parameters and application to potential yield optimization.", "abstract": "BACKGROUND AND AIMS\nPrediction of phenotypic traits from new genotypes under untested environmental conditions is crucial to build simulations of breeding strategies to improve target traits. Although the plant response to environmental stresses is characterized by both architectural and functional plasticity, recent attempts to integrate biological knowledge into genetics models have mainly concerned specific physiological processes or crop models without architecture, and thus may prove limited when studying genotype x environment interactions. Consequently, this paper presents a simulation study introducing genetics into a functional-structural growth model, which gives access to more fundamental traits for quantitative trait loci (QTL) detection and thus to promising tools for yield optimization.\n\n\nMETHODS\nThe GREENLAB model was selected as a reasonable choice to link growth model parameters to QTL. Virtual genes and virtual chromosomes were defined to build a simple genetic model that drove the settings of the species-specific parameters of the model. The QTL Cartographer software was used to study QTL detection of simulated plant traits. A genetic algorithm was implemented to define the ideotype for yield maximization based on the model parameters and the associated allelic combination.\n\n\nKEY RESULTS AND CONCLUSIONS\nBy keeping the environmental factors constant and using a virtual population with a large number of individuals generated by a Mendelian genetic model, results for an ideal case could be simulated. Virtual QTL detection was compared in the case of phenotypic traits--such as cob weight--and when traits were model parameters, and was found to be more accurate in the latter case. The practical interest of this approach is illustrated by calculating the parameters (and the corresponding genotype) associated with yield optimization of a GREENLAB maize model. The paper discusses the potentials of GREENLAB to represent environment x genotype interactions, in particular through its main state variable, the ratio of biomass supply over demand.", "corpus_id": 11022297, "score": 1 }, { "doc_id": "87990863", "title": "Modelling Shoot:Root Relations: the Only Way Forward?", "abstract": "The basic transport-resistance (TR) model of shoot:root carbon:nitrogen allocation is described. This approach assumes that the two processes of substrate transport and chemical conversion determine allocation. It is suggested thatallallocation models, whether built for the purposes of theoretical investigation or practical application, should start with this irreducible framework. Here it is assumed that the processes operate according to: (a) for substrate sources, dependence on shoot and root sizes with possible product inhibition; (b) for transport, movement down a substrate concentration gradient; and (c) for substrate sinks or utilization, linear bisubstrate kinetics. Some dynamic properties of the model are explored. Failure of this approach to allocation flags the need for additional mechanisms to control the processes. Details of the failure will indicate the modifications needed, which may involve hormones or reflect teleonomy (apparently goal-seeking behaviour), and which are added to the irreducible framework. However, these additions should not replace the irreducible framework of transport and chemical conversions, because they do not in reality. Modifications to the basic model to represent possibilities such as ontogenesis with the transition from exponential growth towards a steady state or with the scaling of within-plant transport resistances with plant size, the influence of hormones, and active transport, are described.", "corpus_id": 87990863, "score": 0 }, { "doc_id": "364410", "title": "Root system architecture: opportunities and constraints for genetic improvement of crops.", "abstract": "Abiotic stresses increasingly curtail crop yield as a result of global climate change and scarcity of water and nutrients. One way to minimize the negative impact of these factors on yield is to manipulate root system architecture (RSA) towards a distribution of roots in the soil that optimizes water and nutrient uptake. It is now established that most of the genetic variation for RSA is driven by a suite of quantitative trait loci. As we discuss here, marker-assisted selection and quantitative trait loci cloning for RSA are underway, exploiting genomic resources, candidate genes and the knowledge gained from Arabidopsis, rice and other crops. Nonetheless, efficient and accurate phenotyping, modelling and collaboration with breeders remain important challenges, particularly when defining ideal RSA for different crops and target environments.", "corpus_id": 364410, "score": 0 }, { "doc_id": "85076090", "title": "A model-based analysis of the dynamics of carbon balance at the whole-plant level in Arabidopsis thaliana.", "abstract": "Arabidopsis thaliana (L.) Heynh. is used as a model plant in many research projects. However, few models simulate its growth at the whole-plant scale. The present study describes the first model of Arabidopsis growth integrating organogenesis, morphogenesis and carbon-partitioning processes for aerial and subterranean parts of the plant throughout its development. The objective was to analyse competition among sinks as they emerge from patterns of plant structural development. The model was adapted from the GreenLab model and was used to estimate organ sink strengths by optimisation against biomass measurements. Dry biomass production was calculated by a radiation use efficiency-based approach. Organogenesis processes were parameterised based on experimental data. The potential of this model for growth analysis was assessed using the Columbia ecotype, which was grown in standard environmental conditions. Three phases were observed in the overall time course of trophic competition within the plant. In the vegetative phase, no competition was observed. In the reproductive phase, competition increased with a strong increase when lateral inflorescences developed. Roots and internodes and structures bearing siliques were strong sinks and had a similar impact on competition. The application of the GreenLab model to the growth analysis of A. thaliana provides new insights into source-sink relationships as functions of phenology and morphogenesis.", "corpus_id": 85076090, "score": 0 }, { "doc_id": "14391945", "title": "Computational Modeling and Molecular Physiology Experiments Reveal New Insights into Shoot Branching in Pea[C][W]", "abstract": "Bud outgrowth is regulated by the interplay of multiple hormones, including auxin, cytokinin, strigolactones, and an unidentified long-distance feedback signal that moves from shoot to root. The model of bud outgrowth regulation in pea (Pisum sativum) includes these signals and a network of five RAMOSUS (RMS) genes that operate in a shoot-root-shoot loop to regulate the synthesis of, and response to, strigolactones. The number of components in this network renders the integration of new and existing hypotheses both complex and cumbersome. A hypothesis-driven computational model was therefore developed to help understand regulation of shoot branching. The model evolved in parallel with stepwise laboratory research, helping to define and test key hypotheses. The computational model was used to verify new mechanisms involved in the regulation of shoot branching by confirming that the new hypotheses captured all relevant biological data sets. Based on cytokinin and RMS1 expression analyses, this model is extended to include subtle but important differences in the function of RMS3 and RMS4 genes in the shoot and rootstock. Additionally, this research indicates that a branch-derived signal upregulates RMS1 expression independent of the other feedback signal. Furthermore, we propose xylem-sap cytokinin promotes sustained bud outgrowth, rather than acting at the earlier stage of bud release.", "corpus_id": 14391945, "score": 0 }, { "doc_id": "85380713", "title": "Stay‐green: A consequence of the balance between supply and demand for nitrogen during grain filling?", "abstract": "Retention of green leaf area in grain sorghum under post-anthesis drought, known as stay-green, is associated with greater biomass production, lodging resistance and yield. The stay-green phenomenon can be examined at a cell, leaf, or whole plant level. At a cell level, the retention of chloroplast proteins such as LHCP2, OEC33 and Rubisco until late in senescence has been reported in sorghum containing the KS19 source of stay-green, indicating that photosynthesis may be maintained for longer during senescence in these genotypes. At a leaf level, longevity of photosynthetic apparatus is intimately related to nitrogen (N) status. At a whole plant level, stay-green can be viewed as a consequence of the balance between N demand by the grain and N supply during grain filling. To examine some of these concepts, nine hybrids varying in the B35 and KS19 sources of stay-green were grown under a postanthesis water deficit. Genotypic variation in delayed onset and reduced rate of leaf senescence were explained by differences in specific leaf nitrogen (SLN) and N uptake during grain filling. Matching N supply from age-related senescence and N uptake during grain tilling with grain N demand found that the shortfall in N supply for grain filling was greater in the senescent than stay-green hybrids, resulting in more accelerated leaf senescence in the former. We hypothesise that increased N uptake by stay-green hybrids is a result of greater biomass accumulation during grain filling in response to increased sink demand (higher grain numbers) which, in turn, is the result of increased radiation use efficiency and transpiration efficiency due to higher SLN. Delayed leaf senescence resulting from higher SLN should, in turn, allow snore carbon and nitrogen to be allocated to the roots of stay-green hybrids during grain filling, thereby maintaining a greater capacity to extract N from the soil compared with senescent hybrids.", "corpus_id": 85380713, "score": 0 }, { "doc_id": "85589625", "title": "Flowering time control: gene network modelling and the link to quantitative genetics", "abstract": "Flowering is a key stage in plant development that initiates grain production and is vulnerable to stress. The genes controlling flowering time in the model plant Arabidopsis thaliana are reviewed. Interactions between these genes have been described previously by qualitative network diagrams. We mathematically relate environmentally dependent transcription, RNA processing, translation, and protein–protein interaction rates to resultant phenotypes. We have developed models (reported elsewhere) based on these concepts that simulate flowering times for novel A. thaliana genotype–environment combinations. Here we draw 12 contrasts between genetic network (GN) models of this type and quantitative genetics (QG), showing that both have equal contributions to make to an ideal theory. Physiological dominance and additivity are examined as emergent properties in the context of feed-forwards networks, an instance of which is the signal-integration portion of the A. thaliana flowering time network. Additivity is seen to be a complex, multi-gene property with contributions from mass balance in transcript production, the feed-forwards structure itself, and downstream promoter reaction thermodynamics. Higher level emergent properties are exemplified by critical short daylength (CSDL), which we relate to gene expression dynamics in rice (Oryza sativa). Next to be discussed are synergies between QG and GN relating to the quantitative trait locus (QTL) mapping of model coefficients. This suggests a new verification test useful in GN model development and in identifying needed updates to existing crop models. Finally, the utility of simple models is evinced by 80 years of QG theory and mathematical ecology.", "corpus_id": 85589625, "score": 0 }, { "doc_id": "86749736", "title": "Developmental and physiological traits associated with high yield and stay-green phenotype in wheat", "abstract": "Water availability is a key limiting factor in wheat production in the northern grain belt of Australia. Varieties with improved adaptation to such conditions are actively sought. The CIMMYT wheat line SeriM82 has shown a significant yield advantage in multi-environment screening trials in this region. The objective of this study was to identify the physiological basis of the adaptive traits underpinning this advantage. Six detailed experiments were conducted to compare the growth, development, and yield of SeriM82 with that of the adapted cultivar, Hartog. The experiments were undertaken in field environments that represented the range of moisture availability conditions commonly encountered by winter crops grown on the deep Vertosol soils of this region. The yield of SeriM82 was 6-28% greater than that of Hartog, and SeriM82 exhibited a stay-green phenotype by maintaining green leaf area longer during the grain-filling period in all environments where yield was significantly greater than Hartog. However, where the availability of deep soil moisture was limited, SeriM82 failed to exhibit significantly greater yield or to express the stay-green phenotype. Thus, the stay-green phenotype was closely associated with the yield advantage of SeriM82. SeriM82 also exhibited higher mean grain mass than Hartog in all environments. It is suggested that small differences in water use before anthesis, or greater water extraction from depth after anthesis, could underlie the stay-green phenotype. The inability of SeriM82 to exhibit stay-green and higher yield where deep soil moisture was depleted indicates that extraction of deep soil moisture is important.", "corpus_id": 86749736, "score": 0 }, { "doc_id": "4095406", "title": "Evaluating Plant Breeding Strategies by Simulating Gene Action and Dryland Environment Effects", "abstract": "In quantitative genetics, computer simulation is commonly used to evaluate alternative plant breeding strateFunctional genomics is the systematic study of genome-wide effects gies on the basis of stochastic descriptions of gene action of gene expression on organism growth and development with the ultimate aim of understanding how networks of genes influence traits. and interaction (e.g., Hospital et al., 1997; Podlich and Here, we use a dynamic biophysical cropping systems model (APSIMCooper, 1998). Our aim is to demonstrate how linkages Sorg) to generate a state space of genotype performance based on between gene action and crop performance in dryland 15 genes controlling four adaptive traits and then search this space environments can be investigated by combining the biousing a quantitative genetics model of a plant breeding program (QUphysical response simulation of the of crops to the moisGENE) to simulate recurrent selection. Complex epistatic and gene ture environment with the quantitative genetics simulaenvironment effects were generated for yield even though gene action tion of plant breeding programs. A review of present at the trait level had been defined as simple additive effects. Given research will reveal that substantial resources are being alternative breeding strategies that restricted either the cultivar matuinvested into the cellular and molecular basis for adaptarity type or the drought environment type, the positive ( ) alleles tion to dry environments while plant breeding compafor 15 genes associated with the four adaptive traits were accumulated at different rates over cycles of selection. While early maturing genonies and public programs continue to make advances in types were favored in the Severe-Terminal drought environment type, yield through conventional means. Exploitation of the late genotypes were favored in the Mild-Terminal and Midseason investment in the former requires the integration of drought environment types. In the Severe-Terminal environment, knowledge from agronomy and cellular, plant, and crop there was an interaction of the stay-green (SG) trait with other traits: physiology as well as plant breeding and quantitative Selection for alleles of the SG genes was delayed until alleles genetics. For those less familiar with the breeding and for genes associated with the transpiration efficiency and osmotic quantitative genetics, there are some useful background adjustment traits had been fixed. Given limitations in our current texts (e.g., Hallauer et al., 1988; Falconer and Mackay, understanding of trait interaction and genetic control, the results are 1996) in addition to Podlich and Cooper (1998) and not conclusive. However, they demonstrate how the per se complexity Chapman et al. (2002a). of gene gene environment interactions will challenge the application of genomics and marker-assisted selection in crop improvement In combining gene sequencing, gene cloning, and for dryland adaptation. plant transformation with biochemical and genome databases, scientists in private and public industry have identified and constructed genes that control relatively linear pathways like herbicide tolerance, disease resisW this paper focuses on the simulation of plant tance, and product quality (Somerville and Somerville, breeding programs from an understanding of gene 1999; Mazur et al., 1999). Molecular biology is beginning action, it is useful to begin with a description of how to investigate the role of the other genes that relate to connections between crop modeling, genomics (the unadaptation to the abiotic environment. For these genoderstanding of how multiple genes function together), type–environment systems, thousands of genes interact and plant breeding are developing. Crop simulation in complex ways to generate crop responses to the enmodels have been used to integrate physiological undervironment via mediation of responses over both short standing and evaluate alternative strategies of system time scales (e.g., cellular response to environment shocks management to account for the soil, climate, and agrolike frost) and long time scales (e.g., morphological nomic technologies available. The principal objective of growth responses of crop development and morphola plant-breeding program is the generation and selection ogy). Some pathways for abiotic adaptation are comparof new gene combinations to create genotypes with trait atively straightforward, e.g., direct cellular tolerance of performance that is superior to current genotypes, withsalt stresses (see review by Hasegawa et al., 2000). Howin the target population of environments (TPE) (Comever, it will be some time ( 20 yr?) before we understock, 1977). This objective applies equally to conventional, molecular, and combined approaches. stand how the interactions of developmental and signaling genes control yield of crops as a function of responses at the biochemical, cellular, plant, and canopy or crop S. Chapman, CSIRO Plant Industry, Long Pocket Lab., 120 Meiers Rd., Indooroopilly, 4068, QLD, Australia; M. Cooper and D. Podlich, levels of organization. Until then, we need to deal with School of Land and Food Sci., The University of Queensland, Brisadaptive traits at a more integrative level (i.e., traits bane, 4072, QLD, Australia; and G. Hammer, Agric. Prod. Syst. Res. observable at the plant or crop level) while beginning Unit, Queensland Dep. of Primary Industries, P.O. Box 102, Toowoomba, QLD, 4350, Australia. M. Cooper and D. Podlich, current address: Pioneer Hi-Bred Int., 7300 N.W. 62nd Ave., P.O. Box 1004, Abbreviations: G E, genotype environment; MET, multienvironJohnston, IA 50131. Received 1 May 2001. *Corresponding author ment trial; OA, osmotic adjustment; PH, flowering time; QTLs, quan(scott.chapman@csiro.au). titative trait loci; SG, stay-green; TE, transpiration efficiency; TPE, target population of environments. Published in Agron. J. 95:99–113 (2003).", "corpus_id": 4095406, "score": 0 }, { "doc_id": "84742195", "title": "Physiology and modelling of traits in crop plants: implications for genetic improvement", "abstract": "Abstract Crop growth models have excellent potential for evaluating genetic improvement, for analyzing past genetic improvement from experimental data, and for proposing plant ideotypes for target environments. Crop models used for these plant breeding applications should be sufficiently mechanistic that processes can be investigated in a manner familiar to crop physiologists and plant breeders. In addition, the crop models must consider a sufficient number of cultivar-specific traits descriptive of life cycle phases, vegetative traits, and reproductive growth attributes. In this paper, we discuss how crop models consider genetic variability within a species (cultivar variation), how varietal characteristics can be determined from variety trial or other data, how crop models can be used to evaluate past genetic improvement, and how crop models can be used to hypothesize ideotypes for specific environments. We conclude that crop growth models can partially reproduce genotype by environment interactions when considered across broad ranges of weather and sites, and that crop models can be used to help plant breeders target cultivar improvement for specific environments. However, more physiological insight into primary processes such as source–sink relationships and morphological development will be needed for enhanced application of the models in breeding programmes.", "corpus_id": 84742195, "score": 0 }, { "doc_id": "86119390", "title": "Genotype by environment interactions affecting grain sorghum. II. Frequencies of different seasonal patterns of drought stress are related to location effects on hybrid yields.", "abstract": "Genotype × environment (G×E) interactions due to variation in soil moisture and rainfall complicate the interpretation of sorghum hybrid performance trials over locations (L) and years (Y). This paper aims to use pattern analysis to explain measures of the G×L interaction for yield, and whether these can, in turn, be explained using simulation models to determine the occurrence of environment types (within-season patterns of drought). The aim of this work is to simplify the analysis of G×E by explaining it in terms of interactions of genotypes with envi- ronment types (ET) that are not 'fixed' to locations and years. In a sequential analysis of 17 seasons, 18 locations were separated into groups that tended to represent either the northern (i.e. central Queensland, CQ) or southern Queensland (SQ) regions. For a subset of 6 locations, ordination partially explained differences among locations as being related to latitude (r = 0.88) and rainfall (r = -0.46), but they were better related (r > 0.9) to the frequencies of 3 stress ETs as determined by long-term crop simulations. These 3 environment types were: (1) low stress (occurring in 33% of seasons); (2) severe terminal stress with an early-season (9%) or midseason time (29%) of onset; and (3) intermediate terminal stress with a midseason (9%) or late-season (20%) time of onset. Low stress ETs were more common in two SQ locations than in CQ. Stress ETs as defined by simulation models and pattern analysis had more consistent relationships with simulated yields than did the fixed descriptors of locations and years. Sorghum hybrid trials for broad adaptation in Queensland should include locations at least from each of the 2 regions and the results should be interpreted in the context of the season in which they are conducted. To match the long-term patterns in the 6 locations of the analysis, trial yields would need to sample from at least 3 yield ranges: 3.5 t/ha. Additional seasons of testing are likely to be required when the locations used during a season do not adequately represent the target population of environments over all locations and years.", "corpus_id": 86119390, "score": 0 }, { "doc_id": "86547184", "title": "Computer simulation of a selection strategy to accommodate genotype environment interactions in a wheat recurrent selection programme", "abstract": "Multi-environment trials (METs) are used in plant breeding programmes to evaluate genotypes (lines/families) as a basis for selection on expected performance (yield and/or quality) in a target population of environments (TPE). When a large component of the genotype-environment (G x E) interactions results from crossover interactions, samples of environments in METs that deviate From the TPE provide a suboptimal basis for selection of genotypes on performance expected in the TPE. To adjust for the negative effects of these deviations, a selection strategy that weights the data from the MET according to their expected frequency of occurrence in the TPE (i.e. a weighted selection strategy)was investigated. Computer simulation methodology was used to obtain preliminary information on the weighted selection strategy and compare it to the traditional unweighted selection strategy For a range of MET scenarios and G x E interaction models. The evaluation of the weighted selection strategy was conducted in context with the germplasm enhancement programme (GEP) of the Northern Wheat Improvement Programme in Australia. The results indicated that when the environments sampled in the MET matched those expected in the TPE, the unweighted and weighted selection strategies achieved a similar response to selection in the TPE. However. when the environments sampled in the MET did not match the expectations in the TPE and a large component of the G x E interactions resulted from crossover interactions, the weighted selection strategy achieved a greater response to selection in the TPE. The advantage of the weighted strategy increased as the amount of crossover G x E interaction increased or fewer environments were sampled in the METs.", "corpus_id": 86547184, "score": 0 }, { "doc_id": "41613952", "title": "Use of crop models to understand genotype by environment interactions for drought in real-world and simulated plant breeding trials", "abstract": "Crop simulation models of plant processes capture the biological interactions between the sensing of signals at an organ level (e.g. drought affecting roots), the response of the plant at a biochemical level (e.g. change in development rate) and the result at the organ (or crop) level (e.g. reduced growth). In dissecting the complex control of phenotypes like yield, simulation models have several roles. Models have been used to generate an index of the climatic environment (e.g. of drought stress) for breeding programme trials. In wheat and sorghum grown in northern Australia, this has shown that mid-season drought generates large genotype by environment interaction. By defining gene action to calculate the value of input trait parameters to crop models, simulated multi-environment trials estimate the yield of ‘synthetic’ sorghum cultivars grown in historical or artificial climates with current or potential management regimes. In this way, the biological interactions among traits constrain the crop yields to only those that are biologically possible in the given set of environments. This allows the construction of datasets that are more ‘realistic’ representations of gene by trait by environment interaction than is possible using only the statistical attributes (e.g. means, variances and correlations) of real-world trait datasets. This approach has an additional advantage in that ‘biological and experimental noise’ can be manipulated separately. These ‘testbeds’ for statistical techniques can be extended to the interpretation of a crossing and selection programme where the processes of chromosomal recombination are simulated using a quantitative genetics model and applied to the trait parameters. Statisticians are challenged to develop improved methods for the resulting simulated phenotype datasets, with the objective of revealing the (known) underlying genetic and environment structure that was input to the simulations. These improved methods can then be applied to existing plant breeding programmes.", "corpus_id": 41613952, "score": 0 }, { "doc_id": "20986798", "title": "Detection and use of QTL for complex traits in multiple environments.", "abstract": "QTL mapping methods for complex traits are challenged by new developments in marker technology, phenotyping platforms, and breeding methods. In meeting these challenges, QTL mapping approaches will need to also acknowledge the central roles of QTL by environment interactions (QEI) and QTL by trait interactions in the expression of complex traits like yield. This paper presents an overview of mixed model QTL methodology that is suitable for many types of populations and that allows predictive modeling of QEI, both for environmental and developmental gradients. Attention is also given to multi-trait QTL models which are essential to interpret the genetic basis of trait correlations. Biophysical (crop growth) model simulations are proposed as a complement to statistical QTL mapping for the interpretation of the nature of QEI and to investigate better methods for the dissection of complex traits into component traits and their genetic controls.", "corpus_id": 20986798, "score": 0 }, { "doc_id": "26354409", "title": "QU-GENE: a simulation platform for quantitative analysis of genetic models", "abstract": "MOTIVATION\nClassical quantitative genetics theory makes a number of simplifying assumptions in order to develop mathematical expressions that describe the mean and variation (genetic and phenotypic) within and among populations, and to predict how these are expected to change under the influence of external forces. These assumptions are often necessary to render the development of many aspects of the theory mathematically tractable. The availability of high-speed computers today provides opportunity for the use of computer simulation methodology to investigate the implications of relaxing many of the assumptions that are commonly made.\n\n\nRESULTS\nQU-GENE (QUantitative-GENEtics) was developed as a flexible computer simulation platform for the quantitative analysis of genetic models. Three features of the QU-GENE software that contribute to its flexibility are (i) the core E(N:K) genetic model, where E is the number of types of environment, N is the number of genes, K indicates the level of epistasis and the parentheses indicate that different N:K genetic models can be nested within types of environments, (ii) the use of a two-stage architecture that separates the definition of the genetic model and genotype-environment system from the detail of the individual simulation experiments and (iii) the use of a series of interactive graphical windows that monitor the progress of the simulation experiments. The E(N:K) framework enables the generation of families of genetic models that incorporate the effects of genotype-by-environment (G x E) interactions and epistasis. By the design of appropriate application modules, many different simulation experiments can be conducted for any genotype-environment system. The structure of the QU-GENE simulation software is explained and demonstrated by way of two examples. The first concentrates on some aspects of the influence of G x E interactions on response to selection in plant breeding, and the second considers the influence of multiple-peak epistasis on the evolution of a four-gene epistatic network.\n\n\nAVAILABILITY\nQU-GENE is available over the Internet at (http://pig.ag.uq.edu.au/qu-gene/)\n\n\nCONTACT\nm.cooper@mailbox.uq.edu. au", "corpus_id": 26354409, "score": 0 } ]

{ "doc_id": "55344130", "title": "Community structure of epibenthic megafauna in the Chukchi Sea", "abstract": "Climate change and increased focus on resource development in Arctic Seas have fueled interest in the Chukchi Sea, yet few quantitative studies have been conducted on the larger, epifaunal component of seafloor communities, which serves important roles in sediment biogeo- chemical processes and provides a food source for fishes and marine mammals. Here we provide quantitative data on the present condition of benthic epifaunal abundance and biomass from the Chukchi shelf and examine the influence of environmental variables on epifaunal communities. We collected 45 beam trawl samples in the Russian and United States sectors of the Chukchi Sea in 2004, 2007 and 2008. Gross abundance estimates ranged from 229 to 70 879 ind. 1000 m -2 , and gross bio- mass estimates ranged from 1628 to 217 023 g wet wt 1000 m -2 . Overall, abundance and biomass were dominated by echinoderms (66 and 45%, respectively) and crustaceans (17 and 31%, respec- tively). The ophiuroid Ophiura sarsi and the snow crab Chionoecetes opilio overwhelmingly domi- nated abundance and biomass. The holothurian Myriotrochus rinkii also occurred in large numbers, and the urchin Strongylocentrotus pallidus was another major contributor to biomass. A total of 165 taxa (mostly species) were identified; the highest numbers were Mollusca (45) and Crustacea (33). Cluster analysis identified 6 distinct groups plus 6 unique stations with 54 to 88% between-cluster dissimilarity, with separation based largely on substrate type and latitude. Water mass characteristics and indices of food availability appeared less influential in generating the observed composition, abundance and biomass patterns. Comparisons with previous studies suggested an increase in over- all epibenthic biomass since 1976, including an increase in the biomass of C. opilio.", "corpus_id": 55344130 }

[ { "doc_id": "126474385", "title": "Bering Strait the Regional Physical Oceanography", "abstract": "Find loads of the bering strait the regional physical oceanography book catalogues in this site as the choice of you visiting this page. You can also join to the website book library that will show you numerous books from any types. Literature, science, politics, and many more catalogues are presented to offer you the best book to find. The book that really makes you feels satisfied. Or that's the book that will save you from your job deadline.", "corpus_id": 126474385, "score": 0 }, { "doc_id": "129471327", "title": "Ecosystem dynamics of the Pacific-influenced Northern Bering and Chukchi Seas in the Amerasian Arctic", "abstract": "Abstract The shallow continental shelves and slope of the Amerasian Arctic are strongly influenced by nutrient-rich Pacific waters advected over the shelves from the northern Bering Sea into the Arctic Ocean. These high-latitude shelf systems are highly productive both as the ice melts and during the open-water period. The duration and extent of seasonal sea ice, seawater temperature and water mass structure are critical controls on water column production, organic carbon cycling and pelagic–benthic coupling. Short food chains and shallow depths are characteristic of high productivity areas in this region, so changes in lower trophic levels can impact higher trophic organisms rapidly, including pelagic- and benthic-feeding marine mammals and seabirds. Subsistence harvesting of many of these animals is locally important for human consumption. The vulnerability of the ecosystem to environmental change is thought to be high, particularly as sea ice extent declines and seawater warms. In this review, we focus on ecosystem dynamics in the northern Bering and Chukchi Seas, with a more limited discussion of the adjoining Pacific-influenced eastern section of the East Siberian Sea and the western section of the Beaufort Sea. Both primary and secondary production are enhanced in specific regions that we discuss here, with the northern Bering and Chukchi Seas sustaining some of the highest water column production and benthic faunal soft-bottom biomass in the world ocean. In addition, these organic carbon-rich Pacific waters are periodically advected into low productivity regions of the nearshore northern Bering, Chukchi and Beaufort Seas off Alaska and sometimes into the East Siberian Sea, all of which have lower productivity on an annual basis. Thus, these near shore areas are intimately tied to nutrients and advected particulate organic carbon from the Pacific influenced Bering Shelf-Anadyr water. Given the short food chains and dependence of many apex predators on sea ice, recent reductions in sea ice in the Pacific-influenced sector of the Arctic have the potential to cause an ecosystem reorganization that may alter this benthic-oriented system to one more dominated by pelagic processes.", "corpus_id": 129471327, "score": 1 }, { "doc_id": "128891413", "title": "Tracking the Arctic's shrinking ice cover: Another extreme September minimum in 2004", "abstract": "[1] Satellite passive microwave observations document an overall downward trend in Arctic sea ice extent and area since 1978. While the record minimum observed in September 2002 strongly reinforced this downward trend, extreme ice minima were again observed in 2003 and 2004. Although having three extreme minimum years in a row is unprecedented in the satellite record, attributing these recent trends and extremes to greenhouse gas loading must be tempered by recognition that the sea ice cover is variable from year to year in response to wind, temperature and oceanic forcings.", "corpus_id": 128891413, "score": 0 }, { "doc_id": "84465795", "title": "Role of echinoderms in benthic remineralization in the Chukchi Sea", "abstract": "Abstract. The role of large, epibenthic organisms in carbon cycling at high latitudes is difficult to assess using standard ship-board collection techniques. We used a remotely operated vehicle equipped with video imaging to examine the distribution and abundance of epibenthic organisms in the northeast Chukchi Sea during June 1998. At each of 11 sites, we collected between 25 and 50 images from a minimum of 20 min of video. We observed 15 different epibenthic taxa, with the echinoderms (Ophiura sarsia, O. maculata, Ophiopholis aculeata, Stegophiura nodosa, and Echinarachinus parma) overwhelmingly dominating the epibenthos. Echinoderm density was highly variable, ranging from 0.2 to 256.6 individuals m–2 (median=16.3), and echinoderm biomass varied between <0.5 and 4,988 mg C m–2 (median=737). The highest biomass of ophiuroids recorded (3,388 mg C m–2) is 30% higher than the highest previously reported from an Arctic shelf. Using a relationship between biomass and respiration developed for deep-sea organisms living at cold temperatures, we estimated respiration rates from <0.1 to 15.0 mg C m–2 day–1 (median=1.9). Respiration rates measured on board were several orders of magnitude higher than those obtained from the predictive equation. Further work is needed to assess echinoderm respiration rates accurately under in situ conditions. Even with calculated minimal values for respiration rates, a comparison of epifaunal and infaunal respiration at four stations revealed that echinoderm respiration accounted for as much as 25% of total respiration. High epifaunal respiration rates and biomass values are likely supported by high concentrations of particulate organic carbon carried by Bering Sea water flowing through the eastern Chukchi Sea. Our observations support observations from the Eurasian Arctic that echinoderms dominate the epibenthos of Arctic shelves and that the role of these organisms in carbon remineralization must be considered if we are to generate accurate models of carbon cycling in the Arctic.", "corpus_id": 84465795, "score": 1 }, { "doc_id": "59404365", "title": "Partitioning of benthic community respiration in the Arctic (northwestern Barents Sea)", "abstract": "For marine benthos communities, the assessment of a respiration budget encompassing the entire size range from microbes to mobile megafauna has seldom been attempted. An interdisciplinary field study in high Arctic waters (northwestern Barents Sea) in June/July 1991 provided the opportunity to concurrently est~rnate the oxygen uptake of the different benthic community fractions by a variety of approaches at water depths of 80 to 1010 m. The bulk respiration of micro-, meioand small macrobenthos was assessed by sediment community oxygen consumption (SCOC) rates measured by shipboard sediment-water incubations of virtually undisturbed cores. The oxygen uptake of community portions not sampled adequately by corers (megabenthic inand epifauna, including fish) was estimated by applying individual metabolic rates to density or biomass figures derived from seabed images, box corer samples or trawl catches. The respiration estimates of the various community fractions were subsequently compiled in synoptic models of the total benthic community oxygen consumption (BCOC) and its partitioning. In the study area, 2 benthic habitat types were distinguished, differing substantially in depth, sediment texture and, thus, benthic respiration pattern: (1) shallow shelf banks (<200 m) where the seabed is composed of coarse sediments and stones, and (2) deeper trenches or slopes (>200 m) characterized by fine sediments. On the banks, the patchiness of epibenthic brittle stars, which locally occurred in very high densities (up to 700 ind. m-'), controlled the benthic community respiration. On average, the megafauna was estimated to contribute about 25% to the median BCOC of about 90 pm01 0, m-' h-' (equivalent to an organic carbon mineralizat~on rate of 21 mg C m-? d-'). In the shelf trenches and on the slope, however, smaller endobenthic organisms predominated. SCOC, according to our estimates of meioand macrofaunal respiration, was dominated by the oxygen uptake of microorganisms and accounted for about 85% of the median BCOC of about 140 ~lmol 0, m-' h-' (35 mg C n r 2 d-l). Our results suggest that current models of benthic community respiration should be amended, particularly for Arctic shelf b~otopes where abundant megafauna may represent an important pathway of the benth~c energy flow.", "corpus_id": 59404365, "score": 0 }, { "doc_id": "129678223", "title": "Mollusks in the Northeastern Chukchi Sea", "abstract": "Infaunal and epifaunal mollusks of the northeastern Chukchi Sea were sampled and 139 molluscan taxa were identified. The pattern of spatial distribution of molluscan species was determined by cluster analysis, which resulted in six infaunal and five epifaunal station groups. Species characterizing various faunal groups are defined. Stepwise multiple discriminant analysis was applied to correlate benthic biological associations with environmental variables. Delineation of infaunal groups was mainly due to percentage of sand and bottom salinity, while epifaunal groups were separated by percent gravel and bottom temperature. An increase in abundance and biomass of infaunal mollusks occurred adjacent to and north and northwest of an identified bottom front between the Bering Shelf and Resident Chukchi Water and Alaska Coastal Water. Epifaunal molluscan abundance and biomass were highest near the coast. Mollusks, especially smaller species and the juvenile stages of larger species, represent a food resource for bottom-feeding predators in the study area. Key words: Chukchi Sea, mollusk, benthic, infauna, epifauna, bottom front, bottom-feeding predators, cluster analysis, discriminant analysis", "corpus_id": 129678223, "score": 0 }, { "doc_id": "129373065", "title": "The paradox of pelagic food webs in the northern Bering Sea—III. Patterns of primary production", "abstract": "Abstract The advective supply of nutrients to the Bering-Chukchi continental shelf via a north-flowing “river” of oceanic water originating along the continental slope in the Bering Sea maintains a large portion of these shelf waters in eutrophic bloom summer-long. Known as the Anadyr Stream, this nutrient injection sustains conditions of high phytoplankton productivity and biomass in a region of the western Arctic that would otherwise be unproductive, as are adjacent shelf areas unaffected by the current. A production plume dominated by large chain-forming diatoms extends from the Gulf of Anadyr in the south to the southern Chukchi Sea in the north, has daily carbon uptake rates as high as 16 g C m −2 day −1 , and has an estimated annual production of about 470 g C m −2 year −1 . Maximum production occurs in three pools of especially prolific growth (Gulf of Anadyr, Chirikov Basin and southern Chukchi Sea) where rates could be as great as 720–840 g C m −2 year −1 . Outside of the plume, nutrients remain low following the spring bloom and a typical successional flora is dominated by flagellates and small diatoms throughout summer. Post-bloom productivity in this region is generally about 0.5 g C m −2 day −1 , and annual production is approximately 80 g C m −2 year −1 . The contrasting primary production regimes lead to major differences in food webs and in the energy transferred to higher trophic levels within the western Arctic.", "corpus_id": 129373065, "score": 0 }, { "doc_id": "54174530", "title": "Pelagic-benthic coupling on the shelf of the northern Bering and Chukchi Seas. I. Food supply source and benthic bio-mass", "abstract": "The shelf waters of the northern Bering and Chukchi Seas are ice-covered for 7 mo of the year, but despite thls harsh environment, they are characterized by high benthic biomass. Coupling between water column primary production and the benthos was investigated in summers 1984 to 1986 by measurements of sediment characteristics in relation to those of the water column. Low surface sediment C/N ratios (5.8 to 7.6) suggested a higher quality, nitrogen-rich marine carbon supply to the benthos in the highly productive (ca 250 to 300 g C m-' yr-') Bering Shelf-Anadyr Water (BSAW) compared to lower quality, higher C/N ratios (7 7 to 14 0) in sediment under the less productive (ca 50 g C m-' yr-l) Alaska Coastal Water (ACW). Stable carbon isotope ratios suggested a manne origin for organic matter in BSAW compared to a mixture of manne and terrestrial input in ACW. Mean benthic biomass was significantly different between water locations, with mean benthic biomass decreasing from 20.2 g C m-* under BSAW to 6.3 g C m-2 under ACW Summer benthic biomass remained seasonally constant for the 3 yr. Benthic communities underlying BSAW received a high quality marine food supply on a regular basis interannually, while those in ACW received an interannually variable amount of temgenous organic matter in addition to marine organic matter. We conclude that the quality and quantity of organic carbon deposited to the benthos directly influence benthic biomass.", "corpus_id": 54174530, "score": 0 }, { "doc_id": "4354919", "title": "High productivity of northern Bering Sea benthic amphipods", "abstract": "POLAR regions, particularly Arctic seas covered by ice for a significant portion of the year, have been considered to be relatively unproductive1–4. In the western Arctic, including the northern Bering Sea, high water column productivity5,6, and well developed benthic communities7–9 have recently been reported. Ampeliscid amphipod crustaceans are the benthic community dominants in vast areas of the northern Bering Sea and are the major prey of the migratory California grey whale, Eschrichtius robustus 10,11. Our study indicates that productivity of the benthic amphipods is remarkably high, given the latitude. The dominant species, Ampelisca macrocephala, is the most productive benthic marine amphipod ever reported and the amphipod community is more productive then entire benthic communities investigated elsewhere. biomassPolar marine ecosystems clearly have the potential to be highly productive", "corpus_id": 4354919, "score": 0 }, { "doc_id": "67758614", "title": "Productivity of arctic amphipods relative to gray whale energy requirements", "abstract": "Amphipod crustaceans domlnate the ben th~c community in vast areas of the northern Benng Sea, they are the major prey of the California gray whale Eschncht~us robustus The protected whale population is growing steadily and may be approaching the carrying capacity of the arnphipod community, one of the most productive benthic communities in the world The abundance and biomass of the amphipod community decreased dunng the 3 yr penod 1986 to 1988, resulting in a 30 % decline in production High-latitude amphipod populations are characterized by low fecundity and long generation t ~ m e s Large long-lived individuals are responsible for the malonty of amphipod secondary production A substantial reduction in the density of large individuals in the population wlll result in a significant, long-term decrease in production", "corpus_id": 67758614, "score": 0 }, { "doc_id": "25532188", "title": "Unusual abundance of macrobenthos and biological invasions in the Chukchi Sea", "abstract": "The data from the expedition of the program RUSALCA conducted in 2004 showed unexpectedly high quantitative indices of macrobenthos in the southeastern Chukchi Sea. Extensive areas of the bottom northwest of the Bering Strait were dominated by the bivalve Macoma calcarea. The greatest biomass of benthos in Macoma-dominated areas was 4232 g/m2 with an average of 1382 g/m2 for the investigated region. Such a high biomass of soft-bottom communities, which is extremely uncommon even in the temperature regions of the oceans, is reported for the Arctic for the first time. The long-term existence (more than 70 years) of highly productive benthic communities dominated by Macoma calcarea in one and the same area of the Chukchi Sea can most likely be attributed to gyres, which constantly arise in the region northwest of the Bering Strait. These cyclonic gyres carry nutrient-rich bottom water to the surface and hinder larval transport away from mother populations. They also keep and concentrate major food sources of benthos (live and dead phyto-and zooplankton and fecal pellets) over the benthic community locations. Most likely, a significant proportion of the primary production in the southeastern Chukchi Sea is used by benthos within the investigated Macoma community. Findings of three relatively large warm-water Pacific species near Point Hope in the Chukchi Sea are probably indicative of the progressive climate warming during the last century.", "corpus_id": 25532188, "score": 1 }, { "doc_id": "129714921", "title": "Studies of pelagic-benthic coupling extended onto the Soviet continental shelf in the northern Bering and Chukchi seas", "abstract": "Abstract Studies of pelagic-benthic coupling and benthic carbon cycling in the northern Bering and Chukchi seas were extended onto the Soviet continental shelf as part of the third U.S.A.-U.S.S.R. Oceanographic Expedition to the Bering and Chukchi seas in 1988. High sediment oxygen uptake rates (an indicator of food supply to the benthos) and benthic biomass were observed in the western shelf regions of the Gulf of Anadyr, Chirikov Basin and southern Chukchi Sea. Low sediment respiration and faunal biomass were observed in the central and slope areas of the Gulf of Anadyr and near the Alaska coastline. Both high sediment respiration and benthic biomass were related to regions of high carbon deposition to the benthos and sediment organic carbon content. Preliminary studies of sediment accumulation, measured using organic carbon content and atmospherically-derived 210 Pb values in surface sediments, were low in the sandy regions of the northern Bering Sea, with higher sediment accumulation zones occurring in the silt and clay regions in the central Gulf of Anadyr and southern Chukchi Sea. Hydrodynamics have a major influence on organic carbon loading and sediment composition, which in turn influences benthic community structure, biomass and sediment respiration in this Arctic region.", "corpus_id": 129714921, "score": 0 }, { "doc_id": "129112024", "title": "The Bering Sea Green Belt: shelf-edge processes and ecosystem production", "abstract": "The concept of a highly productive habitat, or Green Belt, along the edge of the continental shelf in the Bering Sea is based upon compelling but fragmentary and often anecdotal observations of a variety of physical and biological features acquired from many sources over many years. Enhanced production at continental margins is not a novel concept, but in the case of the Bering Sea its importance has been overlooked during studies of the unusually broad continental shelf. The limited data reported from the vicinity of the shelf edge in the Bering Sea indicate that annual primary production can be as high as 175 to 275 g C m˜ year-, or approximately 60% greater than production in the adjacent outer shelf domain and 270% greater than in the oceanic domain. Estimates of annual secondary production at the eastern shelf edge also average approximately 60% higher than estimates for the outer domain and 260% higher than those for the oceanic domain. Physical processes at the shelf edge, such as intensive tidal mixing and transverse circulation and eddies in the Bering Slope Current, bring nutrients into the euphoric zone and contribute to enhanced primary and secondary production and elevated biomass of phytoplankton and zooplankton. Fishes and squids concentrate in this narrow corridor because of favourable feeding conditions and because of a thermal refuge from cold shelf-bottom temperatures that can be found at the shelf edge from fall to spring. The abundance of zooplankton, fishes and squids, in turn, attracts large numbers of marine birds and mammals. In aggregate, the observations suggest that sustained primary productivity, intense food web exchange and high transfer efficiency at the shelf edge are important to biomass yield at numerous trophic levels and to ecosystem production of the Bering Sea.", "corpus_id": 129112024, "score": 0 }, { "doc_id": "36434130", "title": "Southeastern Chukchi Sea (Alaska) macrobenthos", "abstract": "Macrobenthos in the southeastern Chukchi Sea, inclusive of the Chukchi Bight and Kotzebue Sound, were collected in 1985–1987 to determine factors influencing faunal distribution, abundance and biomass. Polychaetes, crustaceans, bivalve mollusks, and ophiuroid echinoderms dominated abundance. Polychaetes, bivalve mollusks, and ophiuroid echinoderms dominated carbon biomass with barnacles, amphipods, bryozoans, and tunicates occasionally dominant. Cluster analysis and ordination revealed relatively high faunal abundance and biomass under Bering Shelf Anadyr Water (BSAW) as well as under Alaska Coastal Water (ACW) in the Bight and Sound. Advected particulate carbon from the highly productive BSAW supported the abundant macrobenthos that served as food for numerous epifauna, which in turn furnished food for resident and transient populations of demersal fishes and marine mammals.", "corpus_id": 36434130, "score": 1 }, { "doc_id": "25789978", "title": "Southeastern Chukchi Sea (Alaska) epibenthos", "abstract": "Epibenthos of the southeastern Chukchi Sea, inclusive of Kotzebue Sound, was sampled in 1976. Crustaceans dominated abundance while echinoderms, mainly sea stars, dominated biomass. Spatial distribution of fauna was determined by cluster analysis. Scavenger-predators were dominant trophic groups, although suspension feeders dominated some regions. Unexpected high abundance and biomass under Alaska Coastal Water and factors related to presence and distribution of fauna are discussed. Dissimilarities between the benthic systems of the southeastern and northeastern Chukchi Seas are attributed to more complex water mass and flow patterns in the southern system. Entrained particulate organic carbon disperses through the area to support an abundant and apparently highly productive benthic fauna, which sustains resident and transient populations of demersal fishes and marine mammals. Epibenthos was sampled again in 1998 and, although little change was apparent in community composition, many taxa had higher abundance and biomass than 22 years earlier, a trend similar to findings observed in the northeastern Bering Sea.", "corpus_id": 25789978, "score": 1 }, { "doc_id": "51749196", "title": "WALRUS, ODOBENUS ROSMARUS, FEEDING IN THE BERING SEA: A BENTHIC PERSPECTIVE", "abstract": "Walrus, Odobenusrosmarus, feed primarily on benthic bivalves and create a distinct record of their feeding activities on the sea floor. The record consists offurrows, pits, and discarded bivalve shells which were ob­ served and sampled with scuba Documentation of this benthic feeding record suggested that walrus com­ monly search for visually conspicuous prey by sight; that, in addition to \"rooting\" with the snout and vibrissae, walrus excavate bivalve prey by hydraulic jetting; that tusks are notused to excavate prey; and that all prey are excavated before consumption, which generally occurs close to the site of excavation. The mechanism of consumption appears to involve suction from between the shells. Continuous pit·furrow sys­ tems indicate the number of prey consumed in single dives, and suggest that a walrus can locate, excavate, and consume more then six clams per minute. The abundance of small infauna that are not walrus prey (e.g., polychaete worms, small bivalves, and crustaceans) was lower inside all excavations, indicating that the structure of bottom communities is highly modified by the extraction of a few large prey.", "corpus_id": 51749196, "score": 0 }, { "doc_id": "25863203", "title": "Diet and body condition of spectacled eiders wintering in pack ice of the Bering Sea", "abstract": "Spectacled eiders (Somateria fischeri) winter among leads in the Bering Sea pack ice, where they dive 40–70 m for benthic prey. During the first icebreaker cruises into that area, esophagi of collected eiders contained only clams, mostly Nuculana radiata, with no trace of the once-dominant Macoma calcarea. Alternative prey used elsewhere (snails, amphipods, other bivalves) were available but not eaten. Eiders ate mainly N. radiata 18–24 mm long, although M. calcarea of this length contained 62% more energy. Percent body lipid of eiders averaged 12±3% (SD) for 26 adult males and 14±3% for 12 adult females. Mean body mass (±SE) of these males in late March (1,688±21 g) was higher than reported for 53 males after arriving at breeding areas in late May (1,494±14 g). Body mass of these females (1,550±35 g) was lower (but not significantly) than reported for 11 females upon arrival at breeding sites (1,623±46 g). In 1999, the last spectacled eiders left the wintering area on 21 April, 4–8 weeks before their typical arrival at breeding sites. Their location is unknown in the interim, when habitats used appear critical to acquiring reserves for reproduction.", "corpus_id": 25863203, "score": 0 }, { "doc_id": "83689740", "title": "Distribution, abundance, biomass, and mineralization potential of the epibenthic megafauna of the Northeast Greenland shelf", "abstract": "The epibenthic megafauna of the high-Arctic Northeast Greenland shelf was investigated by means of seafloor photography and Agassiz trawl catches. At 54 stations in water depths between 40 and 770 m, sequences of color slides, each depicting about 1 m2 of the seafloor, were obtained along photographic transects of about 100 to 600 m length. The photographs were quantitatively analyzed for abundance of epibenthic organisms identified by comparison with specimens collected from trawl catches. Megabenthic biomass was estimated by multiplying density values with averge body mass figures. For five dominant brittle star species, the population oxygen uptake and, thus, organic carbon mineralization potential were approximated by applying individual respiration rates of average-sized specimens to density figures. Multivariate analyses of the megabenthic species distribution revealed a distinct depth zonation. Shallow shelf banks (<150 m), characterized by coarse sediments, many stones and boulders as well as negative bottom water temperatures, housed a rich epifauna (30 to 340 ind m−2, 1.8 to 10.5 g AFDW m−2), strongly dominated (80 to 98% by numbers) by the brittle stars Ophiocten sericeum and Ophiura robusta. The oxygen uptake by brittle stars ranged from 0.4 to 95 μmol O2 m−2 h−1 (i.e., assuming a respiratory quotient of 0.8, an organic carbon mineralization of 0.1 to 21.9 mg C m−2 d−1). At the bank flanks sloping to the shelf troughs (100 to 580 m), finer sediments prevailed, stones were rare, and bottom water temperatures were positive due to the inflow of Atlantic water. Compared to bank sites, total epibenthic abundances as well as carbon mineralization by brittle stars were roughly ten times and total biomass about four times smaller. In deep shelf depressions as well as at the continental slope (200 to 770 m), stones were completely lacking, and sediments very fine. Epibenthic standing stock and carbon mineralization were one to two orders of magnitude lower than on the banks. The estimation of brittle star oxygen uptake indicates that a considerable portion of the organic carbon produced in the polynya and partitioned to the benthos may be remineralized by epibenthic bank assemblages.", "corpus_id": 83689740, "score": 0 }, { "doc_id": "84936577", "title": "Mega-epibenthic communities in Arctic and Antarctic shelf areas", "abstract": "Abstract Mega-epibenthic shelf assemblages were investigated off Northeast Greenland and in the Weddell, Bellingshausen and Amundsen Seas in the Antarctic using underwater video. In the Arctic a total of 94 taxa represented by more than 100 000 individuals were identified. Echinoderms, particularly brittle stars, were the most important elements of the mega-epibenthic fauna on the shelf off Northeast Greenland. Multivariate analyses of the species distribution revealed a conspicuous depth zonation in which an assemblage on the shallow banks can be clearly distinguished from that in the troughs. Between these a transitional zone with a heterogeneous benthic fauna was found. Physical disturbances are supposed to be responsible for the pronounced dominance patterns observed on the shallow banks. The fauna in the troughs, which consists of more than 50% suspension feeders, is diverse but low in numbers of individuals. In the Antarctic more than 115 000 individuals belonging to 169 taxa were analyzed. Obvious faunal differences exist between the stations in the Weddell Sea and the Bellingshausen/Amundsen Seas. Assemblages of suspension feeders dominated by sponges and bryozoans are prevalent on the shelf of the eastern Weddell Sea, but almost absent in the Bellingshausen and Amundsen Seas. These assemblages seem to be restricted to areas where bottom currents provide favourable feeding conditions. However, motile deposit feeders are more abundant in both regions where there is a soft bottom substrate with presumably slow bottom currents and reduced horizontal transport of organic particles.", "corpus_id": 84936577, "score": 0 }, { "doc_id": "83151097", "title": "Arctic brittle stars (Echinodermata: Ophiuroidea)", "abstract": "Knowledge of Arctic brittle stars (Echinodermata: Ophiuroidea) has greatly increased over the past 15 yr. Here, I synoptically review novel findings collected by seabed imaging and trawl catches from continental shelves and slopes (14 m to 1100 m) of the Greenland, Barents and Laptev Seas with regard to zoogeography, diversity, standing stock, distribution patterns, community control and carbon demand. In accordance with previous reports, few endemic-Arctic species were found in the study areas. The recurrent finding that most brittle stars are widespread boreal-Arctic species corroborates the paradigm of a comparatively young age and low degree of zoogeographic isolation of Arctic seas. The total number of ophiuroid species known to occur in all Arctic seas is low (15 to 22), especially if compared with Antarctica where more than 100 species have been reported. A comparative case study showed, however, that in the eastern Weddell Sea (Antarctica) both regional and local diversity figures were indeed significantly higher than off northeast Greenland (Arctic), whereas the values assessed for ophiuroid assemblages inhabiting the southern Weddell Sea shelf and shelf trenches were not. These findings indicate that the paradigm of a pronounced Arctic-Antarctic diversity difference is an over-generalisation, at least with regard to the brittle star fauna and to regional or local scales. Numerous faunal inventories in Arctic seas have shown that epibenthic communities are dominated by brittle stars, especially on the shelves. At several locations, dense brittle star beds forming high standing stocks of up to several hundred ind. m -2 and up to several g organic C m - 2 were recorded. These stock figures are among the highest hitherto observed in northern seas, being in the same order of magnitude as those reported for ophiuroid mass occurrences in sublittoral and bathyal habitats of non-polar regions. Within dense brittle star beds, individuals showed a pronounced non-random dispersion on a 1-100 m scale, most likely caused by seabed heterogeneity. A depth zonation in the composition of the brittle star fauna, accompanied by a significant decline of standing stock over two (biomass) to three (abundance) orders of magnitude, was the most conspicuous large-scale spatial pattern. All shelf assemblages ( 10 mg C m -2 d -1 Considering production and assimilation efficiencies of 30% and 80%, respectively, their carbon demand was assessed as up to 20 mg C m - 2 d -1 .", "corpus_id": 83151097, "score": 0 }, { "doc_id": "44393952", "title": "Macrozoobenthic community structure in a high-arctic East Greenland fjord", "abstract": "Abstract A macrozoobenthic community study was conducted in an East Greenlandic fjord (Young Sound, 74°18′N; 20°15′W) during the ice-free period from July to August in 1996. Grab samples as well as underwater photography were used for quantifying the macrozoobenthos at water depths between 20 and 85 m. Abundance decreased with depth from 2700 ind. · m−2 at 20 m to 900 ind. · m−2 at 85 m. At a time series station at 35 m, abundance increased from 700 ind. · m−2 in mid-July to 1400 ind. · m−2 in mid-August. Polychaetes dominated in grab samples but bivalves constituted an important part of the benthic fauna, especially at the shallow part of the depth gradient. Photographs revealed high abundances of large epifaunal species, especially brittle stars. Diversity was generally high, with around 45 species per 201 individuals, as calculated by Hurlbert's rarefaction term. A gradual change in community structure with depth was observed, which could be related to variation in sediment composition and disturbance intensity.", "corpus_id": 44393952, "score": 0 }, { "doc_id": "84967256", "title": "Gray whale distribution relative to forage habitat in the northern Bering Sea: current conditions and retrospective summary", "abstract": "Hundreds of gray whales (Eschrichtius robustus) stranded dead along beaches from Mexico to Alaska in 1999 and 2000. The cause of the mortalities remains unknown, but starvation resulting from a reduction in prey, especially in the Chirikov Basin, was suggested as the cause. In the 1980s, the Chirikov Basin was considered a prime gray whale feeding area, but there has been no recent comprehensive assessment of whale or prey distribution and abundance. In 2002, a 5-day survey for gray whales revealed restricted distribution in the basin and a 3- to 17-fold decline in sighting rates. To put these data in context, a retrospective summary of gray whale and benthic fauna distribution and abundance was undertaken. During the 1980s, gray whale sighting rates in the Chirikov Basin were highly variable. Ampeliscid amphipods dominated the benthos where gray whale sighting rates were highest. Available measures of biomass suggest a downturn in amphipod productivity from 1983 to 2000, when estimates of gray whale popu...", "corpus_id": 84967256, "score": 0 }, { "doc_id": "128419605", "title": "Multi-decadal synthesis of benthic–pelagic coupling in the western arctic: Role of cross-shelf advective processes", "abstract": "Abstract Using geographic information systems (GIS) software and geostatistical techniques, we utilized three decades of water-column chlorophyll a data to examine the relative importance of autochthonous versus allochthonous sources of reduced carbon to benthic communities that occur from the northern Bering to the eastern Beaufort Sea shelf. Spatial trend analyses revealed areas of high benthic biomass (>300 g m−2) and chlorophyll (>150 mg m−2) on both the southern and northern Chukchi shelf; both areas are known as depositional centers for reduced organic matter that originates on the Bering Sea shelf and is advected northward in Anadyr and Bering shelf water masses. We found a significant correlation between biomass and chlorophyll a in the Chukchi Sea, reflective of the strong benthic–pelagic coupling in a system that is utilized heavily by benthic-feeding marine mammals. In contrast, there was no significant correlation between biomass and chlorophyll in the Beaufort Sea, which by comparison, is considerably less productive (biomass and chlorophyll,", "corpus_id": 128419605, "score": 0 }, { "doc_id": "140151792", "title": "Analyses of Bering Sea bottom-trawl surveys in Norton Sound: absence of regime shift effect on epifauna and demersal fish", "abstract": "Hamazaki, T., Fair, L., Watson, L., and Brennan, E. 2005. Analyses of Bering Sea bottomtrawl surveys in Norton Sound: absence of regime shift effect on epifauna and demersal fish.e ICES Journal of Marine Science, 62: 1597e1602. This study retrospectively examined evidence of ocean climate regime shift effects on epifauna and demersal fish of Norton Sound, Alaska, northeast Bering Sea, based on triennial bottom-trawl surveys from 1976 to 2002. Throughout the period, benthic fauna was dominated by sea stars (48e78%), followed by cods (5e19%), flatfish (5e15%), sculpins (1.5e7%), and crabs (2e6%). From 1976 to 2002, the cpue index of total species increased exponentially (4.5% y 1 ) by threefold with some declines in 1991 and 1999. The increase was also observed in sea stars (5.1% y 1 ), flatfish (6.1% y 1 ), and crabs (2.5% y 1 ). However, trends of cods and sculpins were mixed. Regression analysis showed the cpue index of total species to be positively correlated with survey years and bottom-water temperature. However, bottom-water temperature, when considered by itself, was not significant. Results suggest that regime shifts caused biomass increases of Norton Sound epifauna and demersal fish.", "corpus_id": 140151792, "score": 0 }, { "doc_id": "129927006", "title": "Retrospective analysis of Bering Sea bottom trawl surveys: regime shift and ecosystem reorganization", "abstract": "Abstract This paper compiles data from bottom trawl surveys using variations on a 400-mesh eastern trawl gear into a 38-year time series (1963–2000), using a robust index of median catch per unit effort (CPUE) as an indicator of regional abundance. Time series are presented for three index sites in the southeastern Bering Sea: the inner shelf in Bristol Bay, the middle shelf north of Unimak Island, and the outer shelf near the Pribilof Islands. All three sites show strong evidence of a shift in benthic biomass and community structure in the early to mid-1980s. During this period, all three sites showed substantial increases in the abundances of walleye pollock, Pacific cod, rock sole, flathead sole, cartilaginous fishes (skates) and non-crab benthic invertebrates. Species composition, especially of flatfish, differs at the three sites, but the trend for groundfish abundance to increase was consistent at all three sites. The similarity in trends both across the region and across both commercial and unexploited groups suggests to us that a complete reorganization of benthic and demersal food webs may have taken place. The timing of change in trawl catch weight is consistent with effects of the strong regime shift observed in climate indices in 1976–1977. There is little evidence of similar biological responses to subsequent, less pronounced changes in climate. Our data are also consistent with recently documented shifts in ecosystem dynamics resulting from changes in ice cover and thermal structure in the eastern Bering Sea. Our analysis indicates that there was a much higher biomass of groundfish at all three sites during 1980–2000 than in 1960–1980. This result provides evidence against the hypothesis that the overall productivity of the eastern Bering Sea has decreased. The precipitous decline of the endangered Steller sea lion in this region from 1975–1985 was concurrent with an overall increase in abundance of groundfish prey.", "corpus_id": 129927006, "score": 0 }, { "doc_id": "15010603", "title": "Application of a sequential regime shift detection method to the Bering Sea ecosystem", "abstract": "A common problem of existing methods for regime shift detection is their poor performance at the ends of time-series. Consequently, shifts in environmental and biological indices are usually detected long after their actual appearance. A recently introduced method based on sequential t-test analysis of regime shifts (STARS) treats all incoming data in real time, signals the possibility of a regime shift as soon as possible, then monitors how perception of the magnitude of the shift changes over time. Results of a STARS application to the eastern Bering Sea ecosystem show how the 1989 and 1998 regime shifts manifest themselves in biotic and abiotic indices in comparison with the 1977 shift. 2005 Published by Elsevier Ltd on behalf of International Council for the Exploration of the Sea.", "corpus_id": 15010603, "score": 0 }, { "doc_id": "53696101", "title": "Pathways of Pacific water across the Chukchi Sea: A numerical model study", "abstract": "[1] Pathways of Pacific Water flowing from the North Pacific Ocean through Bering Strait and across the Chukchi Sea are investigated using a two-dimensional barotropic model. In the no-wind case, the flow is driven only by a prescribed steady northward flow of 0.8 Sv through Bering Strait. The resulting steady state circulation consists of a broad northeasterly flow, basically following the topography, with a few areas of intensified currents. About half of the inflow travels northwest through Hope Valley, while the other half turns somewhat toward the northeast along the Alaskan coast. The flow through Hope Valley is intensified as it passes through Herald Canyon, but much of this flow escapes the canyon to move eastward, joining the flow in the broad valley between Herald and Hanna Shoals, another area of slightly intensified currents. There is a confluence of nearly all of the flow along the Alaskan coast west of Pt. Barrow to create a very strong and narrow coastal jet that follows the shelf topography eastward onto the Beaufort shelf. Thus in this no-wind case, nearly all of the Pacific Water entering the Chukchi Sea eventually ends up flowing eastward along the narrow Beaufort shelf, with no discernable flow across the shelf edge toward the interior Canada Basin. Travel times for water parcels to move from Bering Strait to Pt. Barrow vary tremendously according to the path taken; e.g., less than 6 months along the Alaskan coast, but about 30 months along the westernmost path through Herald Canyon. This flow field is relatively insensitive to idealized wind-forcing when the winds are from the south, west or north, in which cases the shelf transports tend to be intensified. However, strong northeasterly to easterly winds are able to completely reverse the flows along the Beaufort shelf and the Alaskan coast, and force most of the throughflow in a more northerly direction across the Chukchi Sea shelf edge, potentially supplying the surface waters of the interior Canada Basin with Pacific Water. The entire shelf circulation reacts promptly to changing wind conditions, with a response time of ∼2–3 days. The intense coastal jet between Icy Cape and Pt. Barrow implies that dense water formed here from winter coastal polynyas may be quickly swept away along the coast. In contrast, there is a relatively quiet nearshore region to the west, between Cape Lisburne and Icy Cape, where dense water may accumulate much longer and continue to become denser before it is carried across the shelf.", "corpus_id": 53696101, "score": 0 }, { "doc_id": "129045024", "title": "The Siberian Coastal Current: A wind‐ and buoyancy‐forced Arctic coastal current", "abstract": "We describe circulation and mixing in the Siberian Coastal Current (SCC) using fall shipboard measurements collected between 1992 and 1995 in the western Chukchi Sea. The SCC, forced by winds, Siberian river outflows, and ice melt, flows eastward from the East Siberian Sea. It is bounded offshore by a broad (∼60 km) front separating cold, dilute Siberian Coastal Water from warmer, saltier Bering Sea Water. The alongshore flow is incoherent, because the current contains energetic eddies and squirts probably generated by frontal (baroclinic) instabilities. These enhance horizontal mixing and weaken the cross-shore density gradient along the SCC path. Eventually, the SCC converges with the northward flow from Bering Strait, whereupon it deflects offshore and mixes with that inflow. Deflection occurs where the alongshore pressure gradient vanishes. That location varies on synoptic and seasonal timescales, because this gradient depends on the winds, buoyancy fluxes, and the sea level difference between the Pacific and Arctic Oceans. Deflection usually occurs on the Chukchi shelf, but the SCC occasionally flows southward through Bering Strait. Such events are short lived (1–10 days) and occur mainly in fall and winter under northerly winds. SCC transport is likely small (∼0.1 Sv), but its dilute waters could substantially freshen the Bering Strait inflow and affect the disposition of Pacific waters in the Arctic Ocean. Arctic river outflows should preferentially form surface-advected fronts rather than bottom-advected fronts because vertical-mixing energy is low on arctic shelves. Surface-advected fronts are more susceptible to upwelling winds (and for the SCC, the pressure gradient between the Pacific and Arctic Oceans) than bottom-advected fronts. The SCC never developed in fall 1995 because of anomalously steady upwelling winds. The western Chukchi shelf could have formed upper halocline source water in the winter of 1995–1996.", "corpus_id": 129045024, "score": 0 }, { "doc_id": "54494710", "title": "Epibenthic community patterns on the continental slope off East Greenland at 75* N", "abstract": "Megabenthic assemblages on the East Greenland continental slope at 75\" N were surveyed at 8 locations between 190 and 2800 m depth using sea floor images taken vertically with a still camera. A total of 91 epibenthic species with 14447 indiv~duals were identified from 422 photographs depicting 297 n12 of the sea floor. Classification and ordination analysis defined 3 fauna1 zones that corresponded to different depth regions of the continental margin: shelf break, upper slope and lower slope. Megafaunal abundance was highest on the shelf (about 200 ind. m-2). In the other zones, the densities were distinctly lower (15 to 30 ind. m-2). Assemblages were frequently dominated by 1 or 2 species, such a s the polychaete Onuphis conchylega at the shelf break and the sponge Polymastia sp. at the lower slope The upper slope was characterized by a diverse octocoral-sponge assemblage. A statistical analysis of the correlation between megafaunal and environmental data at a 10 km scale (between stations) indicated that epibenthic distribution patterns were best explained by sea floor characteristics, whereas no evidence for a direct benthic-pelaglc coupling was found, irrespective of water depth. Additionally, the withln-station distribution of megabenthic organisms (100 m scale) was clearly affected by sea floor properties.", "corpus_id": 54494710, "score": 1 }, { "doc_id": "128492851", "title": "Distribution patterns of Canadian Beaufort Shelf macrobenthos", "abstract": "Abstract Variation in macrofaunal composition in relation to sediment and water variables was analysed in nine regions of the western Canadian Arctic on the Beaufort Shelf and in Amundsen Gulf. We hypothesized that benthic community composition was distinctive (1) in a recurrent polynya in Amundsen Gulf and (2) in upwelling regions (Cape Bathurst and Mackenzie Canyon) and (3) changed in a linear gradient across the Beaufort Shelf. Analysis was based on 497 taxa > 0.4 mm from 134 samples at 52 stations sampled over 2002–4 in 11–1000 m water depth. Abundance ranged from 490.7 m− 2 in eastern Amundsen Gulf to 17,950 m− 2 off Cape Bathurst. (1) Community composition in Amundsen Gulf was not significantly different from the Beaufort Shelf at similar depth, indicating a lack of benthic effect of the polynya in Amundsen Gulf. (2) The Mackenzie Canyon macrofauna, although abundant and diverse, were similarly indistinct from the shelf community at similar depth. However, there was a 10-fold increase in inshore abundance in the upwelling region of Cape Bathurst due to large numbers of the amphipod Ampelisca macrocephala and the polychaete Barantolla americana, species that were not abundant elsewhere. (3) In the inshore fast ice and flaw lead regions of the Beaufort Shelf, under the influence of ice scour, storm effects, coastal erosion and the Mackenzie River, the macrofauna were dominated by the bivalve Portlandia arctica and the polychaete Micronephthys minuta. Offshore, where these influences were less and upwelling of deep Atlantic water occurred, the polychaete Maldane sarsi dominated. Faunal distribution across the Beaufort Shelf correlated with depth, water and sediment changes but was not significantly linear.", "corpus_id": 128492851, "score": 0 }, { "doc_id": "129380563", "title": "The Kara Sea ecosystem: phytoplankton, zooplankton and benthos communities influenced by river run-off", "abstract": "Phytoplankton, zooplankton and macrozoobenthos in the estuaries of Ob and Yenisei and the adjacent southern Kara Sea were investigated during three expeditions with RV \"Akademik Boris Petrov\" in August/September 1997, 1999 and 2000. Plankton and macrobenthic community structures were distinguished by cluster analysis and multidimensional scaling. Differences in species number, abundance and biomass as well as the zonation pattern of biological assemblages reflected the continental outflow from the rivers Ob and Yenisei along a salinity gradient from south to north. Additionally, strong regional variability in species composition between the two river systems Ob and Yenisei was obvious. The spatial biomass distribution of phytoplankton, zooplankton and macrozoobenthos along a transect from the inner Yenisei to the open Kara Sea was related to the influence of different water masses.", "corpus_id": 129380563, "score": 0 }, { "doc_id": "127861935", "title": "Distributional Patterns of Echinoderms in the Eurasian Sector of the Arctic Ocean", "abstract": "Our knowledge of echinoderms, including echinoids, asteroids, and ophiuroids from the Eurasian Arctic seas (Barents, Kara, Laptev, East Siberian, and Chukchi seas), were established with the studies of Diakonov (1926, 1933, 1950, 1952, 1954), Shorygin (1982), Gorbunov (1932, 1933a,b), Baranova (1964, 1977), Khodkina (1964), and Moskalyov (1980).", "corpus_id": 127861935, "score": 0 }, { "doc_id": "128960790", "title": "Spatial structure within a dense bed of the brittle starOphiura sarsi (Ophiuroidea: Echinodermata) in the bathyal zone off otsuchi, Northeastern Japan", "abstract": "Photographic observations of the brittle starOphiura sarsi were conducted at a depth of approximately 280 m in the Pacific Ocean off Ōtsuchi, northeastern Japan. Bottom photographs showed that this ophiuroid occurred in high densities, uniformly covering the sea floor and that other megafauna was rare. The mean density and biomass of ophiuroids in the dense bed were estimated to be 373 m−2 and 124 g m−2, respectively. Ophiuroids comprised 99% of all megabenthic organisms in terms of number of individuals, and megafaunal assemblage of the dense bed showed very low species diversity.O. sarsi exhibited a regular spatial pattern avoiding contact with conspecific neighbors. This regular spatial pattern was disrupted by certain other organisms, around which halo-like, bare areas were observed. The size and shape of these halo-like areas varied and were apparently related to the body size and/or motility of the organisms. In the present observation areaO. sarsi covered 96% of the sea bottom, and the remaining 4% was occupied by other organisms and their halo-like bare areas.", "corpus_id": 128960790, "score": 0 }, { "doc_id": "84865770", "title": "Energy content of macrobenthic invertebrates: general conversion factors from weight to energy", "abstract": "In ecological studies, especially in those dealing with energy circulation in nature, determinations of the energy content of organisms are inevitable. Energy determinations are, however, laborious and time-consuming. Average conversion factors based on different species form various areas and seasons may often be a shortcut for overcoming this problem. To establish general energy conversion factors for aquatic invertebrate groups, we used 376 values of J · mg−1 DW and 255 values of J · mg−1 AFDW, representing 308 and 229 species, respectively. The dry-weight-to-energy factors were highly variable both within and between taxonomic groups, e.g.: Porifera, 6.1 J · mg−1 DW; insect larvae, 22.4 J · mg−1 DW (median values). The energy-conversion factors related to AFDW showed a much smaller dispersion with a minimum median value of 19.7 J · mg−1 AFDW (Ascidiacea) and a maximum of 23.8 J · mg−1 AFDW (insect larvae). Within taxonomic groups, the 95% confidence intervals (AFDW) were only a few percent of the median values. The use of energy-conversion factors based on AFDW is preferable due to their lower dispersion. For aquatic macrobenthic invertebrates, a general conversion factor of 23 J · mg−1 AFDW can be used.", "corpus_id": 84865770, "score": 0 }, { "doc_id": "56212536", "title": "A photographic survey of the epibenthic megafauna of the Arctic Laptev Sea shelf: distribution, abundance, and estimates of biomass and organic carbon demand", "abstract": "The epibenthic megafauna of the high-Arctic Laptev Sea shelf was investigated in August/September 1993 and October 1995. At 13 stations in water depths of between 14 and 45 m, series of 5 to 29 photographs, each depicting about 1 m2 of the seabed, were taken to assess epifaunal dis t r~but~on patterns and abundances. Furthermore, population biomass of dominant br~ttle stars was estimated by combining abundance values with size-mass relationships and size frequencies established by measuring specimens on scaled photographs. A total of 13 epibenthic species were identified. Species numbers per station were low, ranging between 1 and 6. Total epibenthic abundances, averaging 173.7 ind. m-2, ranged considerably between 0.1 and 579.5 ind. m-2 Except for some stations on shallow shelf banks 30 m, it reached maximum density and biomass values of 566 ~ n d . m-2 and 1.5 g ash-free dry mass (AFDM) m ', respectively. At some sites, the brittle star Ophlura sarsi occurred in abundances of up to 35 ind. m-' and attained a biomass of 3.8 g AFDM m-2 Of local importance were the sea cucumber Myrjotrochus rinckii (up to 7 0 ind. m-') and the bivalve Arctinula greenlandica (up to 33 ind. m-2). All other species were recorded with distinctly lower densities (S1 ind. mT2). Gross estimates of population respiration and production of dominant brittle stars suggest that their organic carbon demand may amount to a pooled average of about 4 mg C m-' d-' in the Laptev Sea, locally even to a maximum of >l0 mg C m-2 d-' This finding indicates that a substantial portion of the energy flow in this high-Arctic shelf ecosystem may be channelled through dense brittle star assemblages.", "corpus_id": 56212536, "score": 0 }, { "doc_id": "129155239", "title": "Long-term change in the megabenthos of the Porcupine Abyssal Plain (NE Atlantic)", "abstract": "A radical change in the abundance of invertebrate megafauna on the Porcupine Abyssal Plain is reported over a period of 10 years (1989–1999). Actiniarians, annelids, pycnogonids, tunicates, ophiuroids and holothurians increased significantly in abundance. However, there was no significant change in wet weight biomass. Two holothurian species, Amperima rosea and Ellipinion molle, increased in abundance by more than two orders of magnitude. Samples from the Porcupine Abyssal Plain over a longer period (1977–1999) show that prior to 1996 these holothurian species were always a minor component of the megafauna. From 1996 to 1999 A. rosea was abundant over a wide area of the Porcupine Abyssal Plain indicating that the phenomenon was not a localised event. Several dominant holothurian species show a distinct trend in decreasing body size over the study period. The changes in megafauna abundance may be related to environmental forcing (food supply) rather than to localised stochastic population variations. Inter-annual variability and long-term trends in organic matter supply to the seabed may be responsible for the observed changes in abundance, species dominance and size distributions.", "corpus_id": 129155239, "score": 0 }, { "doc_id": "28571656", "title": "Food web structure of the benthic community at the Porcupine Abyssal Plain (NE Atlantic): a stable isotope analysis", "abstract": "Abstract The deep-sea benthic community at the Porcupine Abyssal Plain (NE Atlantic) is a highly food limited system. The annual input of sedimenting phytodetritus, which reaches the sea floor around May/June, is the major input of energy. The relative trophic position of the most abundant components of the benthos (90 species or higher taxonomic groups), including meiofaunal, macrofaunal, and megafaunal organisms, was evaluated by stable isotope analysis. The majority of the macro- and megafaunal organisms investigated were deposit feeders (N=35), less numerous were suspension feeders (N=17) and predators/scavengers (N=29). Stable nitrogen values overlap and cover a large range within feeding types, indicating a strong overlap in food sources and a high degree of competition for food. Suspension feeders, mainly cnidarians, have a broad trophic spectrum through feeding on resuspended material as well as capturing pelagic prey; thus during the greater part of the year they can compensate for any shortage in sedimenting fresh POM. Benthic deposit feeders use a variety of feeding strategies to exploit their common food resource. The holothurians, the dominant megabenthic group at PAP, included some highly mobile species, which seem to be quite efficient in tracing and exploiting localised patches of nutritious phytodetritus. Other holothurian species, however, forage successfully on more refractory material, possibly assisted by enteric bacteria. Predators/scavengers fall into two groups, representing two major trophic pathways. Firstly, several of the invertebrate predators prey on deposit-feeding organisms and so are the end consumers of an exclusively benthic food web. Secondly, there are highly mobile benthopelagic predators/scavengers, which are a major link with the benthopelagic food web through their feeding on pelagic prey. Generally, within the benthic community at PAP competition for food is reduced by two alternative evolutionary adaptations: (1) specialization on slightly different food sources and (2) vertical expansion of the trophic spectrum. This leads to a rather complex food web, covering a total δ15N range of at least 10‰.", "corpus_id": 28571656, "score": 0 }, { "doc_id": "21173070", "title": "Distribution, standing stock, growth, mortality and production of Strongylocentrotus pallidus (Echinodermata: Echinoidea) in the northern Barents Sea", "abstract": "Abstract The regular sea urchin, Strongylocentrotus pallidus (G.O. Sars, 1871), is a widespread epibenthic species in high-Arctic waters. However, little is known about its distribution, standing stock, population dynamics and production. In the northern Barents Sea, S. pallidus was recorded on seabed still photographs at 10 out of 11 stations in water depths of 80–360 m. Mean abundances along photographic transects of 150–300 m length ranged between <0.1 and 14.7 ind. m−2 yielding a grand average of 3.6 ind. m−2. The small-scale distribution along the transects was patchy, with densities varying from nil to an overall maximum of 25.5 ind. m−2, and exhibited a significant relation to the number of stones present. Sea urchin test diameters, measured on scaled photographs, extended from 7 to 90 mm. Median values at single stations varied from 14 to 46 mm, showing a significant inverse relationship to water depth. Biomass, estimated by combining photographic abundances, size frequencies and a size-mass function established with trawled specimens, ranged between <0.1 and 3.0 g ash-free dry mass m−2, averaging about 1.0 g ash free dry mass m−2. An analysis of skeletal growth bands in genital plates was carried out with 143 trawled individuals ranging in test diameter (D) from 4 to 48 mm. Assuming these bands to represent annual growth marks, the ages of the specimens analysed ranged between 3 and 42 years. A von Bertalanffy function was fitted to size-at-age data to model individual growth pattern (D∞ = 102.3 mm, k = 0.011 year−1, t0 = 0.633 year). The annual mortality rate Z of the population in the northern Barents Sea was estimated from a size-converted catch curve to be 0.08 year−1. Applying the weight-specific growth rate method, the average P/B ratio and the mean annual production of this population were estimated as 0.07 year−1 and 0.076 g AFDM m−2 year−1, respectively. In conclusion, S. pallidus is characterized by slow growth, low mortality, high longevity and low productivity. Because of its relatively high biomass, it is considered to contribute significantly to total benthic standing stock and carbon flux in the study area.", "corpus_id": 21173070, "score": 0 }, { "doc_id": "6443048", "title": "Antarctic reptant decapods: more than a myth?", "abstract": "The impoverished Antarctic decapod fauna is one of the most conspicuous biodiversity phenomena in polar science. Although physiological and ecological approaches have tried to explain the reason for the low decapod biodiversity pattern in the Southern Ocean, the complexity of this problem is still not completely understood. The scant records of crabs south of the Polar Front were always considered as exceptional, and have mostly been ignored by marine biologists world-wide, creating one of the most dogmatic paradigms in polar science. We herein review the record of both adults and larvae of reptants from the Southern Ocean. At present, several species of only lithodid crabs maintain considerable adult populations in circum-Antarctic waters, although they remain absent from the high-Antarctic shelves.", "corpus_id": 6443048, "score": 0 }, { "doc_id": "17690865", "title": "Haemolymph Mg(2+) regulation in decapod crustaceans: physiological correlates and ecological consequences in polar areas.", "abstract": "Reptant decapod crustaceans are almost absent from the Southern Ocean south of the Antarctic Convergence. We tested the hypothesis that this may be due to the reduced ability of this group to regulate Mg(2+) levels in the haemolymph ([Mg(2+)](HL)). Mg(2+) acts as an anaesthetic in marine invertebrates and its level is higher in Reptantia (crabs such as Cancer spp., Chionoecetes spp., Maja spp., 30-50 mmol l(-)(1)) than in Natantia (prawns such as Pandalus spp., Palaemon spp., Crangon spp., 5-12 mmol l(-)(1)). We varied [Mg(2+)](HL) in three species of reptant decapod crustaceans, Carcinus maenas, Hyas araneus and Eurypodius latreillei, and investigated heart rate, the rate of oxygen consumption and levels of spontaneous and forced activity at different temperatures. The rate of oxygen consumption and heart rate increased significantly with reduction in [Mg(2+)](HL) over the entire temperature range investigated in E. latreillei. In H. araneus, an increase in metabolic and heart rates compared with control values was found only at temperatures below 2 degrees C. Forced and spontaneous activity levels increased significantly in the group of [Mg(2+)](HL)-reduced animals below 0 degrees C, at which control animals were mostly inactive. At a reduced [Mg(2+)](HL) of 5-12 mmol l(-)(1), which is the [Mg(2+)](HL) of caridean shrimps in the Southern Ocean, Q(10) and activation energy were reduced for all these variables and extended the temperature range over which physiological functions were maintained. We suggest that the high [Mg(2+)](HL) in Reptantia causes relaxation of the animals and reduces their scope for activity, especially at temperatures below 0 degrees C. The hypothesis that the synergistic effects of high [Mg(2+)](HL) and low temperature probably prevented the Reptantia from recolonizing the permanently cold water of polar areas is discussed.", "corpus_id": 17690865, "score": 0 }, { "doc_id": "83678498", "title": "Energetically defining the thermal limits of the snow crab", "abstract": "The snow crab, Chionoecetes opilio , is a cold-water species found naturally at temperatures below 5°C. Its physiology and energetics were examined to understand the metabolic limitations that restrict the snow crab to these temperatures. The species is not confined to cold water because of a limited respiratory system. Routine oxygen demand can be met even at lethal temperatures of 18°C (56 mg O 2 kg −1 h −1 , with a Q 10 of 2.2). Blood lactate levels remain below 1.5 mmol l −1 and actually decline slightly with temperature. Energy budgets, which were constructed from an examination of oxygen uptake, activity and food consumption in morphometrically mature male animals between 0 and 18°C, indicate that the snow crab is energetically restricted to cold water. Rising metabolic costs overtake caloric intake around 7°C. This is probably due to digestive metabolism which is temperature-sensitive. Food consumption increases up to 6°C but then falls. Crabs stop feeding above 12°C. Although the growth equation is positive between 1 and 7°C, it becomes slightly negative below 1°C. This observation is unexpected since snow crabs are commonly found between 0 and 1°C. Slight temperature changes in the natural environment may, therefore, regulate growth and reproduction in this species.", "corpus_id": 83678498, "score": 0 }, { "doc_id": "25770320", "title": "Evidence for a permanent establishment of the snow crab (Chionoecetes opilio) in the Barents Sea", "abstract": "In the Atlantic the snow crab (Chionoecetes opilio) is naturally distributed on the northwestern side, i.e. eastern Canada and west Greenland. Until recently, there have been no observations of snow crab in eastern Atlantic. However, in 1990s single and occasional reports were made of crabs captured in the eastern part of the Barents Sea, presumably introduced through ballast water. Special attention during the annual bottom-trawl surveys in the Barents Sea during February 2004–2006 were given to include recordings of snow crab to evaluate if the introduced species has succeeded to establish a self-sustaining population in this region. Recordings of snow crabs were systematically noted and biological measurements carried out. The results confirm previous Russian observations of snow crabs in the northern region of Gåsebanken. In addition, a significant number of crabs were also found in the central region of the Barents Sea, mainly in deeper waters from 180 to 350 m depth. The sizes ranged from 14 to 136 mm carapace width. All females above 70 mm were berried with fertilised eggs. A major fraction (31% in 2005; 76% in 2006) of the crabs consisted of juveniles below 50 mm CW, providing evidence for successful recruitment. The small-sized crabs were exclusively found in Gåsebanken, identifying the main recruiting area at present for snow crab in the Barents Sea. The results obtained show that the snow crab is now adapted to the northeast Atlantic.", "corpus_id": 25770320, "score": 0 }, { "doc_id": "86295684", "title": "THE DIETARY PREFERENCES OF A SUITE OF CARRION-SCAVENGING GASTROPODS (NASSARIIDAE, BUCCINIDAE) IN PRINCESS ROYAL HARBOUR, ALBANY, WESTERN AUSTRALIA", "abstract": "On the seafloor of Shoal Bay, Princess Royal Harbour, Albany, Western Australia, lives a suite of four scavenging gastropod species: Nassarius pyrrhus, N. pauperatus (Nassariidae), Cominella eburnea and C. tasmanica (Buccinidae). Field and laboratory experiments were designed to test whether any of these scavengers showed a preference for (i) either fresh fish or bivalve tissues, (ii) fresh fish or 24-, 48- or 72-h-old fish. In baited-trap field experiments, no preferences were detected, and N. pyrrhus always arrived first, usually followed by either N. pauperatus or C. eburnea, and last by C. tasmanica. Numbers of scavengers on all baits peaked at about 70 min postdeployment and arrived from an estimated surrounding area of 0.5-2.5 m 2 . In laboratory experiments, bait preference results were similar, although fewer N. pyrrhus and N. pauperatus arrived at the 72-h-old fish, and C. eburnea was not attracted to such decaying bait.", "corpus_id": 86295684, "score": 0 }, { "doc_id": "54789122", "title": "Pelagic benthic coupling on the shelf of the northern Bering and Chukchi Seas-II. Benthic community structure", "abstract": "Benthic fauna abundance, biomass and diversity were investigated in the northern Bering and Chukchi Seas to determine factors influencing faunal distribution in this polar region. The hypothesis tested whether sebmen t grain size and water mass charactenstics, such as organic carbon supply to the benthos and temperature, are regulating factors in benthic community structure. Benthic communities under the cold, highly productive (-250 to 300 g C m-2 yr-') Bering Shelf-Anadyr Water (BSAW) are dominated by a high biomass of amphipods (F. Ampeliscidae and F. Isaeidae) and bivalves (F. Nuculidae and F. T e l l ~ n ~ d a e ) . A diverse, low biomass fauna exists in benthic communities under the warmer, less productive (-50 g C m-' yr-l) Alaska Coastal Water (ACW), includ~ng amphipods (F. Isaeidae and F. Ampeliscidae), bivalves (F Tellinidae and F. Thyasiridae), polychaetes (F. Maldanidae and Nephtyidae), and sand dollars (F. Echinarachniidae). Faunal diversities are lowest for stations under BSAW, characterized by high food supply and moderately homogeneous (well-sorted), sandy sediments. Highest diversities occur at stations in ACW, which is characterized by low food supply and a more heterogeneous (poorly-sorted) mixture of silt and clay, sand and gravel sediments. Faunal diversity also increased to the north in the Chukchi Sea, where food availability in the bottom water and surface sediments was greater and more heterogeneous, finer-grain sediments occur. The findings indicate that sediment heterogeneity, silt and clay fractions, and temperature are major regulating factors on benthic community structure, with each positively influencing faunal diversity. Lower diversity was correlated to an increase in fine sand fractions. Food supply, both in the bottom water and surface sediments, has a more variable Influence on benthic community structure, although i t has a direct posit~ve influence on benthic biomass.", "corpus_id": 54789122, "score": 0 }, { "doc_id": "53480025", "title": "VARIATION OF FEMALE SIZE AND STAGE AT MATURITY IN SNOW CRAB (CHIONOECETES OPILIO) (BRACHYURA: MAJIDAE) FROM THE EASTERN BERING SEA", "abstract": "Abstract We investigated geographic variation in size and stage (instar) at maturity of snow crab (Chionoecetes opilio) on the eastern Bering Sea shelf. Size-frequency distribution analysis showed that females can reach maturity at four different instars, presumably Instars VIII to XI. Geographic variation in instar structure generates clinal variation in size at maturity, from small size at high latitudes (colder) to large size at low latitudes (warmer). Different pieces of evidence support the hypothesis that geographic variation in mature female size is a phenotypic response to environmental conditions governed by a single reaction norm. Clinal variation conforms to the “inverse Bergmann's rule”. We argue that a single macroecological rule should not be expected to explain all latitudinal size gradients observed in marine invertebrates. Size at maturity fluctuated cyclically, and was negatively and significantly cross-correlated with strength in the recruitment of females to the mature population. Cycles in the latter were manifested as four commensurate and regularly spaced pulses over the last three decades. Mechanisms that may underlay this intriguing phenomenon, including density-dependent growth rate, require further scrutiny.", "corpus_id": 53480025, "score": 0 }, { "doc_id": "129013944", "title": "The influence of oceanographic processes on pelagic-benthic coupling in polar regions: A benthic perspective", "abstract": "Abstract Benthic community abundance and biomass in polar marine systems is directly influenced by food supply from the overlying water column. Variability in hydrographic regimes, ice coverage, light, water column temperature and pelagic food web structure limit the amount of organic carbon reaching the benthos. Data from the high Arctic and Antarctic indicate that a large percentage of surface-produced organic matter is consumed by both macro- and micro-zooplankton as well as recycled in the water column via the microbial loop. This results in food-limited regimes for the underlying benthos. The few exceptions are nearshore continental shelf systems, such as in the Bering and Chukchi Seas in the western Arctic and portions of the Canadian Archipelago and Barents Sea in the eastern Arctic, where high benthic abundance and biomass occurs due to a tight coupling between water column primary production and benthic secondary production. A major difference between the Antarctic and Arctic is that the nearshore deep Antarctic is characterized by relatively high benthic abundance and biomass despite low water column production, suggesting that stability, low disturbance levels and cold temperatures enable benthic organisms to grow larger than in the Arctic. Both physical and biological disturbance levels are high in the marginal seas of the Arctic may directly influence benthic productivity. The relationship between primary production and sedimentation of organic material to the benthos is nonlinear due to its dependence on the role of the pelagic food web. Therefore, in this review we will only discuss the pelagic system with respect to how it impacts the net food supply reachig the benthos. A major objective of this review paper is demonstrate the influence of oceanographic processes on pelagic-benthic coupling in polar regions from a “bottom-up” perspective, using benthic studies from various regions in both the Arctic and Antarctic. Similarities and differences in oceanographic processes, benthic abundance and biomass, and benthic carbon cycling within these polar marine systems are discussed and areas for further research identified.", "corpus_id": 129013944, "score": 0 }, { "doc_id": "85399151", "title": "Substrate preferences and redistribution of blue king crab Paralithodes platypus glaucothoe and first crab on natural substrates in the laboratory", "abstract": "Abstract Despite the importance of blue king crab (BKC) to the Bering Sea fishery, there has been no detailed study of juvenile habitat preferences. Such information is critical for understanding life history and for development of stock enhancement programs. The aims of this study were to determine the natural substrata that glaucothoe prefer to settle on, and whether they or subsequent crab 1 stage (C1) redistribute to different habitats over time. A laboratory experiment was performed in 24 round containers divided in four equal quadrants each filled with one of the following natural substrata: beach sand, gravel, shells and cobble. Containers were assigned to 8 groups of 3 replicates each and were kept at ~ 6–8 °C. Twenty five glaucothoe were released in each container on day 0, and one group of three replicates was removed for examination at each of the following intervals: 24 h, 7, 14, 21, 28, 35, 42 and 49 days. Numbers of swimming and settled specimens on each substrate and period were recorded. Glaucothoe began to settle immediately after being released since no swimming larvae were found during any sampling periods. Substrata complexity was important for the habitat selection and distribution of blue king crab glaucothoe and crab 1 stage. During the glaucothoe stage, beach sand was rejected and cobble, shell and gravel were chosen equally. After glaucothoe molted to crab 1 stage and became bigger, animals preferred cobble and shell instead of gravel and beach sand. Understanding habitat selection is useful not only for management of crab populations, but also for assessing the potential of various habitats for stock enhancement of blue king crabs.", "corpus_id": 85399151, "score": 0 }, { "doc_id": "83935407", "title": "Water flow over subtidal rock walls: relation to distributions and growth rates of sessile suspension feeders in the Gulf of Maine Water flow and growth rates", "abstract": "Abstract Moving water delivers food resources to sessile suspension feeding invertebrates and the interaction between water motion and substrate topography may dramatically influence the ecology of these animals. Growth rates of two species of sessile suspension feeders were compared between positions within individual 1.5-m high rock walls at an offshore site at 30-m depth in the Gulf of Maine, USA. The site is characterized by strong, highly variable water flow. Growth rates for the active suspension feeding mussel Mytilus edulis (Linnaeus), were greater at upper than at lower wall positions, while growth rates for the facultatively-active suspension feeding sponge Halichondria panicea (Pallas) showed the opposite pattern, with higher rates at lower than upper wall positions. Mussel and sponge growth rates were related both to patterns of bulk fluid flux across the walls and to naturally occurring distributions of sessile suspension feeders. Dissolution of alabaster and plaster solids indicated that upper wall positions experienced significantly higher bulk fluid flux than lower wall positions. Distribution data show non-random suspension feeder abundances across a series of small rock walls at two offshore sites. The abundance of passive suspension feeders was greatest near the top edges, while active and facultatively-active suspension feeders occur in greatest densities at lower wall positions. The results show that the interaction of small scale, abrupt, topographic features with variable local flow conditions can lead to physical gradients within rock walls. These gradients significantly affect the growth of suspension feeders, and may influence the structure sessile of invertebrate communities on subtidal rock walls.", "corpus_id": 83935407, "score": 0 }, { "doc_id": "55587696", "title": "The northeastern Chukchi Sea: benthos-environmental interactions", "abstract": "Benthic faunal abundance, diversity, and biomass were examined in the northeastern Chukchi Sea to determine factors influencing faunal distribution. Four taxon-abundance-based benthic station groups were identified by cluster analysis and ordination techniques. These groups are explained, using stepwise multiple discriminant analysis, by the gravel-sand-mud and water content of bottom sediments, and the organic carbon/nitrogen (OC/N) ratio. In contrast to previous benthic investigations in the northeastern Bering and southeastern Chukchi Seas, faunal diversity between inshore and offshore regions in our study area were not related to differences in sediment sorting. Instead, regional diversity differences in the northeastern Chukchi Sea were related to greater environmental stresses (e.g. ice gouging, wave-current action, marine-mammal feeding activities) inshore than offshore. The presence of a high benthic biomass north of Icy Cape in the vicinity of Point Franklin and seaward of a hydrographic front is presumably related to an enhanced local depositional flux of particulate organic carbon (POC) in the area. We postulate that POC-rich waters derived from the northern Bering and northwestern Chukchi Seas extend to our study area and the flux of the entrained POC provides a persistent source of carbon to sustain the high benthic biomass. Annual POC enrichment of the coastal region north of Icy Cape is reflected by the great abundance of amphipods and other invertebrates present there and the concentration in summer of walrus Odobenus rosmarus djvergens and gray whales Eschrichtius robustus that feed on these invertebrates. This study demonstrates that there can be high standing stocks of benthos in arctic regions with relatively low annual primary production if local carbon is augmented by POC advected from highly productive areas.", "corpus_id": 55587696, "score": 0 }, { "doc_id": "129816755", "title": "Interannual changes in the Bering Strait fluxes of volume, heat and freshwater between 1991 and 2004", "abstract": "Year-round moorings (1990 to 2004) illustrate interannual variability of Bering Strait volume, freshwater and heat fluxes, which affect Arctic systems including sea-ice. Fluxes are lowest in 2001 and increase to 2004. Whilst 2004 freshwater and volume fluxes match previous maxima (1998), the 2004 heat flux is the highest recorded, partly due to ~ 0.5oC warmer temperatures since 2002. The Alaskan Coastal Current, contributing about 1/3 rd of the heat and ¼ of the freshwater fluxes, also shows strong warming and freshening between 2002 and 2004. The increased Bering Strait heat input between 2001 and 2004 (> 2x10 20 J) could melt 640,000 km 2 of 1 m thick ice; the 3-year freshwater increase (~ 800 km 3 ) is about ¼ of annual Arctic river run-off. Weaker southward winds likely explain the increased volume flux (~ 0.7 to ~ 1 Sv), causing ~ 80% of the freshwater and ~ 50% of the heat flux increases. INDEX TERMS: 4207 General Oceanography: Arctic and Antarctic oceanography (9310, 9315); 4215 General Oceanography: Climate and interannual variability (1616, 1635, 3305, 3309, 4513); 4223 General Oceanography: Descriptive and regional oceanography; 4227 General Oceanography: Diurnal, seasonal, and annual cycles (0438).", "corpus_id": 129816755, "score": 0 }, { "doc_id": "18140765", "title": "Selecting Indicator Species to Monitor Ecological Integrity: A Review", "abstract": "We review critical issues that must be considered when selectingindicator species for a monitoring program that aims to maintainor restore ecological integrity. First, we examine the pros andcons of different management approaches on which a conservationprogram can be based and conclude that ecosystem management ismost appropriate. We then identify potential indicators ofecological integrity at various levels of the ecosystem, with aparticular emphasis on the species level. We conclude that,although the use of indicator species remains contentious, it canbe useful if (1) many species representing various taxa and lifehistories are included in the monitoring program, (2) theirselection is primarily based on a sound quantitative databasefrom the focal region, and (3) caution is applied wheninterpreting their population trends to distinguish actualsignals from variations that may be unrelated to thedeterioration of ecological integrity. Finally, we present anddiscuss different methods that have been used to select indicatorspecies.", "corpus_id": 18140765, "score": 0 }, { "doc_id": "53536174", "title": "Indicators for Monitoring Biodiversity: A Hierarchical Approach", "abstract": "Biodiversity is presently a minor consideration in environmental policy. It has been regarded as too broad and vague a concept to be applied to real-world regulatoy and managernentproblems. This problem can be corrected ifbio- diversity is recognized as an end in itsea and if measurable indicators can be selected to assess the status of biodiversity over time. Biodiversity, as presently understood, encom- passes multiple levels of biological organization. In thispa- per, I expand the three primay attributes of biodiversity recognized by Jerry Franklin - composition, structure, and function - into a nested hierarcby that incorporates ele- ments of each attribute at four levels of organization: re- gional landscape, community-ecosystem, population- species, andgenetic. Indicators of each attribute in terrestrial ecosystems, at the four levels of organization, are identified for environmental monitoring purposes. Projects to monitor biodiversity will benefit from a direct linkage to long-term ecological research and a commitment to test hypotheses relevant to biodiversity conservation. A general guideline is to proceed from the top down, beginning with a coarse-scale invent0 y of landscape pattern, vegetation, habitat structure, and species distributions, then overlaying data on stress lev- els to identiD biologically significant areas at high risk of impoverishment. Intensive research and monitoring can be directed to high-risk ecosystems and elements of biodiversity, while less intensive monitoring is directed to the total land- scape (or samples thereon. In any monitoringprogram, par- ticular attention should be paid to specifying the questions that monitoring is intended to answer and validating the relationships between indicators and the components of bio- diversity they represent", "corpus_id": 53536174, "score": 0 } ]

{ "doc_id": "11816723", "title": "Learning Chained Deep Features and Classifiers for Cascade in Object Detection", "abstract": "Cascade is a widely used approach that rejects obvious negative samples at early stages for learning better classifier and faster inference. This paper presents chained cascade network (CC-Net). In this CC-Net, the cascaded classifier at a stage is aided by the classification scores in previous stages. Feature chaining is further proposed so that the feature learning for the current cascade stage uses the features in previous stages as the prior information. The chained ConvNet features and classifiers of multiple stages are jointly learned in an end-to-end network. In this way, features and classifiers at latter stages handle more difficult samples with the help of features and classifiers in previous stages. It yields consistent boost in detection performance on benchmarks like PASCAL VOC 2007 and ImageNet. Combined with better region proposal, CC-Net leads to state-of-the-art result of 81.1% mAP on PASCAL VOC 2007.", "corpus_id": 11816723 }

[ { "doc_id": "206590483", "title": "Histograms of oriented gradients for human detection", "abstract": "We study the question of feature sets for robust visual object recognition; adopting linear SVM based human detection as a test case. After reviewing existing edge and gradient based descriptors, we show experimentally that grids of histograms of oriented gradient (HOG) descriptors significantly outperform existing feature sets for human detection. We study the influence of each stage of the computation on performance, concluding that fine-scale gradients, fine orientation binning, relatively coarse spatial binning, and high-quality local contrast normalization in overlapping descriptor blocks are all important for good results. The new approach gives near-perfect separation on the original MIT pedestrian database, so we introduce a more challenging dataset containing over 1800 annotated human images with a large range of pose variations and backgrounds.", "corpus_id": 206590483, "score": 0 }, { "doc_id": "2715202", "title": "Rapid object detection using a boosted cascade of simple features", "abstract": "This paper describes a machine learning approach for visual object detection which is capable of processing images extremely rapidly and achieving high detection rates. This work is distinguished by three key contributions. The first is the introduction of a new image representation called the \"integral image\" which allows the features used by our detector to be computed very quickly. The second is a learning algorithm, based on AdaBoost, which selects a small number of critical visual features from a larger set and yields extremely efficient classifiers. The third contribution is a method for combining increasingly more complex classifiers in a \"cascade\" which allows background regions of the image to be quickly discarded while spending more computation on promising object-like regions. The cascade can be viewed as an object specific focus-of-attention mechanism which unlike previous approaches provides statistical guarantees that discarded regions are unlikely to contain the object of interest. In the domain of face detection the system yields detection rates comparable to the best previous systems. Used in real-time applications, the detector runs at 15 frames per second without resorting to image differencing or skin color detection.", "corpus_id": 2715202, "score": 0 }, { "doc_id": "192358", "title": "Robust object detection via soft cascade", "abstract": "We describe a method for training object detectors using a generalization of the cascade architecture, which results in a detection rate and speed comparable to that of the best published detectors while allowing for easier training and a detector with fewer features. In addition, the method allows for quickly calibrating the detector for a target detection rate, false positive rate or speed. One important advantage of our method is that it enables systematic exploration of the ROC surface, which characterizes the trade-off between accuracy and speed for a given classifier.", "corpus_id": 192358, "score": 1 }, { "doc_id": "5093465", "title": "Boosting chain learning for object detection", "abstract": "A general classification framework, called boosting chain, is proposed for learning boosting cascade. In this framework, a \"chain\" structure is introduced to integrate historical knowledge into successive boosting learning. Moreover, a linear optimization scheme is proposed to address the problems of redundancy in boosting learning and threshold adjusting in cascade coupling. By this means, the resulting classifier consists of fewer weak classifiers yet achieves lower error rates than boosting cascade in both training and test. Experimental comparisons of boosting chain and boosting cascade are provided through a face detection problem. The promising results clearly demonstrate the effectiveness made by boosting chain.", "corpus_id": 5093465, "score": 1 }, { "doc_id": "12432640", "title": "A coarse-to-fine approach for fast deformable object detection", "abstract": "We present a method that can dramatically accelerate object detection with part based models. The method is based on the observation that the cost of detection is likely to be dominated by the cost of matching each part to the image, and not by the cost of computing the optimal configuration of the parts as commonly assumed. Therefore accelerating detection requires minimizing the number of part-to-image comparisons. To this end we propose a multiple-resolutions hierarchical part based model and a corresponding coarse-to-fine inference procedure that recursively eliminates from the search space unpromising part placements. The method yields a ten-fold speedup over the standard dynamic programming approach and is complementary to the cascade-of-parts approach of [9]. Compared to the latter, our method does not have parameters to be determined empirically, which simplifies its use during the training of the model. Most importantly, the two techniques can be combined to obtain a very significant speedup, of two orders of magnitude in some cases. We evaluate our method extensively on the PASCAL VOC and INRIA datasets, demonstrating a very high increase in the detection speed with little degradation of the accuracy.", "corpus_id": 12432640, "score": 0 }, { "doc_id": "6735187", "title": "Cascade object detection with deformable part models", "abstract": "We describe a general method for building cascade classifiers from part-based deformable models such as pictorial structures. We focus primarily on the case of star-structured models and show how a simple algorithm based on partial hypothesis pruning can speed up object detection by more than one order of magnitude without sacrificing detection accuracy. In our algorithm, partial hypotheses are pruned with a sequence of thresholds. In analogy to probably approximately correct (PAC) learning, we introduce the notion of probably approximately admissible (PAA) thresholds. Such thresholds provide theoretical guarantees on the performance of the cascade method and can be computed from a small sample of positive examples. Finally, we outline a cascade detection algorithm for a general class of models defined by a grammar formalism. This class includes not only tree-structured pictorial structures but also richer models that can represent each part recursively as a mixture of other parts.", "corpus_id": 6735187, "score": 0 }, { "doc_id": "206770307", "title": "Fast R-CNN", "abstract": "This paper proposes a Fast Region-based Convolutional Network method (Fast R-CNN) for object detection. Fast R-CNN builds on previous work to efficiently classify object proposals using deep convolutional networks. Compared to previous work, Fast R-CNN employs several innovations to improve training and testing speed while also increasing detection accuracy. Fast R-CNN trains the very deep VGG16 network 9x faster than R-CNN, is 213x faster at test-time, and achieves a higher mAP on PASCAL VOC 2012. Compared to SPPnet, Fast R-CNN trains VGG16 3x faster, tests 10x faster, and is more accurate. Fast R-CNN is implemented in Python and C++ (using Caffe) and is available under the open-source MIT License at https://github.com/rbgirshick/fast-rcnn.", "corpus_id": 206770307, "score": 0 }, { "doc_id": "3198903", "title": "Object Detection with Discriminatively Trained Part Based Models", "abstract": "We describe an object detection system based on mixtures of multiscale deformable part models. Our system is able to represent highly variable object classes and achieves state-of-the-art results in the PASCAL object detection challenges. While deformable part models have become quite popular, their value had not been demonstrated on difficult benchmarks such as the PASCAL data sets. Our system relies on new methods for discriminative training with partially labeled data. We combine a margin-sensitive approach for data-mining hard negative examples with a formalism we call latent SVM. A latent SVM is a reformulation of MI--SVM in terms of latent variables. A latent SVM is semiconvex, and the training problem becomes convex once latent information is specified for the positive examples. This leads to an iterative training algorithm that alternates between fixing latent values for positive examples and optimizing the latent SVM objective function.", "corpus_id": 3198903, "score": 0 }, { "doc_id": "2804322", "title": "Feature-centric evaluation for efficient cascaded object detection", "abstract": "We describe a cascaded method for object detection. This approach uses a novel organization of the first cascade stage called \"feature-centric\" evaluation which re-uses feature evaluations across multiple candidate windows. We minimize the cost of this evaluation through several simplifications: (1) localized lighting normalization, (2) representation of the classifier as an additive model and (3) discrete-valued features. Such a method also incorporates a unique feature representation. The early stages in the cascade use simple fast feature evaluations and the later stages use more complex discriminative features. In particular, we propose features based on sparse coding and ordinal relationships among filter responses. This combination of cascaded feature-centric evaluation with features of increasing complexity achieves both computational efficiency and accuracy. We describe object detection experiments on ten objects including faces and automobiles. These results include 97% recognition at equal error rate on the UIUC image database for car detection.", "corpus_id": 2804322, "score": 0 }, { "doc_id": "219903", "title": "Fast Feature Pyramids for Object Detection", "abstract": "Multi-resolution image features may be approximated via extrapolation from nearby scales, rather than being computed explicitly. This fundamental insight allows us to design object detection algorithms that are as accurate, and considerably faster, than the state-of-the-art. The computational bottleneck of many modern detectors is the computation of features at every scale of a finely-sampled image pyramid. Our key insight is that one may compute finely sampled feature pyramids at a fraction of the cost, without sacrificing performance: for a broad family of features we find that features computed at octave-spaced scale intervals are sufficient to approximate features on a finely-sampled pyramid. Extrapolation is inexpensive as compared to direct feature computation. As a result, our approximation yields considerable speedups with negligible loss in detection accuracy. We modify three diverse visual recognition systems to use fast feature pyramids and show results on both pedestrian detection (measured on the Caltech, INRIA, TUD-Brussels and ETH data sets) and general object detection (measured on the PASCAL VOC). The approach is general and is widely applicable to vision algorithms requiring fine-grained multi-scale analysis. Our approximation is valid for images with broad spectra (most natural images) and fails for images with narrow band-pass spectra (e.g., periodic textures).", "corpus_id": 219903, "score": 0 }, { "doc_id": "13894144", "title": "FloatBoost learning and statistical face detection", "abstract": "A novel learning procedure, called FloatBoost, is proposed for learning a boosted classifier for achieving the minimum error rate. FloatBoost learning uses a backtrack mechanism after each iteration of AdaBoost learning to minimize the error rate directly, rather than minimizing an exponential function of the margin as in the traditional AdaBoost algorithms. A second contribution of the paper is a novel statistical model for learning best weak classifiers using a stagewise approximation of the posterior probability. These novel techniques lead to a classifier which requires fewer weak classifiers than AdaBoost yet achieves lower error rates in both training and testing, as demonstrated by extensive experiments. Applied to face detection, the FloatBoost learning method, together with a proposed detector pyramid architecture, leads to the first real-time multiview face detection system reported.", "corpus_id": 13894144, "score": 0 }, { "doc_id": "3203206", "title": "CRAFT Objects from Images", "abstract": "Object detection is a fundamental problem in image understanding. One popular solution is the R-CNN framework [15] and its fast versions [14, 27]. They decompose the object detection problem into two cascaded easier tasks: 1) generating object proposals from images, 2) classifying proposals into various object categories. Despite that we are handling with two relatively easier tasks, they are not solved perfectly and there's still room for improvement. In this paper, we push the \"divide and conquer\" solution even further by dividing each task into two sub-tasks. We call the proposed method \"CRAFT\" (Cascade Regionproposal-network And FasT-rcnn), which tackles each task with a carefully designed network cascade. We show that the cascade structure helps in both tasks: in proposal generation, it provides more compact and better localized object proposals, in object classification, it reduces false positives (mainly between ambiguous categories) by capturing both inter-and intra-category variances. CRAFT achieves consistent and considerable improvement over the state-of the-art on object detection benchmarks like PASCAL VOC 07/12 and ILSVRC.", "corpus_id": 3203206, "score": 1 }, { "doc_id": "2843566", "title": "Training Region-Based Object Detectors with Online Hard Example Mining", "abstract": "The field of object detection has made significant advances riding on the wave of region-based ConvNets, but their training procedure still includes many heuristics and hyperparameters that are costly to tune. We present a simple yet surprisingly effective online hard example mining (OHEM) algorithm for training region-based ConvNet detectors. Our motivation is the same as it has always been - detection datasets contain an overwhelming number of easy examples and a small number of hard examples. Automatic selection of these hard examples can make training more effective and efficient. OHEM is a simple and intuitive algorithm that eliminates several heuristics and hyperparameters in common use. But more importantly, it yields consistent and significant boosts in detection performance on benchmarks like PASCAL VOC 2007 and 2012. Its effectiveness increases as datasets become larger and more difficult, as demonstrated by the results on the MS COCO dataset. Moreover, combined with complementary advances in the field, OHEM leads to state-of-the-art results of 78.9% and 76.3% mAP on PASCAL VOC 2007 and 2012 respectively.", "corpus_id": 2843566, "score": 1 }, { "doc_id": "206594120", "title": "Joint Training of Cascaded CNN for Face Detection", "abstract": "Cascade has been widely used in face detection, where classifier with low computation cost can be firstly used to shrink most of the background while keeping the recall. The cascade in detection is popularized by seminal Viola-Jones framework and then widely used in other pipelines, such as DPM and CNN. However, to our best knowledge, most of the previous detection methods use cascade in a greedy manner, where previous stages in cascade are fixed when training a new stage. So optimizations of different CNNs are isolated. In this paper, we propose joint training to achieve end-to-end optimization for CNN cascade. We show that the back propagation algorithm used in training CNN can be naturally used in training CNN cascade. We present how jointly training can be conducted on naive CNN cascade and more sophisticated region proposal network (RPN) and fast R-CNN. Experiments on face detection benchmarks verify the advantages of the joint training.", "corpus_id": 206594120, "score": 0 }, { "doc_id": "4071727", "title": "OverFeat: Integrated Recognition, Localization and Detection using Convolutional Networks", "abstract": "We present an integrated framework for using Convolutional Networks for classification, localization and detection. We show how a multiscale and sliding window approach can be efficiently implemented within a ConvNet. We also introduce a novel deep learning approach to localization by learning to predict object boundaries. Bounding boxes are then accumulated rather than suppressed in order to increase detection confidence. We show that different tasks can be learned simultaneously using a single shared network. This integrated framework is the winner of the localization task of the ImageNet Large Scale Visual Recognition Challenge 2013 (ILSVRC2013) and obtained very competitive results for the detection and classifications tasks. In post-competition work, we establish a new state of the art for the detection task. Finally, we release a feature extractor from our best model called OverFeat.", "corpus_id": 4071727, "score": 0 }, { "doc_id": "14124313", "title": "Very Deep Convolutional Networks for Large-Scale Image Recognition", "abstract": "In this work we investigate the effect of the convolutional network depth on its accuracy in the large-scale image recognition setting. Our main contribution is a thorough evaluation of networks of increasing depth using an architecture with very small (3x3) convolution filters, which shows that a significant improvement on the prior-art configurations can be achieved by pushing the depth to 16-19 weight layers. These findings were the basis of our ImageNet Challenge 2014 submission, where our team secured the first and the second places in the localisation and classification tracks respectively. We also show that our representations generalise well to other datasets, where they achieve state-of-the-art results. We have made our two best-performing ConvNet models publicly available to facilitate further research on the use of deep visual representations in computer vision.", "corpus_id": 14124313, "score": 0 }, { "doc_id": "206592484", "title": "Going deeper with convolutions", "abstract": "We propose a deep convolutional neural network architecture codenamed Inception that achieves the new state of the art for classification and detection in the ImageNet Large-Scale Visual Recognition Challenge 2014 (ILSVRC14). The main hallmark of this architecture is the improved utilization of the computing resources inside the network. By a carefully crafted design, we increased the depth and width of the network while keeping the computational budget constant. To optimize quality, the architectural decisions were based on the Hebbian principle and the intuition of multi-scale processing. One particular incarnation used in our submission for ILSVRC14 is called GoogLeNet, a 22 layers deep network, the quality of which is assessed in the context of classification and detection.", "corpus_id": 206592484, "score": 0 }, { "doc_id": "206594692", "title": "Deep Residual Learning for Image Recognition", "abstract": "Deeper neural networks are more difficult to train. We present a residual learning framework to ease the training of networks that are substantially deeper than those used previously. We explicitly reformulate the layers as learning residual functions with reference to the layer inputs, instead of learning unreferenced functions. We provide comprehensive empirical evidence showing that these residual networks are easier to optimize, and can gain accuracy from considerably increased depth. On the ImageNet dataset we evaluate residual nets with a depth of up to 152 layers - 8× deeper than VGG nets [40] but still having lower complexity. An ensemble of these residual nets achieves 3.57% error on the ImageNet test set. This result won the 1st place on the ILSVRC 2015 classification task. We also present analysis on CIFAR-10 with 100 and 1000 layers. The depth of representations is of central importance for many visual recognition tasks. Solely due to our extremely deep representations, we obtain a 28% relative improvement on the COCO object detection dataset. Deep residual nets are foundations of our submissions to ILSVRC & COCO 2015 competitions1, where we also won the 1st places on the tasks of ImageNet detection, ImageNet localization, COCO detection, and COCO segmentation.", "corpus_id": 206594692, "score": 0 }, { "doc_id": "15276198", "title": "Wide Residual Networks", "abstract": "Deep residual networks were shown to be able to scale up to thousands of layers and still have improving performance. However, each fraction of a percent of improved accuracy costs nearly doubling the number of layers, and so training very deep residual networks has a problem of diminishing feature reuse, which makes these networks very slow to train. To tackle these problems, in this paper we conduct a detailed experimental study on the architecture of ResNet blocks, based on which we propose a novel architecture where we decrease depth and increase width of residual networks. We call the resulting network structures wide residual networks (WRNs) and show that these are far superior over their commonly used thin and very deep counterparts. For example, we demonstrate that even a simple 16-layer-deep wide residual network outperforms in accuracy and efficiency all previous deep residual networks, including thousand-layer-deep networks, achieving new state-of-the-art results on CIFAR, SVHN, COCO, and significant improvements on ImageNet. Our code and models are available at this https URL", "corpus_id": 15276198, "score": 0 }, { "doc_id": "18327841", "title": "Deep Learning with Separable Convolutions", "abstract": "We present an interpretation of Inception modules in convolutional neural networks as being an intermediate step in-between regular convolution and the recently introduced “separable convolution” operation. In this light, a separable convolution can be understood as an Inception module with a maximally large number of towers. This observation leads us to propose a novel deep convolutional neural network architecture inspired by Inception, where Inception modules have been replaced with separable convolutions. We show that this architecture, dubbed Xception, slightly outperforms Inception V3 on the ImageNet dataset (which Inception V3 was designed for), and significantly outperforms Inception V3 on a larger image classification dataset comprising 350 million images and 17,000 classes. Since the Xception architecture has the same number of parameter as Inception V3, the performance gains are not due to increased capacity but rather to a more efficient use of model parameters.", "corpus_id": 18327841, "score": 0 }, { "doc_id": "4206951", "title": "Gated Bi-directional CNN for Object Detection", "abstract": "The visual cues from multiple support regions of different sizes and resolutions are complementary in classifying a candidate box in object detection. How to effectively integrate local and contextual visual cues from these regions has become a fundamental problem in object detection. Most existing works simply concatenated features or scores obtained from support regions. In this paper, we proposal a novel gated bi-directional CNN (GBD-Net) to pass messages between features from different support regions during both feature learning and feature extraction. Such message passing can be implemented through convolution in two directions and can be conducted in various layers. Therefore, local and contextual visual patterns can validate the existence of each other by learning their nonlinear relationships and their close iterations are modeled in a much more complex way. It is also shown that message passing is not always helpful depending on individual samples. Gated functions are further introduced to control message transmission and their on-and-off is controlled by extra visual evidence from the input sample. GBD-Net is implemented under the Fast RCNN detection framework. Its effectiveness is shown through experiments on three object detection datasets, ImageNet, Pascal VOC2007 and Microsoft COCO.", "corpus_id": 4206951, "score": 1 }, { "doc_id": "7148278", "title": "Inside-Outside Net: Detecting Objects in Context with Skip Pooling and Recurrent Neural Networks", "abstract": "It is well known that contextual and multi-scale representations are important for accurate visual recognition. In this paper we present the Inside-Outside Net (ION), an object detector that exploits information both inside and outside the region of interest. Contextual information outside the region of interest is integrated using spatial recurrent neural networks. Inside, we use skip pooling to extract information at multiple scales and levels of abstraction. Through extensive experiments we evaluate the design space and provide readers with an overview of what tricks of the trade are important. ION improves state-of-the-art on PASCAL VOC 2012 object detection from 73.9% to 77.9% mAP. On the new and more challenging MS COCO dataset, we improve state-of-the-art from 19.7% to 33.1% mAP. In the 2015 MS COCO Detection Challenge, our ION model won \"Best Student Entry\" and finished 3rd place overall. As intuition suggests, our detection results provide strong evidence that context and multi-scale representations improve small object detection.", "corpus_id": 7148278, "score": 0 }, { "doc_id": "12867381", "title": "Attend Refine Repeat: Active Box Proposal Generation via In-Out Localization", "abstract": "The problem of computing category agnostic bounding box proposals is utilized as a core component in many computer vision tasks and thus has lately attracted a lot of attention. In this work we propose a new approach to tackle this problem that is based on an active strategy for generating box proposals that starts from a set of seed boxes, which are uniformly distributed on the image, and then progressively moves its attention on the promising image areas where it is more likely to discover well localized bounding box proposals. We call our approach AttractioNet and a core component of it is a CNN-based category agnostic object location refinement module that is capable of yielding accurate and robust bounding box predictions regardless of the object category. \nWe extensively evaluate our AttractioNet approach on several image datasets (i.e. COCO, PASCAL, ImageNet detection and NYU-Depth V2 datasets) reporting on all of them state-of-the-art results that surpass the previous work in the field by a significant margin and also providing strong empirical evidence that our approach is capable to generalize to unseen categories. Furthermore, we evaluate our AttractioNet proposals in the context of the object detection task using a VGG16-Net based detector and the achieved detection performance on COCO manages to significantly surpass all other VGG16-Net based detectors while even being competitive with a heavily tuned ResNet-101 based detector. Code as well as box proposals computed for several datasets are available at:: this https URL", "corpus_id": 12867381, "score": 1 }, { "doc_id": "5808102", "title": "Batch Normalization: Accelerating Deep Network Training by Reducing Internal Covariate Shift", "abstract": "Training Deep Neural Networks is complicated by the fact that the distribution of each layer's inputs changes during training, as the parameters of the previous layers change. This slows down the training by requiring lower learning rates and careful parameter initialization, and makes it notoriously hard to train models with saturating nonlinearities. We refer to this phenomenon as internal covariate shift, and address the problem by normalizing layer inputs. Our method draws its strength from making normalization a part of the model architecture and performing the normalization for each training mini-batch. Batch Normalization allows us to use much higher learning rates and be less careful about initialization, and in some cases eliminates the need for Dropout. Applied to a state-of-the-art image classification model, Batch Normalization achieves the same accuracy with 14 times fewer training steps, and beats the original model by a significant margin. Using an ensemble of batch-normalized networks, we improve upon the best published result on ImageNet classification: reaching 4.82% top-5 test error, exceeding the accuracy of human raters.", "corpus_id": 5808102, "score": 1 }, { "doc_id": "11442196", "title": "Segmentation as selective search for object recognition", "abstract": "For object recognition, the current state-of-the-art is based on exhaustive search. However, to enable the use of more expensive features and classifiers and thereby progress beyond the state-of-the-art, a selective search strategy is needed. Therefore, we adapt segmentation as a selective search by reconsidering segmentation: We propose to generate many approximate locations over few and precise object delineations because (1) an object whose location is never generated can not be recognised and (2) appearance and immediate nearby context are most effective for object recognition. Our method is class-independent and is shown to cover 96.7% of all objects in the Pascal VOC 2007 test set using only 1,536 locations per image. Our selective search enables the use of the more expensive bag-of-words method which we use to substantially improve the state-of-the-art by up to 8.5% for 8 out of 20 classes on the Pascal VOC 2010 detection challenge.", "corpus_id": 11442196, "score": 0 }, { "doc_id": "4246903", "title": "The Pascal Visual Object Classes (VOC) Challenge", "abstract": "The Pascal Visual Object Classes (VOC) challenge is a benchmark in visual object category recognition and detection, providing the vision and machine learning communities with a standard dataset of images and annotation, and standard evaluation procedures. Organised annually from 2005 to present, the challenge and its associated dataset has become accepted as the benchmark for object detection.This paper describes the dataset and evaluation procedure. We review the state-of-the-art in evaluated methods for both classification and detection, analyse whether the methods are statistically different, what they are learning from the images (e.g. the object or its context), and what the methods find easy or confuse. The paper concludes with lessons learnt in the three year history of the challenge, and proposes directions for future improvement and extension.", "corpus_id": 4246903, "score": 0 }, { "doc_id": "11102127", "title": "DeepID-Net: Deformable deep convolutional neural networks for object detection", "abstract": "In this paper, we propose deformable deep convolutional neural networks for generic object detection. This new deep learning object detection framework has innovations in multiple aspects. In the proposed new deep architecture, a new deformation constrained pooling (def-pooling) layer models the deformation of object parts with geometric constraint and penalty. A new pre-training strategy is proposed to learn feature representations more suitable for the object detection task and with good generalization capability. By changing the net structures, training strategies, adding and removing some key components in the detection pipeline, a set of models with large diversity are obtained, which significantly improves the effectiveness of model averaging. The proposed approach improves the mean averaged precision obtained by RCNN [14], which was the state-of-the-art, from 31% to 50.3% on the ILSVRC2014 detection test set. It also outperforms the winner of ILSVRC2014, GoogLeNet, by 6.1%. Detailed component-wise analysis is also provided through extensive experimental evaluation, which provide a global view for people to understand the deep learning object detection pipeline.", "corpus_id": 11102127, "score": 0 }, { "doc_id": "16843664", "title": "Object detection by labeling superpixels", "abstract": "Object detection is often conducted by object proposal generation and classification sequentially. This paper handles object detection in a superpixel oriented manner instead of the proposal oriented. Specially, this paper takes object detection as a multi-label superpixel labeling problem by minimizing an energy function. It uses the data cost term to capture the appearance, smooth cost term to encode the spatial context and label cost term to favor compact detection. The data cost is learned through a convolutional neural network and the parameters in the labeling model are learned through a structural SVM. Compared with proposal generation and classification based methods, the proposed superpixel labeling method can naturally detect objects missed by proposal generation step and capture the global image context to infer the overlapping objects. The proposed method shows its advantage in Pascal VOC and ImageNet. Notably, it performs better than the ImageNet ILSVRC2014 winner GoogLeNet (45.0% V.S. 43.9% in mAP) with much shallower and fewer CNNs.", "corpus_id": 16843664, "score": 0 }, { "doc_id": "5984060", "title": "Edge Boxes: Locating Object Proposals from Edges", "abstract": "The use of object proposals is an effective recent approach for increasing the computational efficiency of object detection. We propose a novel method for generating object bounding box proposals using edges. Edges provide a sparse yet informative representation of an image. Our main observation is that the number of contours that are wholly contained in a bounding box is indicative of the likelihood of the box containing an object. We propose a simple box objectness score that measures the number of edges that exist in the box minus those that are members of contours that overlap the box’s boundary. Using efficient data structures, millions of candidate boxes can be evaluated in a fraction of a second, returning a ranked set of a few thousand top-scoring proposals. Using standard metrics, we show results that are significantly more accurate than the current state-of-the-art while being faster to compute. In particular, given just 1000 proposals we achieve over 96% object recall at overlap threshold of 0.5 and over 75% recall at the more challenging overlap of 0.7. Our approach runs in 0.25 seconds and we additionally demonstrate a near real-time variant with only minor loss in accuracy.", "corpus_id": 5984060, "score": 0 } ]

{ "doc_id": "15168745", "title": "First Report of Ventriculoperitoneal Shunt Infection due to Cyberlindnera fabianii", "abstract": "Fungal infections in the central nervous system (CNS) are associated with significant morbidity and death. Transient fungemia in immunocompetent patients without any other risk factors for fungemia has been suggested as a possible mechanism that may lead to serious fungal ventriculoperitoneal (VP) shunt infections, but evidence is lacking. The clinical spectrum, diagnosis, and optimal therapy of Cyberlindnera fabianii infections remain to be determined. We describe the first case of CNS infection due to C. fabianii that occurred in an immunocompetent adult with a VP shunt. Spontaneous translocation with yeast that is not part of the normal gastrointestinal flora in the setting of ingestion of multiple servings of a fermentation product was the likely source from which Cyberlindnera fabianii gained entrance into the VP shunt system, causing meningitis in this patient. The authors conclude that, in view of the high morbidity associated with yeast infection of the CNS, long-term antifungal therapy should be strongly considered in cases where the VP shunt cannot be completely removed. Transient fungemia may lead to invasive disease in an immunocompetent host with VP shunt, even in the absence of any other risk factors for fungemia and even after remote placement of the VP shunt.", "corpus_id": 15168745 }

[ { "doc_id": "17262404", "title": "Candida Infections of Medical Devices", "abstract": "SUMMARY The number of indwelling medical devices is escalating, and an increasing proportion of device-related infections are being caused by Candida spp. Candida spp. produce biofilms on synthetic materials, which facilitates adhesion of the organisms to devices and renders them relatively refractory to medical therapy. Management of device-related Candida infections can be challenging. Removal of the infected device is generally needed to establish cure of Candida infections of medical devices. However, since the pathogenesis of Candida bloodstream infection is complicated, more studies are necessary to determine the role of catheter exchange in patients with both gastrointestinal tract mucositis and indwelling catheters. The medical and economic impact of these infections is enormous.", "corpus_id": 17262404, "score": 1 }, { "doc_id": "21794329", "title": "Candidal infections of ventriculoperitoneal shunts", "abstract": "Although ventriculoperitoneal (VP) shunt infection is a common complication of shunt procedures, fungal infection is considered to be rare. In the present study, we performed retrospective analysis of six cases in which candida infection occurred. In all these six cases, VP shunt was performed in children for hydrocephalus and the onset of symptoms varied between seven days to one month after the surgical procedure was performed. The commonest clinical signs and symptoms were fever (100%), vomiting (100%), and altered sensorium (50%). The commonest isolate was Candida albicans (66.66%) followed by Candida parapsilosis and Candida glabrata in one case each. All the patients were successfully treated with Amphotericin B and there was no mortality recorded.", "corpus_id": 21794329, "score": 0 }, { "doc_id": "23587131", "title": "Meningitis caused by Candida species: an emerging problem in neurosurgical patients.", "abstract": "Three cases of candida meningitis were encountered in a 3-year period in our hospital; all occurred in neurosurgical patients. We describe these three cases and review the 15 cases of neurosurgery-related candida meningitis previously reported in the English-language literature. Data regarding these 18 patients formed the basis for our review. Most patients with candida meningitis had recently received antibacterial agents, and it is notable that 50% of patients suffered from antecedent bacterial meningitis. The CSF analysis revealed neutrophilic pleocytosis that was indistinguishable from that of bacterial meningitis. The overall mortality was 11%. Administration of amphotericin B combined with flucytosine appeared to be the best therapeutic approach for candida meningitis.", "corpus_id": 23587131, "score": 1 }, { "doc_id": "37745991", "title": "Candida albicans shunt infection.", "abstract": "Seven cases of successfully treated Candida albicans cerebrospinal fluid shunt infections are reported. Treatment consisted of shunt removal and intravenous Amphotericin B in all cases and intraventricular Amphotericin B in 4 cases. Serious underlying medical illness, recent antibiotic therapy, indwelling intravascular and/or Foley catheters, coincident candidiasis and low birth weight prematurity are major risk factors for candida shunt infection. Candida shunt infection appears to occur by either contamination at the time of shunt placement or by hematogenous dissemination.", "corpus_id": 37745991, "score": 0 }, { "doc_id": "20486529", "title": "Genome Sequence of the Yeast Cyberlindnera fabianii (Hansenula fabianii)", "abstract": "ABSTRACT The yeast Cyberlindnera fabianii is used in wastewater treatment, fermentation of alcoholic beverages, and has caused blood infections. To assist in the accurate identification of this species, and to determine the genetic basis for properties involved in fermentation and water treatment, we sequenced and annotated the genome of C. fabianii (YJS4271).", "corpus_id": 20486529, "score": 0 }, { "doc_id": "21087427", "title": "Phylogenetic relationships among species of Pichia, Issatchenkia and Williopsis determined from multigene sequence analysis, and the proposal of Barnettozyma gen. nov., Lindnera gen. nov. and Wickerhamomyces gen. nov.", "abstract": "Relationships among species assigned to the yeast genera Pichia, Issatchenkia and Williopsis, which are characterized by the ubiquinone CoQ-7 and inability to utilize methanol, were phylogenetically analyzed from nucleotide sequence divergence in the genes coding for large and small subunit rRNAs and for translation elongation factor-1alpha. From this analysis, the species separated into five clades. Species of Issatchenkia are members of the Pichia membranifaciens clade and are proposed for transfer to Pichia. Pichia dryadoides and Pichia quercuum are basal members of the genus Starmera. Williopsis species are dispersed among hat-spored taxa in each of the remaining three clades, which are proposed as the new genera Barnettozyma, Lindnera and Wickerhamomyces. Lineages previously classified as varieties of Pichia kluyveri, 'Issatchenkia'scutulata, Starmera amethionina and 'Williopsis'saturnus are elevated to species rank based on sequence comparisons.", "corpus_id": 21087427, "score": 0 }, { "doc_id": "22698749", "title": "Identification of Candida fabianii as a cause of lethal septicaemia", "abstract": "Infections caused by rare fungal species of low pathogenic potential become increasingly common in hospital settings. The identification of these species presents a major challenge for the clinical mycology laboratory. We describe a case of fatal septicaemia caused by Candida fabianii. The use of common biochemical approaches led to misidentification of the isolate as Candida utilis. Sequencing of the internal transcribed spacer regions (ITS1 and ITS2) allowed unequivocal species identification.", "corpus_id": 22698749, "score": 1 }, { "doc_id": "25476890", "title": "Infection in a neonate caused by Pichia fabianii: importance of molecular identification.", "abstract": "Pichiafabianii, an uncommon yeast species recovered from clinical specimens, was documented as the cause of an infection in a 5-week-old female twin delivered at 25 and 3/7 weeks. She developed respiratory distress syndrome and necrotizing enterocolitis. At the time of the infection, she was febrile, thrombocytopenic, and still was requiring minimal ventilatory support. Blood cultures drawn on two consecutive days were positive for a germ tube negative yeast. Phenotypic methods including carbohydrate fermentations and assimilations (API 20C AUX) did not identify the yeast. Sequencing of D1/D2 domain of the large subunit rDNA was performed in one laboratory and sequencing a subunit of D2 performed in a second laboratory identified the yeast as P. fabianii. The organism was susceptible in vitro to amphotericin B, fluconazole and 5-fluorocytosinc. The patient responded to amphotericin B and removal of her vascular catheter. This case illustrates that there are an increasing number of fungi that may be pathogenic. Phenotypic tests may fail to identify them, emphasizing the need for commercially available, molecular based assays for identification.", "corpus_id": 25476890, "score": 1 }, { "doc_id": "8058702", "title": "Pichia fabianii blood infection in a premature infant in China: case report", "abstract": "BackgroundInvasive fungal infections caused by uncommon fungi have increased in recent years. Hospitalized low-birth-weight infants are at high risk for neonatal fungal infections. Pichia fabianii is a rare pathogen causing blood infection, which has reportedly caused only 4 cases of fungemia and 1 case of endocarditis worldwide. Here, we describe the first case of a P. fabianii blood infection in a premature infant in China.Case presentationOn July 28th, a low-birth-weight (LBW, 1760 g) female infant born at 33+4 weeks of gestation was admitted to the pediatric intensive care unit with mild neonatal asphyxia. Until August 2nd, a mechanical respirator was used to assist respiration under the Continuous Positive Airway Pressure (CPAP) model. The baby had an increased body temperature and a fever. To prevent infection, Ceftriaxone Sodium (CS) was administered intravenously for three days, after which Cefepime was administered until August 13th. Chest X-rays showed suspected plaque-like shadows in the right lung. Blood cultures twice tested positive for fungal infection caused by Candida pelliculosa (recognized as Pichia fabianii later), which is first mis-identified by commercial kit. Hence, intravenous fluconazole was administered. However, cultures of other body fluids (e.g., urine, feces and sputum) tested negative for fungal infection. Routine tests and biochemistry of cerebrospinal fluid (CSF) were normal. Latex agglutination of Cryptococcus neoformans and fungi cultures in the CSF were also negative. After 14 days of intravenous fluconazole, blood was re-cultured, the result of which was negative. On August 30th, intravenous fluconazole was suspended. On Sep 3rd, the infant left the hospital in good health.ConclusionsThis is the first case of a blood infection caused by P. fabianii in a LBW premature female infant in China. Risk factors for fungal infection include premature birth, as well as mechanical invasive operation and antibacterial drug usage. Whether such risk factors necessitate prophylactic use of antifungal drugs is an important question that has yet to be fully addressed. Additionally, the pathogen P. fabianii collected in this study was resistant to amphotericin B (AMB) and itraconazole (ITR). With the exception of the azole-resistant endocarditis case, all other cases have not demonstrated such a resistance. Finally, commercial biochemical methods used in routine practice are limited in their ability to identify P. fabianii. Molecular genetic based methods are imperative for identification of uncommon fungal species from disseminated infections.", "corpus_id": 8058702, "score": 1 }, { "doc_id": "39667846", "title": "Lindnera (Pichia) fabianii blood infection after mesenteric ischemia.", "abstract": "Lindnera (Pichia) fabianii (teleomorph of Candida fabianii) is a yeast species rarely involved in human infections. This report describes the first known human case of a Lindnera fabianii blood infection after mesenteric ischemia. The 53-year-old patient was hospitalized in the intensive care unit after a suicide attempt and was suffering from a mesenteric ischemia and acute renal failure. Lindnera fabianii was recovered from an oropharyngeal swab, then isolated from stool and urine samples before the diagnosis of the blood infection. Caspofungin intravenous treatment was associated with a successful outcome. Final unequivocal identification of the strain was done by sequencing the internal transcribed spacer (ITS) region, and regions of 18S rDNA gene and of the translation elongation factor-1α gene. Until our work, the genomic databases did not contain the complete ITS region of L. fabianii as a single nucleotide sequence (encompassing ITS1, the 5.8S rDNA and ITS2), and misidentification with other yeast species, e.g., Lindnera (Pichia) mississippiensis, could have occurred. Our work demonstrates that the usual DNA barcoding method based on sequencing of the ITS region may fail to provide the correct identification of some taxa, and that partial sequencing of the EF1α gene may be much more effective for the accurate delineation and molecular identification of new emerging opportunistic yeast pathogens.", "corpus_id": 39667846, "score": 1 }, { "doc_id": "25742957", "title": "Catheter-related bloodstream infection by Lindnera fabianii in a neutropenic patient.", "abstract": "Lindnera (Pichia) fabianii (Candida fabianii teleomorph) is a yeast species that is an uncommon cause of invasive human infections. This report describes what we believe to be the first human case of a catheter-related L. fabianii bloodstream infection in a neutropenic patient. The Clinical and Laboratory Standards Institute guidelines do not offer antifungal breakpoints in this neutropenic case and empirical chemotherapy was considered. Sharing our experience, we will discuss the choice of an effective antifungal agent in this uncommon clinical situation.", "corpus_id": 25742957, "score": 1 }, { "doc_id": "53491273", "title": "Cyberlindnera fabianii in the neonatal and paediatric intensive care unit: case reports", "abstract": "Introduction:\nThe number of infections due to uncommon yeast species is gradually increasing worldwide. In cases of high-risk paediatric patients, Cyberlindnera fabianii has been identified as the causal agent in a number of countries. In fact, we have recently reported the first proven occurrence, to the best of our knowledge, of this species as a causal agent of fungaemia in three neonatal patients in a Croatian hospital.\nCase presentation:\nWe report here six new instances of clinically manifested bloodstream and urinary tract infections caused by Cyberlindnera fabianii in five high-risk neonates and one child, during a 5-year period (2008–2012) in the aforementioned Croatian hospital. In addition, we have provided an account of their treatment strategy and the outcome, and the susceptibility profiles of 44 isolates of Cyberlindnera fabianii to amphotericin B, flucytosine, triazoles and echinocandins. Furthermore, we have described a novel molecular method suitable for the rapid and specific diagnosis of this species.\nConclusion:\nOur findings demonstrated: (i) the pathogenic activities of Cyberlindnera fabianii species in high-risk children; (ii) that administering fluconazole either prophylactically or therapeutically yielded no results in 50 % of the patients; (iii) that substituting fluconazole by liposomal amphotericin B or caspofungin managed to resolve sepsis in the remaining 50 % of patients; (iv) that, according to the examined sequences, all of the Cyberlindnera fabianii isolates were found to be identical independent of their source or study period; and (v) the existence of a higher proportion of non-susceptible isolates of Cyberlindnera fabianii for echinocandins (especially micafungin) compared with the other tested antifungals.", "corpus_id": 53491273, "score": 1 }, { "doc_id": "13770385", "title": "Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV‐associated cryptococcal meningitis‐infected patients", "abstract": "Objectives The aim of the present study was to assess fluconazole pharmacokinetic measures in serum and cerebrospinal fluid (CSF); and the correlation of these measures with clinical outcomes of invasive fungal infections.", "corpus_id": 13770385, "score": 0 }, { "doc_id": "1754119", "title": "Comparison of Inhibitory Mold Agar to Sabouraud Dextrose Agar as a Primary Medium for Isolation of Fungi", "abstract": "ABSTRACT Clinical specimens cultured on two selective fungal media, inhibitory mold agar (IMA) and Sabouraud dextrose agar (SDA), were compared with respect to recovery of fungi. Of the 840 fungal isolates recovered, 69.3% grew on both IMA and SDA; 24.9% grew only on IMA; and 5.8% grew only on SDA, showing that IMA is superior (P = 0.003).", "corpus_id": 1754119, "score": 0 }, { "doc_id": "32570917", "title": "Identification of Medically Important Yeast Species by Sequence Analysis of the Internal Transcribed Spacer Regions", "abstract": "ABSTRACT Infections caused by yeasts have increased in previous decades due primarily to the increasing population of immunocompromised patients. In addition, infections caused by less common species such as Pichia, Rhodotorula, Trichosporon, and Saccharomyces spp. have been widely reported. This study extensively evaluated the feasibility of sequence analysis of the rRNA gene internal transcribed spacer (ITS) regions for the identification of yeasts of clinical relevance. Both the ITS1 and ITS2 regions of 373 strains (86 species), including 299 reference strains and 74 clinical isolates, were amplified by PCR and sequenced. The sequences were compared to reference data available at the GenBank database by using BLAST (basic local alignment search tool) to determine if species identification was possible by ITS sequencing. Since the GenBank database currently lacks ITS sequence entries for some yeasts, the ITS sequences of type (or reference) strains of 15 species were submitted to GenBank to facilitate identification of these species. Strains producing discrepant identifications between the conventional methods and ITS sequence analysis were further analyzed by sequencing of the D1-D2 domain of the large-subunit rRNA gene for species clarification. The rates of correct identification by ITS1 and ITS2 sequence analysis were 96.8% (361/373) and 99.7% (372/373), respectively. Of the 373 strains tested, only 1 strain (Rhodotorula glutinis BCRC 20576) could not be identified by ITS2 sequence analysis. In conclusion, identification of medically important yeasts by ITS sequencing, especially using the ITS2 region, is reliable and can be used as an accurate alternative to conventional identification methods.", "corpus_id": 32570917, "score": 0 }, { "doc_id": "39483407", "title": "New Heterothallic species of Hansenula", "abstract": "As the genusHansenula is at present constituted,H. fabianii appears to be the first species of its phylogenetic line to have become independent of trees and bark beetles. It is also the last species of its line to occur in nature with the haploid, or basic, number of chromosomes. So near is it to the diploid level of evolution that a sporulation medium rich in malt extract favors the development of diploid vegetative cells in the period between conjugation of opposite sexes and the onset of sporulation. The diploid form is easily isolated from the mixture and, as long as sporulation is prevented, may be kept in pure state. Media that favor vegetative development of the species favor its occurrence as haploid vegetative cell.H. fabianii is most closely related toHansenula subpelliculosa Bedford, which occurs in nature as the diploid form. Both species have been isolated almost exclusively as contaminants of fermentations, and both have been used industrially in Oriental fermentations to make alcoholic beverages or foods.", "corpus_id": 39483407, "score": 0 }, { "doc_id": "43009024", "title": "Evaluation of sporulation media for yeasts obtained from pathological material.", "abstract": "Summary\nNon-pathogenic perfect yeasts isolated from clinical material are sometimes erroneously identified as species of imperfect genera, such as Candida, because sporulation studies have not been made. Such misidentified isolates may be regarded as pathogens.\nThe sporulation characteristics of two haploid mating strains of Hansenula anomala and three homothallic strains of Saccharomyces cerevisiae of indifferent sporing quality were examined, by comparing clonally related isolates derived from single vegetative cells, or from ascospores. The haploid strains produced spores only after mating. The media tested were sodium acetate agar, Gorodkowa agar, and V8 agar, and two temperatures of incubation, 23°C and 30°C, were used.\nAll subcultures of S. cerevisiae spored within 25 days on sodium acetate agar, and sporing occurred more rapidly at 23°C; 67 per cent. spored at 5 days. Subcultures of H. anomala spored within 3 days. This medium is therefore recommended for use in diagnostic laboratories in the investigation of yeast isolates that cannot be identified readily as to genus or species.", "corpus_id": 43009024, "score": 0 }, { "doc_id": "206787886", "title": "Evaluation of a Short, On-Plate Formic Acid Extraction Method for Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry-Based Identification of Clinically Relevant Yeast Isolates", "abstract": "ABSTRACT This report describes a short, on-plate formic acid (FA) extraction method for the identification of clinical yeast isolates using matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI-TOF MS). A total of 41.1% (78/190) and 63.7% (121/190) of yeasts were identified using species log score thresholds of >2.0 and >1.9, respectively. Overall, 97.4% (185/190) of yeasts were identified in combination with conventional FA extraction.", "corpus_id": 206787886, "score": 0 }, { "doc_id": "16191628", "title": "Pichia anomala (Candida pelliculosa) Fungemia in a Patient with Sickle Cell Disease", "abstract": "This case report discusses a patient with sickle cell disease who presented with fungemia from Pichia anomala (teleomorph: Candida pelliculosa). The organism was identified as P. anomala by MALDI-TOF VITEK mass spectrometry and VITEK 2 yeast identification card. Pichia anomala should be considered in sickle cell patients with recurrent fungemia.", "corpus_id": 16191628, "score": 0 }, { "doc_id": "31209641", "title": "Fermentation characteristics of yeasts isolated from traditionally fermented masau (Ziziphus mauritiana) fruits.", "abstract": "Yeast strains were characterized to select potential starter cultures for the production of masau fermented beverages. The yeast species originally isolated from Ziziphus mauritiana (masau) fruits and their traditionally fermented fruit pulp in Zimbabwe were examined for their ability to ferment glucose and fructose using standard broth under aerated and non-aerated conditions. Most Saccharomyces cerevisiae strains were superior to other species in ethanol production. The best ethanol producing S. cerevisiae strains, and strains of the species Pichia kudriavzevii, Pichia fabianii and Saccharomycopsis fibuligera were tested for production of flavor compounds during fermentation of masau fruit juice. Significant differences in the production of ethanol and other volatile compounds during fermentation of masau juice were observed among and within the four tested species. Alcohols and esters were the major volatiles detected in the fermented juice. Trace amounts of organic acids and carbonyl compounds were detected. Ethyl hexanoate and ethyl octanoate were produced in highest amounts as compared to the other volatile compounds. S. cerevisiae strains produced higher amounts of ethanol and flavor compounds as compared to the other species, especially fatty acid ethyl esters that provide the major aroma impact of freshly fermented wines. The developed library of characteristics can help in the design of mixtures of strains to obtain a specific melange of product functionalities.", "corpus_id": 31209641, "score": 0 }, { "doc_id": "35234359", "title": "Molecular identification of yeast species associated with 'Hamei'--a traditional starter used for rice wine production in Manipur, India.", "abstract": "In Manipur state of North-Eastern India, wine from glutinous rice using traditional solid state starter called 'Hamei' is particularly interesting because of its unique flavour. A total of 163 yeast isolates were obtained from fifty four 'Hamei' samples collected from household rice wine preparations in tribal villages of Manipur. Molecular identification of yeast species was carried out by analysis of the restriction digestion pattern generated from PCR amplified internal transcribed spacer region along with 5.8S rRNA gene (ITS1-5.8S-ITS2). Seventeen different restriction profiles were obtained from the size of PCR products and the restriction analysis with three endonucleases (Hae III, Cfo I and Hinf I). Nine groups were identified as S. cerevisiae, Pichia anomala, Trichosporon sp., Candida tropicalis, Pichia guilliermondi, Candida parapsilosis, Torulaspora delbrueckii, Pichia fabianii and Candida montana by comparing this ITS-RFLP profile with type strains of common wine yeasts, published data and insilico analysis of ITS sequence data available in CBS yeast database. ITS-RFLP profile of eight groups was not matching with available database of 288 common wine yeast species. The most frequent yeast species associated with 'Hamei' were S. cerevisiae (32.5%), P. anomala (41.7%) and Trichosporon sp. (8%). The identity of major groups was confirmed by additional restriction digestion of ITS region with Hind III, EcoRI, Dde I and Msp I. The genetic diversity of industrially important S. cerevisiae group was investigated using Pulsed Field Gel Electrophoresis (PFGE). Although most of the 53 strains of S. cerevisiae examined were exhibited a common species specific pattern, a distinct degree of chromosomal length polymorphism and variable number of chromosomal DNA fragments were observed with in the species. Cluster analysis showed seven major karyotypes (K1-K7) with more than 83% similarity. The karyotype pattern K1 was the most frequent (67.9%) among the strains from different samples. Other karyotypes K2-K7 were very unique with less than 80% similarity. Finally using mitochondrial DNA restriction analysis (mt-DNA RFLP), S. cerevisiae strains belonging to the major karyotype K1 were distinctly differentiated with highly polymorphic bands by Hinf I and Hae III endonucleases.", "corpus_id": 35234359, "score": 0 }, { "doc_id": "3797351", "title": "Saccharomyces cerevisiae fungemia: an emerging infectious disease.", "abstract": "BACKGROUND\nSaccharomyces cerevisiae is well known in the baking and brewing industry and is also used as a probiotic in humans. However, it is a very uncommon cause of infection in humans.\n\n\nMETHODS\nDuring the period of 15-30 April 2003, we found 3 patients with S. cerevisiae fungemia in an intensive care unit (ICU). An epidemiological study was performed, and the medical records for all patients who were in the unit during the second half of April were assessed.\n\n\nRESULTS\nThe only identified risk factor for S. cerevisiae infection was treatment with a probiotic containing Saccharomyces boulardii (Ultralevura; Bristol-Myers Squibb). This probiotic is used in Europe for the treatment and prevention of Clostridium difficile-associated diarrhea. The 3 patients received the product via nasograstric tube for a mean duration of 8.5 days before the culture result was positive, whereas only 2 of 41 control subjects had received it. Surveillance cultures for the control patients admitted at the same time did not reveal any carriers of the yeast. Strains from the probiotic capsules and the clinical isolates were identified as S. cerevisiae, with identical DNA fingerprinting. Discontinuation of use of the product in the unit stopped the outbreak of infection. A review of the literature identified another 57 cases of S. cerevisiae fungemia. Overall, 60% of these patients were in the ICU, and 71% were receiving enteral or parenteral nutrition. Use of probiotics was detected in 26 patients, and 17 patients died.\n\n\nCONCLUSIONS\nUse of S. cerevisiae probiotics should be carefully reassessed, particularly in immunosuppressed or critically ill patients.", "corpus_id": 3797351, "score": 0 }, { "doc_id": "3958886", "title": "Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.", "abstract": "Guidelines for the management of patients with invasive candidiasis and mucosal candidiasis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections. Since 2004, several new antifungal agents have become available, and several new studies have been published relating to the treatment of candidemia, other forms of invasive candidiasis, and mucosal disease, including oropharyngeal and esophageal candidiasis. There are also recent prospective data on the prevention of invasive candidiasis in high-risk neonates and adults and on the empiric treatment of suspected invasive candidiasis in adults. This new information is incorporated into this revised document.", "corpus_id": 3958886, "score": 0 }, { "doc_id": "35809773", "title": "Candida infection of the central nervous system following neurosurgery: a 12-year review", "abstract": "BackgroundCandida infection of the central nervous system (CNS) following neurosurgery is relatively unusual but is associated with significant morbidity and mortality. We present our experience with this infection in adults and discuss clinical characteristics, treatment options, and outcome.MethodsAll episodes of Candida isolated from the central nervous system were identified by searching our laboratory database. Review of the cases was performed by means of a retrospective chart review.ResultsEleven episodes of Candida CSF infection following neurosurgery were identified over a 12-year period. Candida albicans was the predominant species isolated (n = 8, 73%). All infections were associated with foreign intracranial material, nine with external ventricular drains (82%), one with a ventriculoperitoneal shunt, one with a lumbar drain, and one with Gliadel wafers (1,3-bis [2-chloroethyl]-1-nitrosurea). Fluconazole or liposomal amphotericin B were the most common anti-fungal agents used. The mortality rate identified in our series was 27%.ConclusionsCandida infection following neurosurgery remains a relatively rare occurrence but one that causes significant mortality. These are complex infections, the management of which benefits from a close liaison between the clinical microbiologist and neurosurgeon. Prompt initiation of antifungal agents and removal of infected devices offers the best hope of a cure.", "corpus_id": 35809773, "score": 0 }, { "doc_id": "25189146", "title": "Cryptococcal ventriculoperitoneal shunt infection", "abstract": "The standard treatment of hydrocephalus is placement of a ventriculoperitoneal (VP) shunt. While infection is a common complication, rarely are fungal organisms implicated. Cryptococcus neoformans has been reported in only nine cases of shunt infection to our knowledge. The timing from shunt placement to symptom onset varies widely from 10 days to 15 months. We present a patient who developed a cryptococcal infection of his VP shunt more than two decades following shunt placement.", "corpus_id": 25189146, "score": 0 } ]

{ "doc_id": "30014827", "title": "Dermoid Cyst of the Parotid Gland: Report of a Rare Entity with Literature Review", "abstract": "Dermoid cysts (DCs)are benign lesions and histologically composed of tissues originating from ectoderm and mesoderm, but not endoderm. Approximately 7 % of all DCs are seen in head and neck area. However, parotid gland is an extremely rare localization in which DCs develop, and only 17 cases have been reported in the literature to date. Correct preoperative diagnosis is difficult to be established due to the rarity and ambiguous radiological findings. We report a case of a 21-year old man. All previous reports reviewed and the pathogenesis as well as the histopathologic and radiologic features are discussed.", "corpus_id": 30014827 }

[ { "doc_id": "41756927", "title": "Dermoid Cyst of the Lateral Neck: A Case Report and Literature Review", "abstract": "Dermoid cysts of the lateral neck are rare, with the majority of head and neck dermoids occurring in the midline. The demonstration of a fat-fluid level on MRI or CT is diagnostic for a cervical dermoid cyst. The treatment of choice remains surgical excision.", "corpus_id": 41756927, "score": 0 }, { "doc_id": "23852095", "title": "An unusual presentation of neck dermoid cyst", "abstract": "Congenital masses are the most common non-inflammatory neck lesions in children. Although usually present at birth, they can appear at any age. Dermoid cysts are benign lesions of congenital origin usually presenting as a midline neck mass. They rarely appear in the lateral region of the neck. Lateral cervical dermoid cyst is presented as a rare, unusual case, and differential diagnosis and management are discussed in light of recent literature.", "corpus_id": 23852095, "score": 0 }, { "doc_id": "45136251", "title": "Nasal Dermoid Sinus Cysts in Children", "abstract": "Thirty‐six children with nasal dermoid sinus cysts were treated in the Department Pediatric Otolaryngology, Armand Trousseau's Children's Hospital (Paris, France) between 1974 and 1994. Ten of the patients presented with a midline cyst only, eight had nasal pits only, and 18 had combined cases. In six of the 36 patients, presurgical imagery indicated signs of intracranial extension of the tract, reaching the foramen caecum without intracranial mass. Three surgical techniques were used: an external rhinoplasty approach with medial crura section in 23 cases, a direct median approach in seven cases, and a paracanthal approach in six cases. Only two cases had meningeal adherences. Two superficial recurrences occurred within the 7‐year follow‐up period. Widening of the scar occurred in four children after verticomedian approach or nasal pit excision. The external rhinoplasty procedure with medial crura section results in a wide surgical approach, low recurrence rate, and good aesthetic results.", "corpus_id": 45136251, "score": 0 }, { "doc_id": "7307382", "title": "Cysts of the parotid gland. Review and report of two unusual cases.", "abstract": "Cysts of the major salivary glands are most frequent in the parotid where they form a small percentage of its benign tumours. They can be congenital or acquired and of parotid or extraparotid origin. Two unusual cysts are reported: a cholesteatoma arising from the ipsilateral mastoid, twenty years after successful radical mastoidectomy, and a deeply located cysts of probably congenital origin. The literature is reviewed and the management discussed. Parotidectomy, often with extensive dissection, remains in general the treatment of choice.", "corpus_id": 7307382, "score": 0 }, { "doc_id": "42500442", "title": "[Dermoid cyst of the parotid gland].", "abstract": "Dermoid cyst of the parotid gland is a rare clinical entity. Definitive clinical diagnosis is often difficult to determine preoperatively because of the lack of pathognomonic features. The most frequent location of a parotid dermoid cyst is a triangular area lying above the pinna. Imaging studies do not definitely diagnose a parotid dermoid cyst. Although parotid dermoid cyst is (generally) well-encapsulated, complete removal of the cyst wall is not sufficient to cure it, so it is mandatory to perform careful excision of the cyst by parotidectomy, in terms of preserving facial nerve integrity. Histopathology of the parotid gland tumor removed by parotidectomy makes a diagnosis of certainty, by revealing a cyst wall with keratinization of the squamous epithelium and the presence of skin annexes (hair follicles, sweat glands, sebaceous glands). We present a rare case of parotid dermoid cyst in a 21-year-old male patient with symptoms and imaging rather suggestive of arch I branchial cyst and a brief review of data in the medical literature of the last 20 years.", "corpus_id": 42500442, "score": 1 }, { "doc_id": "40420561", "title": "Fine‐needle aspiration cytological features of dermoid cyst of the parotid gland: A report of two cases", "abstract": "We describe the cytological features of dermoid cyst of the parotid gland and the value of preoperative diagnosis by fine‐needle aspiration (FNA) cytological evaluation. Both patients had painless parotid masses. On physical examination, a freely movable parotid mass was found in each case. CT scan showed a cystic mass in the parotid gland in each patient. FNA in both cases showed anucleated and nucleated squamous epithelium and keratin debris. The clinical features and cytological findings in each case were interpreted as suggestive of a dermoid cyst. Histological examination of surgical specimens confirmed the presence of a dermoid cyst of the parotid gland in each case. FNA is a reliable method for preoperative diagnosis and permits selection of an appropriate form of surgical procedure for dermoid cyst of the parotid gland. Diagn. Cytopathol. 1999;20:387–388. © 1999 Wiley‐Liss, Inc.", "corpus_id": 40420561, "score": 1 }, { "doc_id": "12657218", "title": "Dermoid cyst of the parotid gland--a case report and brief review of the literature.", "abstract": "There is controversy over the frequency of dermoid cysts in the head and neck area. Some authors report that they are common, whereas others say that only 7% of such cysts occur in the head and neck area. In either case, they are extremely rare in the parotid gland. When PubMed is searched for 'dermoid cyst of the parotid gland', only 11 articles are listed. Only four of the articles written in English are case reports of dermoid cysts of the parotid gland. Due to the rarity of descriptions and the considerable diversity of swellings of the parotid gland diagnosis is difficult. Visualizing options like computed tomography, magnetic resonance imaging and ultrasound cannot give a conclusive preoperative diagnosis. This case report shows the challenges in diagnosis and gives a short review of the literature.", "corpus_id": 12657218, "score": 1 }, { "doc_id": "76808419", "title": "Dermoid Cyst of the Parotid Gland-A Case Report", "abstract": "Dermoid cysts in the head and neck area account for 7% of all dermoid cysts, with their predominant sites being orbital, oral and nasal regions (80% )rarity of the parotid dermoid cyst and diversity of parotid swellings, corect preoperative diagnosis is dificult. Imaging studies such as computed tomography, ultrasonography and magnetic resonance were inconclusive. Fine needle aspiration biopsy may be helpful. In this article, we report a case of parotid dermoid cyst with literature reviews. (Korean J Otorhinolaryngol-Head ;51 :105-7)", "corpus_id": 76808419, "score": 1 }, { "doc_id": "30465514", "title": "Parotid dermoid cyst: a rare entity", "abstract": "Abstract Objective: We report a rare case of parotid dermoid cyst. Method: A case report of parotid dermoid cyst is presented, as well as a brief review of the literature and a summary of the lesion's salient clinicopathological features. Results: A 69-year-old man presented with a slow-growing, soft tissue mass of the left parotid gland. Pre-operative evaluation included fine needle aspiration cytology and computed tomography. He subsequently underwent a superficial lobectomy; both the macroscopic and histopathological findings were consistent with a dermoid cyst. Although dermoids within the head and neck are not uncommon, such cysts have only rarely been encountered in the parotid gland. Conclusion: To our knowledge, there are only four previous case reports of parotid dermoid cyst in the English literature. Although the majority of cases of parotid dermoid cyst are diagnosed retrospectively, our case demonstrates the role of fine needle aspiration cytology and highlights the key cytological features suggestive of this entity.", "corpus_id": 30465514, "score": 1 }, { "doc_id": "42998247", "title": "A mass at fat density in the parotid gland: dermoid cyst or lipoma.", "abstract": "A mass at fat density in the parotid gland: dermoid cyst or lipoma. Dermoid cysts (DC) of the head and neck are uncommon and account for only 7% of all dermoid cysts in the body. DCs of the parotid gland are even rarer. In this article, a 42-year-old female patient with DC of the parotid gland is presented and discussed with a brief review of the literature. Radiologic findings suggested that the mass was a lipoma, but observation of a hair in the cyst during surgery changed the clinical diagnosis to DC; this suspicion was confirmed by pathological analysis. Although DCs are rare among the parotid masses, they should be kept in mind during the differential diagnosis.", "corpus_id": 42998247, "score": 0 }, { "doc_id": "20137816", "title": "Dermoid cyst of the parotid gland", "abstract": "A35-year-old man presented with a five-year history of a slowly enlarging soft tissue mass in the right parotid gland. Physical examination showed a soft, non-tender mass, 4 3 cm in diameter, in the superior portion of the parotid gland. Facial nerve function was normal. Fine-needle aspiration cytology revealed anucleated squamous cells and keratin debris (Fig 1). CT scans showed a cystic mass of the superficial lobe extending to the deep lobe of the right parotid gland (Fig 2). A right parotidectomy was performed and the cystic mass was excised completely. Surgical specimen revealed a cystic mass filled with keratinous material. Pathologic examination revealed a cyst lined by stratified squamous epithelium with underlying sebaceous glands, which was diagnostic of dermoid cyst. Postoperative course was uneventful with normal facial nerve function. The patient was followed-up without recurrence for one year. This report was approved by an institutional review board.", "corpus_id": 20137816, "score": 0 }, { "doc_id": "205340705", "title": "Dermoid cyst of the parotid gland: first pediatric case.", "abstract": "A dermoid cyst is the result of inclusion of epithelial cells along the lines of embryonic closure. Dermoid cysts of the head neck are uncommon and account for only 7% of all such cysts. They are most often reported as arising in the floor of the mouth. Dermoid cyst is rarely seen in the parotid gland. To our knowledge, there have been only six previous case reports in the English literature. Dermoid cyst of the parotid gland in pediatric patient has not been previously reported in the literature. This is the first case report concerning a dermoid cyst in a pediatric patient.", "corpus_id": 205340705, "score": 1 }, { "doc_id": "42838970", "title": "Dermoid cyst of the parotid gland.", "abstract": "A dermoid cyst occurring within the parotid gland of a 37-year-old Chinese man is reported. The diagnostic difficulties, histopathological features and pathogenesis are considered.", "corpus_id": 42838970, "score": 0 }, { "doc_id": "11960032", "title": "Dermoid cyst of the parotid gland", "abstract": "Dermoid cysts of the head and neck are uncommon and account for only 7 % of all such cysts. They are most often reported to arise in the floor of the mouth and orbital and nasal regions; they are rarely seen in the parotid gland. To our knowledge, there have been only nine previous case reports in the literature. The authors report a case of a dermoid cyst with a left parotid location and discuss its nature, diagnosis, and treatment. The previous reports are reviewed and commented upon.", "corpus_id": 11960032, "score": 1 }, { "doc_id": "34890276", "title": "Dermoid cysts of the nose.", "abstract": "Dermoid cysts of the nose may present difficult management problems if inadequately evaluated preoperatively or if incompletely excised. It is most important to differentiate them from nasal gliomas, neurofibromas, encephalocoeles, or meningiocoeles. Confusion with other benign lesions such as sebaceous cysts, mucocoeles, inclusion cysts, hemangiomas, or lipomas is possible but of less consequence. Incompletely excised cysts recur and the final result is usually less acceptable than that following total excision. The use of an operating microscope and microsurgical instruments is strongly advocated.", "corpus_id": 34890276, "score": 0 }, { "doc_id": "79459344", "title": "Dermoid cysts of the head and neck", "abstract": "*국군수도병원 병리과 * Department of Pathology, Capital Armed Forces Ceneral Hospital 이 논문은 1987 년 1 2 월 30 일 접수하여 1988년 2월 8 일에 채택되었음. 하였다. 타액선조영술상 이하선 내에 분엽형 음영결손이 보였 고 이히선관의 분리 및 외측이동이 있었지만 이하선관이 불규 칙하게 좁아지거냐 끊어진 소견은 없었다(Fig.lA) . 초음파 검사상 둥글고 경계가 비교적 뚜렷한 종괴 안에 불균질의 내부에코를 보였으며 변연부 일부에서 저 에코를 관찰할 수 있었다(Fig.lB ) . 전산화단층촬영상 지방밀도의 종 괴가 이하선의 심엽에 있었고 주위 조직과 경계가 뚜렷 했으며 변연부 조영증강은 보이지 않았다 (Fig.1C). 수술소견상 3X4X3 cm 크기의 피냥형성이 잘 된종괴 가 이하선 심엽에 있었고 천엽( superf icia l lobe)을 전 방 및 외측ξ로 밀연서 일부 유착되어 있었다. 병리조직 소견상 단엽성 냥종 ( unilocular cys t) ~로 치즈같은피 지가 차 있었고 낭종의 내벽은 중층상피세포로 이루어 졌으며 그 하부에 많은 모냥과 피지선이 관찰되었다 (Fig. 1 D & E). 2 . 22 세 남자 환자로 우측 이개하$써1 4x4 cm 크 기의 약간 딱딱하고 고정되어 있S며 경계가 불규칙한 우통성 종괴를 주소로 내원하였다. 2 년전 영지손룹 크 기의 종괴가 처음 촉지되어 서서히 커졌으며 내원 8 개 윌전 종괴절제술을 받았으나 재발하였다. 초음파검사상 둥근 종괴로 비교적 경계가 명확했고 내부에는 불균등", "corpus_id": 79459344, "score": 0 }, { "doc_id": "24392508", "title": "Teratomas, dermoids, and epidermoids of the head and neck.", "abstract": "Dermoids and epidermoids are ectoderm-lined inclusion cysts that differ in complexity: Epidermoids have only squamous epithelium; dermoids contain hair, sebaceous and sweat glands, and squamous epithelium. Both arise from trapped pouches of ectoderm, near normal folds, or from failure of surface ectoderm to separate from the neural tube. These slowly expanding, unilocular, cystic masses may produce only mild symptoms. They commonly occur in the orbit, calvarial diploic space, and intracranially (the posterior and middle fossae). They may be complicated by rupture leading to chemical meningitis, and dermoids with a fistulous tract can become infected. Craniofacial teratomas are true neoplasms arising from misplaced embryologic germ cells. They contain a medley of heterogeneous tissues, typically reflecting more than one of the three embryonic germ layers. They are usually multiloculated masses, often large, with complex radiologic characteristics. Craniofacial teratomas may manifest prenatally with macrocrania or polyhydramnios, during a difficult delivery, or postnatally as a life-threatening mass causing brain herniation, hydrocephalus, respiratory distress, or feeding difficulty. In infancy, they can be biologically benign, even when their histologic characteristics are immature. Surgery is the treatment of choice for all three masses and may be curative.", "corpus_id": 24392508, "score": 0 }, { "doc_id": "71677593", "title": "Midline Dermoid Tumors of the Neck", "abstract": "Although the midline dermoid tumor of the neck is supposed to be extremely rare in comparison with thyroglossal duct cyst, 13 patients were treated during a period when 45 thyroglossal duct cysts were seen. It is important to check the thyroid gland and to open the cyst for diagnosis before deciding on the matter of hyoid bone resection.", "corpus_id": 71677593, "score": 0 }, { "doc_id": "19569561", "title": "Teratomas of the head and neck.", "abstract": "Teratomas of the head and neck are a particular type of developmental malformation or tumor that are composed of cells with a full range of histogenic potential. They occur almost exclusively in the newborn and infancy periods. Treatment is directed at complete surgical removal with preservation of normal anatomic structures.", "corpus_id": 19569561, "score": 0 }, { "doc_id": "34008822", "title": "[Submandibular dermoid cyst extended to the cervical region].", "abstract": "INTRODUCTION\nDermoid cysts of the submandibular region are rare. We report an exceptional case with extension to the neck.\n\n\nOBSERVATION\nThe patient presented with a voluminous left submandibular cystic tumor with extension to the neck and to floor of the mouth. Ultrasonography and CT scan contributed to the diagnosis and to chose the best surgical approach in case of large cyst. In our case, the tumor was removed using a double cervical and intraoral approach. Histopathological examination confirmed a dermoid cyst.\n\n\nDISCUSSION\nWe report an exceptional case of dermoid cyst originating from submandibular region. A double surgical approach was necessary for tumor resection. Tumor removal must be complete; the submandibular gland may be removed if necessary.", "corpus_id": 34008822, "score": 0 }, { "doc_id": "27004550", "title": "An alternative surgical approach for sublingual dermoid cysts: a case report.", "abstract": "A 52-year-old woman presented with a painless swelling in the floor of the mouth. She stated that it had existed there for 40 years and had undergone a gradual enlargement within the past year. Examination showed a mass, 5x4 cm in size. An aspiration from the lesion revealed a cyst. The lesion was removed by a U-shaped superior based flap. Histopathological examination showed stratified squamous epithelium lining the cystic lumen. This technique can be an alternative approach in such lesions because it protects the oral mucosa by providing good exposure, and prevents injury to the lingual nerve and submandibular duct.", "corpus_id": 27004550, "score": 0 }, { "doc_id": "13021680", "title": "Parotid masses in patients with previous ear surgery.", "abstract": "This paper describes three cases of patients presenting with lumps in their parotid gland, the origin of which was difficult to define. In each case the past medical history revealed that the patients had undergone previous ipsilateral middle ear surgery. We highlight the fact that where there has been previous incisions in the skin about the ear, there is a risk of epidermal inclusion cysts in the parotid gland. These cysts can occur many years after the initial surgery and therefore may not be identified as an obvious origin to lumps in the parotid gland. Rarely as this series highlights there may also be extension of a cholesteatoma (a collection of keratin which arises from the eardrum and extends into the middle ear space) from the mastoid bone to the parotid gland. We recommend formal ear examination where there is a history of previous ear surgery and an ipsilateral parotid gland lump is present.", "corpus_id": 13021680, "score": 0 }, { "doc_id": "21039929", "title": "An epidermal cyst in the parotid gland following ear surgery: a case report.", "abstract": "PROBLEM/OBJECTIVE\nIatrogenic epidermal cysts have been reported in various locations following otological surgical procedures. Especially after endaural incisions, surgeons may implant squamous epithelium into underlying tissue. An epidermal cyst of the parotid region may appear years after ipsilateral ear surgery.\n\n\nMETHODOLOGY\nA cystic lesion in the superficial lobe of the parotid gland was identified by computed tomography and ultrasonography in a 30-year-old man with a history of myringoplasty and endaural surgery. A superficial parotidectomy was performed to remove the mass.\n\n\nRESULTS\nThe mass was histopathologically diagnosed as an epidermal cyst.\n\n\nCONCLUSION\nIf a cystic lesion is present in the parotid gland in a patient with a history of otologic surgery, it must be considered that the mass is of epidermal origin.", "corpus_id": 21039929, "score": 0 }, { "doc_id": "116085003", "title": "[Epidermal cyst of the parotid gland].", "abstract": "Epidermoid cysts of the parotid gland are rare. We report the case of a 60-year-old man with a cystic tumor of the right parotid gland. The patient had undergone ipsilateral middle ear surgery twice four years previously. The tumor was identified by computed tomography and ultrasonography and removed by total parotidectomy under suspicion of a parotid tumor. Histopathology revealed the diagnosis of an epidermal cyst. The differential diagnosis of a parotid tumor should include (iatrogenic) epidermoid cyst, in particular if there is a history of prior ear surgery via an endaural approach.", "corpus_id": 116085003, "score": 0 }, { "doc_id": "33047012", "title": "Ultrasonographic appearance of dermoid and epidermoid cysts in the head and neck", "abstract": "The ultrasonographic features of 6 histologically proven dermoid and epidermoid cysts in the head and neck are reported. All 6 cysts had internal echoes, with a solid appearance. Five of the 6 were echogenic, with only slight or no posterior echo enhancement. Amorphous keratinous debris from keratinizing stratified squamous epithelium filled the lumen of each cyst, producing the internal echoes. Most of the true solid tumors examined were generally of lower echogenicity, and could be differentiated from dermoid and epidermoid cysts ultrasonographically, although lipomas were indistinguishable from these cysts.", "corpus_id": 33047012, "score": 0 }, { "doc_id": "44495287", "title": "Ovarian teratomas: tumor types and imaging characteristics.", "abstract": "Ovarian teratomas include mature cystic teratomas (dermoid cysts), immature teratomas, and monodermal teratomas (eg, struma ovarii, carcinoid tumors, neural tumors). Most mature cystic teratomas can be diagnosed at ultrasonography (US) but may have a variety of appearances, characterized by echogenic sebaceous material and calcification. At computed tomography (CT), fat attenuation within a cyst is diagnostic. At magnetic resonance (MR) imaging, the sebaceous component is specifically identified with fat-saturation techniques. The US appearances of immature teratoma are nonspecific, although the tumors are typically heterogeneous, partially solid lesions, usually with scattered calcifications. At CT and MR imaging, immature teratomas characteristically have a large, irregular solid component containing coarse calcifications. Small foci of fat help identify these tumors. The US features of struma ovarii are also nonspecific, but a heterogeneous, predominantly solid mass may be seen. On T1- and T2-weighted images, the cystic spaces demonstrate both high and low signal intensity. Familiarity with the US, CT, and MR imaging features of ovarian teratomas can aid in differentiation and diagnosis.", "corpus_id": 44495287, "score": 0 }, { "doc_id": "34202639", "title": "Diagnosis of dermoid cyst of the floor of the mouth by fine‐needle aspiration cytology: A case report", "abstract": "A case of a dermoid cyst in the floor of the mouth in a 17‐yr‐old male is described. The diagnosis was made by fine‐needle aspiration cytology and supported by histologic examination of the subsequently excised tissue. Dermoid cysts are benign lesions that can occur in the floor of the mouth. This case is presented to increase awareness of this entity and its occurrence in this location, and to demonstrate the feasibility of diagnosis by fine‐needle aspiration. The cytologic and histologic features of dermoid cysts are described and discussed. Diagn. Cytopathol. 1999; 20:78–81. © 1999 Wiley‐Liss, Inc.", "corpus_id": 34202639, "score": 0 }, { "doc_id": "23899934", "title": "The place of fine‐needle aspiration in the preoperative diagnosis of the congenital sublingual teratoid cyst", "abstract": "The term “teratoid cyst” was first used by Meyer in his classification of dysontogenetic cysts of the cervicofacial region, which was based on the type of germinative layers included in the cyst wall. Sublingual location of a dermoid cyst is not common, with an incidence of 1.6%. The teratoid cyst is the least common, accounting for 1.8% of sublingual dermoid cysts, and such lesions are extremely rare in infancy. In our case, a 7‐mo‐old male infant was referred with a sublingual mass. Ultrasonography yielded a cystic mass with internal echoes but no specific diagnosis. The smears obtained from fine‐needle aspiration (FNA) displayed sheets of large, benign‐appearing, anucleated and nucleated squamous cells. There were a number of neutrophils, which had no significant importance. No atypical cells were observed. According to the clinical picture and FNA findings, it appeared to be a cystic structure of keratogenous origin and could have been any type of dermoid cyst. The cyst was excised completely by the oral approach. On histopathological examination, the presence of skin appendages along with mature cartilage and respiratory epithelium confirmed the final diagnosis of a teratoid cyst. In conclusion, although FNA is not comparable with computed tomography (CT) and magnetic resonance imaging (MRI), it might be valuable for the diagnosis of lesions occurring in this anatomical location. It is safe, cost‐effective, and reliable. FNA is not only able to help selecting the most appropriate surgical method, but also be used as a therapeutic modality in some emergencies or during surgery. Diagn. Cytopathol. 2003;29:33–37. © 2003 Wiley‐Liss, Inc.", "corpus_id": 23899934, "score": 0 }, { "doc_id": "3368545", "title": "Dermoid cyst of the floor of the mouth diagnosed by fine needle aspiration cytology: a case report.", "abstract": "BACKGROUND\nDermoid cyst of the floor of the mouth is a rare, benign lesion requiring surgical intervention. To our knowledge, the preoperative diagnosis of this entity by fine needle aspiration (FNA) cytology has not been previously reported in the cytologic literature.\n\n\nCASE\nThe patient presented with a massive swelling of the floor of the mouth that displaced the tongue superiorly. A computed tomographic (CT) scan demonstrated a cystic lesion thought to be consistent with a lymphangioma. FNA was performed without complications and demonstrated numerous anucleated and some nucleated squames consistent with a diagnosis of dermoid cyst. Establishment of the correct diagnosis by FNA enabled the surgeon to proceed with the appropriate operation; that outcome might not have been possible had the erroneous CT diagnosis of lymphangioma been trusted.\n\n\nCONCLUSION\nA preoperative diagnosis of dermoid cyst of the floor of the mouth was established by FNA. In contrast to reports in the older literature, the FNA procedure caused no complications. In patients presenting with lesions of the floor of the mouth, FNA should be the diagnostic procedure of first choice.", "corpus_id": 3368545, "score": 0 } ]

{ "doc_id": "52144666", "title": "Correlation of Synaptic Inputs in the Visual Cortex of Awake, Behaving Mice", "abstract": "The subthreshold mechanisms that underlie neuronal correlations in awake animals are poorly understood. Here, we perform dual whole-cell recordings in the visual cortex (V1) of awake mice to investigate membrane potential (Vm) correlations between upper-layer sensory neurons. We find that the membrane potentials of neighboring neurons display large, correlated fluctuations during quiet wakefulness, including pairs of cells with disparate tuning properties. These fluctuations are driven by correlated barrages of excitation followed closely by inhibition (∼5-ms lag). During visual stimulation, low-frequency activity is diminished, and coherent high-frequency oscillations appear, even for non-preferred stimuli. These oscillations are generated by alternating excitatory and inhibitory inputs at a similar lag. The temporal sequence of depolarization for pairs of neurons is conserved during both spontaneous- and visually-evoked activity, suggesting a stereotyped flow of activation that may function to produce temporally precise \"windows of opportunity\" for additional synaptic inputs.", "corpus_id": 52144666 }

[ { "doc_id": "2723062", "title": "Neural correlations, population coding and computation", "abstract": "How the brain encodes information in population activity, and how it combines and manipulates that activity as it carries out computations, are questions that lie at the heart of systems neuroscience. During the past decade, with the advent of multi-electrode recording and improved theoretical models, these questions have begun to yield answers. However, a complete understanding of neuronal variability, and, in particular, how it affects population codes, is missing. This is because variability in the brain is typically correlated, and although the exact effects of these correlations are not known, it is known that they can be large. Here, we review studies that address the interaction between neuronal noise and population codes, and discuss their implications for population coding in general.", "corpus_id": 2723062, "score": 0 }, { "doc_id": "6831069", "title": "Measuring and interpreting neuronal correlations", "abstract": "Mounting evidence suggests that understanding how the brain encodes information and performs computations will require studying the correlations between neurons. The recent advent of recording techniques such as multielectrode arrays and two-photon imaging has made it easier to measure correlations, opening the door for detailed exploration of their properties and contributions to cortical processing. However, studies have reported discrepant findings, providing a confusing picture. Here we briefly review these studies and conduct simulations to explore the influence of several experimental and physiological factors on correlation measurements. Differences in response strength, the time window over which spikes are counted, spike sorting conventions and internal states can all markedly affect measured correlations and systematically bias estimates. Given these complicating factors, we offer guidelines for interpreting correlation data and a discussion of how best to evaluate the effect of correlations on cortical processing.", "corpus_id": 6831069, "score": 0 }, { "doc_id": "24452436", "title": "Decorrelated Neuronal Firing in Cortical Microcircuits", "abstract": "Columns, Connections, and Correlations What is the nature of interactions between neurons in neural circuits? The prevalent hypothesis suggests that dense local connectivity causes nearby cortical neurons to receive substantial amounts of common input, which in turn leads to strong correlations between them. Now two studies challenge this view, which impacts our fundamental understanding of coding in the cortex. Ecker et al. (p. 584) investigated the statistics of correlated firing in pairs of neurons from area V1 of awake macaque monkeys. In contrast to previous studies, correlations turned out to be very low, irrespective of the stimulus being shown to the animals, the distances of the recording sites, and the similarity of the neuron's receptive fields or response properties. In an accompanying modeling and recording paper, Renart et al. (p. 587) demonstrate how it is possible to have zero noise correlation, even among cells with common input. Despite dense connectivity and shared input, the firing rates of nearby neurons are largely uncorrelated. Correlated trial-to-trial variability in the activity of cortical neurons is thought to reflect the functional connectivity of the circuit. Many cortical areas are organized into functional columns, in which neurons are believed to be densely connected and to share common input. Numerous studies report a high degree of correlated variability between nearby cells. We developed chronically implanted multitetrode arrays offering unprecedented recording quality to reexamine this question in the primary visual cortex of awake macaques. We found that even nearby neurons with similar orientation tuning show virtually no correlated variability. Our findings suggest a refinement of current models of cortical microcircuit architecture and function: Either adjacent neurons share only a few percent of their inputs or, alternatively, their activity is actively decorrelated.", "corpus_id": 24452436, "score": 0 }, { "doc_id": "7348059", "title": "The mechanics of state-dependent neural correlations", "abstract": "Simultaneous recordings from large neural populations are becoming increasingly common. An important feature of population activity is the trial-to-trial correlated fluctuation of spike train outputs from recorded neuron pairs. Similar to the firing rate of single neurons, correlated activity can be modulated by a number of factors, from changes in arousal and attentional state to learning and task engagement. However, the physiological mechanisms that underlie these changes are not fully understood. We review recent theoretical results that identify three separate mechanisms that modulate spike train correlations: changes in input correlations, internal fluctuations and the transfer function of single neurons. We first examine these mechanisms in feedforward pathways and then show how the same approach can explain the modulation of correlations in recurrent networks. Such mechanistic constraints on the modulation of population activity will be important in statistical analyses of high-dimensional neural data.", "corpus_id": 7348059, "score": 0 }, { "doc_id": "17933714", "title": "Waking State: Rapid Variations Modulate Neural and Behavioral Responses", "abstract": "The state of the brain and body constantly varies on rapid and slow timescales. These variations contribute to the apparent noisiness of sensory responses at both the neural and the behavioral level. Recent investigations of rapid state changes in awake, behaving animals have provided insight into the mechanisms by which optimal sensory encoding and behavioral performance are achieved. Fluctuations in state, as indexed by pupillometry, impact both the \"signal\" (sensory evoked response) and the \"noise\" (spontaneous activity) of cortical responses. By taking these fluctuations into account, neural response (co)variability is significantly reduced, revealing the brain to be more reliable and predictable than previously thought.", "corpus_id": 17933714, "score": 0 }, { "doc_id": "14151659", "title": "Instantaneous correlation of excitation and inhibition during ongoing and sensory-evoked activities", "abstract": "Temporal and quantitative relations between excitatory and inhibitory inputs in the cortex are central to its activity, yet they remain poorly understood. In particular, a controversy exists regarding the extent of correlation between cortical excitation and inhibition. Using simultaneous intracellular recordings in pairs of nearby neurons in vivo, we found that excitatory and inhibitory inputs are continuously synchronized and correlated in strength during spontaneous and sensory-evoked activities in the rat somatosensory cortex.", "corpus_id": 14151659, "score": 1 }, { "doc_id": "23678786", "title": "Spontaneous firing patterns and axonal projections of single corticostriatal neurons in the rat medial agranular cortex.", "abstract": "1. Spontaneous fluctuations of membrane potential, patterns of spontaneous firing, dendritic branching patterns, and intracortical and striatal axonal arborizations were compared for two types of corticostriatal neurons in the medial agranular cortex of urethan-anesthetized rats: 1) pyramidal tract (PT) cells identified by antidromic activation from the medullary pyramid and 2) crossed corticostriatal (CST) neurons identified by antidromic activation from the contralateral neostriatum. The ipsilateral corticostriatal projections of intracellularly stained PT neurons as well as contralateral corticostriatal neurons were confirmed after labeling by intracellular injection of biocytin. 2. All well-stained PT neurons had intracortical and intrastriatal collaterals. The more common type (6 of 8) was a large, deep layer V neuron that had an extensive intracortical axon arborization but a limited axon arborization in the neostriatum. The less common type of PT neuron (2 of 8) was a medium-sized, superficial layer V neuron that had a limited intracortical axon arborization but a larger and more dense intrastriatal axonal arborization. Both subclasses of PT neurons had anatomic and physiological properties associated with slow PT cells in cats and monkeys and conduction velocities < 10 m/s. All of the PT cells but one were regular spiking cells. The exception cell fired intrinsic bursts. 3. Intracellularly stained CST neurons were located in the superficial half of layer V and the deep part of layer III. Their layer I apical dendrites were few and sparsely branched. Their axons gave rise to an extensive arbor of local axon collaterals that distributed in the region of the parent neuron, frequently extending throughout the more superficial layers, including layer I. Axon collaterals were also traced to the corpus callosum, as expected from their contralateral projections, and they contributed axon collaterals to the ipsilateral neostriatum. In the neostriatum, these axons formed extended arborizations sparsely occupying a large volume of striatal tissue. All CST neurons were regular spiking cells. 4. Both types of cells displayed spontaneous membrane fluctuations consisting of a polarized state (-60 to -90 mV) that was interrupted by 0.1- to 3.0-s periods of depolarization (-55 to -45 mV) accompanied by action potentials. The membrane potential was relatively constant in each state, and transitions between the depolarized and hyperpolarized states were sometimes periodic with a frequency of 0.3-1.5 Hz. A much faster (30-45 Hz) subthreshold oscillation of the membrane potential was observed only in the depolarized state and triggered action potentials that locked to the depolarizing peaks of this rhythm.(ABSTRACT TRUNCATED AT 400 WORDS)", "corpus_id": 23678786, "score": 0 }, { "doc_id": "16535701", "title": "Synchronous Membrane Potential Fluctuations in Neurons of the Cat Visual Cortex", "abstract": "We have recorded intracellularly from pairs of neurons less than 500 microm distant from one another in V1 of anesthetized cats. Cross-correlation of spontaneous fluctuations in membrane potential revealed significant correlations between the cells in each pair. This synchronization was not dependent on the occurrence of action potentials, indicating that it was not caused by mutual interconnections. The cells were synchronized continuously rather than for brief epochs. Much weaker correlations were found between the EEG and intracellular potentials, suggesting local, rather than global, synchrony. The highest correlation occurred among cells with similar connectivity from the LGN and similar receptive fields. During visual stimulation, correlations increased when both cells responded to the stimulus and decreased when neither cell responded.", "corpus_id": 16535701, "score": 1 }, { "doc_id": "4828781", "title": "Neocortical inhibitory activities and long-range afferents contribute to the synchronous onset of silent states of the neocortical slow oscillation.", "abstract": "During slow-wave sleep, neurons of the thalamocortical network are engaged in a slow oscillation (<1 Hz), which consists of an alternation between the active and the silent states. Several studies have provided insights on the transition from the silent, which are essentially periods of disfacilitation, to the active states. However, the conditions leading to the synchronous onset of the silent state remain elusive. We hypothesized that a synchronous input to local inhibitory neurons could contribute to the transition to the silent state in the cat suprasylvian gyrus during natural sleep and under ketamine-xylazine anesthesia. After partial and complete deafferentation of the cortex, we found that the silent state onset was more variable among remote sites. We found that the transition to the silent state was preceded by a reduction in excitatory postsynaptic potentials and firing probability in cortical neurons. We tested the impact of chloride-mediated inhibition in the silent-state onset. We uncovered a long-duration (100-300 ms) inhibitory barrage occurring about 250 ms before the silent state onset in 3-6% of neurons during anesthesia and in 12-15% of cases during natural sleep. These inhibitory activities caused a decrease in cortical firing that reduced the excitatory drive in the neocortical network. That chain reaction of disfacilitation ends up on the silent state. Electrical stimuli could trigger a network silent state with a maximal efficacy in deep cortical layers. We conclude that long-range afferents to the neocortex and chloride-mediated inhibition play a role in the initiation of the silent state.", "corpus_id": 4828781, "score": 0 }, { "doc_id": "4822661", "title": "Global Intracellular Slow-Wave Dynamics of the Thalamocortical System", "abstract": "It is widely accepted that corticothalamic neurons recruit the thalamus in slow oscillation, but global slow-wave thalamocortical dynamics have never been experimentally shown. We analyzed intracellular activities of neurons either from different cortical areas or from a variety of specific and nonspecific thalamic nuclei in relation to the phase of global EEG signal in ketamine-xylazine anesthetized mice. We found that, on average, slow-wave active states started off within frontal cortical areas as well as higher-order and intralaminar thalamus (posterior and parafascicular nuclei) simultaneously. Then, the leading edge of active states propagated in the anteroposterior/lateral direction over the cortex at ∼40 mm/s. The latest structure we recorded within the slow-wave cycle was the anterior thalamus, which followed active states of the retrosplenial cortex. Active states from different cortical areas tended to terminate simultaneously. Sensory thalamic ventral posterior medial and lateral geniculate nuclei followed cortical active states with major inhibitory and weak tonic-like “modulator” EPSPs. In these nuclei, sharp-rising, large-amplitude EPSPs (“drivers”) were not modulated by cortical slow waves, suggesting their origin in ascending pathways. The thalamic active states in other investigated nuclei were composed of depolarization: some revealing “driver”- and “modulator”-like EPSPs, others showing “modulator”-like EPSPs only. We conclude that sensory thalamic nuclei follow the propagating cortical waves, whereas neurons from higher-order thalamic nuclei display “hub dynamics” and thus may contribute to the generation of cortical slow waves.", "corpus_id": 4822661, "score": 0 }, { "doc_id": "26810112", "title": "A novel slow (< 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components", "abstract": "We describe a novel slow oscillation in intracellular recordings from cortical association areas 5 and 7, motor areas 4 and 6, and visual areas 17 and 18 of cats under various anesthetics. The recorded neurons (n = 254) were antidromically and orthodromically identified as corticothalamic or callosal elements receiving projections from appropriate thalamic nuclei as well as from homotopic foci in the contralateral cortex. Two major types of cells were recorded: regular- spiking (mainly slow-adapting, but also fast-adapting) neurons and intrinsically bursting cells. A group of slowly oscillating neurons (n = 21) were intracellularly stained and found to be pyramidal-shaped cells in layers III-VI, with luxuriant basal dendritic arbors. The slow rhythm appeared in 88% of recorded neurons. It consisted of slow depolarizing envelopes (lasting for 0.8–1.5 sec) with superimposed full action potentials or presumed dendritic spikes, followed by long- lasting hyperpolarizations. Such sequences recurred rhythmically at less than 1 Hz, with a prevailing oscillation between 0.3 and 0.4 Hz in 67% of urethane-anesthetized animals. While in most neurons (approximately 70%) the repetitive spikes superimposed on the slow depolarization were completely blocked by slight DC hyperpolarization, 30% of cells were found to display relatively small (3–12 mV), rapid, all-or-none potentials after obliteration of full action potentials. These fast spikes were suppressed in an all-or-none fashion at Vm more negative than -90 mV. The depolarizing envelope of the slow rhythm was reduced or suppressed at a Vm of -90 to -100 mV and its duration was greatly reduced by administration of the NMDA blocker ketamine. In keeping with this action, most (56%) neurons recorded in animals under ketamine and nitrous oxide or ketamine and xylazine anesthesia displayed the slow oscillation at higher frequencies (0.6–1 Hz) than under urethane anesthesia (0.3–0.4 Hz). In 18% of the oscillating cells, the slow rhythm mainly consisted of repetitive (15–30 Hz), relatively short-lasting (15–25 msec) IPSPs that could be revealed by bringing the Vm at more positive values than -70 mV. The long-lasting (approximately 1 sec) hyperpolarizing phase of the slow oscillation was best observed at the resting Vm and was reduced at about -100 mV. Simultaneous recording of another cell across the membrane demonstrated synchronous inhibitory periods in both neurons. Intracellular diffusion of Cl- or Cs+ reduced the amplitude and/or duration of cyclic long- lasting hyperpolaryzations.(ABSTRACT TRUNCATED AT 400 WORDS)", "corpus_id": 26810112, "score": 0 }, { "doc_id": "16232207", "title": "Spontaneous firing patterns of identified spiny neurons in the rat neostriatum", "abstract": "Spontaneous firing patterns of 94 unidentified neurons and 34 identified spiny neurons were compared in the neostriatum of locally anesthetized immobilized rats. Intracellular and extracellular recordings were analyzed using first order interval histograms and autocorrelograms, and neurons were identified by their somatodendritic morphology after intracellular injection of horseradish peroxidase. All neostriatal neurons tended to fire in irregular phasic bursts of activity. Considerable variation in mean firing rate, burst duration, interburst interval and the occurrence and rate of firing between bursts was apparent in both groups of neurons. There was no apparent difference between spiny neurons and the sample of unidentified extracellularly recorded neurons along any of these firing pattern parameters. Intracellular recordings from identified spiny neurons revealed noisy irregular periods of maintained 5-20 mV membrane depolarizations which corresponded to the occurrence of bursts of firing in spontaneously active neurons. These depolarizations occurred in neostriatal neurons exhibiting no spontaneous activity but were of insufficient amplitude to trigger impulse activity.", "corpus_id": 16232207, "score": 0 }, { "doc_id": "1407218", "title": "Membrane Potential Synchrony in Primary Visual Cortex during Sensory Stimulation", "abstract": "When the primary visual cortex (V1) is activated by sensory stimulation, what is the temporal correlation between the synaptic inputs to nearby neurons? This question underlies the origin of correlated activity, the mechanism of how visually evoked activity emerges and propagates in cortical circuits, and the relationship between spontaneous and evoked activity. Here, we have recorded membrane potential from pairs of V1 neurons in anesthetized cats and found that visual stimulation suppressed low-frequency membrane potential synchrony (0-10 Hz), and often increased synchrony at high frequencies (20-80 Hz). The increase in high-frequency synchrony occurred for neurons with similar orientation preferences and for neurons with different orientation preferences and occurred for a wide range of stimulus orientations. Thus, while only a subset of neurons spike in response to visual stimulation, a far larger proportion of the circuit is correlated with spiking activity through subthreshold, high-frequency synchronous activity that crosses functional domains.", "corpus_id": 1407218, "score": 1 }, { "doc_id": "26314243", "title": "Correlating whisker behavior with membrane potential in barrel cortex of awake mice", "abstract": "To investigate synaptic events underlying sensory perception, we made whole-cell membrane potential recordings of barrel cortex neurons in awake mice while recording whisker-related behavior. During quiet periods, we recorded slow, large-amplitude membrane potential changes, which switched during whisking to small, fast fluctuations that were correlated with whisker position. Robust subthreshold responses were evoked by passive whisker stimulation during quiet behavior and by active whisker contact with an object.", "corpus_id": 26314243, "score": 0 }, { "doc_id": "8445122", "title": "Subthreshold Mechanisms Underlying State-Dependent Modulation of Visual Responses", "abstract": "The processing of sensory information varies widely across behavioral states. However, little is known about how behavioral states modulate the intracellular activity of cortical neurons to effect changes in sensory responses. Here, we performed whole-cell recordings from neurons in upper-layer primary visual cortex of awake mice during locomotion and quiet wakefulness. We found that the signal-to-noise ratio for sensory responses was improved during locomotion by two mechanisms: (1) a decrease in membrane potential variability leading to a reduction in background firing rates and (2) an enhancement in the amplitude and reliability of visually evoked subthreshold responses mediated by an increase in total conductance and a depolarization of the stimulus-evoked reversal potential. Consistent with the enhanced signal-to-noise ratio for visual responses during locomotion, we demonstrate that performance is improved in a visual detection task during this behavioral state.", "corpus_id": 8445122, "score": 1 }, { "doc_id": "23018655", "title": "Visually Evoked 3–5 Hz Membrane Potential Oscillations Reduce the Responsiveness of Visual Cortex Neurons in Awake Behaving Mice", "abstract": "Low-frequency membrane potential (Vm) oscillations were once thought to only occur in sleeping and anesthetized states. Recently, low-frequency Vm oscillations have been described in inactive awake animals, but it is unclear whether they shape sensory processing in neurons and whether they occur during active awake behavioral states. To answer these questions, we performed two-photon guided whole-cell Vm recordings from primary visual cortex layer 2/3 excitatory and inhibitory neurons in awake mice during passive visual stimulation and performance of visual and auditory discrimination tasks. We recorded stereotyped 3–5 Hz Vm oscillations where the Vm baseline hyperpolarized as the Vm underwent high amplitude rhythmic fluctuations lasting 1–2 s in duration. When 3–5 Hz Vm oscillations coincided with visual cues, excitatory neuron responses to preferred cues were significantly reduced. Despite this disruption to sensory processing, visual cues were critical for evoking 3–5 Hz Vm oscillations when animals performed discrimination tasks and passively viewed drifting grating stimuli. Using pupillometry and animal locomotive speed as indicators of arousal, we found that 3–5 Hz oscillations were not restricted to unaroused states and that they occurred equally in aroused and unaroused states. Therefore, low-frequency Vm oscillations play a role in shaping sensory processing in visual cortical neurons, even during active wakefulness and decision making. SIGNIFICANCE STATEMENT A neuron's membrane potential (Vm) strongly shapes how information is processed in sensory cortices of awake animals. Yet, very little is known about how low-frequency Vm oscillations influence sensory processing and whether they occur in aroused awake animals. By performing two-photon guided whole-cell recordings from layer 2/3 excitatory and inhibitory neurons in the visual cortex of awake behaving animals, we found visually evoked stereotyped 3–5 Hz Vm oscillations that disrupt excitatory responsiveness to visual stimuli. Moreover, these oscillations occurred when animals were in high and low arousal states as measured by animal speed and pupillometry. These findings show, for the first time, that low-frequency Vm oscillations can significantly modulate sensory signal processing, even in awake active animals.", "corpus_id": 23018655, "score": 1 }, { "doc_id": "1585956", "title": "Cortical Membrane Potential Signature of Optimal States for Sensory Signal Detection", "abstract": "The neural correlates of optimal states for signal detection task performance are largely unknown. One hypothesis holds that optimal states exhibit tonically depolarized cortical neurons with enhanced spiking activity, such as occur during movement. We recorded membrane potentials of auditory cortical neurons in mice trained on a challenging tone-in-noise detection task while assessing arousal with simultaneous pupillometry and hippocampal recordings. Arousal measures accurately predicted multiple modes of membrane potential activity, including rhythmic slow oscillations at low arousal, stable hyperpolarization at intermediate arousal, and depolarization during phasic or tonic periods of hyper-arousal. Walking always occurred during hyper-arousal. Optimal signal detection behavior and sound-evoked responses, at both sub-threshold and spiking levels, occurred at intermediate arousal when pre-decision membrane potentials were stably hyperpolarized. These results reveal a cortical physiological signature of the classically observed inverted-U relationship between task performance and arousal and that optimal detection exhibits enhanced sensory-evoked responses and reduced background synaptic activity.", "corpus_id": 1585956, "score": 0 }, { "doc_id": "17527528", "title": "Cellular mechanisms of brain-state-dependent gain modulation in visual cortex", "abstract": "Visual cortical neurons fire at higher rates to visual stimuli during locomotion than during immobility, while maintaining orientation selectivity. The mechanisms underlying this change in gain are not understood. We performed whole-cell recordings from layer 2/3 and layer 4 visual cortical excitatory neurons and from parvalbumin-positive and somatostatin-positive inhibitory neurons in mice that were free to rest or run on a spherical treadmill. We found that the membrane potential of all cell types became more depolarized and (with the exception of somatostatin-positive interneurons) less variable during locomotion. Cholinergic input was essential for maintaining the unimodal membrane potential distribution during immobility, whereas noradrenergic input was necessary for the tonic depolarization associated with locomotion. Our results provide a mechanism for how neuromodulation controls the gain and signal-to-noise ratio of visual cortical neurons during changes in the state of vigilance.", "corpus_id": 17527528, "score": 1 }, { "doc_id": "14118354", "title": "Pupil Fluctuations Track Fast Switching of Cortical States during Quiet Wakefulness", "abstract": "Neural responses are modulated by brain state, which varies with arousal, attention, and behavior. In mice, running and whisking desynchronize the cortex and enhance sensory responses, but the quiescent periods between bouts of exploratory behaviors have not been well studied. We found that these periods of \"quiet wakefulness\" were characterized by state fluctuations on a timescale of 1-2 s. Small fluctuations in pupil diameter tracked these state transitions in multiple cortical areas. During dilation, the intracellular membrane potential was desynchronized, sensory responses were enhanced, and population activity was less correlated. In contrast, constriction was characterized by increased low-frequency oscillations and higher ensemble correlations. Specific subtypes of cortical interneurons were differentially activated during dilation and constriction, consistent with their participation in the observed state changes. Pupillometry has been used to index attention and mental effort in humans, but the intracellular dynamics and differences in population activity underlying this phenomenon were previously unknown.", "corpus_id": 14118354, "score": 0 }, { "doc_id": "4458670", "title": "A synaptic and circuit basis for corollary discharge in the auditory cortex", "abstract": "Sensory regions of the brain integrate environmental cues with copies of motor-related signals important for imminent and ongoing movements. In mammals, signals propagating from the motor cortex to the auditory cortex are thought to have a critical role in normal hearing and behaviour, yet the synaptic and circuit mechanisms by which these motor-related signals influence auditory cortical activity remain poorly understood. Using in vivo intracellular recordings in behaving mice, we find that excitatory neurons in the auditory cortex are suppressed before and during movement, owing in part to increased activity of local parvalbumin-positive interneurons. Electrophysiology and optogenetic gain- and loss-of-function experiments reveal that motor-related changes in auditory cortical dynamics are driven by a subset of neurons in the secondary motor cortex that innervate the auditory cortex and are active during movement. These findings provide a synaptic and circuit basis for the motor-related corollary discharge hypothesized to facilitate hearing and auditory-guided behaviours.", "corpus_id": 4458670, "score": 1 }, { "doc_id": "8255425", "title": "Membrane Potential Dynamics of GABAergic Neurons in the Barrel Cortex of Behaving Mice", "abstract": "Computations in cortical circuits are mediated by synaptic interactions between excitatory and inhibitory neurons, and yet we know little about their activity in awake animals. Here, through single and dual whole-cell recordings combined with two-photon microscopy in the barrel cortex of behaving mice, we directly compare the synaptically driven membrane potential dynamics of inhibitory and excitatory layer 2/3 neurons. We find that inhibitory neurons depolarize synchronously with excitatory neurons, but they are much more active with differential contributions of two classes of inhibitory neurons during different brain states. Fast-spiking GABAergic neurons dominate during quiet wakefulness, but during active wakefulness Non-fast-spiking GABAergic neurons depolarize, firing action potentials at increased rates. Sparse uncorrelated action potential firing in excitatory neurons is driven by fast, large, and cell-specific depolarization. In contrast, inhibitory neurons fire correlated action potentials at much higher frequencies driven by slower, smaller, and broadly synchronized depolarization.", "corpus_id": 8255425, "score": 0 }, { "doc_id": "594875", "title": "Unique functional properties of somatostatin-expressing GABAergic neurons in mouse barrel cortex", "abstract": "Neocortical GABAergic neurons have diverse molecular, structural and electrophysiological features, but the functional correlates of this diversity are largely unknown. We found unique membrane potential dynamics of somatostatin-expressing (SOM) neurons in layer 2/3 of the primary somatosensory barrel cortex of awake behaving mice. SOM neurons were spontaneously active during periods of quiet wakefulness. However, SOM neurons hyperpolarized and reduced action potential firing in response to both passive and active whisker sensing, in contrast with all other recorded types of nearby neurons, which were excited by sensory input. Optogenetic inhibition of SOM neurons increased burst firing in nearby excitatory neurons. We hypothesize that the spontaneous activity of SOM neurons during quiet wakefulness provides a tonic inhibition to the distal dendrites of excitatory pyramidal neurons. Conversely, the inhibition of SOM cells during active cortical processing likely enhances distal dendritic excitability, which may be important for top-down computations and sensorimotor integration.", "corpus_id": 594875, "score": 0 }, { "doc_id": "982790", "title": "Internal brain state regulates membrane potential synchrony in barrel cortex of behaving mice", "abstract": "Internal brain states form key determinants for sensory perception, sensorimotor coordination and learning. A prominent reflection of different brain states in the mammalian central nervous system is the presence of distinct patterns of cortical synchrony, as revealed by extracellular recordings of the electroencephalogram, local field potential and action potentials. Such temporal correlations of cortical activity are thought to be fundamental mechanisms of neuronal computation. However, it is unknown how cortical synchrony is reflected in the intracellular membrane potential (Vm) dynamics of behaving animals. Here we show, using dual whole-cell recordings from layer 2/3 primary somatosensory barrel cortex in behaving mice, that the Vm of nearby neurons is highly correlated during quiet wakefulness. However, when the mouse is whisking, an internally generated state change reduces the Vm correlation, resulting in a desynchronized local field potential and electroencephalogram. Action potential activity was sparse during both quiet wakefulness and active whisking. Single action potentials were driven by a large, brief and specific excitatory input that was not present in the Vm of neighbouring cells. Action potential initiation occurs with a higher signal-to-noise ratio during active whisking than during quiet periods. Therefore, we show that an internal brain state dynamically regulates cortical membrane potential synchrony during behaviour and defines different modes of cortical processing.", "corpus_id": 982790, "score": 1 }, { "doc_id": "19004279", "title": "Translaminar Cortical Membrane Potential Synchrony in Behaving Mice", "abstract": "Summary The synchronized activity of six layers of cortical neurons is critical for sensory perception and the control of voluntary behavior, but little is known about the synaptic mechanisms of cortical synchrony across layers in behaving animals. We made single and dual whole-cell recordings from the primary somatosensory forepaw cortex in awake mice and show that L2/3 and L5 excitatory neurons have layer-specific intrinsic properties and membrane potential dynamics that shape laminar-specific firing rates and subthreshold synchrony. First, while sensory and movement-evoked synaptic input was tightly correlated across layers, spontaneous action potentials and slow spontaneous subthreshold fluctuations had laminar-specific timing; second, longer duration forepaw movement was associated with a decorrelation of subthreshold activity; third, spontaneous and sensory-evoked forepaw movements were signaled more strongly by L5 than L2/3 neurons. Together, our data suggest that the degree of translaminar synchrony is dependent upon the origin (sensory, spontaneous, and movement) of the synaptic input.", "corpus_id": 19004279, "score": 0 }, { "doc_id": "205231607", "title": "Inhibition dominates sensory responses in awake cortex", "abstract": "The activity of the cerebral cortex is thought to depend on the precise relationship between synaptic excitation and inhibition. In the visual cortex, in particular, intracellular measurements have related response selectivity to coordinated increases in excitation and inhibition. These measurements, however, have all been made during anaesthesia, which strongly influences cortical state and therefore sensory processing. The synaptic activity that is evoked by visual stimulation during wakefulness is unknown. Here we measured visually evoked responses—and the underlying synaptic conductances—in the visual cortex of anaesthetized and awake mice. Under anaesthesia, responses could be elicited from a large region of visual space and were prolonged. During wakefulness, responses were more spatially selective and much briefer. Whole-cell patch-clamp recordings of synaptic conductances showed a difference in synaptic inhibition between the two conditions. Under anaesthesia, inhibition tracked excitation in amplitude and spatial selectivity. By contrast, during wakefulness, inhibition was much stronger than excitation and had extremely broad spatial selectivity. We conclude that during wakefulness, cortical responses to visual stimulation are dominated by synaptic inhibition, restricting the spatial spread and temporal persistence of neural activity. These results provide a direct glimpse of synaptic mechanisms that control sensory responses in the awake cortex.", "corpus_id": 205231607, "score": 1 }, { "doc_id": "4409655", "title": "Sensory stimulation shifts visual cortex from synchronous to asynchronous states", "abstract": "In the mammalian cerebral cortex, neural responses are highly variable during spontaneous activity and sensory stimulation. To explain this variability, the cortex of alert animals has been proposed to be in an asynchronous high-conductance state in which irregular spiking arises from the convergence of large numbers of uncorrelated excitatory and inhibitory inputs onto individual neurons. Signatures of this state are that a neuron’s membrane potential (Vm) hovers just below spike threshold, and its aggregate synaptic input is nearly Gaussian, arising from many uncorrelated inputs. Alternatively, irregular spiking could arise from infrequent correlated input events that elicit large fluctuations in Vm (refs 5, 6). To distinguish between these hypotheses, we developed a technique to perform whole-cell Vm measurements from the cortex of behaving monkeys, focusing on primary visual cortex (V1) of monkeys performing a visual fixation task. Here we show that, contrary to the predictions of an asynchronous state, mean Vm during fixation was far from threshold (14 mV) and spiking was triggered by occasional large spontaneous fluctuations. Distributions of Vm values were skewed beyond that expected for a range of Gaussian input, but were consistent with synaptic input arising from infrequent correlated events. Furthermore, spontaneous fluctuations in Vm were correlated with the surrounding network activity, as reflected in simultaneously recorded nearby local field potential. Visual stimulation, however, led to responses more consistent with an asynchronous state: mean Vm approached threshold, fluctuations became more Gaussian, and correlations between single neurons and the surrounding network were disrupted. These observations show that sensory drive can shift a common cortical circuitry from a synchronous to an asynchronous state.", "corpus_id": 4409655, "score": 0 }, { "doc_id": "9979112", "title": "Millisecond Coupling of Local Field Potentials to Synaptic Currents in the Awake Visual Cortex", "abstract": "Summary The cortical local field potential (LFP) is a common measure of population activity, but its relationship to synaptic activity in individual neurons is not fully established. This relationship has been typically studied during anesthesia and is obscured by shared slow fluctuations. Here, we used patch-clamp recordings in visual cortex of anesthetized and awake mice to measure intracellular activity; we then applied a simple method to reveal its coupling to the simultaneously recorded LFP. LFP predicted membrane potential as accurately as synaptic currents, indicating a major role for synaptic currents in the relationship between cortical LFP and intracellular activity. During anesthesia, cortical LFP predicted excitation far better than inhibition; during wakefulness, it predicted them equally well, and visual stimulation further enhanced predictions of inhibition. These findings reveal a central role for synaptic currents, and especially inhibition, in the relationship between the subthreshold activity of individual neurons and the cortical LFP during wakefulness.", "corpus_id": 9979112, "score": 0 }, { "doc_id": "9742937", "title": "Local Origin of Field Potentials in Visual Cortex", "abstract": "The local field potential (LFP) is increasingly used to measure the combined activity of neurons within a region of tissue. Yet, available estimates of the size of this region are highly disparate, ranging from several hundred microns to a few millimeters. To measure the size of this region directly, we used a combination of multielectrode recordings and optical imaging. We determined the orientation selectivity of stimulus-evoked LFP signals in primary visual cortex and were able to predict it on the basis of the surrounding map of orientation preference. The results show that > 95% of the LFP signal originates within 250 microm of the recording electrode. This quantitative estimate indicates that LFPs are more local than often recognized and provides a guide to the interpretation of the increasing number of studies that rest on LFP recordings.", "corpus_id": 9742937, "score": 0 }, { "doc_id": "10713897", "title": "Imaging Large-Scale Neural Activity with Cellular Resolution in Awake, Mobile Mice", "abstract": "We report a technique for two-photon fluorescence imaging with cellular resolution in awake, behaving mice with minimal motion artifact. The apparatus combines an upright, table-mounted two-photon microscope with a spherical treadmill consisting of a large, air-supported Styrofoam ball. Mice, with implanted cranial windows, are head restrained under the objective while their limbs rest on the ball's upper surface. Following adaptation to head restraint, mice maneuver on the spherical treadmill as their heads remain motionless. Image sequences demonstrate that running-associated brain motion is limited to approximately 2-5 microm. In addition, motion is predominantly in the focal plane, with little out-of-plane motion, making the application of a custom-designed Hidden-Markov-Model-based motion correction algorithm useful for postprocessing. Behaviorally correlated calcium transients from large neuronal and astrocytic populations were routinely measured, with an estimated motion-induced false positive error rate of <5%.", "corpus_id": 10713897, "score": 0 }, { "doc_id": "9093301", "title": "The Subthreshold Relation between Cortical Local Field Potential and Neuronal Firing Unveiled by Intracellular Recordings in Awake Rats", "abstract": "In most of the in vivo electrophysiological studies of cortical processing, which are extracellular, the spike-triggered local field potential average (LFP STA) is the measure used to estimate the correlation between the synaptic inputs of individual neuron and the local population. To understand how the magnitude and shape of LFP STA reflect the underlying correlation of synaptic activities, the membrane potential of the firing neuron has to be recorded together with the LFP. Using intracellular recordings from the cortex of awake rats, we found that for a large range of firing rates and for different behavioral states, the LFP STA represents both in its waveform and its magnitude the cross-correlation between the membrane potential of the neuron and the LFP. This data, supported by further analysis, suggests that LFP STA does not represent large network events specific to the spike times, but rather the synchrony between the mean synaptic activity of the population and the membrane potential of the single neuron, present both around spike times and in the intervals between spikes. Furthermore, it introduces a novel interpretation of the available data from unit and LFP extracellular recording experiments.", "corpus_id": 9093301, "score": 0 }, { "doc_id": "10480680", "title": "Area map of mouse visual cortex", "abstract": "It is controversial whether mouse extrastriate cortex has a “simple” organization in which lateral primary visual cortex (V1) is adjoined by a single area V2 or has a “complex” organization, in which lateral V1 is adjoined by multiple distinct areas, all of which share the vertical meridian with V1. Resolving this issue is important for understanding the evolution and development of cortical arealization. We have used triple pathway tracing combined with receptive field recordings to map azimuth and elevation in the same brain and have referenced these maps against callosal landmarks. We found that V1 projects to 15 cortical fields. At least nine of these contain maps with complete and orderly representations of the entire visual hemifield and therefore represent distinct areas. One of these, PM, adjoins V1 at the medial border. Five areas, P, LM, AL, RL, and A, adjoin V1 on the lateral border, but only LM shares the vertical meridian representation with V1. This suggests that LM is homologous to V2 and that the lateral extrastriate areas do not represent modules within a single area V2. Thus, mouse visual cortex is “simple” in the sense that lateral V1 is adjoined by a single V2‐like area, LM, and “complex” in having a string of areas in lateral extrastriate cortex, which receive direct V1 input. The results suggest that large numbers of areas with topologically equivalent maps of the visual field emerge early in evolution and that homologous areas are inherited in different mammalian lineages. J. Comp. Neurol. 502:339–357, 2007. © 2007 Wiley‐Liss, Inc.", "corpus_id": 10480680, "score": 0 }, { "doc_id": "4383888", "title": "The emergence of functional microcircuits in visual cortex", "abstract": "Sensory processing occurs in neocortical microcircuits in which synaptic connectivity is highly structured and excitatory neurons form subnetworks that process related sensory information. However, the developmental mechanisms underlying the formation of functionally organized connectivity in cortical microcircuits remain unknown. Here we directly relate patterns of excitatory synaptic connectivity to visual response properties of neighbouring layer 2/3 pyramidal neurons in mouse visual cortex at different postnatal ages, using two-photon calcium imaging in vivo and multiple whole-cell recordings in vitro. Although neural responses were already highly selective for visual stimuli at eye opening, neurons responding to similar visual features were not yet preferentially connected, indicating that the emergence of feature selectivity does not depend on the precise arrangement of local synaptic connections. After eye opening, local connectivity reorganized extensively: more connections formed selectively between neurons with similar visual responses and connections were eliminated between visually unresponsive neurons, but the overall connectivity rate did not change. We propose a sequential model of cortical microcircuit development based on activity-dependent mechanisms of plasticity whereby neurons first acquire feature preference by selecting feedforward inputs before the onset of sensory experience—a process that may be facilitated by early electrical coupling between neuronal subsets—and then patterned input drives the formation of functional subnetworks through a redistribution of recurrent synaptic connections.", "corpus_id": 4383888, "score": 0 }, { "doc_id": "1326580", "title": "Modulation of Visual Responses by Behavioral State in Mouse Visual Cortex", "abstract": "Studies of visual processing in rodents have conventionally been performed on anesthetized animals, precluding examination of the effects of behavior on visually evoked responses. We have now studied the response properties of neurons in primary visual cortex of awake mice that were allowed to run on a freely rotating spherical treadmill with their heads fixed. Most neurons showed more than a doubling of visually evoked firing rate as the animal transitioned from standing still to running, without changes in spontaneous firing or stimulus selectivity. Tuning properties in the awake animal were similar to those measured previously in anesthetized animals. Response magnitude in the lateral geniculate nucleus did not increase with locomotion, demonstrating that the striking change in responsiveness did not result from peripheral effects at the eye. Interestingly, some narrow-spiking cells were spontaneously active during running but suppressed by visual stimuli. These results demonstrate powerful cell-type-specific modulation of visual processing by behavioral state in awake mice.", "corpus_id": 1326580, "score": 0 }, { "doc_id": "1546069", "title": "Functional specificity of local synaptic connections in neocortical networks", "abstract": "Neuronal connectivity is fundamental to information processing in the brain. Therefore, understanding the mechanisms of sensory processing requires uncovering how connection patterns between neurons relate to their function. On a coarse scale, long-range projections can preferentially link cortical regions with similar responses to sensory stimuli. But on the local scale, where dendrites and axons overlap substantially, the functional specificity of connections remains unknown. Here we determine synaptic connectivity between nearby layer 2/3 pyramidal neurons in vitro, the response properties of which were first characterized in mouse visual cortex in vivo. We found that connection probability was related to the similarity of visually driven neuronal activity. Neurons with the same preference for oriented stimuli connected at twice the rate of neurons with orthogonal orientation preferences. Neurons responding similarly to naturalistic stimuli formed connections at much higher rates than those with uncorrelated responses. Bidirectional synaptic connections were found more frequently between neuronal pairs with strongly correlated visual responses. Our results reveal the degree of functional specificity of local synaptic connections in the visual cortex, and point to the existence of fine-scale subnetworks dedicated to processing related sensory information.", "corpus_id": 1546069, "score": 0 }, { "doc_id": "2218896", "title": "Disfacilitation and active inhibition in the neocortex during the natural sleep-wake cycle: an intracellular study.", "abstract": "Earlier extracellular recordings during natural sleep have shown that, during slow-wave sleep (SWS), neocortical neurons display long-lasting periods of silence, whereas they are tonically active and discharge at higher rates during waking and sleep with rapid eye movements (REMs). We analyzed the nature of long-lasting periods of neuronal silence in SWS and the changes in firing rates related to ocular movements during REM sleep and waking using intracellular recordings from electrophysiologically identified neocortical neurons in nonanesthetized and nonparalyzed cats. We found that the silent periods during SWS are associated with neuronal hyperpolarizations, which are due to a mixture of K(+) currents and disfacilitation processes. Conventional fast-spiking neurons (presumably local inhibitory interneurons) increased their firing rates during REMs and eye movements in waking. During REMs, the firing rates of regular-spiking neurons from associative areas decreased and intracellular traces revealed numerous, short-lasting, low-amplitude inhibitory postsynaptic potentials (IPSPs), that were reversed after intracellular chloride infusion. In awake cats, regular-spiking neurons could either increase or decrease their firing rates during eye movements. The short-lasting IPSPs associated with eye movements were still present in waking; they preceded the spikes and affected their timing. We propose that there are two different forms of firing rate control: disfacilitation induces long-lasting periods of silence that occur spontaneously during SWS, whereas active inhibition, consisting of low-amplitude, short-lasting IPSPs, is prevalent during REMs and precisely controls the timing of action potentials in waking.", "corpus_id": 2218896, "score": 0 }, { "doc_id": "4110737", "title": "A cortical–hippocampal–cortical loop of information processing during memory consolidation", "abstract": "Hippocampal replay during sharp-wave ripple events (SWRs) is thought to drive memory consolidation in hippocampal and cortical circuits. Changes in neocortical activity can precede SWR events, but whether and how these changes influence the content of replay remains unknown. Here we show that during sleep there is a rapid cortical–hippocampal–cortical loop of information flow around the times of SWRs. We recorded neural activity in auditory cortex (AC) and hippocampus of rats as they learned a sound-guided task and during sleep. We found that patterned activation in AC precedes and predicts the subsequent content of hippocampal activity during SWRs, while hippocampal patterns during SWRs predict subsequent AC activity. Delivering sounds during sleep biased AC activity patterns, and sound-biased AC patterns predicted subsequent hippocampal activity. These findings suggest that activation of specific cortical representations during sleep influences the identity of the memories that are consolidated into long-term stores.", "corpus_id": 4110737, "score": 0 }, { "doc_id": "1956539", "title": "Coordinated Interactions between Hippocampal Ripples and Cortical Spindles during Slow-Wave Sleep", "abstract": "Sleep is characterized by a structured combination of neuronal oscillations. In the hippocampus, slow-wave sleep (SWS) is marked by high-frequency network oscillations (approximately 200 Hz \"ripples\"), whereas neocortical SWS activity is organized into low-frequency delta (1-4 Hz) and spindle (7-14 Hz) oscillations. While these types of hippocampal and cortical oscillations have been studied extensively in isolation, the relationships between them remain unknown. Here, we demonstrate the existence of temporal correlations between hippocampal ripples and cortical spindles that are also reflected in the correlated activity of single neurons within these brain structures. Spindle-ripple episodes may thus constitute an important mechanism of cortico-hippocampal communication during sleep. This coactivation of hippocampal and neocortical pathways may be important for the process of memory consolidation, during which memories are gradually translated from short-term hippocampal to longer-term neocortical stores.", "corpus_id": 1956539, "score": 0 }, { "doc_id": "18609467", "title": "Communication between neocortex and hippocampus during sleep in rodents", "abstract": "Both neocortical and hippocampal networks organize the firing patterns of their neurons by prominent oscillations during sleep, but the functional role of these rhythms is not well understood. Here, we show a robust correlation of neuronal discharges between the somatosensory cortex and hippocampus on both slow and fine time scales in the mouse and rat. Neuronal bursts in deep cortical layers, associated with sleep spindles and delta waves/slow rhythm, effectively triggered hippocampal discharges related to fast (ripple) oscillations. We hypothesize that oscillation-mediated temporal links coordinate specific information transfer between neocortical and hippocampal cell assemblies. Such a neocortical–hippocampal interplay may be important for memory consolidation.", "corpus_id": 18609467, "score": 0 }, { "doc_id": "498489", "title": "Fast-Forward Playback of Recent Memory Sequences in Prefrontal Cortex During Sleep", "abstract": "As previously shown in the hippocampus and other brain areas, patterns of firing-rate correlations between neurons in the rat medial prefrontal cortex during a repetitive sequence task were preserved during subsequent sleep, suggesting that waking patterns are reactivated. We found that, during sleep, reactivation of spatiotemporal patterns was coherent across the network and compressed in time by a factor of 6 to 7. Thus, when behavioral constraints are removed, the brain's intrinsic processing speed may be much faster than it is in real time. Given recent evidence implicating the medial prefrontal cortex in retrieval of long-term memories, the observed replay may play a role in the process of memory consolidation.", "corpus_id": 498489, "score": 0 }, { "doc_id": "3005845", "title": "Choice-specific sequences in parietal cortex during a virtual-navigation decision task", "abstract": "The posterior parietal cortex (PPC) has an important role in many cognitive behaviours; however, the neural circuit dynamics underlying PPC function are not well understood. Here we optically imaged the spatial and temporal activity patterns of neuronal populations in mice performing a PPC-dependent task that combined a perceptual decision and memory-guided navigation in a virtual environment. Individual neurons had transient activation staggered relative to one another in time, forming a sequence of neuronal activation spanning the entire length of a task trial. Distinct sequences of neurons were triggered on trials with opposite behavioural choices and defined divergent, choice-specific trajectories through a state space of neuronal population activity. Cells participating in the different sequences and at distinct time points in the task were anatomically intermixed over microcircuit length scales (<100 micrometres). During working memory decision tasks, the PPC may therefore perform computations through sequence-based circuit dynamics, rather than long-lived stable states, implemented using anatomically intermingled microcircuits.", "corpus_id": 3005845, "score": 0 }, { "doc_id": "11767344", "title": "Relationship between spontaneous and evoked spike-time correlations in primate visual cortex.", "abstract": "Coincident spikes have been implicated in vision-related processes such as feature binding, gain modulation, and long-distance communication. The source of these spike-time correlations is unknown. Although several studies have proposed that cortical spikes are correlated based on stimulus structure, others have suggested that spike-time correlations reflect ongoing cortical activity present even in the absence of a coherent visual stimulus. To examine this issue, we collected single-unit recordings from primary visual cortex (V1) of the anesthetized and paralyzed prosimian bush baby using a 100-electrode array. Spike-time correlations for pairs of cells were compared under three conditions: a moving grating at the cells' preferred orientation, an equiluminant blank screen, and a dark condition with eyes covered. The amplitudes, lags, and widths of cross-correlation histograms (CCHs) were strongly correlated between these conditions although for the blank stimulus and dark condition, the CCHs were broader with peaks lower in amplitude. In both preferred stimulus and blank conditions, the CCH amplitudes were greater when the cells within the pair had overlapping receptive fields and preferred similar orientations rather than nonoverlapping receptive fields and different orientations. These data suggest that spike-time correlations present in evoked activity are generated by mechanisms common to those operating in spontaneous conditions.", "corpus_id": 11767344, "score": 0 }, { "doc_id": "205431067", "title": "Coordinated memory replay in the visual cortex and hippocampus during sleep", "abstract": "Sleep replay of awake experience in the cortex and hippocampus has been proposed to be involved in memory consolidation. However, whether temporally structured replay occurs in the cortex and whether the replay events in the two areas are related are unknown. Here we studied multicell spiking patterns in both the visual cortex and hippocampus during slow-wave sleep in rats. We found that spiking patterns not only in the cortex but also in the hippocampus were organized into frames, defined as periods of stepwise increase in neuronal population activity. The multicell firing sequences evoked by awake experience were replayed during these frames in both regions. Furthermore, replay events in the sensory cortex and hippocampus were coordinated to reflect the same experience. These results imply simultaneous reactivation of coherent memory traces in the cortex and hippocampus during sleep that may contribute to or reflect the result of the memory consolidation process.", "corpus_id": 205431067, "score": 0 }, { "doc_id": "59742572", "title": "Corticonics: Neural Circuits of Cerebral Cortex", "abstract": "Preface 1. Anatomy of the cerebral cortex 2. The probability for synaptic contact between neurons in the cortex 3. Processing of spikes by neural networks 4. Relations between membrane potential and the synaptic response curve 5. Models of neural networks 6. Transmission through chains of neurons 7. Synchronous transmission Appendix Index.", "corpus_id": 59742572, "score": 0 }, { "doc_id": "24970588", "title": "Synaptic Mechanisms of Tight Spike Synchrony at Gamma Frequency in Cerebral Cortex", "abstract": "During the generation of higher-frequency (e.g., gamma) oscillations, cortical neurons can exhibit pairwise tight (<10 ms) spike synchrony. To understand how synaptic currents contribute to rhythmic activity and spike synchrony, we performed dual whole-cell recordings in mouse entorhinal cortical slices generating periodic activity (the slow oscillation). This preparation exhibited a significant amount of gamma-coherent spike synchrony during the active phase of the slow oscillation (Up state), particularly among fast-spiking inhibitory interneurons. IPSCs arriving in pairs of either pyramidal or fast-spiking neurons during the Up state were highly synchronized and exhibited significant coherence at frequencies from 10 to 100 Hz, peaking at ∼40 Hz, suggesting both synchronous discharge of, and synaptic divergence from, nearby inhibitory neurons. By inferring synaptic currents related to spike generation in simultaneously recorded pyramidal or fast-spiking neurons, we detected a decay of inhibition ∼20 ms before spiking. In fast-spiking interneurons, this was followed by an even larger excitatory input immediately before spike generation. Consistent with an important role for phasic excitation in driving spiking, we found that the correlation of excitatory inputs was highly predictive of spike synchrony in pairs of fast-spiking interneurons. Interestingly, spike synchrony in fast-spiking interneurons was not related to the strength of gap junctional coupling, and was still prevalent in connexin 36 knock-out animals. Our results support the pyramidal-interneuron gamma model of fast rhythmic oscillation in the cerebral cortex and suggest that spike synchrony and phase preference arises from the precise interaction of excitatory–inhibitory postsynaptic currents. SIGNIFICANCE STATEMENT We dissected the cellular and synaptic basis of spike synchrony occurring at gamma frequency (30–80 Hz). We used simultaneous targeted whole-cell recordings in an active slice preparation and analyzed the relationships between synaptic inputs and spike generation. We found that both pyramidal and fast-spiking neurons receive large, coherent inhibitory synaptic inputs at gamma frequency. In addition, we found that fast-spiking interneurons receive large, phasic excitatory synaptic inputs immediately before spike generation followed shortly by synaptic inhibition. These data support the principal-interneuron gamma generation model, and reveal how the synaptic connectivity between excitatory and inhibitory neurons supports the generation of gamma oscillations and spike synchrony.", "corpus_id": 24970588, "score": 0 }, { "doc_id": "839664", "title": "Mechanisms of gamma oscillations.", "abstract": "Gamma rhythms are commonly observed in many brain regions during both waking and sleep states, yet their functions and mechanisms remain a matter of debate. Here we review the cellular and synaptic mechanisms underlying gamma oscillations and outline empirical questions and controversial conceptual issues. Our main points are as follows: First, gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition. Second, gamma oscillations are short-lived and typically emerge from the coordinated interaction of excitation and inhibition, which can be detected as local field potentials. Third, gamma rhythm typically concurs with irregular firing of single neurons, and the network frequency of gamma oscillations varies extensively depending on the underlying mechanism. To document gamma oscillations, efforts should be made to distinguish them from mere increases of gamma-band power and/or increased spiking activity. Fourth, the magnitude of gamma oscillation is modulated by slower rhythms. Such cross-frequency coupling may serve to couple active patches of cortical circuits. Because of their ubiquitous nature and strong correlation with the \"operational modes\" of local circuits, gamma oscillations continue to provide important clues about neuronal population dynamics in health and disease.", "corpus_id": 839664, "score": 0 }, { "doc_id": "4846947", "title": "Origin of slow cortical oscillations in deafferented cortical slabs.", "abstract": "An in vivo preparation has been developed to study the mechanisms underlying spontaneous sleep oscillations. Dual and triple simultaneous intracellular recordings were made from neurons in small isolated cortical slabs (10 mm x 6 mm) in anesthetized cats. Spontaneously occurring slow sleep oscillations, present in the adjacent intact cortex, were absent in small slabs. However, the isolated slabs displayed brief active periods separated by long periods of silence, up to 60 s in duration. During these silent periods, 60% of neurons showed non-linear amplification of low-amplitude depolarizing activity. Nearly 40% of the cells, twice as many as in intact cortex, were classified as intrinsically bursting. In cortical network models based on Hodgkin-Huxley-like neurons, the summation of simulated spontaneous miniature excitatory postsynaptic potentials was sufficient to activate a persistent sodium current, initiating action potentials in single neurons that then spread through the network. Consistent with this model, enlarging the isolated cortical territory to an isolated gyrus (30 mm x 20 mm) increased the probability of initiating large-scale activity. In these larger territories, both the frequency and regularity of the slow oscillation approached that generated in intact cortex. The frequency of active periods in an analytical model of the cortical network accurately predicted the scaling observed in simulations and from recordings in cortical slabs of increasing size.", "corpus_id": 4846947, "score": 0 }, { "doc_id": "7563756", "title": "Layer-specific excitatory circuits differentially control recurrent network dynamics in the neocortex", "abstract": "In the absence of external stimuli, the mammalian neocortex shows intrinsic network oscillations. These dynamics are characterized by translaminar assemblies of neurons whose activity synchronizes rhythmically in space and time. How different cortical layers influence the formation of these spontaneous cellular assemblies is poorly understood. We found that excitatory neurons in supragranular and infragranular layers have distinct roles in the regulation of intrinsic low-frequency oscillations in mice in vivo. Optogenetic activation of infragranular neurons generated network activity that resembled spontaneous events, whereas photoinhibition of these same neurons substantially attenuated slow ongoing dynamics. In contrast, light activation and inhibition of supragranular cells had modest effects on spontaneous slow activity. This study represents, to the best of our knowledge, the first causal demonstration that excitatory circuits located in distinct cortical layers differentially control spontaneous low-frequency dynamics.", "corpus_id": 7563756, "score": 0 }, { "doc_id": "4387337", "title": "A neural circuit for spatial summation in visual cortex", "abstract": "The response of cortical neurons to a sensory stimulus is modulated by the context. In the visual cortex, for example, stimulation of a pyramidal cell's receptive-field surround can attenuate the cell’s response to a stimulus in the centre of its receptive field, a phenomenon called surround suppression. Whether cortical circuits contribute to surround suppression or whether the phenomenon is entirely relayed from earlier stages of visual processing is debated. Here we show that, in contrast to pyramidal cells, the response of somatostatin-expressing inhibitory neurons (SOMs) in the superficial layers of the mouse visual cortex increases with stimulation of the receptive-field surround. This difference results from the preferential excitation of SOMs by horizontal cortical axons. By perturbing the activity of SOMs, we show that these neurons contribute to pyramidal cells' surround suppression. These results establish a cortical circuit for surround suppression and attribute a particular function to a genetically defined type of inhibitory neuron.", "corpus_id": 4387337, "score": 0 }, { "doc_id": "17881742", "title": "Motor Cortex Feedback Influences Sensory Processing by Modulating Network State", "abstract": "Long-range corticocortical communication may have important roles in context-dependent sensory processing, yet we know very little about how these pathways influence their target regions. We studied the influence of primary motor cortex activity on primary somatosensory cortex in the mouse whisker system. We show that primary motor and somatosensory cortices undergo coherent, context-dependent changes in network state. Moreover, we show that motor cortex activity can drive changes in somatosensory cortex network state. A series of experiments demonstrate the involvement of the direct corticocortical feedback pathway, providing temporally precise and spatially targeted modulation of network dynamics. Cortically mediated changes in network state significantly impact sensory coding, with activated states increasing the reliability of responses to complex stimuli. By influencing network state, corticocortical communication from motor cortex may ensure that during active exploration the relevant sensory region is primed for enhanced sensory discrimination.", "corpus_id": 17881742, "score": 0 }, { "doc_id": "15216287", "title": "Pupil fluctuations track rapid changes in adrenergic and cholinergic activity in cortex", "abstract": "Rapid variations in cortical state during wakefulness have a strong influence on neural and behavioural responses and are tightly coupled to changes in pupil size across species. However, the physiological processes linking cortical state and pupil variations are largely unknown. Here we demonstrate that these rapid variations, during both quiet waking and locomotion, are highly correlated with fluctuations in the activity of corticopetal noradrenergic and cholinergic projections. Rapid dilations of the pupil are tightly associated with phasic activity in noradrenergic axons, whereas longer-lasting dilations of the pupil, such as during locomotion, are accompanied by sustained activity in cholinergic axons. Thus, the pupil can be used to sensitively track the activity in multiple neuromodulatory transmitter systems as they control the state of the waking brain.", "corpus_id": 15216287, "score": 0 }, { "doc_id": "9731538", "title": "Basal Forebrain Activation Enhances Cortical Coding of Natural Scenes", "abstract": "The nucleus basalis of the basal forebrain is an essential component of the neuromodulatory system controlling the behavioral state of an animal and it is thought to be important in regulating arousal and attention. However, the effect of nucleus basalis activation on sensory processing remains poorly understood. Using polytrode recording in rat visual cortex, we found that nucleus basalis stimulation caused prominent decorrelation between neurons and marked improvement in the reliability of neuronal responses to natural scenes. The decorrelation depended on local activation of cortical muscarinic acetylcholine receptors, whereas the increased reliability involved distributed neural circuits, as evidenced by nucleus basalis–induced changes in thalamic responses. Further analysis showed that the decorrelation and increased reliability improved cortical representation of natural stimuli in a complementary manner. Thus, the basal forebrain neuromodulatory circuit, which is known to be activated during aroused and attentive states, acts through both local and distributed mechanisms to improve sensory coding.", "corpus_id": 9731538, "score": 0 }, { "doc_id": "17323916", "title": "Effects and Mechanisms of Wakefulness on Local Cortical Networks", "abstract": "Mammalian brains generate internal activity independent of environmental stimuli. Internally generated states may bring about distinct cortical processing modes. To investigate how brain state impacts cortical circuitry, we recorded intracellularly from the same neurons, under anesthesia and subsequent wakefulness, in rat barrel cortex. In every cell examined throughout layers 2-6, wakefulness produced a temporal pattern of synaptic inputs differing markedly from those under anesthesia. Recurring periods of synaptic quiescence, prominent under anesthesia, were abolished by wakefulness, which produced instead a persistently depolarized state. This switch in dynamics was unaffected by elimination of afferent synaptic input from thalamus, suggesting that arousal alters cortical dynamics by neuromodulators acting directly on cortex. Indeed, blockade of noradrenergic, but not cholinergic, pathways induced synaptic quiescence during wakefulness. We conclude that global brain states can switch local recurrent networks into different regimes via direct neuromodulation.", "corpus_id": 17323916, "score": 0 }, { "doc_id": "27412323", "title": "Cortical gamma band synchronization through somatostatin interneurons", "abstract": "Gamma band rhythms may synchronize distributed cell assemblies to facilitate information transfer within and across brain areas, yet their underlying mechanisms remain hotly debated. Most circuit models postulate that soma-targeting parvalbumin-positive GABAergic neurons are the essential inhibitory neuron subtype necessary for gamma rhythms. Using cell-type-specific optogenetic manipulations in behaving animals, we show that dendrite-targeting somatostatin (SOM) interneurons are critical for a visually induced, context-dependent gamma rhythm in visual cortex. A computational model independently predicts that context-dependent gamma rhythms depend critically on SOM interneurons. Further in vivo experiments show that SOM neurons are required for long-distance coherence across the visual cortex. Taken together, these data establish an alternative mechanism for synchronizing distributed networks in visual cortex. By operating through dendritic and not just somatic inhibition, SOM-mediated oscillations may expand the computational power of gamma rhythms for optimizing the synthesis and storage of visual perceptions.", "corpus_id": 27412323, "score": 0 }, { "doc_id": "6574883", "title": "Cortical Enlightenment: Are Attentional Gamma Oscillations Driven by ING or PING?", "abstract": "The response of a neuron to sensory stimuli can only give correlational support for functional hypotheses. To experimentally test causal function, the neural activity needs to be manipulated in a cell-type-specific as well as spatially and temporally precise way. We review recent optogenetic experiments on parvalbumin-positive cortical interneurons that link modeling studies of synchronization to experimental studies on attentional modulation of gamma oscillations in primates.", "corpus_id": 6574883, "score": 0 }, { "doc_id": "18684033", "title": "Interaction of sensory responses with spontaneous depolarization in layer 2/3 barrel cortex", "abstract": "The rodent primary somatosensory cortex is spontaneously active in the form of locally synchronous membrane depolarizations (UP states) separated by quiescent hyperpolarized periods (DOWN states) both under anesthesia and during quiet wakefulness. In vivo whole-cell recordings and tetrode unit recordings were combined with voltage-sensitive dye imaging to analyze the relationship of the activity of individual pyramidal neurons in layer 2/3 to the ensemble spatiotemporal dynamics of the spontaneous depolarizations. These were either brief and localized to an area of a barrel column or occurred as propagating waves dependent on local glutamatergic synaptic transmission in layer 2/3. Spontaneous activity inhibited the sensory responses evoked by whisker deflection, accounting almost entirely for the large trial-to-trial variability of sensory-evoked postsynaptic potentials and action potentials. Subthreshold sensory synaptic responses evoked while a cortical area was spontaneously depolarized were smaller, briefer and spatially more confined. Surprisingly, whisker deflections evoked fewer action potentials during the spontaneous depolarizations despite neurons being closer to threshold. The ongoing spontaneous activity thus regulates the amplitude and the time-dependent spread of the sensory response in layer 2/3 barrel cortex.", "corpus_id": 18684033, "score": 0 }, { "doc_id": "45894212", "title": "Precise long-range synchronization of activity and silence in neocortical neurons during slow-wave oscillations [corrected].", "abstract": "Slow-wave sleep is characterized by alternating periods of activity and silence in corticothalamic networks. Both activity and silence are stable network states, but the mechanisms of their alternation remain unknown. We show, using simultaneous multisite intracellular recordings in cats, that slow rhythm involves all neocortical neurons and that both activity and silence started almost synchronously in cells located up to 12 mm apart. Activity appeared predominantly at the area 5/7 border and spread in both anterior and posterior directions. The activity started earlier in fast-spiking cells and intrinsically bursting cells than in regular-spiking neurons. These results provide direct evidence for two mechanisms of active state generation: spread of activity from a local focus and synchronization of weaker activity, originating at multiple locations. Surprisingly, onsets of silent states were synchronized even more precisely than the onsets of activity, showing no latency bias for location or cell type. This most intriguing finding exposes a major gap in understanding the nature of state alternation. We suggest that it is the synchronous termination of activity and occurrence of silent states of the neuronal network that makes the EEG picture during slow-wave sleep so characteristic. Synchronous onset of silence in distant neurons cannot rely exclusively on properties of individual cells and synapses, such as adaptation of neuronal firing or synaptic depression; instead, it implies the existence of a network mechanism. Revealing this yet unknown large-scale mechanism, which switches network activity to silence, will aid our understanding of the origin of brain rhythms in normal function and pathology.", "corpus_id": 45894212, "score": 0 }, { "doc_id": "207218383", "title": "Somatosensory Cortex Plays an Essential Role in Forelimb Motor Adaptation in Mice", "abstract": "Our motor outputs are constantly re-calibrated to adapt to systematic perturbations. This motor adaptation is thought to depend on the ability to form a memory of a systematic perturbation, often called an internal model. However, the mechanisms underlying the formation, storage, and expression of such models remain unknown. Here, we developed a mouse model to study forelimb adaptation to force field perturbations. We found that temporally precise photoinhibition of somatosensory cortex (S1) applied concurrently with the force field abolished the ability to update subsequent motor commands needed to reduce motor errors. This S1 photoinhibition did not impair basic motor patterns, post-perturbation completion of the action, or their performance in a reward-based learning task. Moreover, S1 photoinhibition after partial adaptation blocked further adaptation, but did not affect the expression of already-adapted motor commands. Thus, S1 is critically involved in updating the memory about the perturbation that is essential for forelimb motor adaptation.", "corpus_id": 207218383, "score": 0 }, { "doc_id": "206529164", "title": "Motor Control by Sensory Cortex", "abstract": "By a Whisker Every student learns that the sensory cortex is used for processing sensation and the motor cortex is used for perceiving movement. However, in the real world, this may not always be so neatly arranged. Matyas et al. (p. 1240) have found that sensory and motor fields are specialized for different types of movement, such that in mice the motor cortex controlled the forward movement (protraction) of their whiskers and the sensory cortex controlled backwards movements (retraction) of whiskers. So if a whisker hits an object, then a reasonable first reaction might be a motor command for retraction. Similarly, the motor cortex stimulates protraction for more active exploration. Hence, the sensory cortex is also motor and the motor cortex is also sensory. In an ecological context, these combined reactions offer a repertoire useful for a mouse seeking food and shelter in a complex environment. Mouse whisker movements are controlled by both the sensory and motor cortex. Classical studies of mammalian movement control define a prominent role for the primary motor cortex. Investigating the mouse whisker system, we found an additional and equally direct pathway for cortical motor control driven by the primary somatosensory cortex. Whereas activity in primary motor cortex directly evokes exploratory whisker protraction, primary somatosensory cortex directly drives whisker retraction, providing a rapid negative feedback signal for sensorimotor integration. Motor control by sensory cortex suggests the need to reevaluate the functional organization of cortical maps.", "corpus_id": 206529164, "score": 0 }, { "doc_id": "133982", "title": "Dynamic spike threshold reveals a mechanism for synaptic coincidence detection in cortical neurons in vivo.", "abstract": "Cortical neurons are sensitive to the timing of their synaptic inputs. They can synchronize their firing on a millisecond time scale and follow rapid stimulus fluctuations with high temporal precision. These findings suggest that cortical neurons have an enhanced sensitivity to synchronous synaptic inputs that lead to rapid rates of depolarization. The voltage-gated currents underlying action potential generation may provide one mechanism to amplify rapid depolarizations. We have tested this hypothesis by analyzing the relations between membrane potential fluctuations and spike threshold in cat visual cortical neurons recorded intracellularly in vivo. We find that visual stimuli evoke broad variations in spike threshold that are caused in large part by an inverse relation between spike threshold and the rate of membrane depolarization preceding a spike. We also find that spike threshold is inversely related to the rate of rise of the action potential upstroke, suggesting that increases in spike threshold result from a decrease in the availability of Na(+) channels. By using a simple neuronal model, we show that voltage-gated Na(+) and K(+) conductances endow cortical neurons with an enhanced sensitivity to rapid depolarizations that arise from synchronous excitatory synaptic inputs. Thus, the basic mechanism responsible for action potential generation also enhances the sensitivity of cortical neurons to coincident synaptic inputs.", "corpus_id": 133982, "score": 0 } ]

{ "doc_id": "12027220", "title": "Mirror symmetry and toric degenerations of partial flag manifolds", "abstract": "In this paper we propose and discuss a mirror construction for complete intersections in partial flag manifolds F (n1, . . . , nl, n). This construction includes our previous mirror construction for complete intersection in Grassmannians and the mirror construction of Givental for complete flag manifolds. The key idea of our construction is a degeneration of F (n1, . . . , nl, n) to a certain Gorenstein toric Fano variety P (n1, . . . , nl, n) which has been investigated by Gonciulea and Lakshmibai. We describe a natural small crepant desingularization of P (n1, . . . , nl, n) and prove a generalized version of a conjecture of Gonciulea and Lakshmibai on the singular locus of P (n1, . . . , nl, n). Mathematisches Institut, Eberhard-Karls-Universitat Tubingen, D-72076 Tubingen, Germany, email address: batyrev@bastau.mathematik.uni-tuebingen.de Department of Mathematics, Oklahoma State University, Stillwater, OK 74078, USA email address: ciocan@math.okstate.edu Department of Mathematics, University of California Davis, Davis, CA 95616, USA email address: bumsig@math.ucdavis.edu FB 17, Mathematik, Johannes Gutenberg-Universitat Mainz, D-55099 Mainz, Germany, email address: straten@mathematik.uni-mainz.de", "corpus_id": 12027220 }

[ { "doc_id": "18222916", "title": "Dual Polyhedra and Mirror Symmetry for Calabi-Yau Hypersurfaces in Toric Varieties", "abstract": "We consider families ${\\cal F}(\\Delta)$ consisting of complex $(n-1)$-dimensional projective algebraic compactifications of $\\Delta$-regular affine hypersurfaces $Z_f$ defined by Laurent polynomials $f$ with a fixed $n$-dimensional Newton polyhedron $\\Delta$ in $n$-dimensional algebraic torus ${\\bf T} =({\\bf C}^*)^n$. If the family ${\\cal F}(\\Delta)$ defined by a Newton polyhedron $\\Delta$ consists of $(n-1)$-dimensional Calabi-Yau varieties, then the dual, or polar, polyhedron $\\Delta^*$ in the dual space defines another family ${\\cal F}(\\Delta^*)$ of Calabi-Yau varieties, so that we obtain the remarkable duality between two {\\em different families} of Calabi-Yau varieties. It is shown that the properties of this duality coincide with the properties of {\\em Mirror Symmetry} discovered by physicists for Calabi-Yau $3$-folds. Our method allows to construct many new examples of Calabi-Yau $3$-folds and new candidats for their mirrors which were previously unknown for physicists. We conjecture that there exists an isomorphism between two conformal field theories corresponding to Calabi-Yau varieties from two families ${\\cal F}(\\Delta)$ and ${\\cal F}(\\Delta^*)$.", "corpus_id": 18222916, "score": 0 }, { "doc_id": "16401756", "title": "Generalized hypergeometric functions and rational curves on Calabi-Yau complete intersections in toric varieties", "abstract": "We formulate general conjectures about the relationship between the A-model connection on the cohomology of ad-dimensional Calabi-Yau complete intersectionV ofr hypersurfacesV1,...,Vr in a toric varietyPΣ and the system of differential operators annihilating the special generalized hypergeometric series Φ0 constructed from the fan Σ. Using this generalized hypergeometric series, we propose conjectural mirrorsV′ ofV and the canonicalq-coordinates on the moduli spaces of Calabi-Yau manifolds.In the second part of the paper we consider some examples of Calabi-Yau 3-folds having Picard number >1 in products of projective spaces. For conjectural mirrors, using the recurrent relation among coefficients of the restriction of the hypergeometric function Φ0 on a special line in the moduli space, we determine the Picard-Fuchs equation satisfied by periods of this special one-parameter subfamily. This allows to obtain some sequences of integers which can be conjecturally interpreted in terms of Gromov-Witten invariants. Using standard techniques from enumerative geometry, first terms of these sequence of integers are checked to coincide with numbers of rational curves on Calabi-Yau 3-folds.", "corpus_id": 16401756, "score": 1 }, { "doc_id": "122609279", "title": "Gröbner bases and convex polytopes", "abstract": "Grobner basics The state polytope Variation of term orders Toric ideals Enumeration, sampling and integer programming Primitive partition identities Universal Grobner bases Regular triangulations The second hypersimplex $\\mathcal A$-graded algebras Canonical subalgebra bases Generators, Betti numbers and localizations Toric varieties in algebraic geometry Some specific Grobner bases Bibliography Index.", "corpus_id": 122609279, "score": 0 }, { "doc_id": "123375476", "title": "Degenerations of flag and Schubert varieties to toric varieties", "abstract": "In this paper, we prove the degenerations of Schubert varieties in a minusculeG/P, as well as the class of Kempf varieties in the flag varietySL(n)/B, to (normal) toric varieties. As a consequence, we obtain that determinantal varietes degenerate to (normal) toric varieties.", "corpus_id": 123375476, "score": 0 }, { "doc_id": "16493118", "title": "SCHUBERT VARIETIES , TORIC VARIETIES , AND LADDERDETERMINANTAL", "abstract": "We contruct certain normal toric varieties (associated to nite distribu-tive lattices) which are degenerations of the Grassmannians. We also determine the singular loci for certain normal toric varieties, namely the ones which are certain ladder determinantal varieties. As a consequence, we prove the conjecture of 17] on the components of the singular locus, for certain Schubert varieties in the ag variety.", "corpus_id": 16493118, "score": 1 }, { "doc_id": "16516514", "title": "Stationary Phase Integrals, Quantum Toda Lattices, Flag Manifolds and the Mirror Conjecture", "abstract": "A generalization of the mirror conjecture is proven for the manifolds of complete flags in C^n.", "corpus_id": 16516514, "score": 1 }, { "doc_id": "16250111", "title": "Toric Degenerations of Fano Varieties and Constructing Mirror Manifolds", "abstract": "For an arbitrary smooth n-dimensional Fano variety $X$ we introduce the notion of a small toric degeneration. Using small toric degenerations of Fano n-folds $X$, we propose a general method for constructing mirrors of Calabi-Yau complete intersections in $X$. Our mirror construction is based on a generalized monomial-divisor mirror correspondence which can be used for computing Gromov-Witten invariants of rational curves via specializations of GKZ-hypergeometric series.", "corpus_id": 16250111, "score": 0 }, { "doc_id": "2770458", "title": "On quantum cohomology rings of partial flag varieties", "abstract": "0. Introduction. The main goal of this paper is to give a unified description for the structure of the small quantum cohomology rings for all projective homogeneous spaces SLn(C)/P , where P is a parabolic subgroup. The quantum cohomology ring of a smooth projective variety, or more generally of a symplectic manifoldX, has been introduced by string theorists (see [Va] and [W1]). Roughly speaking, it is a deformation of the usual cohomology ring, with parameter space given byH ∗(X). The multiplicative structure of quantum cohomology encodes the enumerative geometry of rational curves on X. In the past few years, the highly nontrivial task of giving a rigorous mathematical treatment of quantum cohomology has been accomplished both in the realm of algebraic and symplectic geometry. In various degrees of generality, this can be found in [Beh], [BehM], [KM], [LiT1], [LiT2], [McS], and [RT], as well as in the surveys [FP] and [T]. If one restricts the parameter space to H 1,1(X), one gets the small quantum cohomology ring. This ring, in the case of partial flag varieties, is the object of the present paper. In order to state our main results, we first describe briefly the “classical” side of the story. We interpret the homogeneous space F := SLn(C)/P as the complex, projective variety, parametrizing flags of quotients of C of given ranks, say, nk > · · ·> n1. By a classical result of Ehresmann [E], the integral cohomology of F can be described geometrically as the free abelian group generated by the Schubert classes. These are the (Poincare duals of) fundamental classes of certain subvarieties w ⊂ F , one for each element of the subset S := S(n1, . . . ,nk) of the symmetric group Sn, consisting of permutations w with descents in {n1, . . . ,nk}. A description of the multiplicative structure is provided by yet another classical theorem, due to Borel [Bor], which gives a presentation forH ∗(F,Z). Specifically, let σ 1 1 , . . . ,σ 1 n1 ,σ 2 1 , . . . ,σ 2 n2−n1, . . . ,σ k+1 1 , . . . ,σ k+1 n−nk be n independent variables. Define An to be the block-diagonal matrix diag(D1,D2, . . . ,Dk+1), where", "corpus_id": 2770458, "score": 0 }, { "doc_id": "18043336", "title": "THEOREM FOR HOMOGENEOUS SPACES", "abstract": "We formulated a mirror-free approach to the mirror conjecture, namely, quantum hyperplane section conjecture, and proved it in the case of nonnegative complete intersections in homogeneous manifolds. For the proof we followed the scheme of Givental's proof of a mirror theorem for toric complete intersections.", "corpus_id": 18043336, "score": 1 }, { "doc_id": "15109303", "title": "On Hypergeometric Functions Connected with Quantum Cohomology of Flag Spaces", "abstract": "Abstract:The Givental recursion relations for hypergeometric series associated with equivariant quantum cohomology are computed for flags varieties G/B. A simple formula for these functions is obtained in the case G=SL(3).", "corpus_id": 15109303, "score": 0 }, { "doc_id": "2884104", "title": "A mirror theorem for toric complete intersections", "abstract": "We prove a generalized mirror conjecture for non-negative complete intersections in symplectic toric manifolds. Namely, we express solutions of the PDE system describing quantum cohomology of such a manifold in terms of suitable hypergeometric functions. Revision 03.03.97: we correct an error in Introduction.", "corpus_id": 2884104, "score": 1 }, { "doc_id": "119003295", "title": "Introduction to Toric Varieties.", "abstract": "Toric varieties are algebraic varieties arising from elementary geometric and combinatorial objects such as convex polytopes in Euclidean space with vertices on lattice points. Since many algebraic geometry notions such as singularities, birational maps, cycles, homology, intersection theory, and Riemann-Roch translate into simple facts about polytopes, toric varieties provide a marvelous source of examples in algebraic geometry. In the other direction, general facts from algebraic geometry have implications for such polytopes, such as to the problem of the number of lattice points they contain. In spite of the fact that toric varieties are very special in the spectrum of all algebraic varieties, they provide a remarkably useful testing ground for general theories.The aim of this mini-course is to develop the foundations of the study of toric varieties, with examples, and describe some of these relations and applications. The text concludes with Stanley's theorem characterizing the numbers of simplicies in each dimension in a convex simplicial polytope. Although some general theorems are quoted without proof, the concrete interpretations via simplicial geometry should make the text accessible to beginners in algebraic geometry.", "corpus_id": 119003295, "score": 0 }, { "doc_id": "119645049", "title": "Quantum cohomology of partial flag manifolds\n$$F_{n_1 } \\ldots _{n_k }$$\n", "abstract": "AbstractWe compute the quantum cohomology rings of the partial flag manifolds\n$$F_{n_1 } \\ldots _{n_k } = U(n)/(U(n_1 ) \\times \\cdots \\times U(n_k ))$$\n. The inductive computation uses the idea of Givental and Kim [1]. Also we define a notion of the vertical quantum cohomology ring of the algebraic bundle. For the flag bundle\n$$F_{n_1 } \\ldots _{n_k }$$\n(E) associated with the vector bundleE this ring is found.", "corpus_id": 119645049, "score": 0 }, { "doc_id": "119680171", "title": "Quantum Cohomology of Partial Flag Manifolds and a Residue Formula for Their Intersection Parings", "abstract": "As a generalization of our previous paper [GK], we formulate a residue formula and some simple behaviors of equivariant quantum cohomology applying to compute the quantum cohomology of partial flag manifolds $F_{k_1,\\cdots , k_l} $with a try to give a rigorous definition of equivariant quantum cohomology.", "corpus_id": 119680171, "score": 0 } ]

{ "doc_id": "195739861", "title": "Energy-Aware RFID Authentication in Edge Computing", "abstract": "Internet of Things (IoT) devices are basic units in edge computing. Denial of service (DoS) attack is a great threat to low-cost IoT devices, even worse in privacy-preserving authentication protocols for radio frequency identification (RFID) tags. During DoS attacks, the attacker consumes the legal states in a target tag by continuous scanning and further observes its behavior in authentication to break privacy. Due to lack of adequate energy and computing power, it is hard for passive backscattering RFID tags to defend against DoS attacks. In this work, we cast a new insight on the DoS attacks to RFID tags and leverage the malicious scanning behavior as a new energy source. In this way, a passive tag gains more and more energy and can afford more and more complex cryptography computation under a DoS attack. Finally, the victim tag with adequate energy achieves to complete the complicated public key cryptographic computations and defend against the DoS attack. We further propose a protocol, namely the RUND protocol. We define the tracking privacy model and introduce in the notion of tracking interval to define the tracking privacy other than indistinguishable privacy. To guarantee the security and tracking privacy properties of our protocol, we propose 3 rules as designing guidelines. The analysis shows that our approach can achieve $O$ (1) efficiency while providing DoS-defending privacy-preserving authentication. Furthermore, with proper parameters our approach can save about 40% boosting time at least, compared to the directly charging for public key cryptographic computation method.", "corpus_id": 195739861 }

[ { "doc_id": "3986590", "title": "OTrack: Order tracking for luggage in mobile RFID systems", "abstract": "In many logistics applications of RFID technology, goods attached with tags are placed on moving conveyor belts for processing. It is important to figure out the order of goods on the belts so that further actions like sorting can be accurately taken on proper goods. Due to arbitrary goods placement or the irregularity of wireless signal propagation, neither of the order of tag identification nor the received signal strength provides sufficient evidence on their relative positions on the belts. In this study, we observe, from experiments, a critical region of reading rate when a tag gets close enough to a reader. This phenomenon, as well as other signal attributes, yields the stable indication of tag order. We establish a probabilistic model for recognizing the transient critical region and propose the OTrack protocol to continuously monitor the order of tags. To validate the protocol, we evaluate the accuracy and effectiveness through a one-month experiment conducted through a working conveyor at Beijing Capital International Airport.", "corpus_id": 3986590, "score": 0 }, { "doc_id": "8494194", "title": "PLACE: Physical Layer Cardinality Estimation for Large-Scale RFID Systems", "abstract": "Estimating the number of RFID tags is a fundamental operation in RFID systems and has recently attracted wide attentions. Despite the subtleties in their designs, previous methods estimate the tag cardinality from the slot measurements, which distinguish idle and busy slots and based on that derive the cardinality following some probability models. In order to fundamentally improve the counting efficiency, in this paper we introduce PLACE, a physical layer based cardinality estimator. We show that it is possible to extract more information and infer integer states from the same slots in RFID communications. We propose a joint estimator that optimally combines multiple sub-estimators, each of which independently counts the number of tags with different inferred PHY states. Extensive experiments based on the GNURadio/USRP platform and the large-scale simulations demonstrate that PLACE achieves approximately 3 ~ 4× performance improvement over state-of-the-art cardinality estimation approaches.", "corpus_id": 8494194, "score": 0 }, { "doc_id": "18244725", "title": "Tagoram: real-time tracking of mobile RFID tags to high precision using COTS devices", "abstract": "In many applications, we have to identify an object and then locate the object to within high precision (centimeter- or millimeter-level). Legacy systems that can provide such accuracy are either expensive or suffering from performance degradation resulting from various impacts, e.g., occlusion for computer vision based approaches. In this work, we present an RFID-based system, Tagoram, for object localization and tracking using COTS RFID tags and readers. Tracking mobile RFID tags in real time has been a daunting task, especially challenging for achieving high precision. Our system achieves these three goals by leveraging the phase value of the backscattered signal, provided by the COTS RFID readers, to estimate the location of the object. In Tagoram, we exploit the tag's mobility to build a virtual antenna array by using readings from a few physical antennas over a time window. To illustrate the basic idea of our system, we firstly focus on a simple scenario where the tag is moving along a fixed track known to the system. We propose Differential Augmented Hologram (DAH) which will facilitate the instant tracking of the mobile RFID tag to a high precision. We then devise a comprehensive solution to accurately recover the tag's moving trajectories and its locations, relaxing the assumption of knowing tag's track function in advance. We have implemented the Tagoram system using COTS RFID tags and readers. The system has been tested extensively in the lab environment and used for more than a year in real airline applications. For lab environment, we can track the mobile tags in real time with a millimeter accuracy to a median of 5mm and 7.29mm using linear and circular track respectively. In our year- long large scale baggage sortation systems deployed in two airports, our results from real deployments show that Tagoram can achieve a centimeter-level accuracy to a median of 6.35cm in these real deployments.", "corpus_id": 18244725, "score": 0 }, { "doc_id": "62211697", "title": "CBID: A Customer Behavior Identification System Using Passive Tags", "abstract": "Different from online shopping, in-store shopping has few ways to collect the customer behaviors before purchase. In this paper, we present the design and implementation of an on-site Customer Behavior Identification system based on passive RFID tags, named CBID. By collecting and analyzing wireless signal features, CBID can detect and track tag movements and further infer corresponding customer behaviors. We model three main objectives of behavior identification by concrete problems and solve them using novel protocols and algorithms. The design innovations of this work include a Doppler effect based protocol to detect tag movements, an accurate Doppler frequency estimation algorithm, a multi-RSS based tag localization protocol, and a tag clustering algorithm using cosine similarity. We have implemented a prototype of CBID in which all components are built by off-the-shelf devices. We have deployed CBID in real environments and conducted extensive experiments to demonstrate the accuracy and efficiency of CBID in customer behavior identification.", "corpus_id": 62211697, "score": 0 }, { "doc_id": "3987134", "title": "Perceiving the Slightest Tag Motion beyond Localization", "abstract": "Existing methods in RFID systems often employ presence or absence fashion to detect the tags' motions, so they cannot meet motion detection requirement in many applications. Our recent observations suggest that the signal strength backscattered from the tag is hypersensitive to its position, inspiring us to perceive the tag motion through its radio signal strength changes. Motion perception is not trivial and challenged by weak stability of strength in that any other interference or noise may incur significant changes as well, resulting in high false positives. To tackle this issue, we propose to model the strength via the Mixture of Gaussian Model (MoG). The problem is thus converted to foreground segment in computer vision with the help of Strength Image, where the technique of MoG based background subtraction is employed. We then implement a prototype using commercial off-the-shelf products. The evaluation results show that the slightest tag motion (~10 cm) can be precisely perceived, and the accuracy is up to 92.34 percent while the false positive is suppressed under 0.5 percent.", "corpus_id": 3987134, "score": 0 }, { "doc_id": "2395236", "title": "Design of a Passively-Powered, Programmable Sensing Platform for UHF RFID Systems", "abstract": "This paper presents a wireless, battery-free, platform for sensing and computation that is powered and read by a standards compliant ultra-high frequency (UHF) radio frequency identification (RFID) reader. The WISP (wireless identification and sensing platform) includes a fully-programmable 16 bit microcontroller with analog-to-digital converter. The microcontroller firmware implements portions of the electronic product code (EPC) class 1 generation 1 protocol. When queried, the platform communicates arbitrary sensor data by emulating an EPC tag whose ID encodes the desired sensor data; the required 16-bit CRC is computed dynamically by the microcontroller. The RFID reader reports the received tag ID to application software which can interpret the information contained in the tag ID. The programmability of the WISP along with its implementation as a PCB allows for flexible integration of arbitrary low-power sensors. Furthermore, sensors are also exclusively powered from the RFID reader resulting in a completely battery free device. Sensors integrated into the WISP platform so far include light, temperature, and rectified voltage, and are shown experimentally to have an operating range of up to 4.5m. To the authors' knowledge, WISP is the first fully programmable computing platform that can operate using power transmitted from a long-range (UHF) RFID reader and communicate arbitrary, multi-bit data in a single response packet.", "corpus_id": 2395236, "score": 0 }, { "doc_id": "13242205", "title": "Hash Functions and RFID Tags: Mind the Gap", "abstract": "The security challenges posed by RFID-tag deployments are well-known. In response there is a rich literature on new cryptographic protocols and an on-tag hash function is often assumed by protocol designers. Yet cheap tags pose severe implementation challenges and it is far from clear that a suitable hash function even exists. In this paper we consider the options available, including constructions based around compact block ciphers. While we describe the most compact hash functions available today, our work serves to highlight the difficulties in designing lightweight hash functions and (echoing [17]) we urge caution when routinely appealing to a hash function in an RFID-tag protocol.", "corpus_id": 13242205, "score": 0 }, { "doc_id": "11883503", "title": "Privacy-Friendly Authentication in RFID Systems: On Sublinear Protocols Based on Symmetric-Key Cryptography", "abstract": "The recent advent of ubiquitous technologies has raised an important concern for citizens: the need to protect their privacy. So far, this wish was not heard of industrials, but national and international regulation authorities, as the European Commission recently published some guidelines to enforce customers' privacy in RFID systems: \"Privacy by designâ is the way to be followed as stated in EC Recommendation of 12.5.2009. Research on privacy is an active domain but there is still a wide gap between theory and everyday life's applications. Filling this gap will require academia to design protocols and algorithms that fit the real-life constraints. In this paper, we provide a comprehensive analysis of privacy-friendly authentication protocols devoted to RFID that: 1) are based on well-established symmetric-key cryptographic building blocks; 2) require a reader complexity lower than O(N) where N is the number of provers in the system. These two properties are sine qua non conditions for deploying privacy-friendly authentication protocols in large-scale applications, for example, access control in mass transportation. We describe existing protocols fulfilling these requirements and point out their drawbacks and weaknesses. We especially introduce attacks on CHT, CTI,YA-TRAP*, and the variant of OSK/AO with mutual authentication. We also raise that some protocols, such as O-RAP, O-FRAP, and OSK/BF, are not resistant to timing attacks. Finally, we select some candidates that are, according to our criteria, the most appropriate ones for practical uses.", "corpus_id": 11883503, "score": 1 }, { "doc_id": "6800444", "title": "Reducing Time Complexity in RFID Systems", "abstract": "Radio frequency identification systems based on low-cost computing devices is the new plaything that every company would like to adopt. Its goal can be either to improve the productivity or to strengthen the security. Specific identification protocols based on symmetric challenge-response have been developed in order to assure the privacy of the device bearers. Although these protocols fit the devices' constraints, they always suffer from a large time complexity. Existing protocols require O(n) cryptographic operations to identify one device among n. \n \nMolnar and Wagner suggested a method to reduce this complexity to O(log n). We show that their technique could degrade the privacy if the attacker has the possibility to tamper with at least one device. Because low-cost devices are not tamper-resistant, such an attack could be feasible. We give a detailed analysis of their protocol and evaluate the threat. Next, we extend an approach based on time-memory trade-offs whose goal is to improve Ohkubo, Suzuki, and Kinoshita's protocol. We show that in practice this approach reaches the same performances as Molnar and Wagner's method, without degrading privacy.", "corpus_id": 6800444, "score": 0 }, { "doc_id": "18870506", "title": "A Secure High-Speed Identification Scheme for RFID Using Bloom Filters", "abstract": "As pervasive computing environments become popular, RFID tags are introduced into our daily life. However, there exists a privacy problem that an adversary can trace users' behavior by linking the tag's ID. Although a Hash-chain scheme can solve this privacy problem, the scheme needs a long identification time or a large amount of memory. In this paper, we propose an efficient identification scheme using Bloom filters, which are space-efficient probabilistic data structures. Our Bloom pre-calculation scheme provides a high-speed identification with a small amount of memory by storing pre-calculated outputs of the tags in Bloom filters.", "corpus_id": 18870506, "score": 0 }, { "doc_id": "14577100", "title": "Cryptographic Approach to “Privacy-Friendly” Tags", "abstract": "Radio frequency identification (RFID) is expected to become an important and ubiquitous infrastructure technology. As RFID tags are affixed to everyday items, they may be used to support various useful services. However, widespread deployment of RFID tags may create new threats to user privacy, due to the powerful tracking capability of the tags. There are several important technical points when constructing an RFID scheme. Particularly important is ensuring forward security, i.e., data transmitted today will still be secure even if secret tag information is revealed by tampering in the future. Low cost implementation is another key RFID requirement. This paper discusses and clarifies the requirements and restrictions of RFID systems. This paper also examines the features and issues pertinent to several existing RFID schemes. Finally, this paper suggests the use of our previously proposed scheme, which protects user privacy using a low-cost hash chain mechanism.", "corpus_id": 14577100, "score": 0 }, { "doc_id": "3075720", "title": "MAP: Towards Authentication for Multiple Tags", "abstract": "The prevalence of Radio Frequency Identification (RFID) technology requires Privacy-Preserving Authentication (PPA) protocols to prevent privacy leakage during authentication. Existing PPA protocols employ the per-tag authentication, in which the reader has to sequentially authenticate the tags within the detecting region. Such a processing pattern becomes a bottleneck in current RFID enabled systems, especially for those batch-type processing applications. In this paper, we propose an efficient authentication protocol, which leverages the collaboration among multiple tags for accelerating the authentication speed. We also find that the collision, usually being considered as a negative factor, is helpful media to enable collaborative authentication among tags. Our protocol, termed as Multiple-tags privacy-preserving Authentication Protocol (MAP), authenticates a batch of tags concurrently with strong privacy and high efficiency. The analytical and simulation results show that the efficiency of MAP is better than O( log N ) and asymptotically approaches O(1).", "corpus_id": 3075720, "score": 0 }, { "doc_id": "3526499", "title": "Attack gives me power: DoS-defending constant-time privacy-preserving authentication of low-cost devices such as backscattering RFID tags", "abstract": "Denial of service (DoS) attack is a great threaten to privacy-preserving authentication protocols for low-cost devices such as RFID. During such attack, the legal internal states can be consumed by the DoS attack. Then the attacker can observe the behavior of the attacked tag in authentication to break privacy. Due to the inadequate energy and computing power, the low cost devices can hardly defend against the DoS attacks. In this paper, we propose a new insight of the DoS attack on tags and leverage the attacking behavior as a new source of power harvesting. In this way, a low-cost device such as a tag grows more and more powerful under DoS attack. Finally, it can defend against the DoS attack. We further propose a protocol that enables DoS-defending constant-time privacy-preserving authentication.", "corpus_id": 3526499, "score": 0 }, { "doc_id": "10840680", "title": "Time Measurement Threatens Privacy-Friendly RFID Authentication Protocols", "abstract": "Privacy is one of the most important security concerns in radio frequency identification. The publication of hundred RFID-based authentication protocols during the last decade raised the need of designing a dedicated privacy model. An important step has been done with the model of Vaudenay that combines early models into a unified and powerful one. In particular, this model addresses the case where an adversary is able to know whether or not the protocol execution succeeded. This modelizes the fact that the adversary may get information from a side channel about the termination of the protocol, e.g., she notices that the access is granted to the RFID-tag holder. We go one step forward in this paper and stress that the adversary may also have access to a side channel that leaks the computational time of the reader. This modelizes an adversary who measures how long it takes to grant the access. Although this channel could be seen as an implementation flaw, we consider that it is always risky to require the implementation to solve what the design should deal with. This new channel enables to demonstrate that many key-reference protocols are not as privacy-friendly as they claim to be, e.g., WSRE, OSK, C2, O-FRAP, O-FRAKE,... We then introduce the TIMEFUL oracle in the model of Vaudenay, which allows to analyze the resistance of the protocols to time-based attacks as soon as the design phase. Finally, we suggest some methods that make RFID-based authentication protocols immune to such attacks.", "corpus_id": 10840680, "score": 0 }, { "doc_id": "20721117", "title": "QoS Prediction for Web Service Recommendation with Network Location-Aware Neighbor Selection", "abstract": "Web service recommendation is one of the key problems in service computing, especially in the case of a large number of service candidates. The QoS (quality of service) values are usually leveraged to recommend services that best satisfy a user’s demand. There are many existing methods using collaborative filtering (CF) to predict QoS missing values, but very limited works can leverage the network location information in the user side and service side. In real-world service invocation scenario, the network location of a user or a service makes great impact on QoS. In this paper, we propose a novel collaborative recommendation framework containing three novel prediction models, which are based on two techniques, i.e. matrix factorization (MF) and network location-aware neighbor selection. We first propose two individual models that have the capability of using the user and service information, respectively. Then we propose a unified model that combines the results of the two individual models. We conduct sufficient experiments on a real-world dataset. The experimental results demonstrate that our models achieve higher prediction accuracy than baseline models, and are not sensitive to the parameters.", "corpus_id": 20721117, "score": 0 }, { "doc_id": "7959942", "title": "Rethinking RFID: awareness and control for interaction with RFID systems", "abstract": "People now routinely carry radio frequency identification (RFID) tags - in passports, driver's licenses, credit cards, and other identifying cards - from which nearby RFID readers can access privacy-sensitive information. The problem is that people are often unaware of security and privacy risks associated with RFID, likely because the technology remains largely invisible and uncontrollable for the individual. To mitigate this problem, we introduce a collection of novel yet simple and inexpensive tag designs. Our tags provide reader awareness, where people get visual, audible, or tactile feedback as tags come into the range of RFID readers. Our tags also provide information control, where people can allow or disallow access to the information stored on the tag by how they touch, orient, move, press or illuminate the tag.", "corpus_id": 7959942, "score": 0 }, { "doc_id": "7081617", "title": "ECC Is Ready for RFID - A Proof in Silicon", "abstract": "This paper presents the silicon chip ECCon, an Elliptic Curve Cryptography processor for application in Radio-Frequency Identification. The circuit is fabricated on a 180 nm CMOS technology. ECCon features small silicon size (15K GE) and has low power consumption (8.57 μW). It computes 163-bit ECC point-multiplications in 296k cycles and has an ISO 18000-3 RFID interface. ECCon's very low and nearly constant power consumption makes it the first ECC chip that can be powered passively. This major breakthrough is possible because of a radical change in hardware architecture. The ECCon datapath operates on 16-bit words, which is similar to ECC instruction-set extensions. A number of innovations on the algorithmic and on the architectural level substantially increased the efficiency of 163-bit ECC. ECCon is the first demonstration that the proof of origin via electronic signatures can be realized on RFID tags in 180 nm CMOS and below.", "corpus_id": 7081617, "score": 0 }, { "doc_id": "14195263", "title": "Idetic: A high-level synthesis approach for enabling long computations on transiently-powered ASICs", "abstract": "We develop Idetic, a set of mechanisms to enable long computations on ultra-low power Application Specific Integrated Circuits (ASICs) with energy harvesting sources. We address the power transiency and unpredictability problem by optimally inserting checkpoints. Idetic targets highlevel synthesis designs and automatically locates and embeds the checkpoints at the register-transfer level. We define an objective function that aims to find the checkpoints which incur minimum overhead and minimize recomputation energy cost. We develop and exploit a dynamic programming technique to solve the optimization problem. For real time operation, Idetic adaptively adjusts the checkpointing rate based on the available energy level in the system. Idetic is deployed and evaluated on cryptographic benchmark circuits. The test platform harvests RF power through an RFID-reader and stores the energy in a 3.3μF capacitor. For storage of checkpointed data, we evaluate and compare the effectiveness of various non-volatile memories including NAND Flash, PCM, and STTM. Extensive evaluations show that Idetic reliably enables execution of long computations under different source power patterns with low overhead. Our benchmark evaluations demonstrate that the area and energy overheads corresponding to the checkpoints are less than 5% and 11% respectively.", "corpus_id": 14195263, "score": 1 }, { "doc_id": "8900624", "title": "Dewdrop: An Energy-Aware Runtime for Computational RFID", "abstract": "Computational RFID (CRFID) tags embed sensing and computation into the physical world. The operation of the tags is limited by the RF energy that can be harvested from a nearby power source. We present a CRFID run-time, Dewdrop, that makes effective use of the harvested energy. Dewdrop treats iterative tasks as a scheduling problem to balance task demands with available energy, both of which vary over time. It adapts the start time of the next task iteration to consistently run well over a range of distances between tags and a power source, for different numbers of tags in the vicinity, and for light and heavy tasks. We have implemented Dewdrop on top of the WISP CRFID tag. Our experiments show that, compared to normal WISP operation, Dewdrop doubles the operating range for heavy tasks and significantly increases the task rate for tags receiving the least energy, all without decreasing the rate in other situations. Using offline testing, we find that Dewdrop runs tasks at better than 90% of the best rate possible.", "corpus_id": 8900624, "score": 1 }, { "doc_id": "207185520", "title": "Mementos: system support for long-running computation on RFID-scale devices", "abstract": "Transiently powered computing devices such as RFID tags, kinetic energy harvesters, and smart cards typically rely on programs that complete a task under tight time constraints before energy starvation leads to complete loss of volatile memory. Mementos is a software system that transforms general-purpose programs into interruptible computations that are protected from frequent power losses by automatic, energy-aware state checkpointing. Mementos comprises a collection of optimization passes for the LLVM compiler infrastructure and a linkable library that exercises hardware support for energy measurement while managing state checkpoints stored in nonvolatile memory. We evaluate Mementos against diverse test cases in a trace-driven simulator of transiently powered RFID-scale devices. Although Mementos's energy checks increase run time when energy is plentiful, they allow Mementos to safely suspend execution when energy dwindles, effectively spreading computation across zero or more power failures. This paper's contributions are: a study of the runtime environment for programs on RFID-scale devices; an energy-aware state checkpointing system for these devices that is implemented for the MSP430 family of microcontrollers; and a trace-driven simulator of transiently powered RFID-scale devices.", "corpus_id": 207185520, "score": 0 }, { "doc_id": "31072823", "title": "Clank: Architectural support for intermittent computation", "abstract": "The processors that drive embedded systems are getting smaller; meanwhile, the batteries used to provide power to those systems have stagnated. If we are to realize the dream of ubiquitous computing promised by the Internet of Things, processors must shed large, heavy, expensive, and high maintenance batteries and, instead, harvest energy from their environment. One challenge with this transition is that harvested energy is insufficient for continuous operation. Unfortunately, existing programs fail miserably when executed intermittently. This paper presents Clank: lightweight architectural support for correct and efficient execution of long-running applications on harvested energy-without programmer intervention or extreme hardware modifications. Clank is a set of hardware buffers and memory-access monitors that dynamically maintain idempotency. Essentially, Clank dynamically decomposes program execution into a stream of restartable sub-executions connected via lightweight checkpoints. To validate Clank's ability to correctly stretch program execution across frequent, random power cycles, and to explore the associated hardware and software overheads, we implement Clank in Verilog, formally verify it, and then add it to an ARM Cortex M0+ processor which we use to run a set of 23 embedded systems benchmarks. Experiments show run-time overheads as low as 2.5%, with run-time overheads of 6% for a version of Clank that adds 1.7% hardware. Clank minimizes checkpoints so much that re-execution time becomes the dominate contributor to run-time overhead.", "corpus_id": 31072823, "score": 0 }, { "doc_id": "3946858", "title": "Timely Execution on Intermittently Powered Batteryless Sensors", "abstract": "Tiny intermittently powered computers can monitor objects in hard to reach places maintenance free for decades by leaving batteries behind and surviving off energy harvested from the environment--- avoiding the cost of replacing and disposing of billions or trillions of dead batteries. However, creating programs for these sensors is difficult. Energy harvesting is inconsistent, energy storage is scarce, and batteryless sensors can lose power at any point in time--- causing volatile memory, execution progress, and time to reset. In response to these disruptions, developers must write unwieldy programs attempting to protect against failures, instead of focusing on sensing goals, defining tasks, and generating useful data in a timely manner. To address these shortcomings, we have designed Mayfly, a language and runtime for timely execution of sensing tasks on tiny, intermittently-powered, energy harvesting sensing devices. Mayfly is a coordination language and runtime built on top of Embedded-C that combines intermittent execution fragments to form coherent sensing schedules---maintaining forward progress, data consistency, data freshness, and data utility across multiple power failures. Mayfly makes the passing of time explicit, binding data to the time it was gathered, and keeping track of data and time through power failures. We evaluated Mayfly against state-of-the art systems, conducted a user study, and implemented multiple real world applications across application domains in inventory tracking, and wearables.", "corpus_id": 3946858, "score": 0 }, { "doc_id": "8176633", "title": "Maximalist Cryptography and Computation on the WISP UHF RFID Tag", "abstract": "With continuous improvements in the ef?ciency of microelectronics, it is now possible to power a general-purpose microcontroller wirelessly at a reasonable range. Our implementation of RC5-32/18/16 on the WISP UHF RFID tag shows that conventional cryptography is no longer beyond the reach of a general-purpose UHF tag. In this paper, (1) we provide preliminary experimental data on how much computation is available on a TI MSP430F2132 microcontroller-based RFID tag containing approximately 8 KBytes of ?ash and 512 bytes of RAM, and (2) we show that symmetric cryptography is feasible on an RF-powered, general-purpose RFID tag — providing the ?rst implementation of conventional cryptography on an RF-powered UHF RFID tag as far as we are aware", "corpus_id": 8176633, "score": 1 }, { "doc_id": "3975833", "title": "Identification-free batch authentication for RFID tags", "abstract": "Cardinality estimation and tag authentication are two major issues in large-scale Radio Frequency Identification (RFID) systems. While there exist both per-tag and probabilistic approaches for the cardinality estimation, the RFID-oriented authentication protocols are mainly per-tag based: the reader authenticates one tag at each time. For a batch of tags, current RFID systems have to identify them and then authenticate each tag sequentially, incurring large volume of authentication data and huge communication cost. We study the RFID batch authentication issue and propose the first probabilistic approach, termed as Single Echo based Batch Authentication (SEBA), to meet the requirement of prompt and reliable batch authentications in large scale RFID applications, e.g., the anti-counterfeiting solution. Without the need of identifying tags, SEBA provides a provable probabilistic guarantee that the percentage of potential counterfeit products is under the user-defined threshold. The experimental result demonstrates the effectiveness of SEBA in fast batch authentications and significant improvement compared to existing approaches.", "corpus_id": 3975833, "score": 0 }, { "doc_id": "67336635", "title": "Proactive Batch Authentication: Fishing Counterfeit RFID Tags in Muddy Waters", "abstract": "Radio frequency identification technology has been recently employed as an effective solution for anti-counterfeiting. By attaching a tag on each product, a reader can provide a fast and automatic authentication. However, most of existing approaches adopt a per-tag approach to validate each product, which will incur a long scanning time and communication traffic when there are many products to be concurrently authenticated. To address these issues, batch authentication, e.g., SEBA, is proposed in recent literature. Batch authentication is an identification-free and probabilistic approach and aims to authenticate the validity of a batch of tags. Unfortunately, the existing batch authentication still suffers a serious scalability problem where the system cost linearly depends on the total number of genuine tags, e.g., ${\\mathcal {O}(N)}$ . Its efficiency will significantly decrease and even be worse than the per-tag approach when there is a large number of genuine tags in the system. This limitation hinders the batch authentication to be widely used in practice because there are up to millions of total genuine tags in usual. In this paper, we propose FISH, which is also probabilistic batch authentication-based, to overcome the scalability problem by reducing the dependence to ${\\mathcal {O}(\\log (N))}$ . Moreover, FISH owns the following two salient advantages: 1) FISH can identify the genuine products when there is no counterfeit product in the batch although it is identification-free in essence and 2) FISH can defend against silence attack by utilizing Pearson Chi-square test. Last, we also conduct the theoretical analysis and extensive simulation with the real logistics trace", "corpus_id": 67336635, "score": 0 }, { "doc_id": "4805152", "title": "Optimal Key-Trees for Tree-Based Private Authentication", "abstract": "Key-tree based private authentication has been proposed by Molnar and Wagner as a neat way to efficiently solve the problem of privacy preserving authentication based on symmetric key cryptography. However, in the key-tree based approach, the level of privacy provided by the system to its members may decrease considerably if some members are compromised. In this paper, we analyze this problem, and show that careful design of the tree can help to minimize this loss of privacy. First, we introduce a benchmark metric for measuring the resistance of the system to a single compromised member. This metric is based on the well-known concept of anonymity sets. Then, we show how the parameters of the key-tree should be chosen in order to maximize the system's resistance to single member compromise under some constraints on the authentication delay. In the general case, when any member can be compromised, we give a lower bound on the level of privacy provided by the system. We also present some simulation results that show that this lower bound is quite sharp. The results of this paper can be directly used by system designers to construct optimal key-trees in practice; indeed, we consider this as the main contribution of our work.", "corpus_id": 4805152, "score": 0 }, { "doc_id": "14035953", "title": "Reducing RFID reader load with the meet-in-the-middle strategy", "abstract": "When tag privacy is required in radio frequency identification (ID) system, a reader needs to identify, and optionally authenticate, a multitude of tags without revealing their IDs. One approach for identification with lightweight tags is that each tag performs pseudo-random function with his unique embedded key. In this case, a reader (or a back-end server) needs to perform a brute-force search for each tag-reader interaction, whose cost gets larger when the number of tags increases. In this paper, we suggest a simple and efficient identification technique that reduces readers computation to O(√N log N) without increasing communication cost. Our technique is based on the well-known \"meet-in-the- middle\" strategy used in the past to attack symmetric ciphers.", "corpus_id": 14035953, "score": 0 }, { "doc_id": "12694258", "title": "Scalable RFID Systems: A Privacy-Preserving Protocol with Constant-Time Identification", "abstract": "In RFID literature, most “privacy-preserving” protocols require the reader to search all tags in the system in order to identify a single tag. In another class of protocols, the search complexity is reduced to be logarithmic in the number of tags, but it comes with two major drawbacks: it requires a large communication overhead over the fragile wireless channel, and the compromise of a tag in the system reveals secret information about other, uncompromised, tags in the same system. In this work, we take a different approach to address time complexity of private identification in large-scale RFID systems. We utilize the special architecture of RFID systems to propose a symmetric-key privacy-preserving authentication protocol for RFID systems with constant-time identification. Instead of increasing communication overhead, the existence of a large storage device in RFID systems, the database, is utilized for improving the time efficiency of tag identification.", "corpus_id": 12694258, "score": 0 }, { "doc_id": "44089162", "title": "Lightweight and Practical Anonymous Authentication Protocol for RFID Systems Using Physically Unclonable Functions", "abstract": "Radio frequency identification (RFID) has been considered one of the imperative requirements for implementation of Internet-of-Things applications. It helps to solve the identification issues of the things in a cost-effective manner, but RFID systems often suffer from various security and privacy issues. To solve those issues for RFID systems, many schemes have been recently proposed by using the cryptographic primitive, called physically uncloneable functions (PUFs), which can ensure a tamper-evident feature. However, to the best of our knowledge, none of them has succeeded to address the problem of privacy preservation with the resistance of DoS attacks in a practical way. For instance, existing schemes need to rely on exhaustive search operations to identify a tag, and also suffer from several security and privacy related issues. Furthermore, a tag needs to store some security credentials (e.g., secret shared keys), which may cause several issues such as loss of forward and backward secrecy and large storage costs. Therefore, in this paper, we first propose a lightweight privacy-preserving authentication protocol for the RFID system by considering the ideal PUF environment. Subsequently, we introduce an enhanced protocol which can support the noisy PUF environment. It is argued that both of our protocols can overcome the limitations of existing schemes, and further ensure more security properties. By analyzing the performance, we have shown that the proposed solutions are secure, efficient, practical, and effective for the resource-constraint RFID tag.", "corpus_id": 44089162, "score": 0 }, { "doc_id": "24219558", "title": "SLAP: Succinct and Lightweight Authentication Protocol for low-cost RFID system", "abstract": "Data security is crucial for a RFID system. Since the existing RFID mutual authentication protocols encounter the challenges such as security risks, poor performance, an ultra-lightweight authentication protocol named Succinct and Lightweight Authentication Protocol (SLAP) is proposed. SLAP is only composed of bitwise operations like XOR, left rotation and conversion which is easy to implement on a passive tag. The proposed conversion operation as the main security component guarantees the security of RFID system with the properties such as irreversibility, sensibility, full confusion and low complexity, which better performed or even absent in other previous protocols. Security analysis shows that SLAP guarantees the functionalities of mutual authentication as well as resistance to various attacks such as de-synchronization attack, replay attack and traceability attack, etc. Furthermore, performance evaluation also indicates that the proposed scheme outperforms the existing protocols in terms of less computation requirement and fewer communication messages during authentication process.", "corpus_id": 24219558, "score": 0 }, { "doc_id": "6730636", "title": "Ambient backscatter: wireless communication out of thin air", "abstract": "We present the design of a communication system that enables two devices to communicate using ambient RF as the only source of power. Our approach leverages existing TV and cellular transmissions to eliminate the need for wires and batteries, thus enabling ubiquitous communication where devices can communicate among themselves at unprecedented scales and in locations that were previously inaccessible. To achieve this, we introduce ambient backscatter, a new communication primitive where devices communicate by backscattering ambient RF signals. Our design avoids the expensive process of generating radio waves; backscatter communication is orders of magnitude more power-efficient than traditional radio communication. Further, since it leverages the ambient RF signals that are already around us, it does not require a dedicated power infrastructure as in traditional backscatter communication. To show the feasibility of our design, we prototype ambient backscatter devices in hardware and achieve information rates of 1 kbps over distances of 2.5 feet and 1.5 feet, while operating outdoors and indoors respectively. We use our hardware prototype to implement proof-of-concepts for two previously infeasible ubiquitous communication applications.", "corpus_id": 6730636, "score": 0 }, { "doc_id": "14286487", "title": "On the limits of effective hybrid micro-energy harvesting on mobile CRFID sensors", "abstract": "Mobile sensing is difficult without power. Emerging Computational RFIDs (CRFIDs) provide both sensing and general-purpose computation without batteries--instead relying on small capacitors charged by energy harvesting. CRFIDs have small form factors and consume less energy than traditional sensor motes. However, CRFIDs have yet to see widespread use because of limited autonomy and the propensity for frequent power loss as a result of the necessarily small capacitors that serve as a microcontroller's power supply. Our results show that hybrid harvesting CRFIDs, which use an ambient energy micro-harvester, can complete a variety of useful workloads--even in an environment with little ambient energy available.\n Our contributions include (1) benchmarks demonstrating that micro-harvesting from ambient energy sources enables greater range and read rate, as well as autonomous operation by hybrid CRFIDs, (2) a measurement study that stresses the limits of effective ambient energy harvesting for diverse workloads, (3) application studies that demonstrate the benefits of hybrid CRFIDs, and (4) a trace-driven simulator to model and evaluate the expected behavior of a CRFID with different capacitor sizes and operating under varying conditions of mobility and solar energy harvesting. Our results show that ambient harvesting can triple the effective communication range of a CRFID, quadruple the read rate, and achieve 95% uptime in RAM retention mode despite long periods of low light.", "corpus_id": 14286487, "score": 0 }, { "doc_id": "14492274", "title": "Chain: tasks and channels for reliable intermittent programs", "abstract": "Energy harvesting computers enable general-purpose computing using energy collected from their environment. Energy-autonomy of such devices has great potential, but their intermittent power supply poses a challenge. Intermittent program execution compromises progress and leaves state inconsistent. This work describes Chain: a new model for programming intermittent devices. A Chain program is a set of programmer-defined tasks that compute and exchange data through channels. Chain guarantees forward progress at task granularity. A task is restartable and never sees inconsistent state, because its input and output channels are separated. Our system supports language features for expressing advanced data exchange patterns and for encapsulating reusable functionality. Chain fundamentally differs from state-of-the-art checkpointing approaches and does not incur the associated overhead. We implement Chain as C language extensions and a runtime library. We used Chain to implement four applications: machine learning, encryption, compression, and sensing. In experiments, Chain ensured consistency where prior approaches failed and improved throughput by 2-7x over the leading state-of-the-art system.", "corpus_id": 14492274, "score": 1 }, { "doc_id": "49642163", "title": "Toward service selection for workflow reconfiguration: An interface-based computing solution", "abstract": "Abstract Due to the open and diverse features of the Internet, applications need an effective method of performing a workflow reconfiguration to achieve both the functional behaviors and non-functional requirements of workflow changes when a service failure occurs. This paper proposes a service selection method for workflow reconfiguration based on interface operation matching. First, formal models of service workflow and interface operations of Web services are defined, and functional behavior comparisons of service selections are performed to determine the operation coverage set that will fulfill all activities that predefine the form of an abstract process. Second, reconfiguration patterns are introduced to describe different solution types for service patterns, including one-to-one, one-to-many, many-to-many, and many-to-one modes. Third, to consider the quality of service (QoS), the quality of service workflow (QoW) is proposed according to control structures and service interface computing, and the unified QoW formula is then provided to effectively rank each reconfiguration plan to provide a top-k solution recommendation. Fourth, related algorithms and a case study are discussed to show the service selection process during the workflow reconfiguration. To support the engineering implementation, a novel service workflow reconfiguration architecture is designed to provide guidance, which ranges from monitoring to recommendations for project implementation. Finally, experiments are conducted to demonstrate the effectiveness and efficiency of the proposed method.", "corpus_id": 49642163, "score": 0 }, { "doc_id": "31357685", "title": "Probabilistic Model Checking-Based Service Selection Method for Business Process Modeling", "abstract": "Business process modeling is a way to the organizational change management, which provides abstract workflows to describe business logics for customer demands analysis and IT infrastructures improv...", "corpus_id": 31357685, "score": 0 }, { "doc_id": "3760656", "title": "Proper RFID Privacy: Model and Protocols", "abstract": "We approach RFID privacy both from modelling and protocol point of view. Our privacy model avoids the drawbacks of several proposed RFID privacy models that either suffer from insufficient generality or put forward unrealistic assumptions regarding the adversary's ability to corrupt tags. Furthermore, our model can handle multiple readers and introduces two new privacy notions to capture the recently discovered insider attackers. We analyse multiple existing RFID protocols, demonstrating the easy applicability of our model, and propose a new wide-forward-insider private RFID authentication protocol. This protocol provides sufficient privacy guarantees for most practical applications and is the most efficient of its kind, it only requires two scalar-EC point multiplications.", "corpus_id": 3760656, "score": 1 }, { "doc_id": "10432414", "title": "On Privacy Models for RFID", "abstract": "We provide a formal model for identification schemes. Under this model, we give strong definitions for security and privacy. Our model captures the notion of a powerful adversary who can monitor all communications, trace tags within a limited period of time, corrupt tags, and get side channel information on the reader output. Adversaries who do not have access to this side channel are called narrow adversaries. Depending on restrictions on corruption, adversaries are called strong, destructive, forward, or weak adversaries. We derive some separation results: strong privacy is impossible. Narrow-strong privacy implies key agreement. We also prove some constructions: narrow-strong and forward privacy based on a public-key cryptosystem, narrow-destructive privacy based on a random oracle, and weak privacy based on a pseudorandom function.", "corpus_id": 10432414, "score": 0 }, { "doc_id": "9215197", "title": "Automatic verification of correspondences for security protocols", "abstract": "We present a new technique for verifying correspondences in security protocols. In particular, correspondences can be used to formalize authentication. Our technique is fully automatic, it can handle an unbounded number of sessions of the protocol, and it is efficient in practice. It significantly extends a previous technique for the verification of secrecy. The protocol is represented in an extension of the pi calculus with fairly arbitrary cryptographic primitives. This protocol representation includes the specification of the correspondence to be verified, but no other annotation. This representation is then translated into an abstract representation by Horn clauses, which is used to prove the desired correspondence. Our technique has been proved correct and implemented. We have tested it on various protocols from the literature. The experimental results show that these protocols can be verified by our technique in less than 1 s.", "corpus_id": 9215197, "score": 0 }, { "doc_id": "14911411", "title": "Physical-layer identification of UHF RFID tags", "abstract": "In this work, we study physical-layer identification of passive UHF RFID tags. We collect signals from a population of 70 tags using a purpose-built reader and we analyze time domain and spectral features of the collected signals. We show that, based on timing features of the signals, UHF RFID tags can be classified, independently of the location and distance to the reader (evaluated up to 6 meters), with an accuracy of approx. 71% (within our population). Additionally, we show that is possible to uniquely identify a maximum of approx. 26 UHF RFID tags independently of the population size. We analyze the implications of these results on tag holder privacy. We further show that, in controlled environments, UHF RFID tags can be uniquely identified based on their signal spectral features with an Equal Error Rate of 0% (within our population); we discuss the application of those techniques to cloning detection in RFID-enabled supply chains.", "corpus_id": 14911411, "score": 0 }, { "doc_id": "41139207", "title": "Collaborative QoS Prediction for Mobile Service with Data Filtering and SlopeOne Model", "abstract": "The mobile service is a widely used carrier for mobile applications. With the increase of the number of mobile services, for service recommendation and selection, the nonfunctional properties (also known as quality of service, QoS) become increasingly important. However, in many cases, the number of mobile services invoked by a user is quite limited, which leads to the large number of missing QoS values. In recent years, many prediction algorithms, such as algorithms extended from collaborative filtering (CF), are proposed to predict QoS values. However, the ideas of most existing algorithms are borrowed from the recommender system community, not specific for mobile service. In this paper, we first propose a data filtering-extended SlopeOne model (filtering-based CF), which is based on the characteristics of a mobile service and considers the relation with location. Also, using the data filtering technique in FB-CF and matrix factorization (MF), this paper proposes another model FB-MF (filtering-based MF). We also build an ensemble model, which combines the prediction results of FB-CF model and FB-MF model. We conduct sufficient experiments, and the experimental results demonstrate that our models outperform all compared methods and achieve good results in high data sparsity scenario.", "corpus_id": 41139207, "score": 0 }, { "doc_id": "132907468", "title": "QoS Prediction for Service Recommendation with Deep Feature Learning in Edge Computing Environment", "abstract": "Along with the popularity of intelligent services and mobile services, service recommendation has become a key task, especially the task based on quality-of-service (QoS) in edge computing environment. Most existing service recommendation methods have some serious defects, and cannot be directly adopted in edge computing environment. For example, most of existing methods cannot learn deep features of users or services, but in edge computing environment, there are a variety of devices with different configurations and different functions, and it is necessary to learn deep features behind those complex devices. In order to fully utilize hidden features, this paper proposes a new matrix factorization (MF) model with deep features learning, which integrates a convolutional neural network (CNN). The proposed mode is named Joint CNN-MF (JCM). JCM is capable of using the learned deep latent features of neighbors to infer the features of a user or a service. Meanwhile, to improve the accuracy of neighbors selection, the proposed model contains a novel similarity computation method. CNN learns the neighbors features, forms a feature matrix and infers the features of the target user or target service. We conducted experiments on a real-world service dataset under a batch of cases of data densities, to reflect the complex invocation cases in edge computing environment. The experimental results verify that compared to counterpart methods, our method can consistently achieve higher QoS prediction results.", "corpus_id": 132907468, "score": 0 }, { "doc_id": "14104104", "title": "Implementation and performance testing of the SQUASH RFID authentication protocol", "abstract": "We implement and test the performance of an RFID hash algorithm recently proposed by Adi Shamir [1] using a C++ simulation. The algorithm, called SQUASH (short for “SQUarehASH”), allows for an RFID tag design that is simple enough to be implemented on low-cost RFID tags. Shamir has proved mathematically that his SQUASH algorithm is at least as secure as the Rabin cryptosystem [2], which has been extensively tested and scrutinized for nearly 30 years. The SQUASH algorithm is designed to minimize processing time and cost without sacrificing security. Shamir's SQUASH algorithm was developed as a lightweight version of a hash function from the Rabin cryptosystem, c = m2 mod n. The SQUASH algorithm is theoretically faster because rather than storing, computing, and transmitting a large ciphertext, the algorithm allows a low cost RFID tag to compute the bits of the ciphertext in real-time, bit by bit, transmitting them as they are calculated. Although the SQUASH algorithm is provably as secure as the Rabin cryptosystem, the performance of the algorithm has not been carefully scrutinized. Shamir writes that the performance of the SQUASH algorithm should scale linearly as the size of a tag's register increases; we attempt to test this specific claim by using a software simulation.", "corpus_id": 14104104, "score": 0 }, { "doc_id": "10325079", "title": "Analog On-Tag Hashing: Towards Selective Reading as Hash Primitives in Gen2 RFID Systems", "abstract": "Deployment of billions of Commercial Off-The-Shelf (COTS) RFID tags has drawn much of the attention of the research community because of the performance gaps of current systems. In particular, hash-enabled protocol (HEP) is one of the most thoroughly studied topics in the past decade. HEPs are designed for a wide spectrum of notable applications (e.g., missing detection) without need to collect all tags. HEPs assume that each tag contains a hash function, such that a tag can select a random but predicable time slot to reply with a one-bit presence signal that shows its existence. However, the hash function has never been implemented in COTS tags in reality, which makes HEPs a 10-year untouchable mirage. This work designs and implements a group of analog on-tag hash primitives (called Tash) for COTS Gen2-compatible RFID systems, which moves prior HEPs forward from theory to practice. In particular, we design three types of hash primitives, namely, tash function, tash table function and tash operator. All of these hash primitives are implemented through selective reading, which is a fundamental and mandatory functionality specified in Gen2 protocol, without any hardware modification and fabrication. We further apply our hash primitives in two typical HEP applications (i.e., cardinality estimation and missing detection) to show the feasibility and effectiveness of Tash. Results from our prototype, which is composed of one ImpinJ reader and 3,000 Alien tags, demonstrate that the new design lowers 60% of the communication overhead in the air. The tash operator can additionally introduce an overhead drop of 29.7%.", "corpus_id": 10325079, "score": 0 }, { "doc_id": "27438370", "title": "Collaborative Service Selection via Ensemble Learning in Mixed Mobile Network Environments", "abstract": "Mobile Service selection is an important but challenging problem in service and mobile computing. Quality of service (QoS) predication is a critical step in service selection in 5G network environments. The traditional methods, such as collaborative filtering (CF), suffer from a series of defects, such as failing to handle data sparsity. In mobile network environments, the abnormal QoS data are likely to result in inferior prediction accuracy. Unfortunately, these problems have not attracted enough attention, especially in a mixed mobile network environment with different network configurations, generations, or types. An ensemble learning method for predicting missing QoS in 5G network environments is proposed in this paper. There are two key principles: one is the newly proposed similarity computation method for identifying similar neighbors; the other is the extended ensemble learning model for discovering and filtering fake neighbors from the preliminary neighbors set. Moreover, three prediction models are also proposed, two individual models and one combination model. They are used for utilizing the user similar neighbors and servicing similar neighbors, respectively. Experimental results conducted in two real-world datasets show our approaches can produce superior prediction accuracy.", "corpus_id": 27438370, "score": 0 } ]

{ "doc_id": "15302611", "title": "Anesthetic Routines: The Anesthesiologist's Role in GI Recovery and Postoperative Ileus", "abstract": "All patients undergoing bowel resection experience postoperative ileus, a transient cessation of bowel motility that prevents effective transit of intestinal contents or tolerance of oral intake, to varying degrees. An anesthesiologist plays a critical role, not only in the initiation of surgical anesthesia, but also with the selection and transition to effective postoperative analgesia regimens. Attempts to reduce the duration of postoperative ileus have prompted the study of various preoperative, perioperative, and postoperative regimens to facilitate gastrointestinal recovery. These include modifiable variables such as epidural anesthesia and analgesia, opioid-sparing anesthesia and analgesia, fluid restriction, colloid versus crystalloid combinations, prokinetic drugs, and use of the new peripherally acting mu-opioid receptor (PAM-OR) antagonists. Review and appropriate adaptation of these multiple modifiable interventions by anesthesiologists and their surgical colleagues will facilitate implementation of a best-practice management routine for bowel resection procedures that will benefit the patient and the healthcare system.", "corpus_id": 15302611 }

[ { "doc_id": "42294514", "title": "Clinical perspective on postoperative ileus and the effect of opiates", "abstract": "Postoperative ileus (POI) is a mandatory period of cessation of intestinal function, after abdominal surgery. Over the last decade research has continued into this field, and while we continue to learn about pathogenesis, few controlled data are available for management. The clinical manifestations of POI are reviewed. Management techniques are also reviewed, including the use of postoperative care plans with early ambulation and diet, the effects of epidural anaesthesia, benefits of laparoscopic approaches for intestinal resection, and potential avenues for prevention using novel medications.", "corpus_id": 42294514, "score": 0 }, { "doc_id": "9136962", "title": "Neuroimmune mechanisms in postoperative ileus", "abstract": "Postoperative ileus (POI) is a common clinical condition arising after almost every abdominal surgical procedure, leading to increased patient morbidity and prolonged hospitalisation. Recent advances in insight into the underlying pathophysiology have identified intestinal inflammation triggered by handling of the intestine as the main mechanism. Not only does the local inflammatory process compromise the contractile activity of the handled intestine, but it also activates inhibitory neural pathways and possibly triggers inflammation at distant untouched areas, leading to a generalised impairment of gastrointestinal motility. Macrophages residing in the muscularis externa and mast cells are the key players in this inflammatory cascade. Pharmacological interventions preventing the activation of these immune cells reduce the influx of leucocytes into the intestine, an effect associated with a reduction of the duration of POI. New potential therapeutic strategies to shorten POI based on these new insights will undoubtedly enter the clinical arena soon.", "corpus_id": 9136962, "score": 0 }, { "doc_id": "22083169", "title": "Review of postoperative ileus.", "abstract": "Postoperative ileus (POI) is an inevitable adverse consequence of surgical procedures. In fact, prolonged POI can lead to patient discomfort, decreased mobility, delayed enteral feeding, and ultimately, prolonged hospitalizations and increased costs. It is believed that POI occurs as a result of inhibitory neural reflexes and inflammatory processes. The use of postoperative opioids also appears to contribute to ileus. Recently, the potential influence of endogenous opioids, in addition to exogenous opioids, on the pathogenesis of ileus has come to light and spurred investigations into new treatment strategies. Over the years, several treatment modalities have become accepted management options for POI; chief among these are nasogastric suction and prokinetic agents. However, data demonstrating that these agents reduce the duration of POI are limited. Of current treatment modalities, use of epidural local anesthetics appears to be the most effective means of reducing POI. Other potentially effective treatments include early enteral feeding and less invasive surgical procedures. Together, these techniques have reduced the length of stay after colonic surgery to 2 to 3 days. Future studies, including those incorporating investigational agents, such as kappa-opioid agonists and peripheral mu-opioid antagonists, into a multimodal regimen, may offer new treatment options to further impact POI duration.", "corpus_id": 22083169, "score": 0 }, { "doc_id": "28203225", "title": "Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus.", "abstract": "OBJECTIVE\nTo investigate the pathophysiologic mechanisms that lead to ileus after abdominal surgery.\n\n\nSUMMARY BACKGROUND DATA\nThe common supposition is that more invasive operations are associated with a more extensive ileus. The cellular mechanisms of postsurgical ileus remain elusive, and few studies have addressed the mechanisms.\n\n\nMETHODS\nRats were subjected to incremental degrees of surgical manipulation: laparotomy, eventration, \"running,\" and compression of the bowel. On postsurgical days 1 and 7, muscularis infiltrates were characterized immunohistochemically. Circular muscle activity was assessed using mechanical and intracellular recording techniques in vitro.\n\n\nRESULTS\nSurgical manipulation caused an increase in resident phagocytes that stained for the activation marker lymphocyte function-associated antigen (LFA-1). Incremental degrees of manipulation also caused a progressive increase in neutrophil infiltration and a decrease in bethanechol-stimulated contractions. Compression also caused an increase in other leukocytes: macrophages, monocytes, dendritic cells, T cells, natural killer cells, and mast cells.\n\n\nCONCLUSION\nThe data support the hypothesis that the degree of gut paralysis to cholinergic stimulation is directly proportional to the degree of trauma, the activation of resident gut muscularis phagocytes, and the extent of cellular infiltration. Therefore, postsurgical ileus may be a result of an inflammatory response to minimal trauma in which the resident macrophages, activated by physical forces, set an inflammatory response into motion, leading to muscle dysfunction.", "corpus_id": 28203225, "score": 0 }, { "doc_id": "24709024", "title": "Alvimopan for the Management of Postoperative Ileus", "abstract": "OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, safety, dosage, and administration of alvimopan, a peripherally acting μ-opioid receptor antagonist, in the management of postoperative ileus (POI). DATA SOURCES: A literature search (1980–October 2004%) applying the terms alvimopan, ADL 8–2698, and LY246736 was conducted using MEDLINE. Information was also obtained from scientific congress abstracts and data on file with the manufacturer. STUDY SELECTION AND DATA EXTRACTION: Studies and abstracts investigating alvimopan and POI were considered for inclusion; however, they were restricted to English-language articles. DATA SYNTHESIS: Alvimopan is a novel, peripherally acting μ-opioid receptor antagonist that is currently under evaluation for the management of POI. POI presents significant clinical challenges that can delay patient recovery and contribute to increased morbidity and prolonged hospitalization after surgery. Clinical trials have demonstrated that alvimopan, at oral doses of 6 and 12 mg, can accelerate time to recovery of gastrointestinal (GI) function and time to hospital discharge following abdominal surgery. The incidence of adverse events with alvimopan therapy was shown to be similar to that of placebo. CONCLUSIONS: Alvimopan is well tolerated and effective at accelerating GI recovery and time to discharge in patients who have undergone bowel resection or hysterectomy when administered prior to surgery and twice daily thereafter until discharge or for up to 7 days. Alvimopan potentially offers significant benefits for patients with POI over currently available treatments.", "corpus_id": 24709024, "score": 0 }, { "doc_id": "14034422", "title": "Sympathetic input into the enteric nervous system", "abstract": "The basic concepts of the autonomic nervous system of organs and tissues were formulated around the turn of the century and summarised in a classical monograph by Langley (1921).1 The detailed distribution of the sympathetic nerves was, however, not elucidated until it became possible to stain sympathetic neurones specifically using the Falck-Hillarp technique. When this technique was applied to the gastrointestinal tract the picture seen was in some respects surprising. At the time it was generally believed that most organs and tissues had a dual innervation (sympathetic and parasympathetic) with opposite effects on function. It seemed, therefore, puzzling when the Falck-Hillarp technique revealed that innervation of a major part of the gastrointestinal wall, the smooth muscle layers, was very scarce. Instead it was found that most adrenergic fibres make contact with one of the two major plexuses in the alimentary canal. Adrenergic innervation is seen in the mucosa, in particular around the crypt epithelium.2 The functional consequences of this distribution are discussed below.\n\nThis brief review of the interplay between the sympathetic and enteric nervous systems will discuss the control of blood vessels, epithelial transport, motility, and endocrine cells (the enterochromaffin cells in particular).\n\nThere is dense adrenergic innervation of both precapillary and postcapillary vessels in the digestive tract. Stimulating the sympathetic nerves to the gut elicits a blood flow response which is very characteristic. Immediately on electrically stimulating the splanchnic nerves, pronounced vasoconstriction is observed which, however, subsides within a few minutes to reach a steady state level of blood flow. It seems probable that flow during steady state represents the “physiological” response to nerve activation. Intestinal flow resistance is thus only moderately increased (2–3 times) even when stimulating the sympathetic vasoconstrictor nerves at high rates (8–16 Hz). When investigating blood flow distribution within the intestinal wall …", "corpus_id": 14034422, "score": 0 }, { "doc_id": "28554765", "title": "Postoperative ileus: a preventable event", "abstract": "Postoperative ileus has traditionally been accepted as a normal response to tissue injury. No data support any beneficial effect of ileus and indeed it may contribute to delayed recovery and prolonged hospital stay. Efforts should, therefore, be made to reduce such ileus.", "corpus_id": 28554765, "score": 1 }, { "doc_id": "46953804", "title": "Opioid-Induced Bowel Dysfunction", "abstract": "Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction. Postoperative ileus, although attributable to surgical procedures, is often exacerbated by opioid use during and following surgery. Postoperative ileus is marked by increased inhibitory neural input, heightened inflammatory responses, decreased propulsive movements and increased fluid absorption in the gastrointestinal tract. The use of opioids for chronic pain is characterised by a constellation of symptoms including hard dry stools, straining, incomplete evacuation, bloating, abdominal distension and increased gastroesophageal reflux.The current management of opioid-induced bowel dysfunction among patients receiving opioid analgesics consists primarily of nonspecific ameliorative measures. Intensive investigations into the mode of action of opioids have characterised three opioid receptor classes — μ, δ and κ — that mediate the myriad of peripheral and central actions of opioids. Activation of μ-opioid receptors in the gastrointestinal tract is responsible for inhibition of gut motility, whereas receptors in the central nervous system mediate the analgesic actions of opioids. Blocking peripheral opioid receptors in the gut is therefore a logical therapeutic target for managing opioid-induced bowel dysfunction.Available opioid antagonists such as naloxone are of limited use because they are readily absorbed, cross the blood-brain barrier, and act at central opioid receptors to reverse analgesia and elicit opioid withdrawal. Methylnaltrexone and alvimopan are recently developed opioid antagonists with activity that is restricted to peripheral receptors. Both have recently shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs in non-surgical patients receiving opioids for chronic pain. In addition, recent clinical studies with alvimopan suggest that it may normalise bowel function without blocking opioid analgesia in abdominal laparotomy patients with opioid-related postoperative ileus.", "corpus_id": 46953804, "score": 1 }, { "doc_id": "2283969", "title": "The Role of Epidural Anesthesia and Analgesia in Surgical Practice", "abstract": "Objective: To review the potential and proven benefits and complications of epidural anesthesia/analgesia. Summary Background Data: Advances in analgesia/anesthesia have improved patient satisfaction and perioperative outcomes. Epidural anesthesia/analgesia is one of these advances that is gaining rapid acceptance due to a perceived reduction in morbidity and overall patient satisfaction. Methods: A MEDLINE search was conducted for all pertinent articles on epidural anesthesia/analgesia. Results: Retrospective, prospective, and meta-analysis studies have demonstrated an improvement in surgical outcome through beneficial effects on perioperative pulmonary function, blunting the surgical stress response and improved analgesia. In particular, significant reduction in perioperative cardiac morbidity (∼30%), pulmonary infections (∼40%), pulmonary embolism (∼50%), ileus (∼2 days), acute renal failure (∼30%), and blood loss (∼30%) were noted in our review of the literature. Potential complications related to epidural anesthesia/analgesia range from transient paresthesias (<10%) to potentially devastating epidural hematomas (0.0006%). Conclusions: Epidural anesthesia/analgesia has been demonstrated to improve postoperative outcome and attenuate the physiologic response to surgery.", "corpus_id": 2283969, "score": 1 }, { "doc_id": "45965193", "title": "Epidural Anesthesia and Gastrointestinal Motility", "abstract": "P ostoperative ileus, a temporary inhibition of gastrointestinal function, is a universal complication after major abdominal surgery. Treatment for ileus is supportive and has changed little since Wangensteen’s 1932 report (1) that nasogastric suction could delay or replace operative management of bowel obstruction, thereby reducing mortality. Gastric decompression, together with IV hydration and electrolyte replacement, remains the only proven therapy for ileus (2,3). Liu et al. (4) suggest that epidural analgesia may significantly shorten the duration of postoperative ileus. The benefits of a reduction in ileus include decreased patient morbidity and potentially substantial cost-savings, as prolongation of hospitalization in the United States due to ileus has been estimated to cost $1,500 per patient or $750,000,000 annually (3). Nevertheless, clinical guidelines currently promulgated by some consulting firms continue to state that “while epidural analgesia is effective for thoracic surgery and certain major musculoskeletal procedures, it has often been associated with prolonged ileus, delayed oral nutrition, and discharge in patients with gastrointestinal surgery” (Milliman and Robertson, Inc, Actuaries and Consultants, Seattle, WA, written communication, 1996). In this article, the pathophysiology of postoperative ileus is reviewed, and a framework for appreciating the theoretical basis for an effect of epidural anesthesia, especially thoracic epidural anesthesia, on ileus is provided. Potential risks and benefits of epidural anesthesia for bowel surgery are considered, including an examination of relevant animal studies. The major focus of this article is to review recent clinical studies comparing epidural analgesia with systemic analgesia, as well as to review studies comparing epidural narcotics with epidural local anesthetics with regard to postoperative ileus. Catheter location is discussed as a particularly important factor in determining the effects of epidural blockade on gastrointestinal motility. Finally, suggestions for future research are offered.", "corpus_id": 45965193, "score": 0 }, { "doc_id": "8866429", "title": "Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans", "abstract": "The gut is a neurological organ, which implies that many neuroactive drugs such as opioid analgesics can seriously disturb gastrointestinal function, because many of the transmitters and transmitter receptors present in the brain are also found in the enteric nervous system. One of the most common manifestations of opioid-induced bowel dysfunction is constipation which results from blockade of peristalsis and intestinal fluid secretion. The discovery of opioid receptor antagonists with a peripherally restricted site of action, such as N-methylnaltrexone and alvimopan, makes it possible to normalize bowel function in opiate-treated patients without compromising central opioid analgesia. There is emerging evidence that opioid receptor antagonists may also have prokinetic actions, reversing pathological states of gastrointestinal hypomotility that are due to overactivity of the enteric opioid system.", "corpus_id": 8866429, "score": 1 }, { "doc_id": "28352089", "title": "The effect of bupivacaine and morphine on pain and bowel function after colonic surgery", "abstract": "Sixty patients scheduled for colonic surgery were randomly allocated to four groups according to postoperative pain medication: I. Control group, the patients received oxycodone intramuscularly (0.15 mg kg1) on request. II. Epidural bupivacaine (0.25%) continuously administered by infusion pump, 66 ml h‐1, for 48 h. III. Epidural morphine, 2–6 mg, at the end of operation and repeated on the first and second postoperative mornings. IV. Epidural morphine, 2–6 mg per die, administered for 48 h continuously by infusion pump. All patients received a balanced anaesthesia with enflurane, fentanyl and vecuronium. Postoperatively, intramuscular oxycodone was given on request. There were no significant differences between the groups in changes in peak flow, spirometry and blood‐gas analyses postoperatively. Pain intensity (visual analogue scale) was lower in Groups II and III at 3 h and in Group IV at 24 h compared to the control Group I. All the epidurally treated groups needed less additional analgesics than the control Group I. Postoperatively bowel movements occurred on the second day in Group II (bupivacaine) as compared to the fourth day in all other groups (P < 0.05).", "corpus_id": 28352089, "score": 0 }, { "doc_id": "74251436", "title": "Effect of continuous postoperative epidural analgesia on intestinal motility", "abstract": "The effect of postoperative epidural bupivacaine on intestinal motility was studied by measuring the transit time of barium contrast through the intestines in 16 patients after resection of the left colon and/or rectum. Fourteen patients served as controls and received postoperative injections of pentazocine. Mean transit time through the intestinal tract was 35 h in the epidural group and 150 h in the control group, a difference that is significant at the 0·1 per cent level. The average time before passage of flatus and faeces was different between the two groups at the 0·1 per cent level. We conclude that postoperative epidural bupivacaine constitutes an effective means of analgesia after colorectal surgery and is associated with a short duration of intestinal paralysis.", "corpus_id": 74251436, "score": 0 }, { "doc_id": "25371491", "title": "Effects of Perioperative Analgesic Technique on Rate of Recovery after Colon Surgery", "abstract": "Background Choice of perioperative analgesia may affect the rate of recovery of gastrointestinal function and thus duration and cost of hospitalization after colonic surgery.", "corpus_id": 25371491, "score": 1 }, { "doc_id": "39098951", "title": "Epidural anaesthesia and analgesia - effects on surgical stress responses and implications for postoperative nutrition.", "abstract": "BACKGROUND\nSurgical injury leads to an endocrine-metabolic and inflammatory response with protein catabolism, increased cardiovascular demands, impaired pulmonary function and paralytic ileus, the most important release mechanisms being afferent neural stimuli and inflammatory mediators.\n\n\nRESULTS\nEpidural local anaesthetic blockade of afferent stimuli reduces endocrine metabolic responses, and improve postoperative catabolism. Furthermore, dynamic pain relief is achieved with improved pulmonary function and a pronounced reduction of postoperative ileus, thereby providing optimal conditions for improved mobilization and oral nutrition, and preservation of body composition and muscle function. Studies integrating continuous epidural local anaesthetics with enforced early nutrition and mobilization uniformly suggest an improved recovery, decreased hospital stay and convalescence.\n\n\nCONCLUSIONS\nEpidural local anaesthetics should be included in a multi-modal rehabilitation programme after major surgical procedures in order to facilitate oral nutrition, improve recovery and reduce morbidity.", "corpus_id": 39098951, "score": 0 }, { "doc_id": "39503071", "title": "Continuous epidural infusion of bupivacaine and morphine for postoperative analgesia after hysterectomy", "abstract": "The analgesic efficacy and side‐effects of combined epidural infusion of bupivacaine and morphine, in comparison with these drugs alone, for postoperative analgesia after hysterectomy (60 patients) were evaluated. Before general anaesthesia, all patients had an epidural catheter placed (Th11‐12) and 20 ml of 0.5% bupivacaine was injected. In random order, epidural infusion was continued for 24 h with either 0.25% bupivacaine 4 ml‐ h‐1 (BUPI‐group), a bolus of 2 mg of morphine followed by morphine 0.2 mg‐ h‐1 (MO‐group), or a combination of the two drugs (COMB‐group). A urinary bladder catheter was kept for 24 h. Supplementary postoperative pain medications were i.m. morphine 0.1 mg‐ kg‐1 or rectal indomethacin 50 mg, on request. Immediately after awakening from general anaesthesia and transfer to the recovery room, 18/20 of the BUPI‐group patients, 17/20 of the MO‐group patients and 19/20 of the COMB‐group patients were pain‐free. In the postoperative evening and the first postoperative morning, the corresponding figures were 7/20 and 10/20 in the BUPI‐group, 15/20 and 15/20 in the MO‐group, and 18/20 and 15/20 in the COMB‐group (postop. evening; P<0.01 BUPI vs. others). The number of patients requiring supplementary analgesics (morphine and indomethacin) during the first 24 h was greatest in the BUPI‐group (P<0.01). The number of patients who vomited during the 24‐h period was 3 in the BUPI‐group, 9 in the MO‐group and 5 in the COMB‐group. Postoperatively, normal bowel function was restored after 1.9 days in the BUPI‐group, 2.2 days in the MO‐group and 2.6 days in the COMB‐group, on average (P<0.01 BUPI vs. COMB). Recatheterization of the urinary bladder (once) was required in 4 patients in the MO‐group and 2 in the COMB‐group, but in none of the BUPI‐group. It is concluded that although the morphine‐containing epidural infusions (6.8 mg 24 h‐1) were superior to that containing bupivacaine alone with respect to postoperative analgesia after hysterectomy, the occurrence of disturbing emetic and urinary side‐effects made the therapy not totally satisfactory.", "corpus_id": 39503071, "score": 0 }, { "doc_id": "45024927", "title": "Effect of epidural bupivacaine vs combined epidural bupivacaine and morphine on gastrointestinal function and pain after major gynaecological surgery.", "abstract": "In a double-blind study, we investigated the effects of postoperative epidural local anaesthetic, with or without addition of epidural morphine, on postoperative pain and gastrointestinal function in patients scheduled for radical hysterectomy and pelvic lymphadenectomy. Forty patients were randomized into two study groups: 48-h postoperative epidural 0.2% bupivacaine 8 ml h(-1) (bupi group) or 48-h postoperative epidural 0.2% bupivacaine/morphine 50 microg at 4 ml h(-1) (bupi/morph group). Patients were observed for at least 96 h after surgery. No differences in pain at rest, during cough or mobilization were observed. Patients in the bupi group requested a significant greater amount of supplementary analgesics, but times to first flatus and defaecation were reduced compared with patients in the bupi/morph group. Itching was a significant problem in patients in the bupi/morph group. No differences in postoperative nausea and vomiting, mobilization or time to discharge from hospital were observed between groups. The addition of morphine to postoperative epidural bupivacaine has only limited effect on pain relief and increases time to normalization of gastrointestinal function.", "corpus_id": 45024927, "score": 0 }, { "doc_id": "33882182", "title": "Randomized controlled trial comparing the controlled rehabilitation with early ambulation and diet pathway versus the controlled rehabilitation with early ambulation and diet with preemptive epidural anesthesia/analgesia after laparotomy and intestinal resection.", "abstract": "BACKGROUND\nMultimodal postoperative care regimens accelerate recovery after abdominal surgery. The benefit of thoracic epidural (TE) analgesia over patient-controlled analgesia (PCA) remains unproven when used with a fast-track postoperative care plan.\n\n\nMETHODS\nFifty-six patients undergoing major intestinal resection, and on a fast-track postoperative care plan, were randomized to preemptive TE or PCA. Patients were evaluated at standard time points for pain score, quality of life (Short Form-36), and complications. Oral analgesia was substituted for TE and PCA on the second postoperative day. Discharge criteria were identical for both groups.\n\n\nRESULTS\nSix patients (20.6%) had a failed epidural. There was no difference in length of stay (5.8 versus 6.2 days, TE versus PCA, P = .55), total length of stay (including readmissions), pain scores, quality of life, complications, or hospital costs at any time point.\n\n\nCONCLUSION\nTE offers no advantage over PCA for patients undergoing major intestinal resections who are on a fast-track postoperative care plan using PCA.", "corpus_id": 33882182, "score": 0 }, { "doc_id": "41900625", "title": "Effect of adding ketorolac to intravenous morphine patient‐controlled analgesia on bowel function in colorectal surgery patients – a prospective, randomized, double‐blind study", "abstract": "Background:  Postoperative ileus (PI) is the transient impairment of bowel motility due to surgical trauma and the associated physiological responses. Postoperative ileus results in patient discomfort, increases gastrointestinal risks, prolongs hospital stay and increases medical expenses. In this study, we investigated the effect of patient‐controlled analgesia (PCA) morphine with or without ketorolac on bowel functions in patients after colorectal surgeries.", "corpus_id": 41900625, "score": 0 }, { "doc_id": "32858269", "title": "Opioid-sparing Effects of Ketorolac and Its Correlation With the Recovery of Postoperative Bowel Function in Colorectal Surgery Patients: A Prospective Randomized Double-blinded Study", "abstract": "ObjectivesPostoperative ileus (PI) is one of many common complications in major abdominal surgery. PI results in patient discomfort, increased gastrointestinal leakage, prolonged hospital stay, and increased medical expenses. In this study, we have investigated the morphine-sparing effects of ketorolac and its correlation with the duration of PI in patients with colorectal surgeries. MethodsWe collected data from 102 patients who had received elective colorectal resection. The patients were randomly allocated into 2 groups and received intravenous patient-controlled analgesia (IVPCA) morphine (M group) or IVPCA morphine plus ketorolac (M+K group). Time-scale morphine consumption (per 12 h), recovery of bowel functions (the first bowel movement and passage of flatus), pain scores, and opioid-related side effects were then recorded. ResultsPatients in the M+K group received 18.3% less morphine than those in the M group within 72 postoperative hours. The maximal opioid-sparing effects of ketorolac appeared in 12 to 24 postoperative hours. The onset of the first bowel movement and passage of flatus was significantly less in the M+K group than in the M group. The M group showed a 5.25 times greater risk of inducing PI, a result comparable with the M+K group in colorectal surgery patients. DiscussionThe addition of ketorolac to IVPCA morphine has demonstrated a clear opioid-sparing effect and benefits in regards to the shortening of the duration of bowel immobility. We suggest that adding ketorolac to morphine IVPCA be included in the multimodal postoperative rehabilitation program for the early restoration of normal bowel function.", "corpus_id": 32858269, "score": 0 }, { "doc_id": "5931454", "title": "Meta‐analysis of intravenous lidocaine and postoperative recovery after abdominal surgery", "abstract": "Continuous intravenous administration of lidocaine may decrease the duration of ileus and pain after abdominal surgery.", "corpus_id": 5931454, "score": 0 }, { "doc_id": "9178572", "title": "The Analgesic Effects of Gabapentin After Total Abdominal Hysterectomy", "abstract": "We investigated, in a randomized, placebo-controlled, double-blind study, the efficacy and safety of gabapentin on pain after abdominal hysterectomy and on tramadol consumption in patients. The 50 patients were randomized to receive either oral placebo or gabapentin 1200 mg 1 h before surgery. Anesthesia was induced with propofol and maintained with sevoflurane in 50% N2O/O2 with a fresh gas flow of 2 L/min (50% N2O in O2) and fentanyl (2 μg/kg). All patients received patient-controlled analgesia with tramadol with a 50 mg initial loading dose, 20 mg incremental dose, 10-min lockout interval, and 4-h limit of 300 mg. The incremental dose was increased to 30 mg if analgesia was inadequate after 1 h. Patients were studied at 4, 8, 12, 16, 20, and 24 h for visual analog (VAS) pain scores, heart rate, peripheral oxygen saturation, mean arterial blood pressure, respiratory rate, sedation, and tramadol consumption. The VAS scores in the sitting and supine position at 1, 4, 8, 12, 16, and 20 h were significantly lower in the gabapentin group when compared with the placebo group up to 20 h after surgery. The tramadol consumption at 12, 16, 20, and 24 h and total tramadol consumption were significantly less in the gabapentin group when compared with placebo group. Sedation scores were similar at all the measured times. There were no differences between groups in adverse effects. Preoperative oral gabapentin decreased pain scores and postoperative tramadol consumption in patients after abdominal hysterectomy.", "corpus_id": 9178572, "score": 0 }, { "doc_id": "11703618", "title": "Preemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirements in laparoscopic cholecystectomy", "abstract": "PurposeTo evaluate the comparative preemptive effects of gabapentin and tramadol on postoperative pain and fentanyl requirement in laparoscopic cholecystectomy.MethodsFour hundred fifty-nine ASA I and II patients were randomly assigned to receive 300 mg gabapentin, 100 mg tramadol or placebo in a double-blind manner two hours before laparoscopic cholecystectomy under general anesthesia. Postoperatively, patients’ pain scores were recorded on a visual analogue scale every two hours for the initial 12 hr and thereafter every three hours for the next 12 hr. Patients received fentanyl 2μg·kg−1 intravenously on demand. The total fentanyl consumption for each patient was recorded.ResultsPatients in the gabapentin group had significantly lower pain scores at all time intervals (2.65 ± 3.00, 1.99 ± 1.48, 1.40 ± 0.95, 0.65 ± 0.61) in comparison to tramadol (2.97 ± 2.35, 2.37 ± 1.45, 1.89 ± 1.16, 0.87 ± 0.50) and placebo (5.53 ± 2.22, 3.33 ± 1.37, 2.41 ± 1.19, 1.19 ± 0.56). Significantly less fentanyl was consumed in the gabapentin group (221.16 ± 52.39 μg) than in the tramadol (269.60 ± 44.17 μg) and placebo groups (355.86 ± 42.04 μg;P < 0.05). Sedation (33.98%), nausea/retching/vomiting (24.8%) were the commonest side effects in the gabapentin group whereas respiratory depression (3.9%) was the commonest in the tramadol group and vertigo (7.8%) in the placebo group.ConclusionPreemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirement in laparoscopic cholecystectomy.RésuméObjectifÉvaluer et comparer les effets préventifs de la gabapentine et du tramadol sur la douleur postopératoire et les besoins de fentanyl lors d’une cholécystectomie laparoscopique.MéthodeQuatre cent cinquante-neuf patients d’état physique ASA I et II ont été répartis au hasard et ont reçu 300 mg de gabapentine, 100 mg de tramadol ou un placebo, en double aveugle, deux heures avant la cholécystectomie laparoscopique sous anesthésie générale. Après l’opération, les scores de douleur ont été notés sur l’échelle visuelle analogique toutes les deux heures pendant les 12 premières heures et toutes les trois heures pendant les 12 h suivantes. Les patients ont reçu 2 μg·kg−1 de fentanyl intraveineux sur demande et la consommation totale a été notée pour chacun.RésultatsLes patients du groupe gabapentine ont présenté des scores de douleur significativement plus bas pour tous les intervalles de mesures (2,65 ± 3,00; 1,99 ± 1,48; 1,40 ± 0,95; 0,65 ± 0,61) que ceux du groupe tramadol (2,97 ± 2,35; 2,37 ± 1,45; 1,89 ± 1,16; 0,87 ± 0,50) ou placebo (5,53 ± 2,22; 3,33 ± 1,37; 2,41 ± 1,19; 1,19 ± 0,56). La demande de fentanyl a été significativement plus basse avec la gabapentine (221,16 ± 52,39 μg) qu’avec le tramadol (269,60 ± 44,17 μg) ou le placebo (355,86 ± 42,04 μg; P < 0,05). La sédation (33,98 %), les nausées/haut-lec∁ur/vomissements (24,8 %) ont été les effets négatifs les plus fréquents avec la gabapentine tandis que la dépression respiratoire (3,9 %) a été plus fréquente avec le tramadol et le vertige (7,8 %) avec le placebo.ConclusionL’usage préventif de gabapentine diminue significativement la douleur postopératoire et la demande d’analgésique de secours lors de la cholécystectomie laparoscopique.", "corpus_id": 11703618, "score": 0 }, { "doc_id": "942191", "title": "(–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride (Tapentadol HCl): a Novel μ-Opioid Receptor Agonist/Norepinephrine Reuptake Inhibitor with Broad-Spectrum Analgesic Properties", "abstract": "(–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl) is a novel μ-opioid receptor (MOR) agonist (Ki = 0.1 μM; relative efficacy compared with morphine 88% in a [35S]guanosine 5′-3-O-(thio)triphosphate binding assay) and NE reuptake inhibitor (Ki = 0.5 μM for synaptosomal reuptake inhibition). In vivo intracerebral microdialysis showed that tapentadol, in contrast to morphine, produces large increases in extracellular levels of NE (+450% at 10 mg/kg i.p.). Tapentadol exhibited analgesic effects in a wide range of animal models of acute and chronic pain [hot plate, tail-flick, writhing, Randall-Selitto, mustard oil colitis, chronic constriction injury (CCI), and spinal nerve ligation (SNL)], with ED50 values ranging from 8.2 to 13 mg/kg after i.p. administration in rats. Despite a 50-fold lower binding affinity to MOR, the analgesic potency of tapentadol was only two to three times lower than that of morphine, suggesting that the dual mode of action of tapentadol may result in an opiate-sparing effect. A role of NE in the analgesic efficacy of tapentadol was directly demonstrated in the SNL model, where the analgesic effect of tapentadol was strongly reduced by the α2-adrenoceptor antagonist yohimbine but only moderately attenuated by the MOR antagonist naloxone, whereas the opposite was seen for morphine. Tolerance development to the analgesic effect of tapentadol in the CCI model was twice as slow as that of morphine. It is suggested that the broad analgesic profile of tapentadol and its relative resistance to tolerance development may be due to a dual mode of action consisting of both MOR activation and NE reuptake inhibition.", "corpus_id": 942191, "score": 0 }, { "doc_id": "45544605", "title": "A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain", "abstract": "ABSTRACT Objective: To evaluate the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for management of moderate to severe pain following orthopedic surgery (bunionectomy). Methods: Randomized patients (N = 901) received oral tapentadol IR 50 or 75 mg, oxycodone HCl IR 10 mg, or placebo every 4–6 h over a 72-h period following surgery. Acetaminophen (≤2 g) was allowed in the first 12 h after the first dose of study drug. In the primary analysis, tapentadol IR (50 and 75 mg) was evaluated for efficacy superior to placebo and non-inferior to oxycodone HCl IR 10 mg (using sum of pain intensity difference [SPID] over 48 h), and tolerability superior to oxycodone IR (using incidence of treatment-emergent adverse events [TEAEs] of nausea and/or vomiting). Results: Statistically significantly higher mean SPID48 values were observed with tapentadol IR (50 and 75 mg) and oxycodone HCl IR 10 mg than placebo (all p < 0.001). The efficacy of tapentadol IR 50 mg and 75 mg was non-inferior to oxycodone HCl IR 10 mg. The incidence of TEAEs of nausea and/or vomiting was statistically significantly lower with tapentadol IR 50 mg versus oxycodone IR 10 mg (35 vs. 59%; p < 0.001). No statistically significant difference in the incidence of nausea and/or vomiting was observed between tapentadol IR 75 mg and oxycodone IR 10 mg (51 vs. 59%; p = 0.057). A possible limitation of this study was that the intense dose and patient monitoring may not represent real-world situations and may result in higher incidences of TEAEs than expected in a practice setting; this bias would be similar for all treatment groups. Conclusions: Clinically meaningful and statistically significant improvements were observed with tapentadol IR 50 mg and 75 mg compared with placebo for the relief of moderate-to-severe acute pain after orthopedic surgery. Tapentadol IR 50 mg and 75 mg were non-inferior to oxycodone HCl IR 10 mg for the treatment of acute pain based on the primary efficacy endpoint of SPID48 and the pre-specified margin of 48 points. The incidence of nausea and/or vomiting was statistically significantly lower for tapentadol IR 50 mg and numerically lower for tapentadol IR 75 mg than for oxycodone HCl IR 10 mg.", "corpus_id": 45544605, "score": 0 }, { "doc_id": "9357823", "title": "The gastrointestinal tract after anaesthesia.", "abstract": "Gastrointestinal tract motility may be reduced markedly after surgery with delay in gastric emptying. these alterations are induced partly by surgery, partly by the residual effects of anaesthetic agents, and particularly by opioids administered for post-operative pain relief. These changes may be antagonized to a certain extent by administration of prokinetic agents such as cisapride. Post-operative ileus reduces the rate of mobilization and may also reduce or delay absorption of drugs administered by the gastrointestinal tract. Furthermore, post-operative nausea and vomiting, multi-factorial in aetiology, may ensue and also be responsible for delayed mobilization, subjective discomfort and delay in administration of oral agents post-operatively. A serious problem may be leakage from bowel anastomoses. Although the causes are primarily surgical, an increase in bowel contractility may be deleterious and it has been suggested that neostigmine and morphine may be implicated in anastomotic dehiscence.", "corpus_id": 9357823, "score": 0 }, { "doc_id": "23711886", "title": "Anaesthesia, surgery, and challenges in postoperative recovery", "abstract": "Surgical injury can be followed by pain, nausea, vomiting and ileus, stress-induced catabolism, impaired pulmonary function, increased cardiac demands, and risk of thromboembolism. These problems can lead to complications, need for treatment in hospital, postoperative fatigue, and delayed convalescence. Development of safe and short-acting anaesthetics, improved pain relief by early intervention with multimodal analgesia, and stress reduction by regional anaesthetic techniques, beta-blockade, or glucocorticoids have provided important possibilities for enhanced recovery. When these techniques are combined with a change in perioperative care a pronounced enhancement of recovery and decrease in hospital stay can be achieved, even in major operations. The anaesthetist has an important role in facilitating early postoperative recovery by provision of minimally-invasive anaesthesia and pain relief, and by collaborating with surgeons, surgical nurses, and physiotherapists to reduce risk and pain.", "corpus_id": 23711886, "score": 1 }, { "doc_id": "22443213", "title": "Failure of Epidural Anesthesia to Prevent Postoperative Paralytic Ileus", "abstract": "&NA; This study used radiopaque markers and serial abdominal radiographs to assess the effect of epidural anesthesia on postoperative colonic ileus. Epidural anesthesia did not result in significantly faster return of propulsive motility in the colon after surgery as compared with control (P > 0.05). In addition, no significant difference was seen between the groups in colonic transit time and time for the first passage of gas and feces. The level of inhibition of sympathetic efferent nerves to the abdominal cavity was assessed by repeated measurements of blood glucose levels during the first postoperative day. Blood glucose levels were found to be significantly lower in the epidural group, demonstrating an inhibition of efferent sympathetic nerves below the level of T‐5. Results show lack of effect of continuous epidural anesthesia in the prevention of postoperative paralytic ileus and suggest that mechanisms other than spinal reflexes play a major part in the development and maintenance of intestinal paralysis.", "corpus_id": 22443213, "score": 0 }, { "doc_id": "10117694", "title": "Randomized controlled trial to examine the influence of thoracic epidural analgesia on postoperative ileus after laparoscopic sigmoid resection", "abstract": "The aim of the study was to evaluate whether perioperative epidural analgesia had any effect on the duration of postoperative ileus after laparoscopic sigmoid resection.", "corpus_id": 10117694, "score": 0 }, { "doc_id": "24632880", "title": "Allergen-induced increase of eosinophil cationic protein in nasal lavage fluid: effect of the glucocorticoid budesonide.", "abstract": "It was our aim to study the effect of nasal allergen provocation on the concentration of eosinophil cationic protein (ECP) in nasal lavage fluid, with and without glucocorticoid pretreatment. Twenty grass-pollen sensitive volunteers were provoked outside the pollen season on 2 consecutive days after pretreatment for 2 weeks with the glucocorticoid, budesonide, as a nasal spray (400 micrograms/day) and with placebo with a double-blind, crossover design. Nasal lavage fluid was repeatedly collected during a 10-hour period to study both early and late-phase responses. 99mTechnetium-albumin was added to the lavage fluid, making it possible to calculate the amount of secretion and the degree of dilution. The results were as follows: (1) There was no correlation between ECP concentration and dilution factor in the individual samples. (2) The mean concentration of ECP in lavage fluid from untreated, prechallenge noses was 400 micrograms/L. (3) The ECP level did not increase during the early phase response. (4) There was a late occurring increase in the ECP concentration (6 to 24 hours). (5) This increase was completely inhibited by budesonide pretreatment. (6) The glucocorticoid therapy also reduced the prechallenge ECP concentration. In conclusion, allergen provocation in the nose results in a late occurring increase of ECP in nasal lavage fluid, and one of the therapeutic effects of topical glucocorticoid therapy may be an inhibition of the allergen-induced increase of this cytotoxic molecule.", "corpus_id": 24632880, "score": 0 }, { "doc_id": "39652185", "title": "Pathophysiology and clinical implications of perioperative fluid excess.", "abstract": "The practice of perioperative fluid therapy is variable, ranging from ‘high volume’ to ‘dry’ regimen. A review of the data on the effect of ‘high volume’ perioperative fluid therapy suggests that the resulting overhydration may have deleterious effects on cardiac and pulmonary function, and on recovery of gastrointestinal motility (postoperative ileus), tissue oxygenation, wound healing and coagulation. These observations call for randomized studies of the effects of ‘high’ vs ‘low’ volume replacement therapy on postoperative morbidity, in order to establish evidence-based guidelines for perioperative fluid management. Perioperative fluid replacement has been, and still is, the focus of much debate. This debate has primarily focused on the various types of fluid components available for replacement therapy, and not on the actual amount of fluid administered.", "corpus_id": 39652185, "score": 0 }, { "doc_id": "23813068", "title": "Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial", "abstract": "BACKGROUND\nLow concentrations of albumin in serum and long gastric emptying times have been returned to normal in dogs by salt and water restriction, or a high protein intake. We aimed to determine the effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection in human beings.\n\n\nMETHODS\nWe randomly allocated ten patients to receive postoperative intravenous fluids in accordance present hospital practice (> or = 3 L water and 154 mmol sodium per day) and ten to receive a restricted intake (< or = 2 L water and 77 mmol sodium per day). All patients had no disease other than colonic cancer. The primary endpoint was solid and liquid-phase gastric emptying time, measured by dual isotope radionuclide scintigraphy on the fourth postoperative day. Secondary endpoints included time to first bowel movement and length of postoperative hospital stay. Analysis was by intention to treat.\n\n\nFINDINGS\nMedian solid and liquid phase gastric emptying times (T(50)) on the fourth postoperative day were significantly longer in the standard group than in the restricted group (175 vs 72.5 min, difference 56 [95% CI 12-132], p=0.028; and 110 vs 73.5 min, 52 [9-95], p=0.017, respectively). Median passage of flatus was 1 day later (4 vs 3 days, 2 [1-2], p=0.001); median passage of stool 2.5 days later (6.5 vs 4 days, 3 [2-4], p=0.001); and median postoperative hospital stay 3 days longer (9 vs 6 days, 3 [1-8], p=0.001) in the standard group than in the restricted group. One patient in the restricted group developed hypokalaemia, whereas seven patients in the standard group had side-effects or complications (p=0.01).\n\n\nINTERPRETATION\nPositive salt and water balance sufficient to cause a 3 kg weight gain after surgery delays return of gastrointestinal function and prolongs hospital stay in patients undergoing elective colonic resection.", "corpus_id": 23813068, "score": 0 }, { "doc_id": "38075493", "title": "Effect of Intraoperative Fluid Management on Outcome after Intraabdominal Surgery", "abstract": "Background:The debate over the correct perioperative fluid management is unresolved. Methods:The impact of two intraoperative fluid regimes on postoperative outcome was prospectively evaluated in 152 patients with an American Society of Anesthesiologists physical status of I–III who were undergoing elective intraabdominal surgery. Patients were randomly assigned to receive intraoperatively either liberal (liberal protocol group [LPG], n = 75; bolus of 10 ml/kg followed by 12 ml · kg−1 · h−1) or restrictive (restrictive protocol group [RPG], n = 77; 4 ml · kg−1 · h−1) amounts of lactated Ringer's solution. The primary endpoint was the number of patients who died or experienced complications. The secondary endpoints included time to initial passage of flatus and feces, duration of hospital stay, and changes in body weight, hematocrit, and albumin serum concentration in the first 3 postoperative days. Results:The number of patients with complications was lower in the RPG (P = 0.046). Patients in the LPG passed flatus and feces significantly later (flatus, median [range]: 4 [3–7] days in the LPG vs. 3 [2–7] days in the RPG; P < 0.001; feces: 6 [4–9] days in the LPG vs. 4 [3–9] days in the RPG; P < 0.001), and their postoperative hospital stay was significantly longer (9 [7–24] days in the LPG vs. 8 [6–21] days in the RPG; P = 0.01). Significantly larger increases in body weight were observed in the LPG compared with the RPG (P < 0.01). In the first 3 postoperative days, hematocrit and albumin concentrations were significantly higher in the RPG compared with the LPG. Conclusions:In patients undergoing elective intraabdominal surgery, intraoperative use of restrictive fluid management may be advantageous because it reduces postoperative morbidity and shortens hospital stay.", "corpus_id": 38075493, "score": 0 }, { "doc_id": "38751407", "title": "Effect of intraoperative fluid administration and colloid osmotic pressure on the formation of intestinal edema during gastrointestinal surgery.", "abstract": "The effects of intraoperative changes in plasma colloid osmotic pressure (COP) on the formation of intestinal edema were studied in patients during modified Whipple's operation (hemipancreato-duodenectomy). Eighteen patients (ASA physical status I or II) were randomly assigned to one of three groups. They received either lactated Ringer's (RL group, n = 6), 10% hydroxyethyl starch (HES group, n = 6), or 20% human albumin (HA group, n = 6) as a volume replacement solution, which was given to maintain central venous pressure (CVP) at the preoperative level. Jejunal specimens were obtained after the first transsection of the jejunum and prior to the jejuno-jejunostomy. Their water fraction (g H2O/g tissue dry weight) was measured gravimetrically. COP was determined prior to induction of anesthesia and upon removal of the second jejunal sample. In the RL group, 3,850 +/- 584 ml (data are means +/- SEM) of volume replacement solution were infused from induction of anesthesia to removal of the second jejunal sample. In the HES group, 1,358 +/- 45 ml were infused, and in the HA group, 463 +/- 49 ml were infused. During this time, COP decreased from 20.3 +/- 0.5 mmHg to 14.1 +/- 0.6 mmHg in the RL group, remained at 22.0 +/- 0.9 mmHg in the HES group, and increased from 20.7 +/- 0.9 mmHg to 28.1 +/- 0.9 mmHg in the HA group.(ABSTRACT TRUNCATED AT 250 WORDS)", "corpus_id": 38751407, "score": 1 }, { "doc_id": "7298061", "title": "Basic and clinical pharmacology of new motility promoting agents", "abstract": "Abstract  Recent research has provided new information about drugs that could be used to treat functional motility disorders. Promotility drugs accelerate gastric emptying or colonic transit and these properties may contribute to their efficacy in treating symptoms associated with gastroparesis, functional dyspepsia or constipation. 5‐Hydroxytryptamine4 receptors are targets for drugs (tegaserod, renzapride) that treat symptoms in constipated irritable bowel syndrome patients and in gastroparesis. Drugs acting at motilin (erythromycin) and cholecystokinin‐1 (dexloxiglumide) receptors accelerate gastric emptying. Dexloxiglumide might be useful in the treatment of functional dyspepsia particularly that associated with lipid intake. Alvimopan is a μ‐opioid receptor antagonist that does not cross the blood brain barrier. Alvimopan is effective in treating postsurgical ileus and perhaps opiate‐induced bowel dysfunction. Successes and failures of recent efforts to develop promotility agents revealed opportunities and challenges for developing new promotility drugs. The pharmacological properties of partial agonists might be exploited to develop effective promotility drugs. However, opposing actions of promotility agents on motility (increased contraction vs decreased accommodation) limit the clinical efficacy of drugs with these opposing actions. Selection of appropriate patient populations for evaluation of new drugs is also critical.", "corpus_id": 7298061, "score": 0 }, { "doc_id": "35857338", "title": "Prokinetic Agents for the Treatment of Postoperative Ileus in Adults: A Review of the Literature", "abstract": "Metoclopramide, cisapride, and erythromycin are commonly administered to reduce the duration of postoperative ileus (POI). As these agents are not without potential adverse effects, their efficacy in shortening the duration of POI should be evaluated. The etiology of POI is not well understood and therefore the precise treatment is unclear. Nasogastric suction is the mainstay of therapy, and management of fluid and electrolyte imbalances is crucial. The role of prokinetic agents is less understood. Available literature evaluating these drugs specifically for POI were reviewed, but results are confounded by issues such as sample size, variability in types of operations performed, and insensitive end points (flatus, bowel sounds). No literature supports reducing the duration of POI with metoclopramide, and limited data show benefit with cisapride. Data evaluating erythromycin are sparse, and the drug is believed to be ineffective. Domperidone, a prokinetic agent not available in the United States, has not been evaluated in POI. Due to these limitations, treatment remains largely supportive with a limited role for prokinetic agents.", "corpus_id": 35857338, "score": 0 }, { "doc_id": "24812979", "title": "Neostigmine increases postoperative colonic motility in patients undergoing colorectal surgery.", "abstract": "BACKGROUND\nGastrointestinal motility is frequently impaired after abdominal surgery. We investigated the effects of neostigmine on colonic motility in patients after colorectal surgery and in healthy volunteers.\n\n\nMETHODS\nColonic motility was recorded by a manometry/barostat system in 12 patients after left colonic or rectal resection during baseline and after the intravenous administration of increasing doses of neostigmine on postoperative days 1, 2, and 3. In addition, colonic motility was recorded in 7 healthy volunteers.\n\n\nRESULTS\nNeostigmine increased the colonic motility index. This increase was from 135 +/- 28 mm Hg/min at baseline to 574 +/- 219 mm Hg/min after administration of 5 microg/kg neostigmine on day 3 after surgery (mean +/- SEM, P <.05). In healthy volunteers, neostigmine at a dose of 5 microg/kg increased the colonic motility index from 184 +/- 73 to 446 +/- 114 mm Hg/min (P <.05). Barostat bag volumes decreased dose-dependently after neostigmine administration in patients as well as in volunteers, indicating an increase in colonic tone.\n\n\nCONCLUSIONS\nColonic motility and tone increased after neostigmine administration at a dose of 5 microg/kg in postoperative patients and in healthy volunteers. Neostigmine can be used to stimulate colonic motility after colorectal surgery and has a similar effect postoperatively as in healthy volunteers.", "corpus_id": 24812979, "score": 0 }, { "doc_id": "18354437", "title": "Amelioration of intestinal dysmotility and stasis by octreotide early after small-bowel autotransplantation in dogs.", "abstract": "BACKGROUND\nIntestinal dysmotility and stasis after intestinal transplantation are considered to promote bacterial overgrowth and translocation. Two prokinetic agents, KW5139 (13-leu-motilin) and the somatostatin analogue octreotide acetate, were studied to determine whether they can ameliorate intestinal dysmotility during the early postoperative period.\n\n\nMATERIALS AND METHODS\nMotility was recorded by multiple extraluminal strain-gauge transducers in 6 dogs on postoperative days 1, 3, 7, and 14. A barium meal study was performed with a separate group of 8 dogs on postoperative days 3 and 7.\n\n\nRESULTS\nThe agent KW5139 induced brief, weak contractions in the graft and had little effect on the dilated bowel; however, octreotide induced motor activity that propelled accumulated intestinal contents into the colon and reduced dilation of the transplanted bowel.\n\n\nCONCLUSION\nOctreotide, but not KW5139, ameliorates intestinal dysmotility associated with bowel autotransplantation during the early postoperative period. Short-term administration of octreotide may be useful for the treatment of dysmotility following intestinal transplantation.", "corpus_id": 18354437, "score": 0 }, { "doc_id": "46956985", "title": "Postoperative Ileus", "abstract": "The pathogenesis of postoperative ileus (PI) is multifactorial, and includes activation of inhibitory reflexes, inflammatory mediators and opioids (endogenous and exogenous). Accordingly, various strategies have been employed to prevent PI. As single-modality treatment, continuous postoperative epidural analgesia including local anaesthetics has been most effective in the prevention of PI. Choice of anaesthetic technique has no major impact on PI. Minimally invasive surgery reduces PI, in accordance with the sustained reduction in the inflammatory responses, while the effects of early institution of oral nutrition on PI per se are minor. Several pharmacological agents have been employed to resolve PI (propranolol, dihydroergotamine, neostigmine, erythromycin, cisapride, meto-clopramide, cholecystokinin, ceruletide and vasopressin), most with either limited effect or limited applicability because of adverse effects. The development of new peripheral selective opioid antagonists is promising and has been demonstrated to shorten PI significantly. A multi-modal rehabilitation programme including continuous epidural analgesia with local anaesthetics, enforced nutrition and mobilisation may reduce PI to 1–2 days after colonic surgery.", "corpus_id": 46956985, "score": 1 }, { "doc_id": "5185559", "title": "Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel.", "abstract": "Agonists of the serotonin 5-hydroxytryptamine 4 (5-HT4) receptor are widely used to activate motility in the gastrointestinal tract. Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects. Cisapride is a potent blocker of human ether-à-gogo (HERG) K(+) channels and prolongs the cardiac action potential in a reverse use dependence manner. We compared the effects of four different 5-HT4 receptor agonists (cisapride, prucalopride, renzapride and mosapride) on cloned HERG channels with the objective to evaluate and compare their proarrhythmic potential. K(+) currents from HERG-transfected COS-7 cells were recorded under physiological conditions using the whole cell configuration of the patch-clamp technique. Short (500 ms) depolarizing prepulses were used and following deactivating HERG currents were measured. Cisapride inhibited the HERG channels in a concentration-dependent manner with an IC(50) of 2.4 10(-7) M. The IC(50) value for prucalopride to block HERG (5.7 10(-6) M) was 20-fold higher than that of cisapride. Renzapride was slightly more potent than prucalopride (IC(50) = 1.8 10(-6) M). Mosapride produced no significant effects on the recombinant HERG current. The voltage dependence of HERG block was also investigated. The block mediated by cisapride or renzapride was voltage-dependent whereas that produced by prucalopride was not. We conclude that the rank order of potency of 5-HT4 agonists to block HERG is cisapride > renzapride > prucalopride > mosapride. We also conclude that 5-HT4 agonists devoid of side effects on the HERG current such as mosapride can be found as a safe alternative to cisapride.", "corpus_id": 5185559, "score": 0 }, { "doc_id": "32307333", "title": "Use of novel prokinetic agents to facilitate return of gastrointestinal motility in adult critically ill patients", "abstract": "Purpose of reviewIntolerance of enteral feeding due to impaired gastrointestinal motility is common in critically ill patients. Strategies to prevent or treat gastrointestinal hypomotility include the use of prokinetic agents. Many currently employed prokinetic agents are associated with serious adverse drug reactions. The novel prokinetic agents – alvimopan, tegaserod, and dexloxiglumide – are reviewed. Recent findingsAlvimopan exerts mixed, but generally favorable, effects on restoration of gastrointestinal motility in patients with postoperative ileus. The observation of increased opioid requirements (without increased pain scores) and associated clinical ramifications requires further study. Tegaserod stimulates the peristaltic reflex and improves motility in multiple sites along the gastrointestinal tract. Its efficacy in improving gastrointestinal hypomotility in the critically ill population has not yet been determined. Furthermore, its use has been associated with the development of ischemic colitis and increased requirement for abdominal/pelvic surgery. Dexloxiglumide may be beneficial for improving gastric emptying in critically ill patients, especially those receiving lipid-enriched enteral feeds. SummaryNovel prokinetic agents show promise for management of gastrointestinal hypomotility in the critically ill population. However, further study is required before these agents can be recommended for use.", "corpus_id": 32307333, "score": 0 }, { "doc_id": "24224184", "title": "Effect of erythromycin on gastric motility in controls and in diabetic gastroparesis.", "abstract": "The effect of three doses of erythromycin on interdigestive gastrointestinal motility and on plasma motilin levels was studied in healthy volunteers and patients with diabetic gastroparesis. Abnormalities of interdigestive motility were observed in 40% of the patients. In healthy volunteers, 40 mg erythromycin elicited a premature phase 3 that started in the stomach. In contrast to the spontaneous gastric phase 3, this erythromycin-induced phase 3 was not accompanied by a motilin peak. In patients with diabetic gastroparesis, 40 mg erythromycin induced a premature phase 3 in three patients, no response in one patient, and a burst of antral contractions in another patient. Doses of 200 and 350 mg erythromycin elicited a burst of antral phase-3-like contractions in both volunteers and patients, which was not accompanied by a motilin peak. This phase-3-like activity did not migrate to the small intestine and was not followed by a phase 1, but by a prolonged period of antral contractile activity. The number and amplitude of antral contractions after 200 or 350 mg erythromycin were significantly higher than after 40 mg. The motor patterns induced by different doses of erythromycin offer potential therapeutic applications.", "corpus_id": 24224184, "score": 0 }, { "doc_id": "38242445", "title": "Motilin and Clinical Application", "abstract": "Motilin is a regulatory polypeptide of 22 amino acid residues and orginates in motilin cells scattered in the duodenal epithelium of most mammals and chickens. Motilin is released into the general circulation at about 100-min intervals during the interdigestive state and is the most important factor in controlling the interdigestive migrating contractions. Recent studies have revealed that motilin stimulates endogenous release of the endocrine pancreas. Clinical application of motilin as a prokinetic has become possible since erythromycin and its derivatives were proved to be nonpeptide motilin agonists.", "corpus_id": 38242445, "score": 0 }, { "doc_id": "10549472", "title": "Effect of intravenous erythromycin on postoperative ileus.", "abstract": "We attempted to determine whether the administration of erythromycin shortens the period of postoperative ileus by a prospective, double-blind, placebo-controlled study. Seventy-seven patients were randomized and included in the statistical calculations. The patients were stratified according to the operation performed (cholecystectomy, celiotomy, or other major abdominal operations). Forty-one patients (group 1) received 250 mg erythromycin intravenously every 8 h for nine doses upon admission to the recovery room. Thirty-six patients (group 2) received placebo. The time (in hours) to first passage of flatus, first liquid meal, first bowel movement, and total length of hospital stay was recorded. There was no significant difference between group 1 and group 2 in time to first flatus (54.9 +/- 29 vs. 53.9 +/- 27 h, respectively), first meal (70.4 +/- 44 vs. 71.7 +/- 65), first bowel movement (81.8 +/- 32 vs. 80.1 +/- 28), or length of hospital stay (185.2 +/- 183 vs. 182.1 +/- 163). Erythromycin, in the dosage tested in this study, does not seem to alter clinical parameters of gastrointestinal motility after an abdominal operation. New prokinetic agents may deserve further studies.", "corpus_id": 10549472, "score": 0 }, { "doc_id": "37394401", "title": "Prokinetic effect of erythromycin after colorectal surgery", "abstract": "PURPOSE: Nausea and vomiting three to seven days after an elective operation on the colon and rectum remain a persistent clinical problem. Erythromycin, a safe, inexpensive drug that stimulates intestinal motilin receptors, has previously been shown to accelerate gastric emptying significantly after upper gastrointestinal surgery. We aimed to evaluate the effect of postoperative intravenous erythromycin on postoperative ileus in patients undergoing elective surgery for primary colorectal cancer. METHODS: Between May 1998 and April 1999, 150 patients undergoing primary resection of colon or rectal cancer were enrolled in this prospective, randomized, placebo-controlled trial. One hundred thirty-four patients completed the study. Patients were excluded if they had extensive metastatic disease, were taking medications known to interact with erythromycin, or if they required an ileostomy. Patients received either 200 mg of intravenous erythromycin or placebo every six hours. Clinical endpoints were recorded and continuous endpoints are presented as mean ± standard deviation. RESULTS: There were no significant complications related to erythromycin. The erythromycin (n=65) and placebo (n=69) groups were comparable regarding demographic and operative factors. The erythromycin group had a slightly shorter length of time to passage of flatus (4.1 ± 1.3vs. 4.4 ± 1.1 days;P=0.03). There was no significant difference between erythromycin and placebo in time to first solid food (5.6 ± 1.9vs. 5.4 ± 1.8 days), time to first bowel movement (5.2 ± 1.9vs. 5.4 ± 1.3 days), or time to discharge from hospital (7.5 ± 2.0vs. 7.6 ± 2.8 days). There was no difference in the rate of clinically significant nausea (26vs. 26 percent;P=0.99), vomiting (17vs. 16 percent;P=0.88), or nasogastric tube placement (9vs. 7 percent;P=0.68). CONCLUSIONS: Erythromycin does not seem to alter clinically important outcomes related to postoperative ileus in patients undergoing resection for colorectal cancer.", "corpus_id": 37394401, "score": 0 }, { "doc_id": "1107788", "title": "Negative effect of Metoclopramide in postoperative adynamic ileus. A prospective, randomized, double blind study", "abstract": "In a double blind controlled study including 60 patients it was found that Metoclopramide has a negative effect upon the resolution of postoperative adynamic ileus. Metoclopramide causes a delay in the time from operation to the first passage of flatus.", "corpus_id": 1107788, "score": 0 }, { "doc_id": "46494605", "title": "The Effects of Metoclopramide on Postoperative Ileus A Randomized Double‐blind Study", "abstract": "Metoclopramide or placebo was administered postoperativcly in a randomized, double-blind fashion to 115 patients undergoing laparotomy. The effect of metoclopramide on postoperative adynamic ileus (PAI) was evaluated. The patients were stratified into two groups: Group A—those with laparotomy without a gastrointestinal anastomosis or ostomy procedure, and group B—those with laparotomy undergoing an anastomosis or ostomy procedure. Metoclopramide reduced nausea and emesis postoperatively. However, the only significant effect on postoperative adynamic ileus was an earlier return to tolerance of solid foods in the patients in Group A.", "corpus_id": 46494605, "score": 0 }, { "doc_id": "11535740", "title": "Does metoclopramide reduce the length of ileus after colorectal surgery?", "abstract": "Between August 1988 and September 1989, 100 consecutive patients who underwent elective abdominal colorectal surgical procedures were prospectively randomized to receive or not to receive metoclopramide. Metoclopramide was intravenously administered every 8 hours from the completion of surgery until a solid food diet was able to be tolerated. Seven patients were not included in the final tabulations because of one death, one small bowel obstruction requiring laparotomy, one anastomotic leak requiring laparotomy, and four protocol violations. Ninety-three patients, 37 men and 56 women (mean age, 59.5; range, 14–89 years) underwent 40 segmental colectomies, 13 total abdominal colectomies, 8 abdominoperineal resections, 8 ileoanal pouch procedures, 7 small bowel resections, and 17 other colorectal procedures. The 40 patients who received postoperative metoclopramide were in Group 1, and the 53 who did not were in Group 2. The mean length of time between laparotomy and commencement of oral fluid and oral solid intake in Groups 1 and 2 were 3.5 and 4.8 days, and 3.5 and 5.0 days, respectively. These differences were not statistically significant (P>0.05). Prolonged ileus was seen in seven patients in Group 1 and in eight patients in Group 2. These differences were also not statistically significant (P>0.05). Prolonged ileus was defined as the need for nasogastric tube reinsertion or discontinuation of oral intake. We conclude that metoclopramide does not significantly alter the course of postoperative ileus.", "corpus_id": 11535740, "score": 0 }, { "doc_id": "2389953", "title": "Effect of surgical stress on endogenous morphine and cytokine levels in the plasma after laparoscopoic or open cholecystectomy", "abstract": "AbstractBackground: Endogenous morphine in the brain leads to various biological responses after surgery. The aim of this study was to determine whether morphine levels in the plasma would be enhanced by open laparotomy rather than by laparoscopic procedures.\n Methods: We compared 19 patients who underwent laparoscopic cholecystectomy with five patients who underwent resection of the gallbladder by open laparotomy. Morphine levels in the plasma were measured by an electrochemical detection system.\n Results: Postoperative endogenous morphine levels were higher with open laparotomy than with the laparoscopic technique (three h after surgery: open, 200 ± 52.6 fmol/ml vs laparoscopy, 17.6 ± 3.7, p < 0.01). This morphine elevation accounted for higher levels of cytokine, greater pain scores, and longer duration of fasting in open laparotomized patients than in laparoscopic cholecystectomy patients. Stress hormone levels in the plasma were also higher with open laparotomy than with laparoscopy.\n Conclusion: Morphine synthesis was enhanced by open laparotomy, resulting in greater biological response postoperatively than that seen with laparoscopic cholecystectomy.", "corpus_id": 2389953, "score": 0 }, { "doc_id": "35381100", "title": "Analgesic agents for the postoperative period. Opioids.", "abstract": "Opioids are the most commonly used medication for patients with acute pain. Morphine is the prototype with which all other opioids are compared. Synthetic and semisynthetic derivatives of morphine have unique properties, allowing for the use of a larger selection of medication. An understanding of the mechanisms of action, adverse effects, and routes of administration of the various potent opioids is important for good postoperative pain management.", "corpus_id": 35381100, "score": 0 }, { "doc_id": "12927024", "title": "ADL 8‐2698, a trans‐3,4‐dimethyl‐4‐ (3‐hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia", "abstract": "ADL‐8–2698 is a novel peripherally restricted opioid antagonist that may selectively prevent opioid‐induced gastrointestinal effects without reversing analgesia. Gastrointestinal transit time (lactulose hydrogen breath test) was measured in 14 volunteers with oral and intravenous placebo, oral placebo and intravenous morphine (0.05 mg · kg−1), and oral ADL 8–2698 (4 mg) and intravenous morphine (0.05 mg · kg−1) in a double blind, cross‐over study. Morphine prolonged gastrointestinal transit time from 69 to 103 minutes (P = .005); this was prevented by ADL 8–2698 (P = .004). Postoperatively, 45 patients were randomly assigned in a double‐blind fashion to receive ADL 8–2698 (4 mg) or placebo and intravenous morphine (0.15 mg/kg) or to receive oral and intravenous placebo. Analgesia and pupil constriction were measured. Morphine analgesia and pupil constriction were unaffected by ADL 8–2698 and differed from placebo (P < .002). We conclude that ADL 8–2698 prevents morphine‐induced increases in gastrointestinal transit time by means of selective peripheral opioid antagonism without affecting central opioid analgesia.", "corpus_id": 12927024, "score": 0 }, { "doc_id": "19579109", "title": "Effects of enteric‐coated methylnaltrexone in preventing opioid‐induced delay in oral‐cecal transit time", "abstract": "Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine‐induced delay in gastrointestinal transit time.", "corpus_id": 19579109, "score": 0 }, { "doc_id": "41263289", "title": "Antagonism of Gastrointestinal Opioid Effects", "abstract": "The opium poppy has been used for several thousand years to control diarrhea and relieve pain. In 1803, Sertürner reported the isolation of a pure active alkaline substance from opium, and named it “morphine,” after Morpheus, the Greek god of dreams. Today, morphine and other opioids are widely used in clinical settings, especially as analgesics to treat moderate to severe pain. Opioids are also frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic, and analgesic properties. A common side effect of opioids as pain medications is constipation. Constipation is a significant problem in 40% to 45% of patients with metastatic malignancy1,2 and in 90% of patients treated with opioids.3 Data from animal experiments show that the gastrointestinal (GI) tract is very sensitive to opioids, even at very low doses. The ratio between subcutaneous analgesic and constipating doses of morphine in the rat is approximately 4 to 1, i.e., 4 times more morphine needed for analgesia than slowing of motility.4 Another report indicated that approximately 20 times less oral morphine is needed to antagonize castor oil diarrhea than to produce analgesia in mice.5 This gut sensitivity to opioids is probably caused by relatively poor penetration of morphine into the brain and, thus, partly explains why constipation is a severe problem in those patients receiving opioids. In addition, it is well known that tolerance develops with repeated use of opioids to relieve pain, but tolerance does not appear to extend to GI motility and transit. Opioid receptors and endorphins are widely distributed in the central nervous system (CNS) and throughout the GI tract. However, the site of action of exogenous opioid-induced constipation is somewhat controversial. Data from animal experiments show that morphine can act within the CNS to alter autonomic outflow to the gut.6 However, opioids may also affect intestinal motility by a direct effect on the bowel. Manara et al.7 have shown that the inhibition of gastric transit by morphine results primarily from direct drug action on gut opioid sites with no significant contribution from a centrally elicited effect. Loperamide, an opioid receptor agonist with limited ability to access the CNS, is used clinically to treat diarrhea, suggesting that direct, local gut action is present in the opioid-constipating effect in humans. Using human small intestine muscle-strip preparation, we showed that morphine-induced inhibition of muscle-strip contraction elicited by electrical stimulation can be blocked by opioid antagonists.8 We also observed that after opioid antagonists, the force produced by muscle contraction was enhanced up to 27% compared with control levels, suggesting an inhibitory gut modulation by endogenous opioids in humans. The GI effects of morphine are primarily mediated by and -opioid receptors in the bowel. Morphine inhibits gastric emptying and reduces propulsive peristalsis of the intestine, thereby decreasing the rate of intestinal transit and producing constipation. Reduction in gut secretion and increases in intestinal fluid absorption also contribute to morphine’s constipating effect. In palliative care, the management of chronic opioid-induced constipation sometimes is a more difficult issue than the control of pain. Therefore, it is desirable to maintain the central analgesic effect of morphine while preventing or reducing its peripheral gut effects. Nonselective opioid receptor antagonists (e.g., naloxone, naltrexone, and nalmefene) cross the blood-brain barrier and, thus, block both the benFrom the Department of Anesthesia & Critical Care and Committee on Clinical Pharmacology, The Pritzker School of Medicine, The University of Chicago, Chicago, Illinois. Accepted for publication April 13, 2000. Supported in part by a grant from the International Anesthesia Research Society, National Institutes of Health Grant No. R01 CA79042, and Grant No. M01 RR00055 from the US Public Health Service General Clinical Research Center. Methylnaltrexone was originally formulated and subsequently modified by faculty at the University of Chicago. The University of Chicago and Drs. Yuan and Foss stand to benefit financially from the further development of methylnaltrexone. Reprint requests: Chun-Su Yuan, M.D., Ph.D., Department of Anesthesia & Critical Care, The University of Chicago, 5841 S Maryland Ave, MC 4028, Chicago, IL 60637. E-mail: cyuan@ midway.uchicago.edu © 2000 by The American Society of Regional Anesthesia and Pain Medicine. 1098-7339/00/2506-0016$5.00/0 doi:10.1053/rapm.2000.8658", "corpus_id": 41263289, "score": 0 }, { "doc_id": "42374885", "title": "Phase III Trial of Alvimopan, a Novel, Peripherally Acting, Mu Opioid Antagonist, for Postoperative Ileus After Major Abdominal Surgery", "abstract": "PURPOSEPostoperative ileus presents significant clinical challenges that potentially prolong hospital stay, contribute to readmission, and increase morbidity. There is no approved treatment for postoperative ileus. Alvimopan is a novel, peripherally acting, mu opioid receptor antagonist currently in development for the management of postoperative ileus.METHODSPatients undergoing partial colectomy or simple or radical hysterectomy were randomized to receive alvimopan 6 mg (n = 152), alvimopan 12 mg (n = 146), or placebo (n = 153) orally 2 hours before surgery and twice daily thereafter until discharge or for up to seven days. The primary efficacy end point, time to return of gastrointestinal function, was a composite measure of passage of flatus or stool and tolerating solid food. Secondary end points included time to the hospital discharge order written. Adverse events were monitored throughout the study.RESULTSMean time to gastrointestinal recovery was significantly reduced in patients treated with alvimopan 6 mg vs. placebo (hazard ratio = 1.45; P = 0.003), with a smaller reduction seen with alvimopan 12 mg (hazard ratio = 1.28; P = 0.059). Mean time to the hospital discharge order written was significantly accelerated in patients treated with alvimopan 6 mg (hazard ratio = 1.50; P < 0.001). The most common treatment-emergent adverse events across all treatment groups were nausea, vomiting, and hypotension; the incidence of nausea and vomiting was reduced by 53 percent in the alvimopan 12-mg group.CONCLUSIONSIn patients undergoing major abdominal surgery, alvimopan accelerated gastrointestinal recovery and time to the hospital discharge order written compared with placebo and was well tolerated.", "corpus_id": 42374885, "score": 0 }, { "doc_id": "35140862", "title": "Alvimopan, a Novel, Peripherally Acting μ Opioid Antagonist: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Major Abdominal Surgery and Postoperative Ileus", "abstract": "Objective:To demonstrate that alvimopan (6 or 12 mg) accelerates recovery of gastrointestinal (GI) function in patients undergoing laparotomy for bowel resection or radical hysterectomy. Summary Background Data:Postoperative ileus (POI) following laparotomy may increase morbidity and extend hospitalization. Opioids can contribute to the duration of POI. Alvimopan is a novel opioid receptor antagonist in development for the management of POI. Methods:A total of 510 patients scheduled for bowel resection or radical hysterectomy were randomized (1:1:1) to receive alvimopan 6 mg, alvimopan 12 mg, or placebo orally ≥2 hours before surgery, then twice a day (b.i.d.) until hospital discharge or for up to 7 days. The primary efficacy end point was a composite of time to recovery of upper and lower GI function. An associated secondary end point was time to hospital discharge order written. Results:The modified intent-to-treat population included 469 patients (451 bowel resection and 18 radical hysterectomy patients). Time to recovery of GI function was accelerated for the alvimopan 6 mg (hazard ratio [HR] = 1.28; P < 0.05) and 12 mg (HR = 1.54; P < 0.001) groups with a mean difference of 15 and 22 hours, respectively, compared with placebo. The time to hospital discharge order written was also accelerated in the alvimopan 12 mg group (HR = 1.42; P = 0.003) with a mean difference of 20 hours compared with placebo. The incidence of adverse events was similar among treatment groups. Conclusions:Alvimopan accelerated GI recovery and time to hospital discharge order written compared with placebo in patients undergoing laparotomy and was well tolerated.", "corpus_id": 35140862, "score": 0 }, { "doc_id": "15143337", "title": "Peripherally Acting Mu-Opioid Receptor Antagonists and Postoperative Ileus: Mechanisms of Action and Clinical Applicability", "abstract": "Postoperative ileus (POI), a transient cessation of coordinated bowel function after surgery, is an important health care problem. The etiology of POI is multifactorial and related to both the surgical and anesthetic pathways chosen. Opioids used to manage surgical pain can exacerbate POI, delaying gastrointestinal (GI) recovery. Peripherally acting mu-opioid receptor (PAM-OR) antagonists are designed to mitigate the deleterious effects of opioids on GI motility. This new class is investigational for POI management with the goal of accelerating the recovery of upper and lower GI tract function after bowel resection. In this review, we summarize the mechanisms by which POI occurs and the role of opioids and opioid receptors in the enteric nervous system, discuss the mechanism of action of PAM-OR antagonists, and review clinical pharmacology and Phase II/III POI trial results of methylnaltrexone and alvimopan. Finally, the role of anesthesiologists in managing POI in the context of a multimodal approach is discussed.", "corpus_id": 15143337, "score": 0 }, { "doc_id": "24500252", "title": "Clinical trial: alvimopan for the management of post‐operative ileus after abdominal surgery: results of an international randomized, double‐blind, multicentre, placebo‐controlled clinical study", "abstract": "Aliment Pharmacol Ther 28, 312–325", "corpus_id": 24500252, "score": 0 }, { "doc_id": "14741967", "title": "Gastrointestinal tract recovery in patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway.", "abstract": "OBJECTIVE\nTo investigate the efficacy and safety of alvimopan, 12 mg, administered orally 30 to 90 minutes preoperatively and twice daily postoperatively in conjunction with a standardized accelerated postoperative care pathway for managing postoperative ileus after bowel resection.\n\n\nDESIGN, SETTING, AND PATIENTS\nThis multicenter, randomized, placebo-controlled, double-blind, phase 3 trial enrolled adult patients undergoing partial bowel resection with primary anastomosis by laparotomy and scheduled to receive intravenous, opioid-based, patient-controlled analgesia. A standardized accelerated postoperative care pathway including early ambulation, oral feeding, and postoperative nasogastric tube removal was used to facilitate gastrointestinal (GI) tract recovery in all of the patients.\n\n\nMAIN OUTCOME MEASURES\nThe primary end point was time to GI-2 recovery (toleration of solid food and first bowel movement). Secondary end points included time to GI-3 recovery (toleration of solid food and first flatus or bowel movement), hospital discharge order written, and actual hospital discharge. Postoperative length of hospital stay based on calendar day of hospital discharge order written, opioid consumption, and overall postoperative ileus-related morbidity were recorded.\n\n\nRESULTS\nAlvimopan, 12 mg, was well tolerated and significantly accelerated GI-2 recovery, GI-3 recovery, and actual hospital discharge compared with a standardized accelerated postoperative care pathway alone (hazard ratio = 1.5, 1.5, and 1.4, respectively; P < .001 for all). Time to hospital discharge order written as measured by hazard ratio (1.4) and by postoperative calendar days (mean for alvimopan, 5.2 days; mean for placebo, 6.2 days) was also accelerated. Opioid consumption was comparable between groups, and alvimopan was associated with reduced postoperative ileus-related morbidity compared with placebo.\n\n\nCONCLUSIONS\nAlvimopan, 12 mg, administered 30 to 90 minutes before and twice daily after bowel resection is well tolerated, accelerates GI tract recovery, and reduces postoperative ileus-related morbidity without compromising opioid analgesia.", "corpus_id": 14741967, "score": 0 }, { "doc_id": "4832211", "title": "Preoperative Intensive, Community-Based vs. Traditional Stoma Education: A Randomized, Controlled Trial", "abstract": "PURPOSEConventional practice in colorectal surgery involves stoma education being imparted postoperatively. Proficiency in stoma management often delays patients’ discharge following colorectal surgery. The aim of this randomized, controlled trial was to compare preoperative intensive, community-based stoma education with conventional postoperative stoma education after elective colorectal surgery.METHODSForty-two elective colorectal patients requiring a stoma were randomized into an intensive preoperative teaching (study) or postoperative (control) group. Intervention for the study group included two preoperative visits in the community during which patients were taught with audiovisual aids to use and change the stoma pouching system. Goal-directed postoperative stoma education was standardized for both groups. Outcomes measured included time to stoma proficiency, postoperative hospital stay, unplanned stoma-related interventions in the community within six weeks of discharge, and preoperative and postoperative hospital anxiety and depression scores. Cost-effectiveness of the intervention was also evaluated.RESULTSAll outcomes measured were improved in the study group, including time to stoma proficiency(5.5 vs. 9 days; P = 0.0005), hospital stay (8 vs. 10 days; P\n = 0.029), and unplanned stoma-related community interventions per patient (median 0 vs. 0.5; P = 0.0309). No adverse effects of the intervention were noted. The average cost saving per patient was £1,119 ($2,104) for the study group compared with the control group.CONCLUSIONSStoma education is more effective if undertaken in the preoperative setting. It results in shorter times to stoma proficiency and earlier discharge from the hospital. It also reduces stoma-related interventions in the community and has no adverse effects on patient well-being.", "corpus_id": 4832211, "score": 0 }, { "doc_id": "44322873", "title": "An expert opinion on postoperative pain management, with special reference to new developments", "abstract": "Importance of the field: Recently, much attention has been directed towards the effect of opioid-sparing strategies on postoperative morbidity and hospitalization, and on different nociceptive mechanisms involved in various postoperative pain states and surgical procedures. This has resulted in an increased interest in secondary, or adjunct, analgesics and procedure-specific analgesic methods. Areas covered in this review: The present paper aims to review and discuss recent developments within the field of various adjunct, systemic analgesics and local/regional anesthetic methods for management of postoperative pain, based on evidence from randomized, clinical trials published within the last 5 years. What the reader will gain: The reader will gain insight into the current role of pregabalin, glucocorticoids and systemic lidocaine for the management of postoperative pain. In addition, the current status of local infiltration analgesia for hip and knee arthroplasty, transversus abdominis plane block for abdominal operations, and the analgesic effect of wound instillation of capsaicin are reviewed. Take home message: The evidence of a substantial analgesic effect of pregabalin on acute postoperative pain is questionable, and more convincing evidence of the role of glucocorticoids and systemic lidocaine is needed before they should be recommended as analgesics in daily clinical practice. Local infiltration analgesia after hip and knee arthroplasty, transversus abdominis plane block after abdominal operations and local application of capsaicin lend some promise, but there is still a lack of well-performed RCTs to draw any firm conclusions. Procedure-specific analgesic combinations within well-defined rehabilitation paradigms should be explored further to reduce adverse effects associated with the use of conventional analgesic treatment protocols, and to improve postoperative outcome.", "corpus_id": 44322873, "score": 0 }, { "doc_id": "35532599", "title": "Acute pain management for opioid dependent patients", "abstract": "Patients requiring acute pain management may be opioid dependent as a result of either recreational or therapeutic opioid use, including those in opioid addiction programmes. Pain in these patients is often under‐estimated and under‐treated. In addiction, drug‐seeking behaviour differentiates it from simple dependence. With few randomised controlled trials, current evidence predominantly consists of guidelines based on case reports, retrospective studies and expert opinion. Consensus recommendations include maintaining regular provision of the patient's pre‐existing opioid requirement, with additional analgesia, ideally multimodal, in appropriate combinations of short‐acting opioid (as required), local anaesthesia, and adjuvant anti‐inflammatory analgesics and paracetamol. Patient controlled analgesia with higher bolus doses and shorter lock‐out intervals is a recommended strategy. Transdermal opioid patches and implantable pumps will continue to deliver opioid, to which non‐opioid and short‐acting opioids may be added. Re‐exposure to opioid is ideally avoided in previously addicted patients, but if not feasible, opioid therapy should be prescribed.", "corpus_id": 35532599, "score": 0 }, { "doc_id": "2060352", "title": "Opioid consumption in total intravenous anesthesia is reduced with dexmedetomidine: a comparative study with remifentanil in gynecologic videolaparoscopic surgery.", "abstract": "STUDY OBJECTIVE\nTo evaluate the capacity of dexmedetomidine (DEX), an alpha(2) adrenergic agonist drug, as a substitute for remifentanil (REM), a potent opioid, in total intravenous anesthesia (TIVA), in patient undergoing gynecologic videolaparoscopy.\n\n\nDESIGN\nRandomized, single-blinded study.\n\n\nSETTING\nUniversity-affiliated hospital.\n\n\nPATIENTS\n30 ASA physical status I and II women, patients (22-56 yrs), scheduled for gynecologic videolaparoscopy.\n\n\nINTERVENTIONS\nPatients were anesthetized with DEX or REM in continuous venous infusion, associated with propofol, in a target-controlled infusion.\n\n\nMEASUREMENTS\nHeart rate, mean blood pressure (MBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma glucose, and cortisol were determined before anesthetic induction, 5 minutes after tracheal intubations and 30 minutes after initial surgical incision. Extubation and orientation times, and postanesthesia care unit (PACU) discharge times were noted.\n\n\nMAIN RESULTS\nBlood cortisol levels were higher in the DEX group than in the REM group at 30minutes after surgical incision. Cortisol levels decreased as a function of time in the REM group, whereas intheDEX group they decreased in the second sample and returned to basal levels at 30 minutes. Hyperglycemia was higher in DEX than in REM during the second and third sample collection. However, glucose increased as a function of time in both groups. Analysis of MBP and DBP indicated adecrease in blood pressure at 5 minutes after tracheal intubations in both groups. At 30 minutes afterincision, MBP and DBP returned to basal levels in the DEX group, whereas the variables were significantly lower in the REM group. There were significant differences between groups for systolic blood pressure and heart rate at 5 and 30 minutes after incision with a greater decrease in REM. The extubation and orientation times were significantly increased in the DEX group, when compared with those of the REM group. There were no differences in postanesthesia care unit discharge times between groups.\n\n\nCONCLUSIONS\nDexmedetomidine was a clinically effective drug as a REM substitute in TIVA, during minimally invasive video gynecologic surgical procedures; however, patients anesthetized with DEX showed a more prolonged recovery time for some parameters such as orientation and extubation times.", "corpus_id": 2060352, "score": 0 }, { "doc_id": "1983845", "title": "A systematic review of COX‐2 inhibitors compared with traditional NSAIDs, or different COX‐2 inhibitors for post‐operative pain", "abstract": "Background:  We have reviewed the analgesic efficacy of cyclooxygenase‐2 (COX‐2) inhibitors compared with traditional non‐steroidal anti‐inflammatory drugs (NSAIDs), different COX‐2 inhibitors, and placebo in post‐operative pain.", "corpus_id": 1983845, "score": 0 }, { "doc_id": "72512978", "title": "Intravenous Lidocaine Speeds the Return of Bowel Function, Decreases Postoperative Pain, and Shortens Hospital Stay in Patients Undergoing Radical Retropubic Prostatectomy", "abstract": "Postoperative ileus is a concern among surgical patients. Epidural anesthesia nd analgesia with local anesthetics can decrease the duration of ileus. Significant systemic absorption of local anesthesia occurs during epidural use. ln this study, we examined whether many of the beneficial effects on bowel function seen with epidural lidocaine are also present when the drug is given parenterally. Forty patients undergoing radical retropubic prostatectomy were studied with one half of the patients receiving a lidoCaine bolus (1.5 mg/kg) and infusion (3 mg/min, unless weight <70 kg, then 2 mg/min); the other half received a saline infusion. A blind observer recorded the patient’s daily pain score, the time the patient first experienced flatulence and had the first bowel movement, and the total use of analgesics. Lidocaine-treated patients first experienced flatulence in a significantly shorter time (P < 0.01) than control patients. Lidocaine patients’ hospital stay was also significantly shorter (P < 0.05); on average, they spent 1.1 fewer days in the hospital. Iv lidocaine initiated before anesthesia nd continued 1 h postoperatively significantly sped up the return of bowel function. Lidocaine patients were also more comfortable postoperatively. Many of the bowel function benefits attributed to epidural lidocaine are also present when the drug is administered parenterally. Additionally, the length of hospital stay was reduced in lidocaine-treated patients. Implications: This study prospectively examined whether lV lidocaine could affect the return of bowel function after radical prostate surgery. Lidocaine-treated patients had shorter hospita1 stays, less pain, and faster return of bowel function. In this population, lidocaine infusion can be a useful adjunct in anesthetic management.", "corpus_id": 72512978, "score": 0 }, { "doc_id": "1994521", "title": "Acid suppression in the perioperative period.", "abstract": "Aspiration of oropharyngeal and gastric contents during surgery, although infrequent, is a recognized complication of general anesthesia that carries significant risk for serious complications. Complications of aspiration have been reported to cause 10% to 30% of anesthesia-related deaths. Unconsciousness interferes with multiple biologic mechanisms that guard the airway against aspiration, and this is compounded in surgery by anesthesia-induced neurologic impairment and the risks related to placement of nasogastric and endotracheal tubes. Consequences of anesthesia-related aspiration include aspiration pneumonia, acute respiratory distress syndrome, pulmonary edema, and long-term complications such as laryngotracheal damage and decreased lung compliance. Therefore, averting aspiration, particularly in the elderly and other high-risk patients, should be part of the perioperative plan. Although antacids and histamine 2-receptor antagonists have been used perioperatively with some success, they are limited by short duration of action and systemic side effects, among other factors. Proton pump inhibitors are currently being investigated in surgical patients at risk for aspiration or stress ulcers and seem to be potent, extremely effective, and well tolerated. This article reviews the risks for, and potential outcomes of, anesthesia-related aspiration, identifies high-risk populations, and outlines the experience to date with available preventive treatments.", "corpus_id": 1994521, "score": 0 }, { "doc_id": "25663407", "title": "Effect of Dexamethasone on Postoperative Symptoms in Patients Undergoing Elective Laparoscopic Cholecystectomy: Randomized Clinical Trial", "abstract": "BackgroundDexamethasone has been reported to reduce postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy (LC). However, its effects on other surgical outcomes, such as pain and fatigue, have been unclear. We evaluated the efficacy of preoperative dexamethasone for ameliorating postoperative symptoms after LC.MethodsIn this prospective, double-blind, placebo-controlled study, 210 patients scheduled for elective LC were analyzed after randomization to intravenous dexamethasone (8 mg) or a placebo. All patients underwent standardized procedures for general anesthesia and surgery. Episodes of PONV and the pain and fatigue scores were recorded on a visual analog scale. Analgesic and antiemetic requirements were also recorded.ResultsThere were no significant differences between groups with regard to medical or demographic variables. Significantly fewer patients experienced PONV in the dexamethasone group immediately after LC and at 6 and 12 h. The need for ondansetron to relieve PONV was higher in the placebo group (P = 0.001). Patients in the study group reported less postoperative pain during the first 24 h and less fatigue after 6, 12, and 24 h. The need for buprenorphine to relieve intolerable pain was also less in this group (P = 0.009). There were no side effects, and the morbidity was similar in the two groups (6.7 vs. 7.6%).ConclusionsThe regimen we employed is safe and without apparent side effects. Thus, preoperative dexamethasone can significantly reduce the incidence of PONV, pain and fatigue after elective LC.", "corpus_id": 25663407, "score": 0 }, { "doc_id": "19357766", "title": "Systematic review on the short‐term outcome of laparoscopic resection for colon and rectosigmoid cancer", "abstract": "Objective  Several large randomized controlled trials on laparoscopic resection for colon and rectosigmoid cancer have recently been published. There is a need to provide an up‐to‐date systematic review in this subject.", "corpus_id": 19357766, "score": 0 }, { "doc_id": "34219554", "title": "Systematic review of prophylactic nasogastric decompression after abdominal operations", "abstract": "Routine use of nasogastric tubes after abdominal operations is intended to hasten the return of bowel function, prevent pulmonary complications, diminish the risk of anastomotic leakage, increase patient comfort and shorten hospital stay. This meta‐analysis of published studies examines the efficacy of this practice after abdominal surgery in achieving each of these goals.", "corpus_id": 34219554, "score": 0 }, { "doc_id": "20555590", "title": "Pharmacologic Options to Prevent Postoperative Ileus", "abstract": "Objective: To summarize the evidence on pharmacologic options in preventing postoperative ileus (POI). Data Sources: The Cochrane Database of Reviews and OVID databases and Food and Drug Administration (FDA) Web site were searched (1950–April 2009) using the term postoperative ileus. Study Selection and Data Extraction: Meta-analyses and randomized controlled trials were included for review. The FDA Web site was searched for clinical reviews and label information for drugs indicated for the prevention of POI. Data Synthesis: Three meta-analyses, 2 on gum-chewing and 1 on alvimopan, and 18 clinical trials were identified. Only gum chewing and alvimopan were effective in preventing POI. Gum chewing reduced the time to first flatus and bowel movement (weighted mean difference 21h, p = 0.0006 and 33h; p = 0.0002, respectively). In one meta-analysis, gum chewing significantly reduced length of stay (LOS) by 2.4 days (p < 0.00001) but this was not replicated in the second meta-analysis. Alvimopan shortened the time to reach a composite endpoint of solid food intake, plus/minus flatus, and bowel movement (93 vs 105 h; p < 0.001). A higher incidence of myocardial infarction was observed in a 12-month study of alvimopan for the treatment of opioid-induced bowel dysfunction, but not in studies in patients undergoing bowel resection. Alvimopan decreased the time to written hospital discharge order (hazard ratio 1.35; p<0.01), while the significance of a reduction in LOS (0.2–1.3 days) was not reported. Conclusions: Gum chewing and alvimopan are effective in preventing POI, but given safety concerns and higher cost with alvimopan, gum chewing may be preferred.", "corpus_id": 20555590, "score": 0 }, { "doc_id": "24191308", "title": "Colonic Surgery With Accelerated Rehabilitation or Conventional Care", "abstract": "BACKGROUNDFor patients undergoing colonic surgery, the postoperative hospital stay is usually 6 to 10 days, and the morbidity rate is 15 to 20 percent. Fast-track rehabilitation programs have reduced the hospital stay to 2 to 3 days. The aim of this study was to evaluate the postoperative outcome after colonic resection with conventional care compared with fast-track multimodal rehabilitation.METHODSOne hundred thirty consecutive patients receiving conventional care (group 1) in one hospital were compared with 130 consecutive patients receiving multimodal, fast-track rehabilitation (group 2) in another hospital. Outcomes were time to first defecation after surgery, postoperative hospital stay, and morbidity during the first postoperative month.RESULTSMedian age was 74 years (group 1) and 72 years (group 2). American Society of Anesthesiologists (ASA) score was significantly higher in group 2 (P < 0.05). Defecation occurred on day 4.5 in group 1 and day 2 in group 2 (P < 0.05). Median hospital stay was 8 days in group 1 and 2 days in group 2 (P < 0.05). The use of a nasogastric tube was longer in group 1 (P < 0.05). The overall complication rate (35 patients) was lower in group 2 (P < 0.05), especially cardiopulmonary complications (5 patients; P < 0.01). Readmission was necessary in 12 percent of cases for group 1 and 20 percent in group 2 (P > 0.05).CONCLUSIONSTime to first defecation, hospital stay, and morbidity may be reduced after colonic resection with fast-track multimodal rehabilitation.", "corpus_id": 24191308, "score": 0 }, { "doc_id": "25875210", "title": "A clinical pathway to accelerate recovery after colonic resection.", "abstract": "OBJECTIVE\nTo investigate the feasibility of a 48-hour postoperative stay program after colonic resection.\n\n\nSUMMARY BACKGROUND DATA\nPostoperative hospital stay after colonic resection is usually 6 to 12 days, with a complication rate of 10% to 20%. Limiting factors for early recovery include stress-induced organ dysfunction, paralytic ileus, pain, and fatigue. It has been hypothesized that an accelerated multimodal rehabilitation program with optimal pain relief, stress reduction with regional anesthesia, early enteral nutrition, and early mobilization may enhance recovery and reduce the complication rate.\n\n\nMETHODS\nSixty consecutive patients undergoing elective colonic resection were prospectively studied using a well-defined postoperative care program including continuous thoracic epidural analgesia and enforced early mobilization and enteral nutrition, and a planned 48-hour postoperative hospital stay. Postoperative follow-up was scheduled at 8 and 30 days.\n\n\nRESULTS\nMedian age was 74 years, with 20 patients in ASA group III-IV. Normal gastrointestinal function (defecation) occurred within 48 hours in 57 patients, and the median hospital stay was 2 days, with 32 patients staying 2 days after surgery. There were no cardiopulmonary complications. The readmission rate was 15%, including two patients with anastomotic dehiscence (one treated conservatively, one with colostomy); other readmissions required only short-term observation.\n\n\nCONCLUSION\nA multimodal rehabilitation program may significantly reduce the postoperative hospital stay in high-risk patients undergoing colonic resection. Such a program may also reduce postoperative ileus and cardiopulmonary complications. These results may have important implications for the care of patients after colonic surgery and in the future assessment of open versus laparoscopic colonic resection.", "corpus_id": 25875210, "score": 0 }, { "doc_id": "1478618", "title": "Effect of bisacodyl on postoperative bowel motility in elective colorectal surgery: a prospective, randomized trial", "abstract": "BackgroundPostoperative ileus is a common condition after abdominal surgery. Many prokinetic drugs have been evaluated including osmotic laxatives. The data on colon-stimulating laxatives are scarce. This prospective, randomized, double-blind trial investigates the effect of the colon-stimulating laxative bisacodyl on postoperative ileus in elective colorectal resections.Materials and methodsBetween November 2004 and February 2007, 200 consecutive patients were randomly assigned to receive either bisacodyl or placebo. Primary endpoint was time to gastrointestinal recovery (mean time to first flatus passed, first defecation, and first solid food tolerated; GI-3). Secondary endpoints were incidence and duration of nasogastric tube reinsertion, incidence of vomiting, length of hospital stay, and visual analogue scores for pain, cramps, and nausea.ResultsOne hundred sixty-nine patients were analyzed, and 31 patients discontinued the study. Groups were comparable in baseline demographics. Time to GI-3 was significantly shorter in the bisacodyl group (3.0 versus 3.7 days, P = 0.007). Of the single parameters defining GI-3, there was a 1-day difference in time to defecation in favor to the bisacodyl group (3.0 versus 4.0 days, P = 0.001), whereas no significant difference in time to first flatus or tolerance of solid food was seen. No significant difference in the secondary endpoints was seen. Morbidity and mortality did not differ between groups.ConclusionBisacodyl accelerated gastrointestinal recovery and might be considered as part of multimodal recovery programs after colorectal surgery.", "corpus_id": 1478618, "score": 0 }, { "doc_id": "43275806", "title": "Multimodal strategies to improve surgical outcome.", "abstract": "OBJECTIVE\nTo evaluate the effect of modifying perioperative care in noncardiac surgical patients on morbidity, mortality, and other outcome measures.\n\n\nBACKGROUND\nNew approaches in pain control, introduction of techniques that reduce the perioperative stress response, and the more frequent use of minimal invasive surgical access have been introduced over the past decade. The impact of these interventions, either alone or in combination, on perioperative outcome was evaluated.\n\n\nMETHODS\nWe searched Medline for the period of 1980 to the present using the key terms fast track surgery, accelerated care programs, postoperative complications and preoperative patient preparation; and we examined and discussed the articles that were identified to include in this review. This information was supplemented with our own research on the mediators of the stress response in surgical patients, the use of epidural anesthesia in elective operations, and pilot studies of fast track surgical procedures using the multimodality approach.\n\n\nRESULTS\nThe introduction of newer approaches to perioperative care has reduced both morbidity and mortality in surgical patients. In the future, most elective operations will become day surgical procedures or require only 1 to 2 days of postoperative hospitalization. Reorganization of the perioperative team (anesthesiologists, surgeons, nurses, and physical therapists) will be essential to achieve successful fast track surgical programs.\n\n\nCONCLUSIONS\nUnderstanding perioperative pathophysiology and implementation of care regimes to reduce the stress of an operation, will continue to accelerate rehabilitation associated with decreased hospitalization and increased satisfaction and safety after discharge. Developments and improvements of multimodal interventions within the context of \"fast track\" surgery programs represents the major challenge for the medical professionals working to achieve a \"pain and risk free\" perioperative course.", "corpus_id": 43275806, "score": 0 }, { "doc_id": "23301153", "title": "Consensus review of optimal perioperative care in colorectal surgery: Enhanced Recovery After Surgery (ERAS) Group recommendations.", "abstract": "OBJECTIVES\nTo describe a consensus review of optimal perioperative care in colorectal surgery and to provide consensus recommendations for each item of an evidence-based protocol for optimal perioperative care.\n\n\nDATA SOURCES\nFor every item of the perioperative treatment pathway, available English-language literature has been examined.\n\n\nSTUDY SELECTION\nParticular attention was paid to meta-analyses, randomized controlled trials, and systematic reviews.\n\n\nDATA EXTRACTION\nA consensus recommendation for each protocol item was reached after critical appraisal of the literature by the group.\n\n\nDATA SYNTHESIS\nFor most protocol items, recommendations are based on good-quality trials or meta-analyses of such trials.\n\n\nCONCLUSIONS\nThe Enhanced Recovery After Surgery (ERAS) Group presents a comprehensive evidence-based consensus review of perioperative care for colorectal surgery. It is based on the evidence available for each element of the multimodal perioperative care pathway.", "corpus_id": 23301153, "score": 0 }, { "doc_id": "24301350", "title": "Postoperative ileus-related morbidity profile in patients treated with alvimopan after bowel resection.", "abstract": "BACKGROUND\nPostoperative ileus (POI), an interruption of coordinated bowel motility after operation, is exacerbated by opioids used to manage pain. Alvimopan, a peripherally acting mu-opioid receptor antagonist, accelerated gastrointestinal (GI) recovery after bowel resection in randomized, double-blind, placebo-controlled, multicenter phase III POI trials. The effect of alvimopan on POI-related morbidity for patients who underwent bowel resection was evaluated in a post-hoc analysis.\n\n\nSTUDY DESIGN\nIncidence of POI-related postoperative morbidity (postoperative nasogastric tube insertion or POI-related prolonged hospital stay or readmission) was analyzed in four North American trials for placebo or alvimopan 12 mg administered 30 minutes or more preoperatively and twice daily postoperatively until hospital discharge (7 or fewer postoperative days). GI-related adverse events and opioid consumption were summarized for each treatment. Estimations of odds ratios of alvimopan to placebo and number needed to treat (NNT) to prevent one patient from experiencing an event of POI-related morbidity were derived from the analysis.\n\n\nRESULTS\nPatients receiving alvimopan 12 mg were less likely to experience POI-related morbidity than patients receiving placebo (odds ratio = 0.44, p < 0.001). Fewer patients receiving alvimopan (alvimopan, 7.6%; placebo, 15.8%; NNT = 12) experienced POI-related morbidity. There was a lower incidence of postoperative nasogastric tube insertion, and other GI-related adverse events on postoperative days 3 to 6 in the alvimopan group than the placebo group. Opioid consumption was comparable between groups.\n\n\nCONCLUSIONS\nAlvimopan 12 mg was associated with reduced POI-related morbidity compared with placebo, without compromising opioid-based analgesia in patients undergoing bowel resection. Relatively low NNTs are clinically meaningful and reinforce the potential benefits of alvimopan for the patient and health care system.", "corpus_id": 24301350, "score": 0 }, { "doc_id": "24404548", "title": "Economic analysis of alvimopan in North American Phase III efficacy trials.", "abstract": "PURPOSE\nThe economic effect of the use of alvimopan in four randomized, double-blind, placebo-controlled, Phase III, North American efficacy trials was analyzed.\n\n\nMETHODS\nPatients were eligible for the study if they were 18 years or older, were undergoing laparotomy for partial small or large bowel resection with primary anastomosis, and were scheduled for postoperative pain management with opioid-based i.v. patient-controlled analgesia. Patients analyzed in the North American Phase III trials received placebo or alvimopan 12 mg orally before surgery. Doses were administered twice daily beginning the day after surgery until hospital discharge or for a maximum of 15 doses.\n\n\nRESULTS\nCompared with placebo, alvimopan was associated with a significantly shorter mean time to gastrointestinal (GI) recovery and a significantly shorter mean time to a written discharge order. Alvimopan was also associated with a mean hospital length of stay (LOS) of one full day less than placebo. The mean cost of alvimopan based on a mean of 8.9 12-mg doses was $558.00; the alvimopan cost at the upper limit of allowed dosing was $937.50. Combining the alvimopan and hospital costs for each patient, total costs for the alvimopan group were estimated to be lower than for the placebo group.\n\n\nCONCLUSION\nIn a post hoc analysis, alvimopan was associated with significantly faster upper and lower GI recovery after bowel resection and a mean LOS reduction of one day compared with placebo. The mean estimated hospital cost was $879-$977 less for patients who received alvimopan compared with placebo. The base-case and sensitivity analyses suggest that, on average, the use of alvimopan compared with placebo may have a cost-saving effect in the hospital setting.", "corpus_id": 24404548, "score": 0 }, { "doc_id": "25332780", "title": "‘Fast-track’ multimodal rehabilitation program improves outcome after laparoscopic sigmoidectomy: a controlled prospective evaluation", "abstract": "BackgroundLaparoscopic colorectal resection improves patient outcome by reducing pain, postoperative pulmonary dysfunction, gastrointestinal paralysis, and fatigue. A multimodal rehabilitation program (“fast-track”) with epidural analgesia, early oral feeding, and enforced mobilization may further improve the excellent results of laparoscopic colorectal resection, enabling early ambulation of these patients.MethodsFifty two consecutive patients underwent laparoscopic sigmoidectomy with standardized regular perioperative treatment (standard) or multimodal rehabilitation program (“fast-track”). Outcome measures included pulmonary function, duration of postoperative ileus, pain perception, fatigue, morbidity, and mortality.ResultsTwenty nine standard-care patients (19 men and 10 women) and 23 fast-track patients (15 men and eight women) were evaluated. Demographic and operative data were similar for the two groups. On the 1st postoperative day, pulmonary function was improved (p = 0.01) in fast-track patients. Oral feeding was achieved earlier (p < 0.01) and defecation occurred earlier (p < 0.01) in the fast-track group. Visual analogue scale scores for pain were similar for the two groups (p > 0.05), but fatigue was increased in the standard-care group on the 1st (p = 0.06) and 2nd (p < 0.05) postoperative days. Morbidity was not different for the two groups. Fast-track patients were discharged on day 4 (range, 3–6) and standard-care patients on day 7 (range, 4–14) (p < 0.001).ConclusionMultimodal rehabiliation can improve further on the excellent results of laparoscopic sigmoidectomy and decrease the postoperative hospital stay.", "corpus_id": 25332780, "score": 0 }, { "doc_id": "21195434", "title": "‘Fast track’ postoperative management protocol for patients with high co‐morbidity undergoing complex abdominal and pelvic colorectal surgery", "abstract": "A combination of factors has emphasized the need to reduce postoperative stay after surgery. Multimodal care plans may shorten hospital stay, but have been associated with high readmission rates and are generally reserved for straightforward, non‐complicated colonic (not rectal) resections. This study evaluated a ‘fast track’ protocol in patients undergoing major colonic and rectal surgery.", "corpus_id": 21195434, "score": 0 }, { "doc_id": "26028390", "title": "Convalescence after Colonic Resection with Fast-Track versus Conventional Care", "abstract": "Background: Multi-modal rehabilitation programmes may improve early postoperative body composition, pulmonary function, exercise capacity, and reduce hospital stay. So far, no data are available on convalescence after discharge. Aim: The objectives where to compare convalescence data (fatigue, sleep, time to resume normal activities, and functional capabilities) and need for nursing care and contact to general practitioner with fast-track multi-modal rehabilitation compared with conventional care after colonic surgery. Methods: Non-randomised, prospective controlled study in 30 consecutive patients undergoing fast-track rehabilitation with continuous epidural analgesia, enforced oral nutrition, mobilisation, planned early discharge, and 30 consecutive patients undergoing conventional care. Patients were interviewed preoperatively and 14 and 30 days postoperatively. Results: Median hospital stay was 2 vs. 8 days in the fast-track vs. conventional care group, respectively (p < 0.01). Fourteen days postoperatively, total and mid-day sleep were increased in the conventional care group when compared with the fast-track group (p < 0.01). Fatigue was increased significantly at 14 days (p < 0.05) and throughout the study period compared with the fast-track group (p < 0.01). Similarly, ability to walking stairs, cooking, house keeping, shopping and walking outdoor was significantly less reduced at 14 days in the fast-track group, who also regained leisure activities earlier (p < 0.05). There was no significant difference between groups at 30 days or between need for nursing care and visits to general practitioners. Readmission for surgery-related events occurred more frequently (5 vs 1 patient) in the fast-track group. Conclusion: Fast-track rehabilitation with early discharge after colonic surgery results in earlier resumption of normal activities with reduced fatigue and need for sleep postoperatively compared to conventional care, and without increased need for nursing care or visits to general practitioners. However, readmissions may occur more frequently.", "corpus_id": 26028390, "score": 0 }, { "doc_id": "24080071", "title": "Fast-track colonic surgery: status and perspectives.", "abstract": "Multi-modal rehabilitation with an emphasis on preoperative information, reduction of surgical stress responses, optimized dynamic pain relief with continuous epidural analgesia and early mobilization and oral nutrition may reduce hospital stay, morbidity, convalescence, and costs (fast-track surgery). Current results from fast-track colonic surgery suggest that postoperative pulmonary, cardiovascular, and muscle function are improved and body composition preserved as well as a normal oral intake of energy and protein can be achieved. Consequently, hospital stay is reduced to about 2-4 days, with decreased fatigue and need for sleep in the convalescence period. Despite a higher risk for readmissions, overall costs and morbidity seem to be reduced. Existing data from several institutions support the concept of fast-track colonic surgery to improve postoperative organ functions, thereby allowing for early rehabilitation with decreased hospital stay, convalescence, and costs. Further data are needed from multi-national institutions on morbidity, safety, and costs.", "corpus_id": 24080071, "score": 0 }, { "doc_id": "24903227", "title": "Gum chewing enhances early recovery from postoperative ileus after laparoscopic colectomy.", "abstract": "BACKGROUND\nPostoperative ileus limits early hospital discharge for patients who have undergone laparoscopic procedures. Sham feeding has been reported to enhance bowel motility. Here, the effect of gum chewing is evaluated as a convenient method to enhance postoperative recovery from ileus after laparoscopic colectomy.\n\n\nSTUDY DESIGN\nA total of 19 patients who underwent elective laparoscopic colectomy for colorectal cancer participated in the study. Each patient was randomly assigned to one of two groups: a gum-chewing group (n = 10, mean age 58.6 years, range 50 to 71 years) or a control group (n = 9, mean age 60.6 years, range 45 to 80 years). The patients in the gum-chewing group chewed gum three times a day from the first postoperative AM until oral intake. The times of the first passage of flatus and defecation were recorded precisely.\n\n\nRESULTS\nThe first passage of flatus was seen, on average, on postoperative day 2.1 in the gum-chewing group and on day 3.2 in the control group (p < 0.01). The first defecation was 2.7 days sooner in the gum-chewing group (postoperative day 3.1) than in the control group (5.8 days; p< 0.01). All patients tolerated gum chewing on the first operative AM. The postoperative hospital stays for the gum-chewing and control groups were 13.5+/-3.0 days and 14.5+/-6.1 days, respectively.\n\n\nCONCLUSIONS\nGum chewing aids early recovery from postoperative ileus and is an inexpensive and physiologic method for stimulating bowel motility. Gum chewing should be added as an adjunct treatment in postoperative care because it might contribute to shorter hospital stays.", "corpus_id": 24903227, "score": 0 }, { "doc_id": "25076278", "title": "Gum chewing stimulates bowel motility in patients undergoing radical cystectomy with urinary diversion.", "abstract": "OBJECTIVES\nSeveral studies have shown that gum chewing may stimulate bowel motility after gastrointestinal surgery. Because urinary diversion typically uses a segment of bowel, it is conceivable that patients undergoing cystectomy and diversion may benefit from gum chewing. This study aimed to determine whether gum chewing in the immediate postoperative period facilitates a return to bowel function in patients undergoing cystectomy and urinary diversion.\n\n\nMETHODS\nA total of 102 patients underwent radical cystectomy and urinary diversion for clinically localized bladder cancer. Each patient followed our institution's perioperative cystectomy care plan. The first cohort of patients underwent surgery between July 2004 and August 2005 and served as a comparison (control) group in which no gum was dispensed. The second cohort underwent surgery during September 2005 to July 2006. These patients were given chewing gum to begin on postoperative day 1. Outcome measures included time to flatus, time to bowel movement, length of hospital stay, and complications.\n\n\nRESULTS\nThe time to flatus was shorter in patients who received gum compared with controls (2.4 versus 2.9 days; P <0.001). Also, time to bowel movement was reduced in patients who received gum (3.2 versus 3.9 days; P <0.001). There was no significant difference in length of hospital stay between gum-chewing patients and controls (4.7 versus 5.1 days, respectively; P = 0.067). Gum chewing was well tolerated in all patients.\n\n\nCONCLUSIONS\nGum chewing may speed the recovery of bowel function after cystectomy and diversion. These findings are consistent with outcomes in the colorectal surgery published data that support the use of chewing gum as an easy and inexpensive way to enhance recovery after surgery.", "corpus_id": 25076278, "score": 0 }, { "doc_id": "18566518", "title": "Gum chewing reduces ileus after elective open sigmoid colectomy.", "abstract": "HYPOTHESIS\nGum chewing after elective open colon resection may stimulate bowel motility and decrease duration of postoperative ileus.\n\n\nDESIGN AND SETTING\nProspective, randomized study in a community-based teaching hospital.\n\n\nPATIENTS\nThirty-four patients undergoing elective open sigmoid resections for recurrent diverticulitis or cancer.\n\n\nMAIN OUTCOME MEASURES\nFirst feelings of hunger, time to first flatus, time to first bowel movement, length of hospital stay, and complications.\n\n\nRESULTS\nA total of 34 patients were randomized into 2 groups: a gum-chewing group (n = 17) or a control group (n = 17). The patients in the gum-chewing group chewed sugarless gum 3 times daily for 1 hour each time until discharge. Patient demographics, intraoperative, and postoperative care were equivalent between the 2 groups. All gum-chewing patients tolerated the gum. The first passage of flatus occurred on postoperative hour 65.4 in the gum-chewing group and on hour 80.2 in the control group (P = .05). The first bowel movement occurred on postoperative hour 63.2 in the gum-chewing group and on hour 89.4 in the control group (P = .04). The first feelings of hunger were felt on postoperative hour 63.5 in the gum-chewing group and on hour 72.8 in the control group (P = .27). There were no major complications in either group. The total length of hospital stay was shorter in the gum-chewing group (day 4.3) than in the control group (day 6.8), (P = .01).\n\n\nCONCLUSIONS\nGum chewing speeds recovery after elective open sigmoid resection by stimulating bowel motility. Gum chewing is an inexpensive and helpful adjunct to postoperative care after colectomy.", "corpus_id": 18566518, "score": 0 }, { "doc_id": "46136586", "title": "Does gum chewing ameliorate postoperative ileus? Results of a prospective, randomized, placebo-controlled trial.", "abstract": "BACKGROUND\nA preliminary report has been interpreted to suggest that gum chewing reduces duration of postcolectomy ileus.\n\n\nSTUDY DESIGN\nWe rigorously tested this hypothesis in a prospective, randomized, placebo-controlled study. Patients undergoing open colectomy (n = 66) were randomized to receive 1 of 3 postoperative regimens beginning on postoperative day 1: sips (control, n = 21); sips and accupressure wrist bracelet (placebo, n = 23); and sips and gum chewing (treatment, n = 22). Patients were unaware of which regimen constituted placebo or treatment; end points were assessed by blinded investigators. Power was set a priori at 85% to detect a 0.75-day difference in time to first postoperative passage of flatus between placebo and treatment groups. Groups were compared using the log-rank test.\n\n\nRESULTS\nGroups were equivalent with respect to demographic and surgical characteristics. Median times to first postoperative passage of flatus were as follows: sips, 67 hours; bracelet and sips, 72 hours; gum and sips, 60 hours (p = 0.384). There were no significant differences in time to passage of first bowel movement, time until patients were ready for discharge, or time until actual discharge among the three groups. Inpatient and 30-day followup demonstrated no difference in frequency or distribution of postoperative complications.\n\n\nCONCLUSIONS\nIn contrast to findings of a preliminary study, our clinical trial suggests that gum chewing, although safe, does not reduce duration of postcolectomy ileus.", "corpus_id": 46136586, "score": 0 }, { "doc_id": "24987486", "title": "Prospective trial of aggressive postoperative bowel stimulation following radical hysterectomy.", "abstract": "INTRODUCTION\nPostoperative traditional feeding protocols are not based on scientific studies, but rather on anecdotal evidence. We present the first prospective trial of aggressive postoperative bowel stimulation following radical hysterectomy in an attempt to determine its effect on the length of hospital stay.\n\n\nMETHODS\nTwenty consecutive patients undergoing radical hysterectomy were entered onto a prospective trial of aggressive postoperative bowel stimulation, which consisted of 30 cc milk of magnesia p.o. b.i.d. starting on postoperative day 1 and biscolic suppositories q.d. starting on day 2. A clear liquid diet was begun following flatus or bowel movement and patients were discharged 12 h after tolerating a clear liquid diet. Diet was slowly advanced at home.\n\n\nRESULTS\nMedian time to flatus was 3 days, bowel movement 3 days, and clear liquid diet 3 days. Median time to discharge was 4 days. No patients developed ileus or bowel obstructions and there were no readmissions for bowel complications. Our median time to discharge of 4 days represents a 50% reduction in hospital stay compared to our previous prospective study using traditional postoperative bowel management (8 days), which was statistically significant at P = 0.001.\n\n\nCONCLUSION\nAggressive bowel stimulation with milk of magnesia and biscolic suppositories resulted in early return of bowel function and early discharge with no noticeable complications.", "corpus_id": 24987486, "score": 0 }, { "doc_id": "38883425", "title": "Prospective trial of early feeding and bowel stimulation after radical hysterectomy.", "abstract": "OBJECTIVE\nIn an attempt to decrease hospital stay we performed a prospective trial of aggressive bowel stimulation and early postoperative feeding after radical hysterectomy.\n\n\nSTUDY DESIGN\nIn a prospective trial of 20 consecutive patients undergoing class 3 radical hysterectomy, feeding of a clear liquid diet and bowel stimulation with oral 66% sodium phosphate solution (Fleet Phospho-Soda) were instituted on postoperative day 1. Patients were discharged after passage of flatus or stool.\n\n\nRESULTS\nMedian time to discharge was 3.5 days. No patient had emesis, ileus, or bowel obstruction. The decrease in hospital stay with respect to those in our previous trial with traditional postoperative feeding and our original study on postoperative bowel stimulation was statistically significant.\n\n\nCONCLUSION\nAggressive bowel stimulation with Fleet Phospho-Soda and early feeding after radical hysterectomy resulted in early return of bowel function and early discharge without significant intestinal complication.", "corpus_id": 38883425, "score": 0 }, { "doc_id": "2542826", "title": "Normal gastrointestinal transit after colonic resection using epidural analgesia, enforced oral nutrition and laxative", "abstract": "Postoperative ileus usually lasts for 2–5 days after colonic surgery and may contribute to discomfort and pulmonary complications. With multimodal rehabilitation (epidural analgesia, early oral nutrition and mobilization, and laxative) defaecation occurs 1–2 days after colonic surgery. The aim of this study was to assess the transit rate of the entire gastrointestinal tract after colonic resection with multimodal rehabilitation.", "corpus_id": 2542826, "score": 0 }, { "doc_id": "31758059", "title": "Alvimopan, a selective peripherally acting μ‐opioid antagonist *", "abstract": "Abstract  Alvimopan is a novel, peripherally acting μ‐opioid antagonist that is being developed for the management of acute postoperative ileus and for the reversal of the delayed gastrointestinal and colonic transit that result in symptoms such as constipation, nausea and motility disorders in patients treated with opiate analgesics. There is a clinical need for effective medications for the treatment of postoperative ileus and opiate‐induced constipation and other motility disorders. This review addresses the basic and applied pharmacology and current evidence for the use of the medication, alvimopan, in clinical gastroenterology.", "corpus_id": 31758059, "score": 0 }, { "doc_id": "32211106", "title": "Causes of increased hospital stay after radical cystectomy in a clinical pathway setting.", "abstract": "PURPOSE\nOur institution targets postoperative days 6 to 8 for discharge home after radical cystectomy. We examined this population to determine the causes of increased hospital stay and risk factors that may predict prolonged hospitalization.\n\n\nMATERIALS AND METHODS\nWe reviewed the records of 304 consecutive patients who underwent radical cystectomy from October 1995 to July 2000. The variables examined included age, gender, race, American Society of Anesthesiologists score, urinary diversion type, smoking history, estimated blood loss, transfusion requirement, operative time, hospital stay, perioperative minor and major complications, and the mortality rate.\n\n\nRESULTS\nOf the 304 patients 144 (47.4%) underwent ileal conduit diversion and 145 (47.7%) underwent orthotopic bladder substitution. Median hospital stay was 7 days (range 4 to 48). Of 302 patients 225 (74%) were discharged home by postoperative day 8, while 52 of the remaining 77 (67.5%) with increased hospital stay were discharged home by day 12. Postoperative ileus was the most common cause of increased hospitalization (53 of 77 cases or 68.8%). Major complications developed in 15 patients (4.9%), of whom 66% required a hospital stay of greater than 12 days. There was a single perioperative death (0.3%). No preoperative variables other than race predicted increased hospitalization. Of the clinical variables increased estimated blood loss, transfusion and minor or major complications correlated with an increased stay (p <0.05). However, on multivariate analysis only complications were associated with prolonged hospitalization.\n\n\nCONCLUSIONS\nOur cystectomy clinical care pathway targets a hospital discharge date that is safely achieved in the majority of patients. Postoperative ileus is the most common cause of prolonged hospitalization. Age, gender, American Society of Anesthesiologists score, urinary diversion type and pathological stage did not correlate with increased hospital stay.", "corpus_id": 32211106, "score": 0 }, { "doc_id": "43512286", "title": "Methods for decreasing postoperative gut dysmotility.", "abstract": "Postoperative disturbances of gastrointestinal function (postoperative ileus) are among the most significant side-effects of abdominal surgery for cancer. Without specific treatment, major abdominal surgery causes a predictable gastrointestinal dysfunction which endures for 4-5 days and results in an average hospital stay of 7-8 days. Ileus occurs because of initially absent and subsequently abnormal motor function of the stomach, small bowel, and colon. This disruption results in delayed transit of gastrointestinal content, intolerance of food, and gas retention. The aetiology of ileus is multifactorial, and includes autonomic neural dysfunction, inflammatory mediators, narcotics, gastrointestinal hormone disruptions, and anaesthetics. In the past, treatment has consisted of nasogastric suction, intravenous fluids, correction of electrolyte abnormalities, and observation. Currently, the most effective treatment is a multimodal approach. Median stays of 2-3 days after removal of all or part of the colon (colectomy) are now achievable. Recent discoveries have the potential to significantly reduce postoperative ileus in patients with cancer who have had abdominal surgery.", "corpus_id": 43512286, "score": 0 }, { "doc_id": "687257", "title": "Postoperative morbidity and mortality following resection of the colon and rectum for cancer", "abstract": "PURPOSE: The aim of this study was to report the prevalence of postoperative complications and mortality of patients with colorectal cancer when treated by conventional surgery. METHODS: Morbidity and mortality following open resection for colorectal cancer were analyzed in 1,846 patients whose clinical, operative, and pathology data were prospectively documented over a 20-year period. RESULTS: Mortality following elective resection of the left and right colon was low, whereas overall morbidity was high (37.2 percent). Respiratory and cardiac complications were especially common. Incidence of clinically significant leakage was similar following right (0.5 percent) or left (1.1 percent) hemicolectomy. Incidence of anastomotic leakage was significantly higher after emergency right hemicolectomy (4.3 percent). Overall morbidity following excision of the rectum was high (40.2 percent). Respiratory and cardiac complications predominated. Incidence of clinically significant anastomotic leakage following anterior resection was low (2.9 percent). Over the years, there has been a decline in the number of patients with tumor demonstrated histologically in a line of resection, suggesting an improved local surgical clearance. CONCLUSIONS: These results following conventional surgery may be useful when evaluating new techniques.", "corpus_id": 687257, "score": 0 }, { "doc_id": "25856719", "title": "Implementation of a clinical pathway decreases length of stay and cost for bowel resection.", "abstract": "OBJECTIVE\nTo examine the effect of a clinical pathway for small and large bowel resection on cost and length of hospital stay.\n\n\nSUMMARY BACKGROUND DATA\nClinical pathways are designed to streamline patient care delivery and maximize efficiency while minimizing cost. Theoretically, they should be most effective in commonly performed procedures, in which volume and familiarity are high.\n\n\nMETHODS\nA clinical pathway to assist in the management of patients undergoing bowel resection was developed by a multidisciplinary team and implemented. Data about length of stay and cost was collected for all patients undergoing bowel resection 1 year before and 1 year after pathway implementation. Three groups were compared: patients undergoing bowel resection in the year prior to pathway implementation (prepathway), patients in the year after pathway implementation but not included on the pathway (nonpathway), and patients included in the pathway (pathway).\n\n\nRESULTS\nThe mean cost per hospital stay was $19,997.35 +/- 1244.61 for patients in the prepathway group, $20,835.28 +/- 2286.26 for those in the nonpathway group, and $13,908.53 +/- 1113.01 for those in the pathway group (p < 0.05 vs. other groups). Mean postoperative length of stay was 9.98 +/- 0.62 days (prepathway), 9.68 +/- 0.88 days for (nonpathway), and 7.71 +/- 0.37 days (pathway) (p < 0.05 vs. other groups).\n\n\nCONCLUSIONS\nImplementation of the pathway produced significant decreases in length of stay and cost in the pathway group as compared to the prepathway group. These results support the further development of clinical pathways for general surgical procedures.", "corpus_id": 25856719, "score": 0 }, { "doc_id": "15517046", "title": "Patient preferences for acute pain treatment.", "abstract": "BACKGROUND\nOptimal treatment for acute pain is a function of an individual's willingness to make trade-offs between treatment side effects and pain control. The objective was to investigate the degree to which patients are willing to make these trade-offs.\n\n\nMETHODS\nFifty patients undergoing major abdominal surgery were enrolled and completed interviews before and after surgery. Measures included an experience with pain questionnaire and an adaptive conjoint analysis (ACA) interview.\n\n\nRESULTS\nPercentage of pain relief obtained post-surgery was between 70 and 80%. Eight-two per cent reported at least one moderate or severe side effect. ACA results demonstrated that pain efficacy and side effect type/severity have almost equal 'importance' scores. Patients varied in their willingness to trade-off pain efficacy for different or milder side effects.\n\n\nCONCLUSIONS\nWe conclude that people have different relative preferences for different side effects and are willing to trade-off pain relief for less upsetting and/or less severe side effects but to different degrees. Thus, physicians should consider offering pain medications with fewer side effects than narcotics as a first choice. Our study indicates the need to balance analgesia and side effects in order for patients to achieve optimal pain control.", "corpus_id": 15517046, "score": 0 } ]

{ "doc_id": "12929234", "title": "Alternative Splicing and Extensive RNA Editing of Human TPH2 Transcripts", "abstract": "Brain serotonin (5-HT) neurotransmission plays a key role in the regulation of mood and has been implicated in a variety of neuropsychiatric conditions. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT. Recently, we discovered a second TPH isoform (TPH2) in vertebrates, including man, which is predominantly expressed in brain, while the previously known TPH isoform (TPH1) is primarly a non-neuronal enzyme. Overwhelming evidence now points to TPH2 as a candidate gene for 5-HT-related psychiatric disorders. To assess the role of TPH2 gene variability in the etiology of psychiatric diseases we performed cDNA sequence analysis of TPH2 transcripts from human post mortem amygdala samples obtained from individuals with psychiatric disorders (drug abuse, schizophrenia, suicide) and controls. Here we show that TPH2 exists in two alternatively spliced variants in the coding region, denoted TPH2a and TPH2b. Moreover, we found evidence that the pre-mRNAs of both splice variants are dynamically RNA-edited in a mutually exclusive manner. Kinetic studies with cell lines expressing recombinant TPH2 variants revealed a higher activity of the novel TPH2B protein compared with the previously known TPH2A, whereas RNA editing was shown to inhibit the enzymatic activity of both TPH2 splice variants. Therefore, our results strongly suggest a complex fine-tuning of central nervous system 5-HT biosynthesis by TPH2 alternative splicing and RNA editing. Finally, we present molecular and large-scale linkage data evidencing that deregulated alternative splicing and RNA editing is involved in the etiology of psychiatric diseases, such as suicidal behaviour.", "corpus_id": 12929234 }

[ { "doc_id": "29193544", "title": "A unique central tryptophan hydroxylase isoform.", "abstract": "Serotonin (5-hydroxytryptophan, 5-HT) is a neurotransmitter synthesized in the raphe nuclei of the brain stem and involved in the central control of food intake, sleep, and mood. Accordingly, dysfunction of the serotonin system has been implicated in the pathogenesis of psychiatric diseases. At the same time, serotonin is a peripheral hormone produced mainly by enterochromaffin cells in the intestine and stored in platelets, where it is involved in vasoconstriction, haemostasis, and the control of immune responses. Moreover, serotonin is a precursor for melatonin and is therefore synthesized in high amounts in the pineal gland. Tryptophan hydroxylase (TPH) catalyzes the rate limiting step in 5-HT synthesis. Until recently, only one gene encoding TPH was described for vertebrates. By gene targeting, we functionally ablated this gene in mice. To our surprise, the resulting animals, although being deficient for serotonin in the periphery and in the pineal gland, exhibited close to normal levels of 5-HT in the brain stem. This led us to the detection of a second TPH gene in the genome of humans, mice, and rats, called TPH2. This gene is predominantly expressed in the brain stem, while the classical TPH gene, now called TPH1, is expressed in the gut, pineal gland, spleen, and thymus. These findings clarify puzzling data, which have been collected over the last decades about partially purified TPH proteins with different characteristics and justify a new concept of the serotonin system. In fact, there are two serotonin systems in vertebrates, independently regulated and with distinct functions.", "corpus_id": 29193544, "score": 1 }, { "doc_id": "29397518", "title": "Tetrahydropterin-dependent amino acid hydroxylases.", "abstract": "Phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase constitute a small family of monooxygenases that utilize tetrahydropterins as substrates. When from eukaryotic sources, these enzymes are composed of a homologous catalytic domain to which are attached discrete N-terminal regulatory domains and short C-terminal tetramerization domains, whereas the bacterial enzymes lack the N-terminal and C-terminal domains. Each enzyme contains a single ferrous iron atom bound to two histidines and a glutamate. Recent mechanistic studies have begun to provide insights into the mechanisms of oxygen activation and hydroxylation. Although the hydroxylating intermediate in these enzymes has not been identified, the iron is likely to be involved. Reversible phosphorylation of serine residues in the regulatory domains affects the activities of all three enzymes. In addition, phenylalanine hydroxylase is allosterically regulated by its substrates, phenylalanine and tetrahydrobiopterin.", "corpus_id": 29397518, "score": 1 }, { "doc_id": "17841751", "title": "Animal studies of amygdala function in fear and uncertainty: Relevance to human research", "abstract": "This article reviews research in both animals and humans on the considerable progress made in elucidating a brain circuitry of fear, particularly the importance of the amygdala in fear conditioning. While there is considerable agreement about the participation of the amygdala in fear in both animals and humans, there are several issues about the function of the amygdala raised by the human research that have not been addressed by or may be answered by animal research. Three of these are addressed in this article: (1) is the amygdala involved in or necessary for both fear learning and unconditioned fear? (2) Does the amygdala code for intensity of fear? (3) Is the amygdala preferentially involved in fear, or is it also activated when there are no overt fear or aversive stimuli, but where the situation can be described as uncertain? We present evidence indicating that the rodent amygdala is involved in some types of fear (conditioned fear), but not all types (unconditioned fear), and may therefore have significance for a differential neurobiology of certain anxiety disorders in humans. Further, similar to the human amygdala, the rodent amygdala responds to varying intensities of aversive stimulation. Finally, it is suggested that, similar to humans, the rodent amygdala is involved in the evaluation of uncertainty. We conclude that progress on elucidating the role of the amygdala in fear is facilitated by corroboration of findings from both animal and human research.", "corpus_id": 17841751, "score": 0 }, { "doc_id": "3344804", "title": "The amygdala and reward", "abstract": "The amygdala — an almond-shaped group of nuclei at the heart of the telencephalon — has been associated with a range of cognitive functions, including emotion, learning, memory, attention and perception. Most current views of amygdala function emphasize its role in negative emotions, such as fear, and in linking negative emotions with other aspects of cognition, such as learning and memory. However, recent evidence supports a role for the amygdala in processing positive emotions as well as negative ones, including learning about the beneficial biological value of stimuli. Indeed, the amygdala's role in stimulus–reward learning might be just as important as its role in processing negative affect and fear conditioning.", "corpus_id": 3344804, "score": 0 }, { "doc_id": "24891311", "title": "Some assessments of the amygdala role in suprahypothalamic neuroendocrine regulation: a minireview.", "abstract": "The amygdala is a complex structure playing primary role in the processing and memorizing of emotional reactions. The amygdalae send impulses to the hypothalamus for activation of the sympathetic nervous system, to the reticular nucleus for increasing reflexes, to the nuclei of the trigeminal nerve and facial nerve for facial expressions of fear, and to the ventral tegmental area, locus coeruleus, and laterodorsal tegmental nucleus for activation of dopamine, norepinephrine and epinephrine release. The amygdala plays a key role in what has been called the \"general-purpose defense response control network\" and reacts in response to unpleasant sights, sensations, or smells. Anger, avoidance, and defensiveness are emotions activated largely by the amygdale. The amygdala is responsible for activating ancestral signs of distress such as \"tense-mouth\" and defensive postures such as crouching. Poor functioning of amygdala has also been associated with anxiety, autism, depression, narcolepsy, post-traumatic stress disorder, phobias, frontotemporal dementia, and schizophrenia. Impairment of emotional event memory in patients with Alzheimer's disease also correlates with the intensity of amygdalar damage. All these events speak out for the importance to preserve the normal function of the amygdala which can only be achieved by constant deepening of our knowledge about this unique structure.", "corpus_id": 24891311, "score": 0 }, { "doc_id": "7095712", "title": "Synthesis of Serotonin by a Second Tryptophan Hydroxylase Isoform", "abstract": "The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] is causally involved in multiple central nervous facets of mood control and in regulating sleep, anxiety, alcoholism, drug abuse, food intake, and sexual behavior ([1][1]). In peripheral tissues, 5-HT regulates vascular tone, gut motility,", "corpus_id": 7095712, "score": 1 }, { "doc_id": "19908001", "title": "Serotonin regulates mammary gland development via an autocrine-paracrine loop.", "abstract": "Mammary gland development is controlled by a dynamic interplay between endocrine hormones and locally produced factors. Biogenic monoamines (serotonin, dopamine, norepinephrine, and others) are an important class of bioregulatory molecules that have not been shown to participate in mammary development. Here we show that mammary glands stimulated by prolactin (PRL) express genes essential for serotonin biosynthesis (tryptophan hydroxylase [TPH] and aromatic amine decarboxylase). TPH mRNA was elevated during pregnancy and lactation, and serotonin was detected in the mammary epithelium and in milk. TPH was induced by PRL in mammosphere cultures and by milk stasis in nursing dams, suggesting that the gene is controlled by milk filling in the alveoli. Serotonin suppressed beta-casein gene expression and caused shrinkage of mammary alveoli. Conversely, TPH1 gene disruption or antiserotonergic drugs resulted in enhanced secretory features and alveolar dilation. Thus, autocrine-paracrine serotonin signaling is an important regulator of mammary homeostasis and early involution.", "corpus_id": 19908001, "score": 0 }, { "doc_id": "43761967", "title": "Serotonin synthesis in murine embryonic stem cells.", "abstract": "Serotonin (5-HT) is a monoaminergic neurotransmitter involved in various processes in the mammalian nervous system with tryptophan hydroxylase (TPH) as the rate-limiting enzyme in its biosynthesis. Interestingly, there is accumulating evidence that neurotransmitters including 5-HT are directly involved in cleavage divisions and morphogenetic movements during early embryogenesis, even before neurons appear. Clonal cell models will be indispensable for investigating these pre-neuronal actions of neurotransmitter systems. Totipotent embryonic stem (ES) cells represent early embryonic stages, are amenable to genetic manipulations and can be easily induced to differentiate into cells with neuronal and glial properties enabling the recapacitation of neurulation. In this study, we used high-pressure liquid chromatography with fluorometric detection (HPLC-FD) to demonstrate the presence of 5-HT in ES cells. In addition, RNase protection assays and immunohistochemical methods detected TPH mRNA and protein, respectively, confirming the endogeneous production of 5-HT in these cells. Furthermore, TPH protein was detected in mouse zygotes after fertilization. These results indicate that ES cells may be useful for the investigation of neurotransmitters in pre-nervous embryos and their actions during ontogeny.", "corpus_id": 43761967, "score": 1 }, { "doc_id": "34852820", "title": "7‐hydroxytryptophan, a novel, specific, cytotoxic agent for carcinoids and other serotonin‐producing tumors", "abstract": "Carcinoids and small cell lung carcinomas stimulate their growth in an autocrine manner by releasing serotonin, an effect that is blocked by selective serotonergic receptor antagonists that, unfortunately, exert undesirable side effects on serotonergic central nervous function. Moreover, conventional chemotherapeutic agents, such as streptozocin, fluorouracil, cyclophosphamide, and doxorubicin, which target tumor cells directly, have produced disappointing results in the treatment of patients with these tumors in the advanced stage. Therefore, there is still a need for more specific and potent chemotherapeutic agents in the fight against serotonin‐producing tumors.", "corpus_id": 34852820, "score": 0 }, { "doc_id": "16847296", "title": "Serotonylation of Small GTPases Is a Signal Transduction Pathway that Triggers Platelet α-Granule Release", "abstract": "Serotonin is a neurotransmitter in the central nervous system. In the periphery, serotonin functions as a ubiquitous hormone involved in vasoconstriction and platelet function. Serotonin is synthesized independently in peripheral tissues and neurons by two different rate-limiting tryptophan hydroxylase (TPH) isoenzymes. Here, we show that mice selectively deficient in peripheral TPH and serotonin exhibit impaired hemostasis, resulting in a reduced risk of thrombosis and thromboembolism, although the ultrastructure of the platelets is not affected. While the aggregation of serotonin-deficient platelets in vitro is apparently normal, their adhesion in vivo is reduced due to a blunted secretion of adhesive alpha-granular proteins. In elucidating the mechanism further, we demonstrate that serotonin is transamidated to small GTPases by transglutaminases during activation and aggregation of platelets, rendering these GTPases constitutively active. Our data provides evidence for a receptor-independent signaling mechanism, termed herein as \"serotonylation,\" which leads to alpha-granule exocytosis from platelets.", "corpus_id": 16847296, "score": 0 }, { "doc_id": "43189753", "title": "Platelet-Derived Serotonin Mediates Liver Regeneration", "abstract": "The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration.", "corpus_id": 43189753, "score": 0 }, { "doc_id": "19000354", "title": "Intracellular Serotonin Modulates Insulin Secretion from Pancreatic β-Cells by Protein Serotonylation", "abstract": "Non-neuronal, peripheral serotonin deficiency causes diabetes mellitus and identifies an intracellular role for serotonin in the regulation of insulin secretion.", "corpus_id": 19000354, "score": 0 }, { "doc_id": "8548874", "title": "Effect of Tryptophan Hydroxylase 1 Deficiency on the Development of Hypoxia-Induced Pulmonary Hypertension", "abstract": "Tryptophan hydroxylase 1 catalyzes the rate-limiting step in the synthesis of serotonin in the periphery. Recently, it has been shown that expression of the tryptophan hydroxylase 1 gene is increased in lungs and pulmonary endothelial cells from patients with idiopathic pulmonary arterial hypertension. Here we investigated the effect of genetic deletion of tryptophan hydroxylase 1 on hypoxia-induced pulmonary arterial hypertension in mice by measuring pulmonary hemodynamics and pulmonary vascular remodeling before and after 2 weeks of hypoxia. In wild-type mice, hypoxia increased right ventricular pressure and pulmonary vascular remodeling. These effects of hypoxia were attenuated in the tryptophan hydroxylase 1−/−mice. Hypoxia increased right ventricular hypertrophy in both wild-type and tryptophan hydroxylase 1−/−mice suggesting that in vivo peripheral serotonin has a differential effect on the pulmonary vasculature and right ventricular hypertrophy. Contractile responses to serotonin were increased in pulmonary arteries from tryptophan hydroxylase 1−/−mice. Hypoxia increased serotonin-mediated contraction in vessels from the wild-type mice, but this was not further increased by hypoxia in the tryptophan hydroxylase 1−/−mice. In conclusion, these results indicate that tryptophan hydroxylase 1 and peripheral serotonin play an essential role in the development of hypoxia-induced elevations in pulmonary pressures and hypoxia-induced pulmonary vascular remodeling. In addition, the results suggest that, in mice, serotonin has differential effects on the pulmonary vasculature and right ventricular hypertrophy.", "corpus_id": 8548874, "score": 0 }, { "doc_id": "7777109", "title": "Genotyping of the G1463A (Arg441His) TPH2 polymorphism in a geriatric population of patients with major depression", "abstract": "Genotyping of the G1463A (Arg441His) TPH2 polymorphism in a geriatric population of patients with major depression", "corpus_id": 7777109, "score": 0 }, { "doc_id": "27242173", "title": "Support for the involvement of TPH2 gene in affective disorders", "abstract": "Disturbance of the serotonergic system has been suggested as a factor in the pathogenesis of affective disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the serotonin biosynthetic pathway, and a new TPH isoform, TPH2, has been identified in the brain and localized to the long arm of chromosome 12 in a region that has been reported to contain bipolar and major depressive disorder susceptibility genes. An SNP-based association study on a case/control sample gave support to the existence of an affective disorder-associated haplotype in the TPH2 gene.", "corpus_id": 27242173, "score": 0 }, { "doc_id": "2258629", "title": "Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder", "abstract": "Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P=0.049; rs11178997, P=0.034), but not for the third SNP in intron 2 (rs4565946, P=0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P=0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes.", "corpus_id": 2258629, "score": 0 }, { "doc_id": "27821706", "title": "Association between Tph2 gene polymorphism, brain tryptophan hydroxylase activity and aggressiveness in mouse strains", "abstract": "The brain neurotransmitter serotonin is involved in the regulation of aggressive behavior. The main factor determining the brain serotonin level is the activity of the rate‐limiting enzyme in the biosynthesis of the neurotransmitter – tryptophan hydroxylase isoform (TPH) 2 encoded by the Tph2 gene. Recently the C1473G single‐nucleotide polymorphism in the Tph2 gene was reported. Here we study the C1473G polymorphism in 10 inbred mouse strains (C57BL/6J, AKR/J, DD/He, C3H/HeJ, YT/Y, BALB/cJLac, CC57BR/Mv and A/He) and demonstrate the association of the polymorphism with brain TPH activity and intermale aggressiveness. TPH activity in the midbrain of mice homozygous for the 1473C allele was higher than that in mice carrying 1473G alleles. A close association of the 1473C allele with increased number of attacks towards another male was found. The results support a link between the C1473G polymorphism in Tph2 gene, trypthophan hydroxylase activity and intensity of intermale aggression.", "corpus_id": 27821706, "score": 0 }, { "doc_id": "24630985", "title": "Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase Isoform (TPH2) gene in suicide victims", "abstract": "BACKGROUND\nTryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin, represents a major candidate in numerous genetic association analyses of suicidal behavior; however, the results are so far inconclusive. Recently, a second tryptophan hydroxylase isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous postmortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain but not in peripheral tissues.\n\n\nMETHODS\nWe performed single nucleotide polymorphisms, haplotypes, and linkage disequilibrium studies on 263 suicide victims and 266 healthy control subjects with 10 single nucleotide polymorphisms in the TPH2 gene.\n\n\nRESULTS\nSignificant association was detected between one single nucleotide polymorphism (p = .004, global p = .01) and suicide. Additionally, haplotype analysis also produced support for association (p < .0001, global p = .0001).\n\n\nCONCLUSIONS\nThis is the first report about an association between TPH2 gene polymorphisms and completed suicide. Our findings provide evidence for an involvement of genetic variants in the TPH2 gene in suicidal behavior. These results might open up new research strategies for the analysis of the observed disturbances in the serotonergic system in several other psychiatric disorders.", "corpus_id": 24630985, "score": 0 }, { "doc_id": "22794355", "title": "Different properties of the central and peripheral forms of human tryptophan hydroxylase", "abstract": "Tryptophan hydroxylase (TPH) catalyses the rate‐limiting reaction in the biosynthesis of serotonin. In humans, two different TPH genes exist, located on chromosomes 11 and 12, respectively, and encoding two enzymes (TPH1 and TPH2) with an overall sequence identity of 71%. We have expressed both enzymes as various fusion proteins in Escherichia coli and using an in vitro transcription/translation system, and compared their solubility and kinetic properties. TPH2 is more soluble than TPH1, has a higher molecular weight and different kinetic properties, including a lower catalytic efficiency towards phenylalanine than TPH1. Both enzymes are phosphorylated by cAMP‐dependent protein kinase A. TPH2 was phosphorylated at Ser19, a phosphorylation site not present in TPH1. The differences between TPH1 and TPH2 have important implications for the regulation of serotonin production in the brain and the periphery and may provide an explanation for some of the diverging results reported for TPH from different sources in the past.", "corpus_id": 22794355, "score": 0 }, { "doc_id": "45020289", "title": "Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: a post-mortem study.", "abstract": "Dysregulation of brain serotonin transmission is an important contributing factor in many psychiatric disorders. Tryptophan hydroxylase (TPH), the rate limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice which was exclusively expressed in the brain. Due to the lack of data about its anatomic expression in humans we performed a mRNA expression analysis comparing TPH1 and TPH2 mRNA in several regions of the human brain (cortex, thalamus, hypothalamus, hippocampus, amygdala, cerebellum and raphe nuclei). The study was performed with post-mortem specimens obtained from eight individuals with sudden deaths, not directly involving CNS diseases. Our results demonstrate that the mRNA of both genes is expressed in each investigated brain region with variations between the brain areas, as well as between the particular genes. The major finding of this study was the high expression level of TPH2 mRNA in the raphe nuclei ( approximately 4-fold more abundant than that of TPH1). The raphe nuclei showed the highest TPH2 mRNA levels at all, compared to the other regions (7-fold higher levels on average). To our knowledge, this is the fist study which demonstrates the localization of TPH1 and TPH2 mRNA in different regions of the human brain. Our findings provide further support for a duality of the serotonergic system and may open up new research strategies for the analysis of the repeatedly observed disturbances in the serotonergic system in patients suffering from several psychiatric disorders.", "corpus_id": 45020289, "score": 0 }, { "doc_id": "35641733", "title": "Differential tissue distribution of tryptophan hydroxylase isoforms 1 and 2 as revealed with monospecific antibodies", "abstract": "Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of the neurotransmitter serotonin. Once thought to be a single-gene product, TPH is now known to exist in two isoforms-TPH1 is found in the pineal and gut, and TPH2 is selectively expressed in brain. Heretofore, probes used for localization of TPH protein or mRNA could not distinguish between the TPH isoforms because of extensive homology shared by them at the nucleotide and amino acid level. We have produced monospecific polyclonal antibodies against TPH1 and TPH2 using peptide antigens from nonoverlapping sequences in the respective proteins. These antibodies allow the differentiation of TPH1 and TPH2 upon immunoblotting, immunoprecipitation, and immunocytochemical staining of tissue sections from brain and gut. TPH1 and TPH2 antibodies do not cross-react with either tyrosine hydroxylase or phenylalanine hydroxylase. Analysis of mouse tissues confirms that TPH1 is the predominant form expressed in pineal gland and in P815 mastocytoma cells with a molecular weight of 51 kDa. TPH2 is the predominant enzyme form expressed in brain extracts from mesencephalic tegmentum, striatum, and hippocampus with a molecular weight of 56 kDa. Antibody specificity against TPH1 and TPH2 is retained across mouse, rat, rabbit, primate, and human tissues. Antibodies that distinguish between the isoforms of TPH will allow studies of the differential regulation of their expression in brain and periphery.", "corpus_id": 35641733, "score": 0 }, { "doc_id": "25706018", "title": "Characterization of a Functional Promoter Polymorphism of the Human Tryptophan Hydroxylase 2 Gene in Serotonergic Raphe Neurons", "abstract": "BACKGROUND\nTryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin (5-HT) biosynthesis. Although dysfunction of 5-HT neurotransmission has been implicated in a variety of neuropsychiatric conditions, the human TPH2 promoter has not been characterized in vitro.\n\n\nMETHODS\nThe functional relevance of TPH2 promoter polymorphisms was determined with luciferase assays in primary serotonergic neurons from rat raphe nuclei and in human small cell lung carcinoma cells (SHP-77 cells). We also investigated transcription factor binding to the variant promoter sequence with electrophoretic mobility shift assay (EMSA).\n\n\nRESULTS\nThe polymorphism rs11178997 of the human TPH2 promoter significantly reduced TPH2 transcriptional activity by 22% and 7% in primary serotonergic neurons and in SHP-77 cells, respectively. In contrast, no significant differences in promoter activity were observed for the G- and T-alleles of rs4570625. The EMSA revealed reduced binding of the transcription factor POU3F2 (also known as Brn-2, N-Oct-3) to the A-allele of the polymorphism rs11178997. Overexpression of POU3F2 resulted in a robust activation of the TPH2 promoter (2.7-fold).\n\n\nCONCLUSIONS\nOur data suggest that the human TPH2 promoter polymorphism rs11178997 impacts on gene expression, which might have implications for the development and function of the serotonergic system in the brain.", "corpus_id": 25706018, "score": 0 }, { "doc_id": "14662902", "title": "A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity", "abstract": "Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate-limiting synthesis of neuronal serotonin. Genetic variation in the human TPH2 gene (hTPH2) has been associated with altered in vitro enzyme activity as well as increased risk for mood disorders. Here, we provide the first in vivo evidence that a relatively frequent regulatory variant (G(−844)T) of hTPH2 biases the reactivity of the amygdala, a neural structure critical in the generation and regulation of emotional behaviors.", "corpus_id": 14662902, "score": 0 }, { "doc_id": "24755144", "title": "Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation", "abstract": "Summary.The tryptophan hydroxylase-2 gene (TPH2) codes for the enzyme of serotonin (5-HT) synthesis in the brain and variation of TPH2 has been implicated in disorders of emotion regulation. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate that a potentially functional variant of TPH2 modulates amygdala responsiveness to emotional stimuli of both negative and positive valence.", "corpus_id": 24755144, "score": 0 }, { "doc_id": "40910683", "title": "Tryptophan Hydroxylase-2 Controls Brain Serotonin Synthesis", "abstract": "Dysregulation of brain serotonin contributes to many psychiatric disorders. Tryptophan hydroxylase-2 (Tph2), rather than Tph1, is preferentially expressed in the brain. We report a functional (C1473G) single-nucleotide polymorphism in mouse Tph2 that results in the substitution of Pro447 with Arg447 and leads to decreased serotonin levels in PC12 cells. Moreover, in BALB/cJ and DBA/2 mice that are homozygous for the 1473G allele, brain serotonin tissue content and synthesis are reduced in comparison to C57Bl/6 and 129X1/SvJ mice that are homozygous for the 1473C allele. Our data provide direct evidence for a fundamental role of Tph2 in brain serotonin synthesis.", "corpus_id": 40910683, "score": 0 }, { "doc_id": "12975546", "title": "A loss-of-function mutation in tryptophan hydroxylase 2 segregating with attention-deficit/hyperactivity disorder", "abstract": "A loss-of-function mutation in tryptophan hydroxylase 2 segregating with attention-deficit/hyperactivity disorder", "corpus_id": 12975546, "score": 0 }, { "doc_id": "15865069", "title": "Loss-of-Function Mutation in Tryptophan Hydroxylase-2 Identified in Unipolar Major Depression", "abstract": "Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression.", "corpus_id": 15865069, "score": 1 }, { "doc_id": "7769265", "title": "Lack of association of TPH2 exon XI polymorphisms with major depression and treatment resistance", "abstract": "Lack of association of TPH2 exon XI polymorphisms with major depression and treatment resistance", "corpus_id": 7769265, "score": 0 }, { "doc_id": "25690378", "title": "Stress Upregulates TPH1 but not TPH2 mRNA in the Rat Dorsal Raphe Nucleus: Identification of Two TPH2 mRNA Splice Variants", "abstract": "Serotonin is implicated in stress-related psychopathologies. Two isoforms of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, TPH1 and TPH2, are known. We show here that in the rat dorsal raphe nucleus (DRN), the nucleus that contains the highest number of 5-HT neurons in the brain, TPH1 mRNA reveals a low level of expression but is detectable both by quantitative real-time PCR and in situ hybridization whereas in the pineal gland (PiG), TPH1 mRNA is strongly expressed. To examine effects of stress on TPH expression we exposed male Wistar rats to daily restraint stress for 1 week. As shown by quantitative real-time PCR, TPH1 mRNA is 2.5-fold upregulated by the stress in DRN but not in PiG. Using 3′-RACE, we identified two TPH2 mRNA splice variants in the rat DRN which differ in the length of their 3′-untranslated regions (UTRs). TPH2b (with a short 3′-UTR) is the predominant variant in the DRN, whereas TPH2a (with a longer 3′-UTR) shows a low abundance in this nucleus. In the PiG, only TPH2b is detectable revealing a low level of expression. Expression of both TPH2 splice variants is not affected by stress, neither in DRN nor in the PiG. These data indicate that TPH1 in the serotonergic neurons of the DRN might be relevant for stress-induced psychopathologies.", "corpus_id": 25690378, "score": 0 }, { "doc_id": "22771783", "title": "Analysis of the role of Caenorhabditis elegans GC-AG introns in regulated splicing.", "abstract": "GC-AG introns represent 0.7% of total human pre-mRNA introns. To study the function of GC-AG introns in splicing regulation, 196 cDNA-confirmed GC-AG introns were identified in Caenorhabditis elegans. These represent 0.6% of the cDNA- confirmed intron data set for this organism. Eleven of these GC-AG introns are involved in alternative splicing. In a comparison of the genomic sequences of homologous genes between C.elegans and Caenorhabditis briggsae for 26 GC-AG introns, the C at the +2 position is conserved in only five of these introns. A system to experimentally test the function of GC-AG introns in alternative splicing was developed. Results from these experiments indicate that the conserved C at the +2 position of the tenth intron of the let-2 gene is essential for developmentally regulated alternative splicing. This C allows the splice donor to function as a very weak splice site that works in balance with an alternative GT splice donor. A weak GT splice donor can functionally replace the GC splice donor and allow for splicing regulation. These results indicate that while the majority of GC-AG introns appear to be constitutively spliced and have no evolutionary constraints to prevent them from being GT-AG introns, a subset of GC-AG introns is involved in alternative splicing and the C at the +2 position of these introns can have an important role in splicing regulation.", "corpus_id": 22771783, "score": 0 }, { "doc_id": "17372137", "title": "Human GC-AG alternative intron isoforms with weak donor sites show enhanced consensus at acceptor exon positions.", "abstract": "It has been previously observed that the intrinsically weak variant GC donor sites, in order to be recognized by the U2-type spliceosome, possess strong consensus sequences maximized for base pair formation with U1 and U5/U6 snRNAs. However, variability in signal strength is a fundamental mechanism for splice site selection in alternative splicing. Here we report human alternative GC-AG introns (for the first time from any species), and show that while constitutive GC-AG introns do possess strong signals at their donor sites, a large subset of alternative GC-AG introns possess weak consensus sequences at their donor sites. Surprisingly, this subset of alternative isoforms shows strong consensus at acceptor exon positions 1 and 2. The improved consensus at the acceptor exon can facilitate a strong interaction with U5 snRNA, which tethers the two exons for ligation during the second step of splicing. Further, these isoforms nearly always possess alternative acceptor sites and exhibit particularly weak polypyrimidine tracts characteristic of AG-dependent introns. The acceptor exon nucleotides are part of the consensus required for the U2AF(35)-mediated recognition of AG in such introns. Such improved consensus at acceptor exons is not found in either normal or alternative GT-AG introns having weak donor sites or weak polypyrimidine tracts. The changes probably reflect mechanisms that allow GC-AG alternative intron isoforms to cope with two conflicting requirements, namely an apparent need for differential splice strength to direct the choice of alternative sites and a need for improved donor signals to compensate for the central mismatch base pair (C-A) in the RNA duplex of U1 snRNA and the pre-mRNA. The other important findings include (i) one in every twenty alternative introns is a GC-AG intron, and (ii) three of every five observed GC-AG introns are alternative isoforms.", "corpus_id": 17372137, "score": 0 }, { "doc_id": "30868981", "title": "The Pre-nervous Serotonergic System of Developing Sea Urchin Embryos and Larvae: Pharmacologic and Immunocytochemical Evidence", "abstract": "Forty serotonin-related neurochemicals were tested on embryos and larvae of Lytechinus variegatus and other sea urchin species. Some of these substances (agonists of 5-HT1 receptors, antagonists of 5-HT2, 5-HT3 or 5-HT4 receptors, and inhibitors of the serotonin transporter, SERT) perturbed post-blastulation development, eliciting changes in embryonic/larval phenotypes typical for each class of receptor ligand. These developmental malformations were prevented completely or partially by serotonin (5-HT) or 5-HT analogs (5-HTQ, AA-5-HT), providing evidence for the putative localization of cellular targets. Immunoreactive 5-HT, 5-HT receptors and SERT were found in pre-nervous embryos and larvae of both L. variegatus and Strongylocentrotus droebachiensis. During gastrulation, these components of the serotonergic system were localized to the archenteron (primary gut), mesenchyme-like cells, and often the apical ectoderm. These results provide evidence that pre-nervous 5-HT may regulate early events of sea urchin embryogenesis, mediated by 5-HT receptors or the 5-HT transporter.", "corpus_id": 30868981, "score": 0 }, { "doc_id": "40880204", "title": "Roles for serotonin in neuroembryogenesis.", "abstract": "Possible non-transmitter roles for 5-HT in different phases of early neuroembryogenesis have been discussed based upon experimental evidence from the rat and chick. Fluorescence histochemical studies have demonstrated sites of uptake and synthesis of 5-HT in the chick embryo during the first few days of incubation. These sites are located in discrete regions of the notochord and floor plate of the neural tube as well as in extra-neural regions such as the somites and primitive gut. The 5-HT patterns are distinctly different from those observed for the uptake and synthesis of norepinephrine in embryos of the same age. Spatio-temporal changes in the distribution of these sites during closure of the neural tube suggest a role for 5-HT in various aspects of neural tube development. Moreover, the non-overlapping localization of 5-HT and norepinephrine raises the possibility that these two amines may exert different and perhaps cooperative influences on early neurogenic processes in the chick. In the rat, autoradiographic and biochemical studies concerning the consequences of 5-HT depletion in the embryo for development of different brain regions have provided evidence that 5-HT acts as a \"differentiation signal\" regulating the time of neuronal genesis in those cell populations which will eventually receive 5-HT innervation. Although the details of this system are as yet unknown, these studies suggest that 5-HT (and possibly the other monoamine transmitters) may actually \"mold\" the construction of their own circuitry during neurogenesis. Further, the ability of drugs and stress to interact with this process during that period of gestation when the monoamines are required as humoral signals suggests that maternal influences can interfere with ontogeny of this circuitry during pre- and possibly postnatal development. It is not yet clear whether the data in chicks and rats can be directly analogized from the one species to the other. Nevertheless, the evidence that sites of 5-HT uptake and/or synthesis are present during the earliest phases of neurogenesis in the chick and the observation that 5-HT depletion can alter the time of genesis of 5-HT target cells in the rat provide a new context for the consideration of possible actions of 5-HT prior to its role as a neurotransmitter substance.", "corpus_id": 40880204, "score": 0 }, { "doc_id": "7680085", "title": "Functional Domains of Human Tryptophan Hydroxylase 2 (hTPH2)*", "abstract": "Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin biosynthesis. A novel gene, termed TPH2, has recently been described. This gene is preferentially expressed in the central nervous system, while the original TPH1 is the peripheral gene. We have expressed human tryptophan hydroxylase 2 (hTPH2) and two deletion mutants (NΔ150 and NΔ150/CΔ24) using isopropyl β-d-thiogalactopyranoside-free autoinduction in Escherichia coli. This expression system produced active wild type TPH2 with relatively low solubility. The solubility was increased for mutants lacking the NH2-terminal regulatory domain. The solubility of hTPH2, NΔ150, and NΔ150/CΔ24 are 6.9, 62, and 97.5%, respectively. Removal of the regulatory domain also produced a more than 6-fold increase in enzyme stability (t½ at 37 °C). The wild type hTPH2, like other members of the aromatic amino acid hydroxylase superfamily, exists as a homotetramer (236 kDa on size exclusion chromatography). Similarly, NΔ150 also migrates as a tetramer (168 kDa). In contrast, removal of the NH2-terminal domain and the COOH-terminal, putative leucine zipper tetramerization domain produces monomeric enzyme (39 kDa). Interestingly, removal of the NH2-terminal regulatory domain did not affect the Michaelis constants for either substrate but did increase Vmax values. These data identify the NH2-terminal regulatory domain as the source of hTPH2 instability and reduced solubility.", "corpus_id": 7680085, "score": 1 }, { "doc_id": "9532844", "title": "A Perfect Message RNA Surveillance and Nonsense-Mediated Decay", "abstract": "the disposal of nonfunctional by-products of normal The robustness of biological systems depends on the RNA processing. function of proofreading mechanisms against operating NMD—An Enigma in RNA Metabolism errors. Studies in yeast and of human genetic disorders NMD has captured much attention as one of the most have lead the way to a conserved surveillance mechaenigmatic processes in RNA metabolism. Basically, a cell nism that identifies faulty open reading frames (ORFs) must discriminate the normal stop codon from a premaand eliminates “imperfect messages” that contain preture one (discrimination phase). Subsequently, a PTCmature translation termination codons (PTCs) and code mutated mRNA is committed to a pathway (commitment for nonfunctional or even harmful polypeptides; this mechphase) that ultimately results in its degradation (degraanism has been termed nonsense-mediated mRNA decay dation phase). NMD in yeast is becoming increasingly (NMD). well understood (Jacobson and Peltz, 1996; Ruiz-EcheThe Biological and Medical Importance of NMD varria et al., 1998). By contrast, diverse models are conIt was noticed in 1979 that PTC mutations of the yeast sidered for mammalian NMD (Maquat, 1995; Li and Wilura3 gene destabilized the encoded mRNA (Losson and kinson, 1998). We will describe some key findings from Lacroute, 1979). In the same year, the level of PTCthe mammalian and yeast systems and will suggest that mutated b-globin mRNA from a thalassemia patient was most of the available evidence can be integrated into a reported to be very low (Chang and Kan, 1979), forecommon model. shadowing the broad phylogenetic distribution of NMD Mammalian NMD: Nuclear Aspects and its role in human genetic disorders. The vast majorThere is little doubt that mammalian NMD is a posttranity of b-thalassemia heterozygotes are phenotypically scriptional mechanism that involves the nucleus. Two healthy, whereas homozygotes suffer from a severe anetypes of alterations have been described: the abnormal mia. Normal erythropoiesis requires a/b-globin chain splicing of pre-mRNAs, and the degradation of spliced balance. In heterozygotes, the relative excess of insolumRNAs. Both alterations have been referred to as NMD. ble a-globin chains are degraded but accumulate in Regarding the first, examples of both nonsense-associhomozygotes to damage the erythroid precursors. PTC ated alternative splicing (e.g., fibrillin mRNA) and of inmutations in the two 59 proximal exons of the b-globin tron retention (e.g., Igk RNA) have been investigated. In gene are common, and the mRNA is subjected to NMD. these examples, PTCs are associated with an effect In contrast, a dominant form of inheritance is associated on splicing, for which we suggest the term “nonsensewith a rare nonsense mutation in the last exon. This associated altered splicing” (NAS). NAS is intriguing, PTC-mutated mRNA escapes NMD, is normally abunbecause it suggests that the sense of a pre-mRNA can dant, and is translated (Hall and Thein, 1994). This addibe interpreted by a nuclear reading frame scanner betional burden causes the proteolytic system of the eryfore splicing (Li and Wilkinson, 1998). Other alternative, throid precursor cells to fail, which results in the", "corpus_id": 9532844, "score": 0 }, { "doc_id": "2336486", "title": "A Conserved mRNA Export Machinery Coupled to pre-mRNA Splicing", "abstract": "Recent advances have led to a new understanding of how mRNAs are exported from the nucleus to the cytoplasm. This process requires a heterodimeric mRNA export receptor that is part of an elaborate machinery conserved from yeast to humans. Export of mRNAs is coupled to upstream steps in gene expression, such as pre-mRNA splicing, and to downstream events, including nonsense-mediated decay.", "corpus_id": 2336486, "score": 0 }, { "doc_id": "34081059", "title": "Control of human potassium channel inactivation by editing of a small mRNA hairpin", "abstract": "Genomic recoding by A→I RNA editing plays an important role in diversifying the proteins involved in electrical excitability. Here, we describe editing of an intronless potassium channel gene. A small region of human KV1.1 mRNA sequence directs efficient modification of one adenosine by human adenosine deaminase acting on RNA 2 (hADAR2). Mutational analysis shows that this region adopts a hairpin structure. Electrophysiological characterization reveals that the editing event (I/V) profoundly affects channel inactivation conferred by accessory β subunits. Drosophila melanogaster Shaker channels, mimicking this editing event through mutation, exhibit a similar effect. In addition, we demonstrate that mRNAs for the paralogous D. melanogaster Shab potassium channel are edited at the same position by fly ADAR—a clear example of convergent evolution driven by adenosine deamination. These results suggest an ancient and key regulatory role for this residue in KV channels.", "corpus_id": 34081059, "score": 0 }, { "doc_id": "4247011", "title": "Regulation of serotonin-2C receptor G-protein coupling by RNA editing", "abstract": "The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) elicits a wide array of physiological effects by binding to several receptor subtypes. The 5-HT2 family of receptors belongs to a large group of seven-transmembrane-spanning G-protein-coupled receptors and includes three receptor subtypes (5-HT2A, 5-HT2B and 5-HT2C) which are linked to phospholipase C, promoting the hydrolysis of membrane phospholipids and a subsequent increase in the intracellular levels of inositol phosphates and diacylglycerol1. Here we show that transcripts encoding the 2C subtype of serotonin receptor (5-HT2CR) undergo RNA editing events in which genomically encoded adenosine residues are converted to inosines by the action of double-stranded RNA adenosine deaminase(s). Sequence analysis of complementary DNA isolates from dissected brain regions have indicated the tissue-specific expression of seven major 5-HT2C receptor iso-forms encoded by eleven distinct RNA species. Editing of 5-HT2CR messenger RNAs alters the amino-acid coding potential of the predicted second intracellular loop of the receptor and can lead to a 10–15-fold reduction in the efficacy of the interaction between receptors and their G proteins. These observations indicate that RNA editing is a new mechanism for regulating serotonergic signal transduction and suggest that this post-transcriptional modification may be critical for modulating the different cellular functions that are mediated by other members of the G-protein-coupled receptor superfamily.", "corpus_id": 4247011, "score": 1 }, { "doc_id": "25420811", "title": "RNA editing of AMPA receptor subunit GluR-B: A base-paired intron-exon structure determines position and efficiency", "abstract": "A functionally critical position (Q/R site) of the AMPA receptor subunit GluR-B is controlled by RNA editing that operates in the nucleus, since in brain and clonal cell lines of neural origin, unspliced GluR-B transcripts occur edited in the Q/R site CAG codon and, additionally, in intronic adenosines. Transfection of GluR-B gene constructs into PC12 cells revealed that the proximal part of the intron downstream of the unedited exonic site is required for Q/R site editing. This intron portion contains an imperfect inverted repeat preceding a 10 nt sequence with exact complementarity to the exon centered on the unedited codon. Single nucleotide substitutions in this short intronic sequence or its exonic complement curtailed Q/R site editing, which was recovered by restoring complementarity in the respective partner strand. Base conversion in the channel-coding region of GluR-B directed by base paired sequences may be executed by a ubiquitous nuclear adenosine deaminase specific for double-stranded RNA.", "corpus_id": 25420811, "score": 0 }, { "doc_id": "22177229", "title": "RNA editing produces glycine receptor alpha3(P185L), resulting in high agonist potency.", "abstract": "The function of supramedullary glycine receptors (GlyRs) is still unclear. Using Wistar rat collicular slices, we demonstrate GlyR-mediated inhibition of spike discharge elicited by low glycine (10 microM). Searching for the molecular basis of this phenomenon, we identified a new GlyR isoform. GlyR alpha3(P185L), a result of cytidine 554 deamination, confers high glycine sensitivity (EC50 approximately 5 microM) to neurons and thereby promotes the generation of sustained chloride conductances associated with tonic inhibition. The level of GlyR alpha3-C554U RNA editing is sensitive to experimentally induced brain lesion, inhibition of cytidine deamination by zebularine and inhibition of mRNA transcription by actinomycin D, but not to blockade of protein synthesis by cycloheximide. Conditional regulation of GlyR alpha3(P185L) is thus likely to be part of a post-transcriptional adaptive mechanism in neurons with enhanced excitability.", "corpus_id": 22177229, "score": 0 }, { "doc_id": "29281161", "title": "Editor meets silencer: crosstalk between RNA editing and RNA interference", "abstract": "The most prevalent type of RNA editing is mediated by ADAR (adenosine deaminase acting on RNA) enzymes, which convert adenosines to inosines (a process known as A→I RNA editing) in double-stranded (ds)RNA substrates. A→I RNA editing was long thought to affect only selected transcripts by altering the proteins they encode. However, genome-wide screening has revealed numerous editing sites within inverted Alu repeats in introns and untranslated regions. Also, recent evidence indicates that A→I RNA editing crosstalks with RNA-interference pathways, which, like A→I RNA editing, involve dsRNAs. A→I RNA editing therefore seems to have additional functions, including the regulation of retrotransposons and gene silencing, which adds a new urgency to the challenges of fully understanding ADAR functions.", "corpus_id": 29281161, "score": 0 }, { "doc_id": "29567806", "title": "C-to-U RNA Editing: Mechanisms Leading to Genetic Diversity*", "abstract": "Substitutional RNA Editing: Biochemical Mechanisms and Targets for C-to-U RNA Editing in Mammals RNA editing is an important mechanism for regulating genetic plasticity through the generation of alternative protein products from a single structural gene. Substitutional RNA editing employs a variety of genetic mechanisms, the biochemical basis of which has been elucidated following the development of in vitro assays that recapitulate important elements of this process. Two types of substitutional RNA exist in mammals, namely A-to-I and C-to-U RNA editing (1, 2). Important biochemical distinctions between these two processes provide an informative basis for understanding the mechanisms of C-to-U RNA editing and the adaptations that control target specificity. A-to-I RNA editing is mediated by a family of adenosine deaminases acting on double-stranded RNA (ADARs) with partially overlapping target specificity (1, 2). The absolute requirement for a double-stranded RNA template distinguishes A-to-I and C-to-U RNA editing because the former requires a pre-mRNA template containing intronic regions and is thus biochemically confined to unspliced transcripts. A further distinction biochemically is that ADAR enzymes do not require additional cofactors. ADARs contain both double-stranded RNA binding domains and a deaminase domain and function as modular editing enzymes (2, 3). The best characterized example of C-to-U RNA editing involves the nuclear transcript encoding intestinal apolipoprotein B (apoB) (4). ApoB RNA editing changes a CAA to a UAA stop codon, generating a truncated protein, apoB48 (4). ApoB RNA editing has important effects on lipoprotein metabolism, and its emergence defines distinct pathways for intestinal and hepatic lipid transport in mammals (4). C-to-U editing of apoB RNA requires a single-strand template (Fig. 1) with well defined characteristics in the immediate vicinity of the edited base, as well as protein cofactors that assemble into a functional complex referred to as a holoenzyme or editosome. This functional complex includes a minimal core composed of apobec-1, the catalytic deaminase, and a competence factor, apobec-1 complementation factor (ACF), that functions as an adaptor protein by binding both the deaminase and the RNA substrate (Fig. 1). The interaction of these protein components and their higher order interactions with the nuclear transcript illustrates the complexity of site-selectivity in C-to-U RNA editing. A second example of C-to-U RNA editing in mammals involves site-specific deamination of a CGA to UGA codon in the neurofibromatosis type 1 (NF1) mRNA (5). NF1 RNA editing generates a translational termination codon at position 3916 that is predicted to truncate the protein product neurofibromin at the 5 end of a critical domain (6) involved in GTPase activation (Fig. 2). Unlike apoB RNA editing, there is no formal proof that a truncated protein is generated. This example of C-to-U RNA editing has been demonstrated in peripheral nerve sheath tumors from patients with NF1 and may share elements of the same machinery as apoB RNA editing, as discussed below. A third target for C-to-U editing, NAT1, was revealed following forced transgenic overexpression of apobec-1 in murine and rabbit hepatocytes (7). NAT1 is homologous to the translational repressor eIF4G and undergoes C-to-U editing at multiple sites, with the creation of stop codons that in turn reduce protein abundance (7).", "corpus_id": 29567806, "score": 0 }, { "doc_id": "36872359", "title": "The apolipoprotein B mRNA editing complex performs a multifunctional cycle and suppresses nonsense‐mediated decay", "abstract": "The C to U editing of apolipoprotein B (apoB) mRNA is mediated by a minimal complex composed of an RNA‐binding cytidine deaminase (APOBEC1) and a complementing specificity factor (ACF). This editing generates a premature termination codon and a truncated open reading frame. We demonstrate that the APOBEC1—ACF holoenzyme mediates a multifunctional cycle. The atypical APOBEC1 nuclear localization signal is involved in RNA binding and is used to import ACF into the nucleus as cargo. APOBEC1 alone induces nonsense‐mediated decay (NMD). The APOBEC1—ACF complex edits and remains associated with the edited RNA to protect it from NMD. The APOBEC1 nuclear export signal is involved in the export of ACF and the edited apoB mRNA together, to the site of translation.", "corpus_id": 36872359, "score": 0 }, { "doc_id": "6344385", "title": "Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business.", "abstract": "Alteration of mRNA sequence through base modification mRNA editing frequently generates protein diversity. Several proteins have been identified as being similar to C-to-U mRNA editing enzymes based on their structural domains and the occurrence of a catalytic domain characteristic of cytidine deaminases. In light of the hypothesis that these proteins might represent novel mRNA editing systems that could affect proteome diversity, we consider their structure, expression and relevance to biomedically significant processes or pathologies.", "corpus_id": 6344385, "score": 0 }, { "doc_id": "45913364", "title": "An Overview of Cytidine Deaminases", "abstract": "Enzymes that deaminate cytidine to uridine play an important role in a variety of pathways from bacteria to man.Ancestral members of this family were able to deaminate cytidine only in a mononucleotide or nucleoside context. Recently, a family of enzymes has been discovered with the ability to deaminate cytidines on RNA or DNA. The first member of this new family is APOBEC1, which deaminates apolipoprotein B messenger RNA to generate a premature stop codon. APOBEC1 has the conserved active site motif found in Escherichia coli cytidine deaminase. In addition, APOBEC1 has a unique motif containing 2 phenylalanine residues and an insert of 4 amino acid residues across the active site motif. This motif is present in APOBEC family members including activation-induced cytidine deaminase (AID), APOBEC2, and APOBEC3A through APOBEC3G. AID is essential for initiating class-switch recombination, somatic hypermutation, and gene conversion. The APOBEC3 family is unique to primates. APOBEC3G is able to protect cells from human immunodeficiency virus and other viral infections.This function is not unique to APOBEC3G; other APOBEC3 family members also have this ability. Overexpression of enzymes in this family can cause cancer, suggesting that the genes for the APOBEC family of proteins are proto-oncogenes. Recent advances in the understanding of the mechanism of action of this family are summarized in this review.", "corpus_id": 45913364, "score": 0 }, { "doc_id": "18620982", "title": "How Stress and Fluoxetine Modulate Serotonin 2C Receptor Pre-mRNA Editing", "abstract": "In two inbred strains of mice, C57BL/6 and 129Sv, the majority of forebrain neocortical pre-mRNA encoding the serotonin 2C (5-HT2C) receptor is altered by adenosine-to-inosine editing. As a result, >60% of all mRNAs encode receptors with reduced constitutive and agonist-stimulated activity. However, in the BALB/c strain, a genetically distinct inbred strain with lower forebrain serotonin levels, spontaneously elevated anxiety, and increased stress reactivity, the majority of 5-HT2C mRNA is nonedited and encodes receptors with the highest constitutive activity and the highest agonist affinity and potency. Neither acute stress (the forced swim test) nor chronic treatment with the serotonin-selective reuptake inhibitor fluoxetine elicit significant changes in 5-HT2C pre-mRNA editing in C57BL/6 mice. In contrast, exposure of BALB/c mice to acute stress and chronic treatment of nonstressed BALB/c mice with fluoxetine elicit significant, site-specific increases in 5-HT2C pre-mRNA editing that increase the pool of mRNA encoding receptors with reduced function. These changes in 5-HT2C pre-mRNA editing resemble those detected previously in the prefrontal cortex of subjects with major depression. However, when chronic fluoxetine treatment is combined with stress exposure of BALB/c mice, these changes in 5-HT2C pre-mRNA editing are no longer detected. These findings illustrate that 5-HT2C pre-mRNA editing responses to stress and chronic fluoxetine are modulated by the genetic background, as well as the behavioral state of the animal. They suggest further that the changes in 5-HT2C pre-mRNA editing found in major depression reflect a previously unrecognized molecular response to stress that can be prevented by chronic antidepressant treatment.", "corpus_id": 18620982, "score": 0 }, { "doc_id": "25363004", "title": "Altered RNA editing of serotonin 2C receptor in a rat model of depression", "abstract": "Altered RNA editing of serotonin 2C receptor (HTR2C) has been suggested to be involved in the pathophysiology of major depression. Here we examined RNA editing status of HTR2C in the learned helplessness (LH) rats, one of well-established animal models of depression. LH rats showed the significantly increased RNA editing of site E, and tendency for increased RNA editing of other editing sites. Treatment with fluoxetine, a selective serotonin reuptake inhibitor, or imipramine, a tricyclic antidepressant, affected the RNA editing status of the LH rats. Although, these antidepressants differentially altered RNA editing status, they commonly reduced RNA editing efficiency of site E. We further revealed that altered RNA editing in the LH rats and by antidepressants was not explained by altered expression of RNA editing enzymes or their substrates (adenosine deaminases that act on RNA, HTR2C, and spliced form of HTR2C). These results suggest that alteration of RNA editing of HTR2C may play a role in the pathophysiology of depression and action of antidepressants.", "corpus_id": 25363004, "score": 0 }, { "doc_id": "32837865", "title": "A-to-I RNA Editing and Human Disease", "abstract": "The post-transcriptional modification of mammalian transcripts by A-to-I RNA editing has beenrecognized as an important mechanism for the generation of molecular diversity and alsoregulates protein function through recoding of genomic information. As the molecular players ofediting are characterized and an increasing number of genes become identified that are subject toA-to-I modification, the potential impact of editing on the etiology or progression of humandiseases is realized. Here we review the recent knowledge on where disturbances in A-to-I RNAediting have been correlated with human disease phenotypes.", "corpus_id": 32837865, "score": 0 }, { "doc_id": "24098717", "title": "RNA editing: a molecular mechanism for the fine modulation of neuronal transmission.", "abstract": "The term \"RNA editing\" is used to identify any mechanism responsible for producing mRNA molecules with sequence information not specifically encoded in the DNA. RNA editing is therefore an important event in gene modification, which takes place at a post-transcriptional level. The molecular mechanism of RNA editing involves site-selective deamination of adenosine to inosine in pre-mRNA, which leads to altering translation codons and splicing in nuclear transcripts, whereby functionally distinct proteins can be produced from a single gene. The mammalian editing enzymes ADARs (adenosine deaminases acting on RNA) are widely expressed in brain and other tissues: however, up until now their substrates have mainly been found in the Central Nervous System (CNS). Of particular relevance in the CNS is the editing occurring at the ionotropic glutamate receptors (GluRs) level. Three AMPA and two Kainate receptors are subject to RNA editing. The consequence of this process is the substitution of specific amino acids in functionally critical positions of the receptors. Depending on the GluR involved, the consequences of editing will involve: activation and/or inhibition of splicing sites; modulation of the trafficking of the receptor to the plasma membrane; the process of tetramerization of the receptor subunits; modification of the ions passage through the receptor channel; modulation of the desensitization and action potential recovery times. All these events are specific to the different GluRs and are genetically and developmentally controlled. RNA editing is therefore a crucial event involved in controlling transmission of the action potential at the postsynaptic level. This modulation involves the transmission of all sensory stimuli to the CNS and gives rise to the \"Sensotype\". The Sensotype therefore defines the \"way\" in which the information acquired from the environment by the sensory systems is transmitted to the brain. The signals and inputs deriving from the Sensotype are transmitted to the brain, which processes and stores these signals thus generating the \"Brainotype\". Brainotype and Sensotype are genetically and environmentally determined; they are individually unique and specific to every living organism with a nervous system. Their characteristics are, at least in part, dependent on the modulation of the \"RNA editing\" process since glutamate receptors represent the main neurotransmitter system in the CNS.", "corpus_id": 24098717, "score": 0 }, { "doc_id": "199040", "title": "RNA editing in the Wilms' tumor susceptibility gene, WT1.", "abstract": "Rat kidney WT1 cDNAs contain either a thymidine or a cytosine residue at position 839. Genomic WT1 DNA contains only T839. To explain these results, we propose the WT1 transcript undergoes RNA editing in which U839 is converted to C, resulting in the replacement of leucine 280 in WT1 by proline. RNA editing at the same nucleotide was observed in WT1 cDNAs from human testis. In functional assays, the WT1-leucine280 polypeptide repressed the EGR-1 promoter in in vitro assays approximately 30% more efficiently than WT1-proline. Edited WT1-C839 mRNA was barely detectable in neonatal kidney, whereas adult rat kidneys contained both U839 and C839-WT1 mRNA, suggesting a role for the two protein isoforms in growth and differentiation.", "corpus_id": 199040, "score": 0 }, { "doc_id": "6181218", "title": "The DNA methyltransferases of mammals.", "abstract": "The biological significance of 5-methylcytosine was in doubt for many years, but is no longer. Through targeted mutagenesis in mice it has been learnt that every protein shown by biochemical tests to be involved in the establishment, maintenance or interpretation of genomic methylation patterns is encoded by an essential gene. A human genetic disorder (ICF syndrome) has recently been shown to be caused by mutations in the DNA methyltransferase 3B (DNMT3B) gene. A second human disorder (Rett syndrome) has been found to result from mutations in the MECP2 gene, which encodes a protein that binds to methylated DNA. Global genome demethylation caused by targeted mutations in the DNA methyltransferase-1 (Dnmt1) gene has shown that cytosine methylation plays essential roles in X-inactivation, genomic imprinting and genome stabilization. The majority of genomic 5-methylcytosine is now known to enforce the transcriptional silence of the enormous burden of transposons and retroviruses that have accumulated in the mammalian genome. It has also become clear that programmed changes in methylation patterns are less important in the regulation of mammalian development than was previously believed. Although a number of outstanding questions have yet to be answered (one of these questions involves the nature of the cues that designate sites for methylation at particular stages of gametogenesis and early development), studies of DNA methyltransferases are likely to provide further insights into the biological functions of genomic methylation patterns.", "corpus_id": 6181218, "score": 0 }, { "doc_id": "20289727", "title": "Computational analyses show A-to-G mutations correlate with nascent mRNA hairpins at somatic hypermutation hotspots.", "abstract": "Activation-induced cytidine deaminase (AID) initiates Phase I somatic hypermutation (SHM) of antibody genes by deaminating deoxy-cytosine to deoxy-uracil (C-to-U). These lesions trigger Phase II, a poorly understood process of error-prone repair targeting A-T pairs by DNA polymerase eta (Pol eta). Since Pol eta is also a reverse transcriptase, Phase II could involve copying off RNA as well as DNA templates. We explore this idea further since in an RNA-based pathway it is conceivable that adenosine-to-inosine (A-to-I) RNA editing causes A-to-G transitions since I like G pairs with C. Adenosine deaminases (ADARs) are known to preferentially edit A nucleotides that are preceded by an A or U (W) in double-stranded RNA substrates. On this assumption and using a theoretical bioinformatics approach we show that a significant and specific correlation (P<0.002) exists between the frequency of WA-to-WG mutations and the number of mRNA hairpins that could potentially form at the mutation site. This implies roles for both RNA editing and reverse transcription during SHM in vivo and suggests definitive genetic experiments targeting the appropriate ADAR1 isoform (gammaINF-ADAR1) and/or Ig pre-mRNA templates.", "corpus_id": 20289727, "score": 0 }, { "doc_id": "31884033", "title": "Generation of G-to-A and C-to-U changes in HIV-1 transcripts by RNA editing.", "abstract": "RNA editing involves posttranscriptional alterations of messenger RNA (mRNA) sequences modifying the information content encoded by the genetic message. Here, it is shown that, in chronically infected H9 cells, human immunodeficiency virus-type 1 (HIV-1) mRNAs undergo guanine-to-adenine (G-to-A) and cytosine-to-uracil (C-to-U) changes. G-to-A modification in the untranslated region of exon 1 was present only in spliced HIV-1 mRNAs. The creation of stop codons in HIV-1 mRNAs may function to control the translation of viral proteins, such as viral protein R, that are involved in the regulation of HIV-1 expression and the survival of chronically infected cells.", "corpus_id": 31884033, "score": 0 }, { "doc_id": "25406357", "title": "Transmitter uptake and release in PC12 cells overexpressing plasma membrane monoamine transporters", "abstract": "Transmitter uptake and exocytosis of secretory vesicles are two essential aspects of neurotransmission. Here we show that transient overexpression of plasma membrane monoamine transporters in rat pheochromocytoma PC12 cells induced an approximate 20‐fold enhancement of cellular uptake of monoamines. Intravesicular amine concentration was greatly increased, as demonstrated directly by carbon fibre amperometry. However, the amount of stored monoamines diminished over a 5‐h period, unless monoamine oxidase was inhibited, indicating that monoamines leak out from secretory vesicles. This efflux of monoamines accounts for the reported dependence of vesicular monoamine content (the quantal size) on the kinetics of vesicular monoamine uptake. Measuring radiolabelled monoamines release from the cell population provided accurate determination of the secretory activity of the subpopulation (10–20%) of cells transfected with monoamine transporters, since they contained about 95% of the radiolabel. Accordingly, significant modification of the secretory responses was observed, at the cell population level, upon transient expression of the serotonin transporter and of proteins known to interfere with exocytosis, such as botulinum neurotoxin C1, GTPase‐deficient Rab3 proteins, truncated Rabphilin constructs or Rim. The co‐transfection assay described here, based on transient expression of monoamine transporters, should prove useful in functional studies of the secretory machinery.", "corpus_id": 25406357, "score": 0 }, { "doc_id": "9409764", "title": "Altered Editing of Serotonin 2C Receptor Pre-mRNA in the Prefrontal Cortex of Depressed Suicide Victims", "abstract": "Five adenosines within the coding sequence of the serotonin 2C receptor (5-HT2C) pre-mRNA are converted to inosines by RNA editing (named A, B, C' (E), C, and D sites). In human prefrontal cortex (PFC), the most abundant 5-HT2C mRNA sequences result from editing at the A site, or from the editing combinations AC'C, ABCD, and ABD. In suicide victims with a history of major depression, C' site editing is significantly increased, D site editing is significantly decreased, and the C site shows a trend toward increased editing. Treatment of mice with the antidepressant drug fluoxetine (Prozac) causes changes in C', C, and D site editing that are exactly opposite to those seen in suicide victims. Thus, one outcome of fluoxetine treatment may be to reverse the abnormalities in 5-HT2C pre-mRNA editing seen in depressed suicide victims.", "corpus_id": 9409764, "score": 0 }, { "doc_id": "25405124", "title": "RNA Editing of the Human Serotonin 5-HT2C Receptor: Alterations in Suicide and Implications for Serotonergic Pharmacotherapy", "abstract": "RNA encoding the human serotonin 5-HT2C receptor (5-HT2CR) undergoes adenosine-to-inosine RNA editing events at five positions, resulting in an alteration of amino acids in the second intracellular loop. Several edited 5-HT2CRs possess a reduced G-protein coupling efficiency compared to the completely non-edited isoform. The current studies show that the efficacy of the hallucinogenic drug lysergic acid diethylamide and of antipsychotic drugs is regulated by RNA editing, suggesting that alterations in editing efficiencies or patterns might result in the generation of a 5-HT2CR population differentially responsive to serotonergic drugs. An examination of the efficiencies of RNA editing of the 5-HT2CR in prefrontal cortex of control individuals vs. subjects diagnosed with schizophrenia or major depressive disorder revealed no significant differences in RNA editing among the three populations. However, subjects who had committed suicide (regardless of diagnosis) exhibited a statistically significant elevation of editing at the A-site, which is predicted to change the amino acid sequence in the second intracellular loop of the 5-HT2CR. These findings suggest that alterations in RNA editing may contribute to or complicate therapy in certain psychiatric disorders.", "corpus_id": 25405124, "score": 0 }, { "doc_id": "24977282", "title": "RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders", "abstract": "The importance of serotonin 2C receptor (HTR2C) in mental disorders has been implicated by studies of HTR2C-deficient mice and linkage and association studies. Recent studies have revealed that RNA editing of HTR2C is involved in mental disorders. Here we examined RNA editing efficiencies of site A and D of HTR2C in the prefrontal cortex samples of patients with bipolar disorder, schizophrenia, and major depression as well as control subjects by using primer extension combined with denaturing high performance liquid chromatography. Postmortem samples were donated by the Stanley Foundation Brain Collection. We could not find significant alterations of RNA editing efficiencies of these sites in patients. However, we found trends for increased RNA editing efficiencies of site D in depressive patients (P=0.08) and site A in suicide victims (P=0.07). These findings are in accordance with the previous findings, and suggest that altered RNA editing of HTR2C may have some significance in major depression and suicide.", "corpus_id": 24977282, "score": 0 }, { "doc_id": "15784125", "title": "RNA editing of the 5-HT2C receptor is reduced in schizophrenia", "abstract": "5-HT2C receptor (5HT2CR, serotonin-2C) RNA undergoes editing to produce several receptor variants, some with pharmacological differences. This investigation comprised two parts: the characterisation of 5-HT2CR RNA editing in a larger human control sample than previously examined, and a comparative study in subjects with schizophrenia. Secondary structure analysis of the putative edited region of the human 5-HT2CR gene predicted the existence of a double stranded (ds) RNA loop, essential for RNA editing in this receptor. RNA was then extracted from frontal cortex of five controls and five subjects with schizophrenia. RT-PCR products of the edited region were cloned and sequenced (n = 100). Reduced RNA editing, increased expression of the unedited 5-HT2C-INI isoform in schizophrenia (P = 0.001) and decreased expression of the 5-HT2C-VSV and 5-HT2C-VNV isoforms were detected in the schizophrenia group. In addition, two novel mRNA edited variants were identified: 5-HT2C-MNI and 5-HT2C-VDI. Screening of the 5-HT2CR gene did not reveal any mutations likely to disrupt the dsRNA loop, suggesting that the reduced RNA editing in schizophrenia may instead be caused by altered activity of the editing enzyme(s). Since the unedited 5-HT2C-INI is more efficiently coupled to G proteins than the other isoforms, its increased expression in schizophrenia may lead to enhanced 5-HT2CR-mediated effects. The results also illustrate that potentially important receptor alterations may occur in schizophrenia which are not detectable merely in terms of receptor abundance.", "corpus_id": 15784125, "score": 0 }, { "doc_id": "11376543", "title": "Modulation of Serotonin 2C Receptor Editing by Sustained Changes in Serotonergic Neurotransmission", "abstract": "Serotonin 2C (5-HT2C) receptor pre-mRNA is a substrate for RNA editing enzymes that convert five adenosines (named A, B, C′, C, and D editing sites) to inosines. Editing of two of these sites (C′ and C) is crucial for decreasing the efficiency of the receptor to activate G-protein. Nucleotide sequence analysis of mouse forebrain neocortical 5-HT2C mRNA isoforms revealed that editing at these two sites is regulated in a serotonin-dependent manner. In serotonin-depleted mice, C′- and C-site editing is significantly decreased. This results in an increased expression of 5-HT2C mRNA isoforms encoding receptors with higher sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT2A/2C agonist (±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the editing frequency at the C′ site and leads to increased expression of 5-HT2C mRNA isoforms encoding receptors that activate G-protein least efficiently. None of the drug treatments led to alterations in cytoplasmic 5-HT2C mRNA levels. These data indicate that editing of 5-HT2C pre-mRNA is a mechanism that retains basic response properties of 5-HT2Creceptors in the face of changing synaptic input to keep receptor activation within an optimal range for information processing.", "corpus_id": 11376543, "score": 0 }, { "doc_id": "44527461", "title": "The snoRNA HBII-52 Regulates Alternative Splicing of the Serotonin Receptor 2C", "abstract": "The Prader-Willi syndrome is a congenital disease that is caused by the loss of paternal gene expression from a maternally imprinted region on chromosome 15. This region contains a small nucleolar RNA (snoRNA), HBII-52, that exhibits sequence complementarity to the alternatively spliced exon Vb of the serotonin receptor 5-HT2CR. We found that HBII-52 regulates alternative splicing of 5-HT2CR by binding to a silencing element in exon Vb. Prader-Willi syndrome patients do not express HBII-52. They have different 5-HT2CR messenger RNA (mRNA) isoforms than healthy individuals. Our results show that a snoRNA regulates the processing of an mRNA expressed from a gene located on a different chromosome, and the results indicate that a defect in pre-mRNA processing contributes to the Prader-Willi syndrome.", "corpus_id": 44527461, "score": 0 }, { "doc_id": "21377462", "title": "Neuronal Tryptophan Hydroxylase mRNA Expression in the Human Dorsal and Median Raphe Nuclei: Major Depression and Suicide", "abstract": "Major depressive disorder (MDD) and suicide are associated with deficient serotonergic neurotransmission. Tryptophan hydroxylase (TPH) is the rate-limiting biosynthetic enzyme for serotonin. Previously, we reported elevated levels of TPH protein in the dorsal raphe nucleus (DRN) of depressed suicides and now examine expression of neuronal TPH2 mRNA in a cohort of matched controls and depressed suicides (n=11 pairs). DRN TPH2 mRNA was measured by densitometric analysis of autoradiograms from in situ hybridization histochemistry experiments. TPH2 mRNA is confirmed as the raphe-specific isoform of TPH in human brain, and is expressed in neurons throughout the anteroposterior extent of the DRN and median raphe nucleus (MRN). TPH2 mRNA expression correlates with TPH protein distribution in the DRN, and has a negative correlation with age. In drug-free suicides, TPH2 expression is 33% higher in the DRN and 17% higher in the MRN as compared to matched nonpsychiatric controls. Higher levels of TPH2 mRNA were found throughout the entire extent of the rostrocaudal axis of the DRN, and were not specific to any single subnucleus. Higher TPH2 mRNA expression may explain more TPH protein observed in depressed suicides and reflect a homeostatic response to deficient brain serotonergic transmission.", "corpus_id": 21377462, "score": 0 }, { "doc_id": "9285250", "title": "Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides", "abstract": "Deficient levels of serotonin are associated with suicide and depression. Paradoxically, in the dorsal raphe nucleus (DRN) there are more serotonin neurons and more neuronal tryptophan hydroxylase-2 (TPH2) expression postmortem in depressed suicides. In this study, we sought to determine whether greater TPH2 expression in depressed suicides was the result of more TPH2 expression per neuron. In situ hybridization and computer-assisted image analysis were performed on tissue sections throughout the extent of the raphe nuclei at the level of silver grains per neuron to systematically quantify TPH2 neuronal expression. Depressed suicides have 26.5% more TPH2 grain density per neuron in the DRN compared with matched controls (P=0.04). The difference in grain density is greater at mid- and caudal anatomical levels across the rostrocaudal axis of the DRN. Densitometric analysis of TPH2 expression in the DRN subnuclei showed that higher expression levels were observed at posterior anatomical levels of depressed suicides (121% of control in the caudal subnucleus). Higher TPH2 expression in depressed suicides may explain more TPH2 protein and reflect a homeostatic response to deficient serotonin levels in the brains of depressed suicides. Localized changes in TPH2 expression in specific subnuclei of the DRN suggest that the serotonergic compensatory mechanism in depression and suicide is specifically regulated within the DRN and has implications for regions innervated by this subnucleus.", "corpus_id": 9285250, "score": 0 }, { "doc_id": "7224462", "title": "Tryptophan hydroxylase 2 gene expression and promoter polymorphisms in bipolar disorder and schizophrenia", "abstract": "The tryptophan hydroxylase isoform-2 gene (Tph2) is located on chromosome 12 and is expressed primarily in brain tissue. Although the tryptophan hydroxylase isoform-1 gene (Tph1) has been reported to have a genetic association with bipolar disorder and schizophrenia, the Tph1 isoform is expressed at much lower levels than Tph2 (150-fold less in the mouse brain). We hypothesized that bipolar disorder and schizophrenia are associated with abnormal levels of TPH2 mRNA in the brain. TPH2 and β-actin mRNA levels in postmortem brain were quantified using real-time PCR. mRNA samples provided by the Stanley Foundation Array Collection were derived from the dorsolateral prefrontal cortex (Brodmann Area 46) of 35 bipolar, 35 schizophrenic, and 35 control subjects. There were significant differences in the mRNA levels among bipolar, schizophrenic, and normal subjects [F(2,102)=3.58; p=0.031]. A greater amount of TPH2 mRNA was found in the bipolar group in comparison with control subjects (Tukey's test: p=0.024). Further investigations of Tph2 are needed to clarify the potential role of this gene in the pathophysiology of bipolar disorder.", "corpus_id": 7224462, "score": 0 }, { "doc_id": "32065552", "title": "Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression", "abstract": "Impaired brain serotonin neurotransmission is a potential component of the diathesis of major depression. Tryptophan hydroxylase-2 (TPH2), is the rate limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and a cause of impaired serotonin transmission. Here, we identify a novel TPH2 short isoform with truncated catalytic domain expressed in human brainstem, prefrontal cortex, hippocampus and amygdala. An exploratory study of 166 Caucasian subjects revealed association with major depression or suicide of a novel single nucleotide polymorphism (SNP) g.22879A>G located in exon 6 of this short isoform. This SNP and additional SNPs were discovered through a systematic characterization of the genetic architecture of the TPH2 gene for further genetic and functional investigations of its relationship to major depression and other psychopathology.", "corpus_id": 32065552, "score": 0 }, { "doc_id": "32086828", "title": "SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression", "abstract": "Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed single-nucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P=0.0012, global P=0.0051) and MD. Haplotype analysis produced additional support for association (P<0.0001, global P=0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders.", "corpus_id": 32086828, "score": 0 } ]

{ "doc_id": "89673035", "title": "Effect of chemotherapeutic drugs on telomere length and telomerase activity", "abstract": "Telomeres are specialized nucleoproteic complexes localized at the ends of eukaryotic chromosomes, that maintain their stability and integrity. They protect chromosome ends from fusion and from being recognized as sites of DNA damage, i.e., they distinguish natural DNA ends from DNA ends resulting from breakage events. In mammalian cells, telomeres consist of tandem arrays of the hexanucleotide TTAGGG, oriented 5′ to 3′ towards the end of the chromosomes and associated proteins (the so-called “shelterin” complex), and a large non-coding RNA (named TERRA) which forms an integral component of telomeric heterochromatin. Telomere length is maintained by a dynamic process of telomere shortening and lengthening. Shortening can occur due to nucleolytic degradation and incomplete DNA replication due to the inability of lagging strand synthesis to completely replicate chromosomal ends (i.e., the “end replication problem”), whereas lengthening is primarily accomplished by the action of the enzyme telomerase and occasionally by the so-called Alternative Lengthening of Telomeres (“ALT”) mechanism, which involves homologous recombination. The maintenance of telomere function is crucial for genomic stability and cell viability. Cells respond to dysfunctional telomeres by undergoing senescence, cell death, or genomic instability. Since telomeres play a fundamental role in maintaining chromosomal/genomic stability and telomerase activity and telomere lengthening play a key role in cancer development and progression, a proper knowledge of the effects of chemotherapeutic drugs on telomere length and telomerase activity in normal as well as tumor cells is of great importance to understand the genomic instability associated with chemotherapy regimens. Therefore, in this review we will summarize our current knowledge concerning the main data available about the effects of chemotherapeutic drugs on telomere length and telomerase activity in mammalian cells.", "corpus_id": 89673035 }

[ { "doc_id": "26674893", "title": "Telomeres: Beginning to Understand the End", "abstract": "Telomeres are the protein-DNA structures at the ends of eukaryotic chromosomes. In yeast, and probably most other eukaryotes, telomeres are essential. They allow the cell to distinguish intact from broken chromosomes, protect chromosomes from degradation, and are substrates for novel replication mechanisms. Telomeres are usually replicated by telomerase, a telomere-specific reverse transcriptase, although telomerase-independent mechanisms of telomere maintenance exist. Telomere replication is both cell cycle- and developmentally regulated, and its control is likely to be complex. Because telomere loss causes the kinds of chromosomal changes associated with cancer and aging, an understanding of telomere biology has medical relevance.", "corpus_id": 26674893, "score": 0 }, { "doc_id": "16000395", "title": "Switching and Signaling at the Telomere", "abstract": "This review describes the structure of telomeres, the protective DNA-protein complexes at eukaryotic chromosomal ends, and several molecular mechanisms involved in telomere functions. Also discussed are cellular responses to compromising the functions of telomeres and of telomerase, which synthesizes telomeric DNA.", "corpus_id": 16000395, "score": 0 }, { "doc_id": "6531571", "title": "Telomeres: protecting chromosomes against genome instability", "abstract": "The natural ends of linear chromosomes require unique genetic and structural adaptations to facilitate the protection of genetic material. This is achieved by the sequestration of the telomeric sequence into a protective nucleoprotein cap that masks the ends from constitutive exposure to the DNA damage response machinery. When telomeres are unmasked, genome instability arises. Balancing capping requirements with telomere replication and the enzymatic processing steps that are obligatory for telomere function is a complex problem. Telomeric proteins and their interacting factors create an environment at chromosome ends that inhibits DNA repair; however, the repair machinery is essential for proper telomere function.", "corpus_id": 6531571, "score": 1 }, { "doc_id": "34177421", "title": "Conservation of the human telomere sequence (TTAGGG)n among vertebrates.", "abstract": "To determine the evolutionary origin of the human telomere sequence (TTAGGG)n, biotinylated oligodeoxynucleotides of this sequence were hybridized to metaphase spreads from 91 different species, including representative orders of bony fish, reptiles, amphibians, birds, and mammals. Under stringent hybridization conditions, fluorescent signals were detected at the telomeres of all chromosomes, in all 91 species. The conservation of the (TTAGGG)n sequence and its telomeric location, in species thought to share a common ancestor over 400 million years ago, strongly suggest that this sequence is the functional vertebrate telomere.", "corpus_id": 34177421, "score": 0 }, { "doc_id": "23675465", "title": "A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes.", "abstract": "A highly conserved repetitive DNA sequence, (TTAGGG)n, has been isolated from a human recombinant repetitive DNA library. Quantitative hybridization to chromosomes sorted by flow cytometry indicates that comparable amounts of this sequence are present on each human chromosome. Both fluorescent in situ hybridization and BAL-31 nuclease digestion experiments reveal major clusters of this sequence at the telomeres of all human chromosomes. The evolutionary conservation of this DNA sequence, its terminal chromosomal location in a variety of higher eukaryotes (regardless of chromosome number or chromosome length), and its similarity to functional telomeres isolated from lower eukaryotes suggest that this sequence is a functional human telomere.", "corpus_id": 23675465, "score": 0 }, { "doc_id": "1858104", "title": "TERRA biogenesis, turnover and implications for function", "abstract": "Telomeres are heterochromatic structures at the ends of eukaryotic chromosomes. As other heterochromatin regions, telomeres are transcribed, from the subtelomeric region towards chromosome ends into the long non‐coding RNA TERRA. Telomere transcription is a widespread phenomenon as it has been observed in species belonging to several kingdoms of the eukaryotic domain. TERRA is part of telomeric heterochromatin in addition to being present in the nucleoplasm. Here, we review the current knowledge of TERRA structure, biogenesis and turnover. In addition, we discuss presumed roles of this RNA during replication of telomeric DNA, heterochromatin formation and the regulation of telomerase.", "corpus_id": 1858104, "score": 0 }, { "doc_id": "16397181", "title": "Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity", "abstract": "Telomeres are dynamic nucleoprotein structures that protect the ends of chromosomes from degradation and activation of DNA damage response. For this reason, telomeres are essential to genome integrity. Chromosome ends are enriched in heterochromatic marks and proper organization of telomeric chromatin is important to telomere stability. Despite their heterochromatic state, telomeres are transcribed giving rise to long noncoding RNAs (lncRNA) called TERRA (telomeric repeat-containing RNA). TERRA molecules play critical roles in telomere biology, including regulation of telomerase activity and heterochromatin formation at chromosome ends. Emerging evidence indicate that TERRA transcripts form DNA-RNA hybrids at chromosome ends which can promote homologous recombination among telomeres, delaying cellular senescence and sustaining genome instability. Intriguingly, TERRA RNA-telomeric DNA hybrids are involved in telomere length homeostasis of telomerase-negative cancer cells. Furthermore, TERRA transcripts play a role in the DNA damage response (DDR) triggered by dysfunctional telomeres. We discuss here recent developments on TERRA's role in telomere biology and genome integrity, and its implication in cancer.", "corpus_id": 16397181, "score": 0 }, { "doc_id": "3846767", "title": "Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies", "abstract": "Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.", "corpus_id": 3846767, "score": 1 }, { "doc_id": "45688533", "title": "Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?", "abstract": "Mild oxidative stress as exerted by culture of human WI-38 fibroblasts under 40% oxygen partial pressure blocks proliferation irreversibly after one to three population doublings. Hyperoxically blocked cells are similar to senescent ones in terms of general morphology and lipofuscin accumulation. Moreover, they, like senescent fibroblasts, are blocked preferentially in G1 as evident from DNA content measurements by flow cytometry. Southern blotting of AluI- and HinfI-restricted genomic DNA shows an increase of the rate of telomere shortening from 90 bp per population doubling under normoxia to more than 500 bp per population doubling under hyperoxia. In every case, proliferation is blocked if a telomere cutoff length of about 4 kb is arrived at. The fact that telomere length correlates with the final inhibition of proliferation under conditions of varied oxidative stress, while the population doubling level does not, suggests that telomere shortening provides the signal for cell cycle exit in senescence. In postmitotic cells, no further telomere shortening occurs. However, the sensitivity of terminal restriction fragments to S1 nuclease increases, indicating the accumulation of single-strand breaks in telomeres of nondividing fibroblasts. This effect is found both under normoxic and hyperoxic culture, although it is more pronounced under conditions of higher oxidative stress. It might be speculated that accumulation of single-strand breaks and the resultant loss of distal single-stranded fragments during replication could be a major cause of telomere shortening, possibly more important than incomplete replication per se.", "corpus_id": 45688533, "score": 0 }, { "doc_id": "25933117", "title": "Mechanism of Telomere Shortening by Oxidative Stress", "abstract": "Abstract: We investigated whether oxidative stress, which contributes to aging, accelerates the telomere shortening in human cultured cells. The terminal restriction fragment (TRF) from WI‐38 fibroblasts irradiated with UVA (365‐nm light) decreased with increasing of the irradiation dose. Furthermore, UVA irradiation dose‐dependently increased the formation of 8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine (8‐oxodG) in both WI‐38 fibroblasts and HL‐60 cells. In order to clarify the mechanism of the acceleration of telomere shortening, we investigated site‐specific DNA damage induced by UVA irradiation in the presence of endogenous photosensitizers using 32P 5′ end‐labeled DNA fragments containing telomeric oligonucleotide (TTAGGG)4. UVA irradiation with riboflavin induced 8‐oxodG formation in the DNA fragments containing telomeric sequence, and Fpg protein treatment led to chain cleavages at the central guanine of 5′‐GGG‐3′ in telomere sequence. Human 8‐oxodG‐DNA glycosylase introduces a chain break in a double‐stranded oligonucleotide specifically at an 8‐oxodG residue. The amount of 8‐oxodG formation in DNA fragment containing telomere sequence [5′‐CGC(TTAGGG)7CGC‐3′] was approximately five times more than that in the DNA fragment containing nontelomere sequence [5′‐CGC(TGTGAG)7CGC‐3′]. Furthermore, H2O2 plus Cu(II) caused DNA damage, including 8‐oxodG formation, specifically at the GGG sequence in the telomere sequence (5′‐TTAGGG‐3′). It is concluded that the formation of 8‐oxodG at the GGG triplet in telomere sequence induced by oxidative stress could participate in acceleration of telomere shortening.", "corpus_id": 25933117, "score": 0 }, { "doc_id": "13366934", "title": "Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA", "abstract": "To examine the role of telomerase in normal and neoplastic growth, the telomerase RNA component (mTR) was deleted from the mouse germline. mTR-/- mice lacked detectable telomerase activity yet were viable for the six generations analyzed. Telomerase-deficient cells could be immortalized in culture, transformed by viral oncogenes, and generated tumors in nude mice following transformation. Telomeres were shown to shorten at a rate of 4.8+/-2.4 kb per mTR-/- generation. Cells from the fourth mTR-/- generation onward possessed chromosome ends lacking detectable telomere repeats, aneuploidy, and chromosomal abnormalities, including end-to-end fusions. These results indicate that telomerase is essential for telomere length maintenance but is not required for establishment of cell lines, oncogenic transformation, or tumor formation in mice.", "corpus_id": 13366934, "score": 0 }, { "doc_id": "26106433", "title": "Telomeres: hallmarks of radiosensitivity.", "abstract": "Telomeres are the very ends of the chromosomes. They can be seen as natural double-strand breaks (DSB), specialized structures which prevent DSB repair and activation of DNA damage checkpoints. In somatic cells, attrition of telomeres occurs after each cell division until replicative senescence. In the absence of telomerase, telomeres shorten due to incomplete replication of the lagging strand at the very end of chromosome termini. Moreover, oxidative stress and accumulating reactive oxygen species (ROS) lead to an increased telomere shortening due to a less efficient repair of SSB in telomeres. The specialized structures at telomeres include proteins involved in both telomere maintenance and DNA repair. However when a telomere is damaged and has to be repaired, those proteins might fail to perform an accurate repair of the damage. This is the starting point of this article in which we first summarize the well-established relationships between DNA repair processes and maintenance of functional telomeres. We then examine how damaged telomeres would be processed, and show that irradiation alters telomere maintenance leading to possibly dramatic consequences. Our point is to suggest that those consequences are not restricted to the short term effects such as increased radiation-induced cell death. On the contrary, we postulate that the major impact of the loss of telomere integrity might occur in the long term, during multistep carcinogenesis. Its major role would be to act as an amplificator event unmasking in one single step recessive radiation-induced mutations among thousands of genes and providing cellular proliferative advantage. Moreover, the chromosomal instability generated by damaged telomeres will favour each step of the transformation from normal to fully transformed cells.", "corpus_id": 26106433, "score": 0 }, { "doc_id": "19751939", "title": "Telomere dysfunction and chromosome instability.", "abstract": "The ends of chromosomes are composed of a short repeat sequence and associated proteins that together form a cap, called a telomere, that keeps the ends from appearing as double-strand breaks (DSBs) and prevents chromosome fusion. The loss of telomeric repeat sequences or deficiencies in telomeric proteins can result in chromosome fusion and lead to chromosome instability. The similarity between chromosome rearrangements resulting from telomere loss and those found in cancer cells implicates telomere loss as an important mechanism for the chromosome instability contributing to human cancer. Telomere loss in cancer cells can occur through gradual shortening due to insufficient telomerase, the protein that maintains telomeres. However, cancer cells often have a high rate of spontaneous telomere loss despite the expression of telomerase, which has been proposed to result from a combination of oncogene-mediated replication stress and a deficiency in DSB repair in telomeric regions. Chromosome fusion in mammalian cells primarily involves nonhomologous end joining (NHEJ), which is the major form of DSB repair. Chromosome fusion initiates chromosome instability involving breakage-fusion-bridge (B/F/B) cycles, in which dicentric chromosomes form bridges and break as the cell attempts to divide, repeating the process in subsequent cell cycles. Fusion between sister chromatids results in large inverted repeats on the end of the chromosome, which amplify further following additional B/F/B cycles. B/F/B cycles continue until the chromosome acquires a new telomere, most often by translocation of the end of another chromosome. The instability is not confined to a chromosome that loses its telomere, because the instability is transferred to the chromosome donating a translocation. Moreover, the amplified regions are unstable and form extrachromosomal DNA that can reintegrate at new locations. Knowledge concerning the factors promoting telomere loss and its consequences is therefore important for understanding chromosome instability in human cancer.", "corpus_id": 19751939, "score": 0 }, { "doc_id": "16777755", "title": "Telomere and Telomerase Therapeutics in Cancer", "abstract": "Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics.", "corpus_id": 16777755, "score": 0 }, { "doc_id": "31019024", "title": "Telomere Length Maintenance, Shortening, and Lengthening", "abstract": "Telomeres maintain chromosome stability and cell replicative capacity. Telomere shortening occurs concomitant with aging. Short telomeres are associated with some diseases, such as dyskeratosis congenita, idiopathic pulmonary fibrosis, and aplastic anemia. Telomeres are longer in pluripotent stem cells than in somatic cells and lengthen significantly during preimplantation development. Furthermore, telomere elongation during somatic cell reprogramming is of great importance in the acquisition of authentic pluripotency. This review focuses primarily on regulatory mechanisms of telomere length maintenance in pluripotent cells, telomere length extension in early embryo development, and also telomere rejuvenation in somatic cell reprogramming. Telomere related diseases are also discussed in this review. J. Cell. Physiol. 229: 1323–1329, 2014. © 2014 Wiley Periodicals, Inc.", "corpus_id": 31019024, "score": 0 }, { "doc_id": "22269962", "title": "Telomere recombination and the ALT pathway: a therapeutic perspective for cancer.", "abstract": "Telomeres are essential for cell proliferation and tumor cell immortalization requires the presence of a telomere maintenance mechanism. Thus, interfering with this mechanism constitutes a potential means to impede cell proliferation and tumor progression. Many cancer cells rely on telomerase activity to ensure indefinite proliferation capacity and developing therapeutic approaches that target telomerase has attracted much attention in the last couple of decades. Nevertheless, a non-negligible proportion of tumors utilize telomerase- independent, alternative mechanisms to lengthen telomeres (ALT). Here we briefly discuss both our current understanding of ALT mechanisms and the potential to develop a therapeutic approach targeting ALT.", "corpus_id": 22269962, "score": 0 }, { "doc_id": "23195340", "title": "Telomerase activity and telomere length in pediatric patients with malignancies undergoing chemotherapy", "abstract": "Telomerase activity and telomere length in mononuclear cells (MNCs) and granulocytes from peripheral blood (PB) and bone marrow (BM) specimens were studied in pediatric acute leukemia (ALL, n = 15; AML, n = 1) and pediatric solid tumor (ST) patients (n = 9) at diagnosis, during and after chemotherapy. In four ST patients, tumor tissue was also available. For comparative analysis, MNCs from healthy donors (n = 53) were analyzed. Telomerase was evaluated using a modified telomeric repeat amplification protocol (TRAP) assay, and telomere length by terminal restriction fragment (TRF) analysis. At diagnosis, high telomerase activity was detected in MNCs from all leukemia patients, which was similar to the activity from ST biopsy specimens. This exceeded by 10- to 20-fold the activity in PB MNCs from ST patients and healthy donors (P < 0.05). granulocyte fractions lacked telomerase activity in all groups. bm mncs in leukemia patients revealed a four-fold higher telomerase activity than pb (P = 0.005). After induction chemotherapy and response to treatment, telomerase activity decreased to borderline or undetectable levels in PB MNCs in leukemia (P < 0.01). average telomeres in pb mncs from pediatric patients were significantly longer (n = 25; 10.9 kbp) than telomeres in PB and BM MNCs from adult healthy donors (7.45 kbp) (P < 0.0001). at diagnosis, telomeres were shorter from bm compared to pb specimens in leukemia (P < 0.05), and two peak trfs were observed corresponding to the malignant and normal cell clones. with the attainment of remission, the lower trf peak, reflecting the leukemic population, was lost. in leukemia patients, mean trfs increased on average 2.2 kbp after induction chemotherapy, but decreased thereafter on consolidation and maintenance chemotherapy (1 kbp). this was comparable to an average telomere loss of 1.2 kbp in pb specimens from st patients after chemotherapy. in all patients, telomere loss in granulocytes as compared to mncs was more pronounced with 1.8 vs 1 kbp, respectively (P = 0.014). Our results demonstrate that at diagnosis, telomerase was consistently and highly upregulated in BM and PB specimens in leukemia, decreased after induction therapy, and correlated with remission. BM specimens in leukemia had higher telomerase activity, probably due to the greater leukemic burden than in PB. Telomeres were significantly longer in children than in adults, but shortened as a consequence of chemotherapy with repeated cycles of hematopoietic regeneration. In acute leukemia, with the loss of the leukemic burden after induction chemotherapy, longer mean TRFs were found, a reflection of the repopulation with normal cells. Our findings suggest that telomerase activity may be useful in the management of childhood malignancies. The significance of telomere length shortening in pediatric patients undergoing chemotherapy and possible telomere regeneration after myelosuppressive treatment remain to be determined.", "corpus_id": 23195340, "score": 0 }, { "doc_id": "23271343", "title": "Telomere dynamics in childhood leukemia and solid tumors: a follow-up study", "abstract": "Telomeres of hematopoietic cells shorten with age, possibly contributing to the aging-associated hematopoietic pathology (immunosenescence, malignant transformation). Accelerated telomere shortening is seen with replicative stress, such as during administration of serial chemotherapy cycles for the treatment of childhood cancer. To define the long-term consequences of pediatric cancer treatment on hematopoietic cell telomere length, we undertook a prospective 4-year follow-up study of a 61-patient cohort of pediatric malignancies in a community-based setting. We found that mononuclear cells (MNC) and granulocytes of children with standard-risk acute lymphoblastic leukemia (ALL) suffered minimal telomere shortening throughout therapy (less than 1 kbp; average follow-up, 20 months), while those of children with solid tumors showed greater and more heterogenous telomere attrition (0.5–2.8 kbp, average follow-up, 9 months). In addition, we evaluated the role of telomerase, the enzyme commonly up-regulated in pediatric leukemic and solid tumor cells for telomere length maintenance, as a disease marker. Serial determinations of telomerase in MNC were useful to confirm disease remission in leukemia, but play no role in the follow-up of children with solid tumors.", "corpus_id": 23271343, "score": 0 }, { "doc_id": "195227363", "title": "Telomere length shortening in non-Hodgkin's lymphoma patients undergoing chemotherapy", "abstract": "We investigated telomere length changes in patients with non-Hodgkin's lymphoma (NHL) receiving conventional-dose chemotherapy. Using Southern blot analysis, telomere length was measured in peripheral blood mononuclear cells from five NHL patients at diagnosis, 15 NHL patients after chemotherapy, and 39 healthy controls. Compared with age-matched putative normal controls, telomeres were significantly shorter in NHL patients at diagnosis. Mean telomere length was shorter after chemotherapy than before chemotherapy and was shorter after chemotherapy than in age-matched putative healthy controls. There was no correlation between the extent of telomere shortening and time elapsed after chemotherapy. These findings suggest that in NHL patients hematopoietic stem cells lose telomere length during the recovery period from bone marrow suppression after conventional-dose chemotherapy.", "corpus_id": 195227363, "score": 0 }, { "doc_id": "25286681", "title": "Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF", "abstract": "The purpose of the study was to compare telomere length (TL) in peripheral blood progenitor cells (PBPC) collected after two tightly spaced high-dose (hd) chemotherapy courses. We assessed 37 previously untreated lymphoma patients undergoing a hd-chemotherapy program with autografting. They sequentially received hd-cyclophosphamide (CY) and hd-Ara-C, both followed by PBPC harvesting. Both post-CY and post-Ara-C harvests were assessed for TL by Southern blot analysis. In 12 patients, the assay was also performed on purified CD34+ cells. All patients displayed high PBPC mobilization following both hd-CY and hd-Ara-C. In all but one patient, TL was shorter in PBPC collected after Ara-C compared to CY: 7226 bp (range: 4135–9852) vs 8282 bp (range 4895–14860) (P<0.0001). This result was confirmed on CD34+ cells. Platelet recovery in patients receiving post-Ara-C PBPC was significantly slower compared to those receiving post-CY PBPC. In conclusion, (i) administration of tightly spaced hd-chemotherapy courses induces marked telomere shortening on harvested PBPC; (ii) engraftment kinetics seem slower, with delayed platelet recovery, in patients autografted with PBPC suffering marked TL erosion; (iii) long-term follow-up is required to verify whether PBPC with shortened telomeres display defective engraftment stability and/or risk of secondary leukemia; (iv) TL evaluation is advisable whenever new mobilization procedures are developed.", "corpus_id": 25286681, "score": 0 }, { "doc_id": "3156440", "title": "Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation", "abstract": "High-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) may accelerate telomere length loss in haematopoietic stem cells. As data including pre-and post-treatment samples are lacking, we studied leukocyte telomere length and telomerase activity before and after treatment in breast cancer patients randomized to receive 5 adjuvant courses FEC (5-FU, epirubicin and cyclophosphamide) (n= 17), or 4 × FEC followed by high-dose cyclophosphamide, thiotepa, carboplatin and autologous PBSCT (n= 16). Haemoglobin, MCV, leukocyte-and platelet numbers were assessed prior to (t0), 5 months after (t1) and 9 months after chemotherapy (t2); these parameters were decreased at t1and t2compared to t0(high-dose: all parameters; standard-dose: leukocytes and platelets), and all parameters were lower after high-dose than standard-dose treatment at t1. Paired individual leukocyte samples of t0 and t1showed telomere length change (determined by telomere restricted fragment (TRF) assay) ranging from +0.8 to –2.2 kb, with a decreased TRF length in 9 patients of both groups. Telomerase activity (determined by TRAP assay) was below detection limit in leukocyte samples of t0 and t1. Thus, standard-and high-dose chemotherapy negatively affect haematological reconstitution in this setting. In individual patients, telomere length can be remarkably changed following haematological proliferative stress after treatment. http://www.bjcancer.com © 2001 Cancer Research Campaign", "corpus_id": 3156440, "score": 0 }, { "doc_id": "12814298", "title": "Acceleration of Telomere Loss by Chemotherapy Is Greater in Older Patients with Locally Advanced Head and Neck Cancer", "abstract": "Purpose: Chronic viral infection and combinations of chemotherapeutic drugs have been reported to accelerate telomere erosion. Here, we asked if chemoradiotherapy, using the single agent cisplatin, would accelerate telomere loss in head and neck cancer patients, and whether loss was linked to smoking status, age, gender, or stage of disease at diagnosis. Experimental Design: Blood samples were collected from 20 patients with squamous cell cancer of the head and neck before, during, and after chemoradiotherapy. Following DNA isolation from peripheral blood mononuclear cells, telomere length was measured by terminal restriction fragment analysis. Results: Chemoradiotherapy increased the rate of telomere erosion >100-fold. Telomere length before treatment in chemoradiotherapy patients was similar to age-matched controls. Although smokers began with significantly shorter telomeres, smoking status did not affect chemoradiotherapy-induced attrition, nor did gender or stage of disease. We also make the novel observation that a significantly greater telomere loss occurred in response to treatment in older patients, with those younger than 55 years losing an average of 400 bp of telomeric DNA compared with the 880 bp lost by those over 55 years. Conclusions: The lack of telomere length difference before treatment suggests that shortened telomeres may not be a risk factor for development of head and neck cancer in the age range we examined. Chemoradiotherapy caused a severe telomere length reduction in all patients. The significant difference seen in the elderly (P = 0.018) suggests that chemoradiotherapy may have more severe effects on the replicative capacity of blood cells in older patients.", "corpus_id": 12814298, "score": 0 }, { "doc_id": "23533554", "title": "Telomere dysfunction induced by chemotherapeutic agents and radiation in normal human cells.", "abstract": "The number of long-term survivors of patients with various malignancies (>5 years) is increasing mainly owing to advances in cancer therapeutics, but long-term side effects of the cancer treatment in this population have emerged as an important health and socio-economical issue. Telomeres and telomerase are known to be essential for regulation of cellular life-span and maintenance of genomic stability, and earlier studies have demonstrated that cancer patients who receive chemotherapy have shorter telomeres in their blood cells, indicating accelerated telomere erosion and a potential contribution of telomere loss to late side-effects. Little is currently known about the effect of chemotherapeutic agents and radiation on telomere dynamics including potential effects on telomere length, structure, function, telomerase activity, and telomere shelterin proteins in normal human cells. In the present study, we had addressed this issue experimentally. The treatment of normal human T lymphocytes and fibroblasts with chemotherapeutic agents doxorubicin (DOX) or etoposide (VP16) led to significant shortening of telomeres, down-regulation of telomerase activity, and diminished expression of telomerase reverse transcriptase (hTERT) and the telomere binding proteins TPP1 and POT1. More importantly, telomere dysfunction was observed in cells treated with DOX or VP16. Furthermore, all the above alterations were similarly found in the cells receiving γ-irradiation. Taken together, both chemotherapy and radiotherapy significantly impair telomere maintenance and function in normal human cells. Conceivably telomere dysfunction causes shortened life-span and genomic instability of normal human cells, and thereby contributes to tissue/organ damage and secondary malignancies in long-term survivors of cancer.", "corpus_id": 23533554, "score": 1 }, { "doc_id": "6495027", "title": "FISH analysis of telomeric repeat sequences and their involvement in chromosomal aberrations induced by radiomimetic compounds in hamster cells.", "abstract": "The behaviour of telomeric repeat sequences in Chinese hamster CHO and CHE cell lines treated with the radiomimetic drugs bleomycin (BLM) and streptonigrin (STN) and the effect of these drugs on telomerase activity was investigated. Fluorescence in situ hybridisation revealed that 18% of the scored aberrations induced by BLM and 14% of those induced by STN in CHO cells exhibited telomeric repeat signals. In CHE cells, 29% of the total aberrations induced by BLM and 45% of those induced by STN involved telomeric repeat sequences. Acentric fragments labelled along their entire length and translocations of telomeric repeat sequences were also found in both cell lines. These results suggest that telomeric repeat sequences are preferentially involved in chromosome breakage, fragility and recombination induced by radiomimetic agents. In addition, some of the damaged CHE cells exhibited one or more chromosomes with additional zones of hybridisation, indicating the possible amplification of (TTAGGG)(n) repeats by telomerase. However, the fact that none of the radiomimetic compounds tested produced any effect on telomerase activity suggests that this enzyme is not related to the assumed amplification events induced by BLM and STN in CHE cells.", "corpus_id": 6495027, "score": 1 }, { "doc_id": "34715255", "title": "Induction of telomerase activity in fibroblasts from bleomycin-injured lungs.", "abstract": "Bleomycin-induced lung injury causes increased fibroblast numbers in the lung and pulmonary fibrosis. Studies of fibroblasts isolated from such injured lungs have revealed evidence of increased intrinsic proliferative capacity, but the mechanism is unknown. Telomerase catalyzes the addition of telomeric DNA repeats onto chromosomal ends, which is associated with increased cellular life span or immortality. To examine whether telomerase might play a role in regulating fibroblast proliferative capacity in pulmonary fibrosis, lung fibroblasts were isolated from rats treated with endotracheal injections of phosphate-buffered saline or bleomycin. At selected time points, the rats were killed and lung fibroblasts isolated. The isolated cells and lung tissue were then used in experiments for measurement of telomerase activity. The results show undetectable telomerase activity in fibroblasts isolated from control uninjured lungs, or in the control lung tissue extracts. Similar results were obtained in cells and lung tissue from Days 1, 3, and 28 bleomycin-injured lungs. However, significant telomerase activity was detected in fibroblasts and tissue extracts isolated from Days 7, 14, and 21 bleomycin-treated rat lungs, with maximal activity observed in the Day 14 samples. Analysis of the isolated cells for telomerase messenger RNA or reverse transcriptase expression, combined with alpha-smooth-muscle actin expression by immunohistochemistry, revealed that telomerase expression localized primarily to nonmyofibroblasts. These findings suggest that in addition to elevated growth factor expression, the injured lung fibroblast population may contain cells with increased life span, which could contribute to the observed overall increase in lung fibroblast numbers.", "corpus_id": 34715255, "score": 0 }, { "doc_id": "15495022", "title": "Telomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosis", "abstract": "Epithelial cell injury and apoptosis are recognised as early features in idiopathic pulmonary fibrosis and bleomycin-induced fibrosis in mice. Telomerase is a known apoptosis-alleviating factor. The role of telomerase was studied during bleomycin-induced lung epithelial cell (LEC) apoptosis in vitro in a mouse LEC line, and in vivo in LECs isolated from bleomycin-treated mice. The current authors evaluated changes in murine telomerase reverse transcriptase (mTERT) mRNA levels and changes in telomerase activity with the TRAPeze Detection Kit, telomeric length with the TeloTTAGGG Telomere Length Kit, and LEC apoptosis with FACScan and 4,6-diamino-2-phenylindole dihydrochloride stain. There was a significant elevation in mTERT mRNA and a transient 41% increase in telomerase activity 24 h after in vitro bleomycin treatment. At 72 h, telomerase activity had fallen to 26% below levels in untreated cells. Reduction of telomerase activity over time, or by direct inhibition, significantly elevated LEC apoptosis. No change in average telomeric length was noted. In vivo, telomerase activity of LECs from bleomycin-treated mice increased at 7 and 14 days. In conclusion, telomerase activity may play a protective role against robust bleomycin-induced lung epithelial cell apoptosis. Moreover, stabilising telomerase activity may decrease epithelial cell apoptosis and the resulting lung fibrosis.", "corpus_id": 15495022, "score": 0 }, { "doc_id": "32810747", "title": "Inhibition of telomerase activity by cisplatin in human testicular cancer cells.", "abstract": "Telomerase, a ribonucleoprotein, elongates and/or maintains telomeres by adding TTAGGG tandem repeat sequences using the RNA component of the enzyme as a template. Enzyme activity appears to be associated with cell immortalisation and malignant progression as telomerase activity has been found in the majority of human tumours, but not in most somatic cells or tissues. Telomerase inhibition has, therefore, been proposed as a novel and potentially selective target for therapeutic intervention. Since telomeric tandem repeats as well as the human telomerase RNA component (hTR) and its gene are guanosine-rich, we examined whether the sequence specific, G-Pt-G, cross-linking agent cisplatin is capable of inhibiting telomerase activity. The TRAP assay was used to measure telomerase activity in cisplatin treated cell extracts and RT-PCR strategies used to examine hTR expression after drug exposure. Cisplatin reduced telomerase activity in a specific and concentration-dependent manner in human testicular tumour cells, whilst doxorubicin, bleomycin, methotrexate, melphalan and transplatin had no effect. It is proposed that telomerase inhibition might be a component of the efficacy of cisplatin in the treatment of testicular cancer.", "corpus_id": 32810747, "score": 1 }, { "doc_id": "205360703", "title": "Effects of Four Chemotherapeutic Agents, Bleomycin, Etoposide, Cisplatin, and Cyclophosphamide, on DNA Damage and Telomeres in a Mouse Spermatogonial Cell Line1", "abstract": "ABSTRACT Treatment with chemotherapeutics agents may induce persistent DNA damage in male germ cells with the possibility of long-term consequences on fertility and progeny outcome. Telomeres, specialized structures at the physical ends of chromosomes, play an important role in the maintenance of genetic stability and in the response of somatic cells to anticancer drugs. Our objective was to test the hypothesis that exposure to bleomycin, etoposide, or cisplatin (the drugs used to treat testicular cancer) or cyclophosphamide (an anticancer agent and immunosuppressant) targets telomeres in the male germ line. C18-4 spermatogonial cells were exposed to bleomycin, etoposide, cisplatin, or 4-hydroperoxycyclophosphamide (4OOH-CPA, a preactivated analog of cyclophosphamide). All four anticancer drugs induced a significant increase in DNA damage in C18-4 cells, as assessed by gamma-H2AX immunofluorescence. Interestingly, the gamma-H2AX signal was localized to telomeres after treatment with bleomycin, cisplatin, and 4OOH-CPA, but not etoposide. Mean telomere lengths, the intensity of the telomere fluorescence in situ hybridization signal, telomerase activity, and the expression of the telomerase enzyme mRNA components, Tert and Terc, were reduced by exposure to cisplatin and 4OOH-CPA, but not by bleomycin or etoposide. Thus, although all four anticancer drugs induced DNA damage in this spermatogonial cell line, telomeres were not specifically affected by etoposide and only the two alkylating agents, cisplatin and 4OOH-CPA, induced telomere dysfunction. This telomere dysfunction may contribute to infertility and developmental defects in the offspring.", "corpus_id": 205360703, "score": 1 }, { "doc_id": "205809137", "title": "Interstitial telomeric sequences are not preferentially involved in the chromosome damage induced by the methylating compound streptozotocin in chinese hamster cells", "abstract": "The effect of the methylating compound streptozotocin (STZ) on interstitial telomeric sequences (ITSs) was investigated in Chinese hamster ovary (CHO) cells by using peptide nucleic acid‐fluorescence in situ hybridization with a pantelomeric probe. Cells were exposed to increasing concentrations of STZ, and chromosomal aberrations were analyzed at the first mitosis after treatment. The frequency of chromosomal aberrations directly involving ITSs increased in STZ‐treated cells by a factor of 2.6 (2 mM) and 3.6 (4 mM) when compared with the frequency of these aberrations in control cells (P < 0.05). However, no significant differences were found between control and exposed cells in the percentage of aberrations directly involving ITSs, demonstrating that these repeat regions were not preferentially involved in the chromosome damage induced by STZ. In addition, STZ did not alter telomerase activity, suggesting that this enzyme may not be involved in the induction of chromosomal aberrations by this compound. Environ. Mol. Mutagen., 2013. © 2012 Wiley Periodicals, Inc.", "corpus_id": 205809137, "score": 0 }, { "doc_id": "34591554", "title": "The methylating agent streptozotocin induces persistent telomere dysfunction in mammalian cells.", "abstract": "We analyzed chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the methylating agent and antineoplastic/diabetogenic drug streptozotocin (STZ), to test whether it induces long-term telomere instability (by chromosome end loss and/or telomere dysfunction). Rat cells (ADIPO-P2 cell line, derived from Sprague-Dawley rat adipose cells) were treated with a single concentration of STZ (2mM). Chromosomal aberrations were analyzed 18h, 10 days, and 15 days after treatment, using PNA-FISH with a pan-telomeric probe [Cy3-(CCCTAA)3] to detect (TTAGGG)n repeats. Cytogenetic analysis revealed a higher frequency of chromosomal aberrations in STZ-exposed cultures vs. untreated cultures at each time point analyzed. The yield of induced aberrations was very similar at each time point. Induction of aberrations not involving telomere dysfunction was only observed 18h and 15 days after treatment, whereas induction of telomere dysfunction-related aberrations by STZ (mainly in the form of telomere FISH signal loss and duplications, most of them chromatid-type aberrations) was observed at each time point. Our results show that STZ induces persistent telomere instability in mammalian cells, cytogenetically manifested as telomere dysfunction-related chromosomal aberrations. Neither telomere length nor telomerase activity is related to the telomere dysfunction.", "corpus_id": 34591554, "score": 0 }, { "doc_id": "1353660", "title": "Cell-killing by paclitaxel in a metastatic murine melanoma cell line is mediated by extensive telomere erosion with no decrease in telomerase activity.", "abstract": "The purpose of this study was to investigate and compare the effects of paclitaxel and its water-soluble conjugates (sodium-pentetic acid-paclitaxel; polyethylene glycol-paclitaxel, and poly[L-glutamic acid]-paclitaxel) on chromosome morphology and induction of apoptosis in a metastatic murine melanoma cell line (K1735 clone X-21). For this, murine melanoma cells were treated continuously for 72 h with three concentrations (1.2 microM, 2.4 microM, and 4.8 microM) of each of paclitaxel, and conjugates. Another set of cells were pulse-treated at 2.4 microM, 4.8 microM and 9.6 microM concentrations of each of these drugs for 4 h and the recovered cells were examined after 72 h. Control cultures received only the solvents (dimethyl sulfoxide or water). Our results showed a significant increase in the frequencies of telomeric associations, chromosome aberrations, polyploidization, distorted and disintegrated chromosome morphology, and reduced telomeric signal intensity by fluorescence in situ hybridization, in treated cultures as compared to the controls. However, we detected no change in telomerase activity. In addition, the majority of interphase nuclei in treated cells showed apoptotic bodies, with chromatin condensation. These in vitro results suggest that cell death induced by paclitaxel and its water-soluble conjugates is due to the loss of telomeric repeats, as shown by reduced signal flourescence and increased telomeric associations.", "corpus_id": 1353660, "score": 0 }, { "doc_id": "22088871", "title": "Cell death in paclitaxel-dependent chinese hamster ovary cells is initiated by the loss of telomeric DNA repeats.", "abstract": "We have reported earlier that cell death in a metastatic murine melanoma cell line induced by paclitaxel and its water-soluble conjugates is mediated through the extensive erosion of telomeric repeats. The purpose of this study was to investigate if loss of telomeric repeats was also involved in cell death of Tax-18 and Tax-2-4, two paclitaxel-requiring mutant Chinese hamster ovary (CHO) cell lines. Tax-18 and Tax-2-4 cells were grown in paclitaxel-free culture medium for 24, 48, 72, and 96 h at 37 degrees C and then harvested for cytological preparations. Control cultures of both cell lines were grown in paclitaxel-supplemented medium and harvested simultaneously. We found that: 1) the frequency of telomeric associations in metaphase preparations was increased with the duration of paclitaxel-depleted culture; 2) Tax-18 cells showed a higher incidence (33.0%) of endoreduplicated metaphases at 24 h of paclitaxel-depleted culture than did Tax-2-4 cells, in which endoreduplicated metaphases were rare; 3) the frequency of polyploid cells was increased after 48, 72, and 96 h of paclitaxel-depleted culture for Tax-18 relative to that for Tax-2-4 cells; 4) both cell lines showed reductions in telomeric signals at chromosomal termini, but not in the interphase nuclei; and 5) both cell lines had shorter terminal telomeric restriction fragments after culture in paclitaxel-depleted medium. These results support our earlier observations and indicate that reduction of telomeric repeats is involved in G2/M cell arrest (endoreduplication) followed by severe DNA fragmentation, and then cell death of two CHO mutant cell lines that require paclitaxel for cell division.", "corpus_id": 22088871, "score": 0 }, { "doc_id": "6001925", "title": "Simultaneous targeting of telomeres and telomerase as a cancer therapeutic approach.", "abstract": "Telomeres, which are important for maintaining chromosome integrity and functions, shorten with each cell division. Telomerase, responsible for telomere synthesis, is expressed in approximately 90% of human tumor cells but seldom in normal somatic cells. This study evaluated the hypothesis that simultaneous shortening of telomeres and inhibition of telomerase results in synergistic and tumor-selective cytotoxicity. In telomerase-positive human pharynx FaDu tumor cells, paclitaxel caused telomere erosion (first detected at 1 h) and apoptosis. Expression of antisense to the RNA component of human telomerase (hTR) inhibited telomerase activity, shortened telomere length, reduced cell growth rate, and resulted in a significant higher sensitivity to paclitaxel. Another telomerase inhibitor, 3'-azido-3'-deoxythymidine (AZT), at a concentration that produced little or no cell detachment or apoptosis, inhibited the telomerase activity and enhanced the paclitaxel-induced cell detachment and apoptosis. AZT also enhanced the activity of paclitaxel in mice bearing well-established s.c. FaDu xenograft tumors (i.e., reduced residual tumor size, enhanced apoptotic cell fraction, and prolonged survival time), without enhancing host toxicity. In contrast, AZT did not enhance the paclitaxel activity in the telomerase-negative osteosarcoma Saos-2 cells nor in FaDu cells where telomerase was already suppressed by antisense hTR, confirming that the AZT effect in parent FaDu cells is mediated through telomerase inhibition. These results demonstrate that combined use of agents targeting both telomere and telomerase yielded synergistic activity selective for tumors that depend on telomerase for telomere maintenance.", "corpus_id": 6001925, "score": 1 }, { "doc_id": "10343398", "title": "Correlation of chemosensitivity to anticancer drugs and telomere length, telomerase activity and telomerase RNA expression in human ovarian cancer cells.", "abstract": "BACKGROUND\nWe examined the correlations among telomere length (TRF), telomerase activity (TA) and the steady-state level of telomerase RNA expression (hTR) of human ovarian cancer cells with different phenotypes and investigated whether the cells' sensitivities to anticancer agents correlate with TRF, TA or hTR.\n\n\nMATERIALS AND METHODS\nThe TRF, TA and hTR of 11 human ovarian cancer cell lines and 2 cisplatin-resistant ovarian cancer cell lines were determined by genomic Southern blotting, a telomeric repeat amplification protocol and reverse transcription-polymerase chain reaction. The chemosensitivities of the cell lines to cisplatin (CDDP), paclitaxel (TAX), etoposide (ETO), CPT-11 (CPT), cyclophosphamide (CYC), ifomide (IFO) and doxorubicin (DOX) were decided as IC50 values by calorimetric assay.\n\n\nRESULTS\nAll 11 cell lines presented shorter mean TRFs (5.0 kb) than normal control tissue (8.0 kb); 10 cell lines presented a 3.2-fold higher mean TA than the control and all 11 cell lines expressed hTR. Quantitatively, the steady-state levels of hTR correlated with the TRF (p < 0.05). Significant positive correlations between hTR and CDDP sensitivities (at 24 hours of exposure), ETO (72 hours), CPT (48 hours) and CYC/IFO (24-72 hours) were observed. The same was true for TRF and the CDDP sensitivities (at 24 hours). TAX and DOX did not have any impact on these factors. The TRF, TA and hTR values in the two CDDP-resistant cell lines were generally reduced, compared to their parent cell lines.\n\n\nCONCLUSIONS\nAlkylating agents (CDDP, CYC and IFO) and topoisomerase inhibitors (ETO, CPT) may have the potential to influence the structural alteration of hTRs and telomeres and thus, the down-regulation of the TA in ovarian cancer cells.", "corpus_id": 10343398, "score": 1 }, { "doc_id": "20474929", "title": "Synergy Between 3′Azido-3′deoxythymidine and Paclitaxel in Human Pharynx FaDu Cells", "abstract": "AbstractPurpose. We recently demonstrated simultaneous targeting of telomere and telomerase as a novel cancer therapeutic approach, and that telomerase inhibitors such as 3′azido-3′deoxythymidine (AZT) significantly enhanced the antitumor activity of paclitaxel, which causes telomere erosion, in telomerase-positive human pharynx FaDu tumors in vitro and in vivo (1). The present study evaluated the synergy between AZT and paclitaxel to identify optimal combinations for future clinical evaluation.\nMethods. FaDu cells were incubated with or without AZT for 24 h and then treated with AZT with or without paclitaxel for an additional 48 h. Under these conditions, single agent paclitaxel produced a 60% maximum reduction of cell number (IC50 was 7.3 nM), and single agent AZT produced a 97% reduction (IC50 was 5.6 μM). Synergy was evaluated using fixed-concentration and fixed-ratio methods, and data were analyzed by the combination index method.\nResults. The results indicate a concentration-dependent synergy between the two drugs; the synergy was higher for combinations containing greater paclitaxel-to-AZT concentration ratios and increased with the level of drug effect. For example, in combinations containing 1 μM AZT, synergy was 1.3-fold at the 20% effect level and 3.1-fold at the 60% effect level. Because the major antitumor activity, determined by comparing the posttreatment cell number to the pretreatment cell number, was antiproliferation at the 20% effect level and cell kill at the 60% effect level, our results suggest that AZT mainly enhances the cell kill effect of paclitaxel.\nConclusion. In summary, the present study demonstrates a synergistic interaction between paclitaxel and AZT and supports a combination using a low and nontoxic AZT dose in combination with a therapeutically active dose of paclitaxel.", "corpus_id": 20474929, "score": 0 }, { "doc_id": "42416570", "title": "Telomere loss in cells treated with cisplatin.", "abstract": "Telomeres play an important role in the immortalization of proliferating cells. The long tandem repeats of 5'-TTAGGG-3' sequences in human telomeres are potential targets for the anticancer drug cisplatin, which forms mainly intrastrand d(GpG) and d(ApG) cross-links on DNA. The present study reveals that telomeres in cisplatin-treated HeLa cells are markedly shortened and degraded. A dose that killed 61% of the cells but allowed one round of cell division resulted in shortened telomeres before the induction of apoptosis. Higher doses of cisplatin halted cell cycle progression during the first S phase and triggered apoptosis followed by degradation of telomere repeats. A model in which both cell division with incomplete replication and induction of apoptosis by cisplatin could occur was devised to explain the drug-induced telomere loss.", "corpus_id": 42416570, "score": 0 }, { "doc_id": "30718116", "title": "Inhibition of telomerase activity in endometrial cancer cells by selenium-cisplatin conjugate despite suppression of its DNA-damaging activity by sodium ascorbate.", "abstract": "Telomerase activation can be considered as a critical step in cell immortalization. The enzyme elongates or maintains telomere length by adding to its end tandem TTAGGG repeats by using its endogenous RNA template. Telomerase is not detectable in most somatic cells but is upregulated in germ line cells and in 85-90% of human cancers, which suggests important role of telomerase in neoplastic transformation. Consequently, telomerase has been proposed as a potentially highly selective target for the development of antiproliferative agents. Platinum complexes are widely administrated in cancer therapy. A conjugate of selenite with diammineplatinum [(NH(3))(2)Pt(SeO(3))(2)] is a novel potential anticancer drug. Using alkaline single cell gel electrophoresis (comet assay), we showed that the drug at 5-30 microM induced concentration-dependent damage to DNA of endometrial cancer cells derived from tumor samples. Sodium ascorbate at 10 and 50 microM reduced the extent of the DNA damage evoked by the drug. (NH(3))(2)Pt(SeO(3)) reduced telomerase activity in the cells in a concentration-dependent manner as measured by using the telomere repeat amplification protocol (TRAP) assay. This effect was independent of sodium ascorbate. Therefore, mutagenic effects of the conjugate can be reduced by well-recognized antimutagen, sodium ascorbate, but it can still retain ability to affect neoplastic transformation. The results obtained indicate that (NH(3))(2)Pt(SeO(3)) may specifically inhibit telomerase activity in endometrial cancer cells.", "corpus_id": 30718116, "score": 0 }, { "doc_id": "28627808", "title": "Telomerase inhibition and telomere loss in BEL-7404 human hepatoma cells treated with doxorubicin.", "abstract": "AIM\nTo study the effects of doxorubicin on telomerase activity and telomere length in hepatocellular carcinoma.\n\n\nMETHODS\nTelomerase activity was assayed with a non-radioisotopic quantitative telomerase repeat amplification protocol-based method. The effect of doxorubicin (DOX) on the growth of BEL-7404 human hepatoma cells was determined by microculture tetrazolium assay. Mean telomere length (terminal restriction fragment) was detected by Southern blot method. The expression of telomerase subunits genes was investigated by RT-PCR. Cell apoptosis and cell cycle distribution were evaluated by flow cytometry.\n\n\nRESULTS\nTelomerase activity was inhibited in a dose and time-dependent manner in BEL-7404 human hepatoma cells treated with DOX for 24, 48 or 72 h in concentrations from 0.156 to 2.5 microM which was correlated with the inhibition of cell growth. No changes were found in the mRNA expression of three telomerase subunits (hTERT, hTR and TP1) after drug exposure for 72 h with indicated concentrations. The cells treated with DOX showed shortened mean telomere length and accumulated at the G(2)/M phase. However, there was almost no effects on cell apoptosis by DOX.\n\n\nCONCLUSION\nThe telomerase inhibition and the telomere shortening by DOX may contribute to its efficiency in the treatment in hepatocellular carcinoma.", "corpus_id": 28627808, "score": 1 }, { "doc_id": "23423408", "title": "Down-regulation of telomerase activity by anticancer drugs in human ovarian cancer cells", "abstract": "Maintenance of telomere length is crucial for survival of cells. Telo-merase, an enzyme that is responsible for elongation of shortened telomeres, is active in human germ cells as well as most tumor tissues and experimentally immortalized cells. In contrast, most mature somatic cells in human tissues express undetectable or low telomerase activity, implying the existence of a stringent and negative regulatory mechanism. In this study we report the effects of anticancer drugs on telomerase activity in human cancer cells. In assaying for telomerase activity, we basically followed the original TRAP assay system, but with some modifications. A down-regulation of telomerase activity was found when cells of a human ovarian cancer cell line, A2780, were treated with;cis-diamminedichloroplatinum(II) (CDDP; cisplatin). However, down-regulation of telomerase activity was not found in cells of a cisplatin-resistant cell line, A2780CP, treated with cisplatin. On the other hand, telomerase activity in both the cell lines A2780 and A2780CP was reduced when A2780 or A2780CP was treated with adriamycin, an anthracycline antibiotic having a broad spectrum of antineoplastic activity. The different effects on the telomerase activity of the two types of anticancer drugs may be due the distinct chemical functions of these drugs. The present results may indicate a positive relationship between anticancer effects and down-regulation of telomerase activity by anticancer drugs.", "corpus_id": 23423408, "score": 1 }, { "doc_id": "18960547", "title": "Change of the Expression of Human Telomerase Reverse Transcriptase mRNA and Human Telomerase RNA after Cisplatin and 5-Fluorouracil Exposure in Head and Neck Squamous Cell Carcinoma Cell Lines", "abstract": "Telomerase activity appears to be associated with cell immortalization and malignant progression. Understanding how telomerase activity is regulated in vivo is important not only for understanding the molecular biology of telomerase but also for the potential clinical application of anticancer drugs. This study evaluated telomerase activity and quantified the expression of human telomerase reverse transcriptase (hTERT) mRNA and human telomerase RNA (hTR) using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) method before and after the exposure of cisplatin and 5-fluorouracil (5-FU) in two head and neck squamous cell carcinoma (HNSCC) cell lines. Two human HNSCC cell lines (PNUH-12 and SNU-899) were studied. Cell cytotoxicity, the change of telomerase activity, and hTERT mRNA and hTR expression by 5-FU and cisplatin exposure were assessed by MTT assay, TRAP assay, and real-time RT-PCR, respectively. In two cell lines, after cisplatin exposure, the telomerase activity and hTERT mRNA expression decreased, but hTR expression increased according to the concentration of drug. However, in both cell lines, the telomerase activity and hTR did not show any significant change after 5-FU treatment, but the expression of hTERT mRNA decreased. These results suggest that there may be other important regulating mechanism except hTERT mRNA as the regulation factor of telomerase activity in HNSCC cell lines.", "corpus_id": 18960547, "score": 1 }, { "doc_id": "23456396", "title": "Adriamycin-induced Senescence in Breast Tumor Cells Involves Functional p53 and Telomere Dysfunction*", "abstract": "Direct experimental evidence implicates telomere erosion as a primary cause of cellular senescence. Using a well characterized model system for breast cancer, we define here the molecular and cellular consequences of adriamycin treatment in breast tumor cells. Cells acutely exposed to adriamycin exhibited an increase in p53 activity, a decline in telomerase activity, and a dramatic increase in β-galactosidase, a marker of senescence. Inactivation of wild-type p53 resulted in a transition of the cellular response to adriamycin treatment from replicative senescence to delayed apoptosis, demonstrating that p53 plays an integral role in the fate of breast tumor cells treated with DNA-damaging agents. Stable introduction of hTERT, the catalytic protein component of telomerase, into MCF-7 cells caused an increase in telomerase activity and telomere length. Treatment of MCF-7-hTERT cells with adriamycin produced an identical senescence response as controls without signs of telomere shortening, indicating that the senescence after treatment is telomere length-independent. However, we found that exposure to adriamycin resulted in an overrepresentation of cytogenetic changes involving telomeres, showing an altered telomere state induced by adriamycin is probably a causal factor leading to the senescence phenotype. To our knowledge, these data are the first to demonstrate that the mechanism of adriamycin-induced senescence is dependent on both functional p53 and telomere dysfunction rather than overall shortening.", "corpus_id": 23456396, "score": 0 }, { "doc_id": "45689967", "title": "Telomerase activity and telomere lengths in various cell lines: changes of telomerase activity can be another method for chemosensitivity evaluation.", "abstract": "For the cancer cells which have overcome the second mitotic clock (M2), activated telomerase is essential and used as another marker of immortality. Many trials had been initiated to target telomerase, which is known to be specific to tumors. To determine the best in vitro cell system for testing the efficacy of telomerase inhibitors, we evaluated the telomerase activity of various cancer cell lines and measured their telomere lengths. We also treated some cancer cell lines with adriamycin and measured the changes of telomerase activity. Telomerase activity was evaluated in various cell lines with the TRAP (telomeric repeat amplification protocol) assay. Telomerase activity was calculated and translated into arbitrary units by computer-assisted densitometry with the control of telomerase activity in the 293 control cell line. Also, terminal restriction fragment lengths were measured using Southern blotting. We also measured telomerase activity and telomere lengths in 11 benign breast tumor tissues and 19 paired stomach cancer and normal tissues. Cancer cell lines treated with adriamycin we evaluated for changes of telomerase activity and the cell proliferation by MTT assay and dye exclusion test. Telomerase activity of cell lines was 95.3 24.1 unit with a range of 27.6-129.6 unit, while the telomere lengths of those cell lines were variable from 5.0 to 10.4 kbp with a median of 6 kbp. In 11 cancer cell lines which were not yet firmly established, we could not detect any telomerase activity. Low telomerase activity was detected in only 2 benign tumor tissues of breast with a median telomere length of 8.8 (7-10.5) kbp. Among paired 19 gastric cancer and normal tissues, only 7 cancer tissues showed weak telomerase activity. After adriamycin treatment, telomerase activity in YCC-S-1, YCC-S-3, MCF-7 and MCF-7/ADR was decreased in accordance with the changes of the cell numbers. Telomerase is specific to cancer tissues and is expressed differently from organ to organ. Telomerase activity by TRAP assay could be used as a chemosensitivity assay.", "corpus_id": 45689967, "score": 0 }, { "doc_id": "25650992", "title": "The Role of Telomeres in Etoposide Induced Tumour Cell Death", "abstract": "Etoposide, a topoisomerase II poison is used in the treatment of a number of solidtumours. Contradictory data exist on the role of the telomere/telomerase complex inetoposide induced apoptosis. Therefore we examined the effects of etoposidetreatment in the neuroblastoma cell line SHSY5Y, with very short telomeres and theacute lymphoblastic T cell line 1301, which displays extremely long telomeres. Bothshort-term and continuous exposure to the drug was examined. Etoposide inducedwidespread DNA damage followed by DNA damage foci formation and ultimatelygrowth arrest and apoptosis in a concentration-dependent manner. However, length oftelomeres and of single stranded telomeric G rich overhangs did not changesignificantly under the treatments in any cell line. There was no significant inductionof single-strand breaks in the G- rich strand of telomeres. Telomerase activity wastransiently upregulated under low concentrations of etoposide, while highconcentrations resulted in decreased telomerase activity only after onset of apoptosis.Telomerase overexpression protected against etoposide induced apoptosis infibroblasts. The data suggest that telomeres are not major signal transducers towardsgrowth arrest or apoptosis after etoposide treatment. However, upregulation oftelomerase might be part of an attempted adaptative response, which protects cells bya mechanism that might be independent of telomere length maintenance.", "corpus_id": 25650992, "score": 0 }, { "doc_id": "19869753", "title": "Rapid upregulation of telomerase activity in human leukemia HL-60 cells treated with clinical doses of the DNA-damaging drug etoposide", "abstract": "The enzyme telomerase is implicated in cellular resistance to apoptosis, but the mechanism for this resistance remains to be elucidated. The ability of telomerase to synthesize new DNA at telomeres suggests that this enzyme might function in the repair of double-stranded DNA breaks. To distinguish the effects of double-stranded DNA break damage and apoptosis on human telomerase activity, we treated the HL-60 human hematopoietic cancer cell line with clinical doses of the chemotherapeutic drug etoposide (0.5 to 5 μM), which allowed us to distinguish between events associated with DNA damage-induced cell cycle arrest, and events associated with apoptosis. Large (three- to seven-fold) upregulation of telomerase activity occurred soon after etoposide treatment (3 h) in S/G2/M-arresting populations; this upregulation was abolished at onset of apoptotic cell death. No upregulation of telomerase activity was observed in cells treated with a larger dose of etoposide (5 μM) that caused cells to undergo rapid apoptosis without intervening cell cycle arrests. These observations are consistent with a possible role for telomerase upregulation during the DNA damage response.", "corpus_id": 19869753, "score": 0 }, { "doc_id": "533727", "title": "DNA damage transiently increases TRF2 mRNA expression and telomerase activity", "abstract": "Telomerase activity transiently increases when HL60 cells are treated with the topoisomerase II inhibitor etoposide. A quantitative assessment revealed that telomerase is activated by etoposide treatment in a number of cell lines and that the increase is reversible after withdrawal of etoposide from the cell culture. Telomerase activation correlated with the occurrence of DNA damage but not with cell cycle arrest. We did not detect any transcriptional upregulation of hTERT mRNA, suggesting a post-transcriptional mechanism of telomerase activation. Furthermore, the mRNA expression of the telomere binding protein TRF2 was upregulated early and reversibly after etoposide treatment. TRF1 mRNA expression levels were unchanged after DNA damage, but increased when the cells accumulated in the G2/M phase. The data show that the telosome reacts after DNA damage by upregulating telomerase activity and TRF2 expression in malignant cells. It has previously been shown that overexpression of TRF2 can repress senescence signals arising from critically shortened telomeres. We show here that TRF2 is upregulated by undirected DNA damage that also affects the telomeric DNA. These data suggest that upregulation of telomerase activity and TRF2 expression might act as antiapoptotic mechanisms in the DNA-damage response of malignant cells.", "corpus_id": 533727, "score": 0 }, { "doc_id": "23752629", "title": "Inhibition of telomerase activity by PKC inhibitors in human nasopharyngeal cancer cells in culture.", "abstract": "Telomerase is a specialized ribonucleoprotein polymerase that adds hexanucleotides (TTAGGG) onto human chromosomal ends. The expression of telomerase activity has been associated with cell immortalization and the malignant phenotype in most cancers. How the telomerase activity is regulated in cancer cells is presently not known. In this work, the effects of cell cycle blockers, DNA damaging agents, TopII inhibitors and proteins kinase inhibitors on the telomerase activity were examined in cultured nasopharyngeal carcinoma cells NPC-076. Agents which interfere with tubulin assembly (Taxol and vinblastine) and agents which arrest cells at S phase (methotrexate and 5-fluorouracil) did not inhibit telomerase activity of treated cells. Agents which damage DNA (cisplatin, methyl methanesulfonate, and UV radiation) and TopII inhibitors (etoposide and daunorubicin) also did not inhibit telomerase activity of treated cells. Among the protein kinase inhibitors examined, no significant inhibition of telomerase activity was observed with cells treated with quercetin, H-89, or herbimycin A. On the other hand, two protein kinase C (PKC) inhibitors (bisindolylmaleimide I and H-7) were found to produce a big inhibition of telomerase activity in treated cells. Staurosporine produced a moderate inhibition, and sphingosine had a small inhibitory effect. The inhibition of telomerase activity by PKC inhibitors appears to be specific since the treated cells were mostly viable (i.e., greater than 75%) and still retained significant levels of protein synthesis capability. These results implicate that protein kinase C is involved in the regulation of telomerase activity in vivo.", "corpus_id": 23752629, "score": 0 }, { "doc_id": "7845594", "title": "The aging effect of chemotherapy on cultured human mesenchymal stem cells.", "abstract": "Various agents, including chemotherapeutic drugs, can induce cell senescence. However, the mechanisms involved in the aging pathway, particularly the stress that chemotherapy imposes on telomeres, are still undefined. To address these issues, human mesenchymal stem cells (MSCs) were assessed as target cells to investigate the initiation of the aging process by chemotherapy. The MSCs were obtained from bone marrow (BM) cells from normal adults and grown in the presence of platelet lysates. Cultured MSCs were identified for immunophenotype, and for growth and differentiation properties. The MSCs were exposed to 10 nM doxorubicin and 500 ng/mL etoposide, sublethal doses that induce DNA double-stranded breaks. Telomere length (TL) was assessed by flow-fluorescence in situ hybridization and Southern blotting. Initial TL shortening was detectable in MSCs at 5 days after drug exposure, with progressive reduction compared with untreated cells at 7, 14, 21, and 28 days in culture. After a single exposure, MSCs were unable to regain the lost telomere sequences for up to 28 days in culture. The ATM phosphorylation was documented early after drug exposure, while no telomerase activation was observed. Chemotherapy-induced TL shortening was associated with reduced clonogenic activity in vitro and accelerated adipose differentiation. Analogous behavior in the differentiation pattern was observed in naturally aged MSCs. These results indicate that cultured MSCs represent a useful cellular model to investigate novel drugs that may favor or, conversely, might prevent TL loss in human stem cells. The TL shortening is a permanent signature of previous chemotherapy-mediated DNA damage, and predicts impaired proliferative and differentiation potential.", "corpus_id": 7845594, "score": 0 }, { "doc_id": "21940318", "title": "The effects of chemotherapy with bleomycin, etoposide, and cis‐platinum on telomeres in rat male germ cells", "abstract": "Co‐administration of bleomycin, etoposide, and cis‐platinum (BEP) has increased the 5‐year survival rate of testis cancer patients to over 90%; however, this treatment induces chemotoxic effects on male germ cells. Treatment of male rats with BEP, using a similar schedule to that used in man, affects reproductive organ weights and sperm count, motility, and DNA integrity, as well as pup survival rates. Telomeres, specialized structures at the termini of chromosomes, play an important role in the maintenance of genetic stability. In previous studies, we demonstrated, using a spermatogonial cell line, that cis‐platinum and bleomycin damage telomeres and that cis‐platinum also inhibits telomerase activity. Our objective here was to test the hypothesis that in vivo exposure to the BEP regimen used to treat testis cancer targets telomeres in the male germ line. Adult male Brown Norway rats received chronic treatment with a BEP regimen. DNA double strand breaks were increased significantly in zygotene germ cells, as assessed by γ‐H2AX immunofluorescence. Interestingly, treatment with this BEP regimen increased γ‐H2AX foci in the telomere region of zygotene spermatocytes, but not in other germ cell types, such as pachytene cells, round spermatids, or elongating spermatids. Mean telomere lengths were reduced in zygotene, pachytene, round spermatid, elongating spermatid and cauda epididymal spermatozoa compared with the saline control group. Thus, telomere lengths did not recover during germ cell development. These studies demonstrate that BEP treatment is associated with an effect on telomeres.", "corpus_id": 21940318, "score": 0 }, { "doc_id": "5800590", "title": "Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortalized human cell lines", "abstract": "The ribonucleoprotein telomerase, a specialized cellular reverse transcriptase, synthesizes one strand of the telomeric DNA of eukaryotes. We analyzed telomere maintenance in two immortalized human cell lines: the B-cell line JY616 and the T-cell line Jurkat E6-1, and determined whether known inhibitors of retroviral reverse transcriptases could perturb telomere lengths and growth rates of these cells in culture. Dideoxyguanosine (ddG) caused reproducible, progressive telomere shortening over several weeks of passaging, after which the telomeres stabilized and remained short. However, the prolonged passaging in ddG caused no observable effects on cell population doubling rates or morphology. Azidothymidine (AZT) caused progressive telomere shortening in some but not all T- and B-cell cultures. Telomerase activity was present in both cell lines and was inhibited in vitro by ddGTP and AZT triphosphate. Prolonged passaging in arabinofuranyl-guanosine, dideoxyinosine (ddI), dideoxyadenosine (ddA), didehydrothymidine (d4T), or phosphonoformic acid (foscarnet) did not cause reproducible telomere shortening or decreased cell growth rates or viabilities. Combining AZT, foscarnet, and/or arabinofuranyl-guanosine with ddG did not significantly augment the effects of ddG alone. Strikingly, with or without inhibitors, telomere lengths were often highly unstable in both cell lines and varied between parallel cell cultures. We propose that telomere lengths in these T- and B-cell lines are determined by both telomerase and telomerase-independent mechanisms.", "corpus_id": 5800590, "score": 0 }, { "doc_id": "25420580", "title": "Irreversible telomere shortening by 3'-azido-2',3'-dideoxythymidine (AZT) treatment.", "abstract": "Telomeres shorten by 30 to 50 bp with each cell division. Germ line, tumor and stem cells overcome progressive shortening by elongating their telomeres with telomerase. Previously we demonstrated that 3'-azido-2',3'-dideoxythymidine (AZT), incorporates into telomeric DNA. To determine if telomeric AZT incorporation was a telomerase mediated phenomenon, we subjected tumor cells to long-term AZT exposure. Here we report the shortening of the telomeric sequences of HeLa cells cultured with 800 microM AZT for 15 passages. Southern blots of HeLa DNA cultured with AZT and digested with SAU 3AI, Alu I, and Rsa I revealed a progressive shortening of the telomeric repeats when probed with a human biotinylated telomeric probe. The shortened telomeric repeats did not elongate after culturing without AZT for an additional 25 passages. No evidence of senescence could be detected.", "corpus_id": 25420580, "score": 0 }, { "doc_id": "31660270", "title": "Inhibition of telomerase activity and cell proliferation by a reverse transcriptase inhibitor in gynaecological cancer cell lines.", "abstract": "Telomerase is a ribonucleoprotein which has a RNA template to bind and extend telomere ends, so prolonging the life of tumour cells. The aim of this study was to determine whether transcriptase function of telomerase could be inhibited by the reverse transcriptase inhibitors (RTI); azydothymidine (AZT), dideoxyinosine (ddI) and AZT-5' triphosphate (AZT-TP). We examined their effects on the proliferation of cancer cells and the antitumour effects of cisplatin in vitro. The three agents did not cause major changes in telomerase activity or telomere length in MCAS cells. However, in HEC-1 cells changes in telomerase activity and telomere length were observed that were dependent on the RTI concentration and duration of exposure. ddI and AZT-TP reduced telomerase activity and shortened the length of the telomere. In the presence of RTI, the antitumour effects of cisplatin were enhanced. This was particularly evident in HEC-1 cells where there was a marked reduction in cell proliferation, appearance of morphological changes and senescent-like cells in the presence of ddI or AZT-TP. In MCAS cells, TP53 expression was increased by ddI and AZT-TP, while p21 expression was unchanged. In HEC-1 cells the expression of both TP53 and P21 was increased by ddI. Continuous administration of RTI enhanced the cell growth inhibition of cisplatin. RTI also inhibited the proliferation of some cells.", "corpus_id": 31660270, "score": 0 }, { "doc_id": "11190565", "title": "Chronic In Vitro Exposure to 3′-Azido-2′, 3′-Dideoxythymidine Induces Senescence and Apoptosis and Reduces Tumorigenicity of Metastatic Mouse Mammary Tumor Cells", "abstract": "Normal cells in culture divide a certain amount of times and undergo a process termed replicative senescence. Telomere loss is thought to control entry into senescence. Activation of telomerase in tumors bypasses cellular senescence and is thus a requirement for tumor progression. We reported previously the preferential incorporation of 3′-azido-2′, 3′-dideoxythymidine (AZT) in telomeric sequences of immortalized cells in culture. In this work, we have investigated the effects of chronic in vitro AZT exposure on F3II mouse mammary carcinoma cells. We demonstrate, for the first time, that AZT-treated tumor cells have a reduced tumorigenicity in syngeneic BALB/c mice. Tumor incidence was reduced and survival was prolonged in animals inoculated with AZT-treated cells when comparing with control counterparts. The number and size of spontaneous metastases were also decreased in animals inoculated with AZT-treated cells. In addition, we present evidence of morphological and biochemical signs of senescence, as shown by the staining for senescence associated ß-galactosidase activity, and induction of programmed cell death, as demonstrated by an increase of caspase-3 activity, in tumor cells exposed to AZT. These data indicate that chronic exposure of mammary carcinoma cells to AZT may be sufficient to induce a senescent phenotype and to reduce tumorigenicity.", "corpus_id": 11190565, "score": 0 }, { "doc_id": "28238897", "title": "Azidothymidine Induces Apoptosis and Inhibits Cell Growth and Telomerase Activity of Human Parathyroid Cancer Cells in Culture", "abstract": "Telomerase activity has been correlated to parathyroid carcinoma. Because its role in acquisition of a malignant phenotype by parathyroid cells is unclear, we treated telomerase‐positive cultured human parathyroid cancer cells with the telomerase inhibitor AZT, evaluating cell telomerase activity, cytotoxic effects, growth, and morphological changes. In vitro exposure of these cells to AZT correlated with inhibition of cell proliferation.", "corpus_id": 28238897, "score": 0 }, { "doc_id": "28617939", "title": "Synergic effect of 3′-azido-3′-deoxythymidine and arsenic trioxide in suppressing hepatoma cells", "abstract": "The aim of this study was to investigate the synergic antitumor effects of arsenic trioxide (As2O3) and 3′-azido-3′-deoxythymidine (AZT) on hepatoma cells and explore the possible molecular basis of these effects. These results showed that AZT enhanced the inhibitory effect of As2O3 on HepG2 and SMMC-7721 cell growth. The IC50 of As2O3 in combination with AZT was lower than that of As2O3 alone. A concentration-dependent synergic effect of As2O3 and AZT (CI <1) was observed in all the tested combinations of these compounds. These results also showed that the combination of As2O3 and AZT dramatically and significantly increased the number of apoptotic cells in HepG2 and SMMC-7721 cells. Studies in vivo showed that the combination of As2O3 and AZT was statistically superior to either As2O3 or AZT alone in the treatment of tumor-bearing mice. As2O3 (1 mg/kg) containing AZT (50 mg/kg) inhibits proliferation of implanted hepatoma 22 by 56.35%. These results suggest that treating hepatoma with a combinination of As2O3 and AZT offers the advantages of reduced toxic side effects and improved therapeutic efficacy. To understand the mechanism through which As2O3 and AZT suppress tumors, we studied the effects of these compounds, both separately, and in combination, on telomerase and caspase-3 activity. The results showed that the growth inhibitory and apoptotic effects of As2O3 and AZT on human hepatoma cells could be related to the inhibition of telomerase and the activation of caspase 3.", "corpus_id": 28617939, "score": 0 }, { "doc_id": "43657352", "title": "AZT exerts its antitumoral effect by telomeric and non-telomeric effects in a mammary adenocarcinoma model.", "abstract": "Limitless replicative potential is one of the hallmarks of cancer that is mainly due to the activity of telomerase. This holoenzyme maintains telomere length, adding TTAGGG repetitions at the end of chromosomes in each cell division. In addition to this function, there are extratelomeric roles of telomerase that are involved in cancer promoting events. It has been demonstrated that TERT, the catalytic component of telomerase, acts as a transcriptional modulator in many signaling pathways. Taking into account this evidence and our experience on the study of azidothymidine (AZT) as an inhibitor of telomerase activity, the present study analyzes the effect of AZT on some telomeric and extratelomeric activities. To carry out the present study, we evaluated the transcription of genes that are modulated by the Wnt/β-catenin pathway, such as c-Myc and cyclin-D1 (Cyc-D1) and cell processes related with their expression, such as, proliferation, modifications of the actin cytoskeleton, cell migration and cell cycle in a mammary carcinoma cell line (F3II). Results obtained after treatment with AZT (600 µM) for 15 passages confirmed the inhibitory effect on telomerase. Regarding extratelomeric activities, our results showed a decrease of 64, 38 and 25% in the transcription of c-Myc, Cyc-D1 and TERT, respectively (p<0.05) after AZT treatment. Furthermore, we found an effect on cell migration, reaching an inhibition of 48% (p<0.05) and a significant passage-dependent increase on cell doubling time during treatment. Finally, we evaluated the effect on cell cycle, obtaining a decline in G0/G1 in AZT-treated cells. These results allow us to postulate that AZT is not only an inhibitor of telomerase activity, but also a potential modulator of extratelomeric processes involved in cancer promotion.", "corpus_id": 43657352, "score": 0 }, { "doc_id": "22144883", "title": "Azidothymidine hinders arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells by induction of p21 and attenuation of G2/M arrest", "abstract": "To enhance anticancer efficacy of the arsenic trioxide (ATO), the combination of ATO and azidothymidine (AZT), with convergence anti-telomerase activity, were examined on acute promyelocytic leukemia (APL) cell line, NB4. In spite of an induction of apoptosis by both drugs separately and a synergistic effect of them on hTERT down-regulation and telomerase inhibition, the ATO-induced cytotoxicity was reduced when it was used in combination with AZT. AZT attenuated the ATO effects on viability, metabolic activity, DNA synthesis, and apoptosis. These observations, despite the deflection from the main goal of this study, dedicate an especial opportunity to elucidate the importance of some of the mechanisms that have been suggested by which ATO induces apoptosis. Cell cycle distribution, ROS level, and caspase-3 activation analyses suggest that AZT reduced the ATO-induced cytotoxic effect possibly via relative induction and diminution of cells accumulated in (G1, S) and (G2/M) phase, respectively, as well as through attenuation of ROS generation and subsequent caspase-3 inhibition. QRT-PCR assay revealed that induction of p21expression by the combined AZT/ATO compared to ATO alone could be a reason for the relative decline of cells accumulation in G2/M and the increase of cells in G1 and S phases. Therefore, the G2/M arrest and ROS generation are likely principle mediators for the ATO-induced apoptosis and can be used as a guide to design rational combinatorial strategies involving ATO and agents with G2/M arrest or ROS generation capacity to intensify ATO-induced apoptosis.", "corpus_id": 22144883, "score": 0 }, { "doc_id": "13065923", "title": "Telomerase Inhibition Using Azidothymidine in the HT-29 Colon Cancer Cell Line", "abstract": "AbstractBackground: We investigated the effects of telomerase inhibition by using the reverse transcriptase inhibitor azidothymidine (AZT) in the human colorectal cancer cell line HT-29 in the presence and absence of 5-fluorouracil (5-FU).\nMethods: HT-29 cells were cultured in the presence of AZT. Telomerase activity was measured by using the telomerase repeat amplification protocol. Telomere length was determined by Southern analysis. The colorimetric microtiter assay was performed to determine the cytotoxic effects of AZT, alone and in combination with 5-FU.\nResults: The presence of 3′-azido-3′-deoxythymidine triphosphate (AZT-TP) effectively inhibited telomerase extracted from HT-29 cells. HT-29 cells cultured with 125 μM of AZT underwent fewer total population doublings over 91 days. Southern analysis revealed that telomere attrition occurred within this period. Exposure to 125 μM of AZT resulted in slightly reduced viability (10%) of HT-29 cells. However, the presence of AZT increased 5-FU cytotoxicity, suggesting that the effects of these two drugs are synergistic.\nConclusions: The data are consistent with telomerase inhibition having growth-inhibitory effects in addition to those predicted to accompany loss of telomere function. Further studies using specific small-molecule inhibitors will confirm whether the growth-inhibitory and 5-FU–sensitivity effects seen here are a direct result of telomerase inhibition.", "corpus_id": 13065923, "score": 0 }, { "doc_id": "3261361", "title": "The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression", "abstract": "DNA methyltransferase inhibitors (DNMTIs) such as 5-azacytidine (5-AZA) have been used for treatment of acute myeloid leukemia (AML) and other malignancies. Although inhibiting global/gene-specific DNA methylation is widely accepted as a key mechanism behind DNMTI anti-tumor activity, other mechanisms are likely involved in DNMTI's action. Because telomerase reverse transcriptase (TERT) plays key roles in cancer through telomere elongation and telomere lengthening-independent activities, and TERT has been shown to confer chemo- or radio-resistance to cancer cells, we determine whether DNMTIs affect telomere function and whether TERT/telomerase interferes with their anti-cancer efficacy. We showed that 5-AZA induced DNA damage and telomere dysfunction in AML cell lines by demonstrating the presence of 53-BP1 foci and the co-localization of 53-BP1 foci with telomere signals, respectively. Telomere dysfunction was coupled with diminished TERT expression, shorter telomere and apoptosis in 5-AZA-treated cells. However, 5-AZA treatment did not lead to changes in the methylation status of subtelomere regions. Down-regulation of TERT expression similarly occurred in primary leukemic cells derived from AML patients exposed to 5-AZA. TERT over-expression significantly attenuated 5-AZA-mediated DNA damage, telomere dysfunction and apoptosis of AML cells. Collectively, 5-AZA mediates the down-regulation of TERT expression, and induces telomere dysfunction, which consequently exerts an anti-tumor activity.", "corpus_id": 3261361, "score": 0 }, { "doc_id": "18793233", "title": "The effect of chemotherapeutic agents on telomere length maintenance in breast cancer cell lines", "abstract": "Mammalian telomeric DNA consists of tandem repeats of the sequence TTAGGG associated with a specialized set of proteins, known collectively as Shelterin. These telosomal proteins protect the ends of chromosomes against end-to-end fusion and degradation. Short telomeres in breast cancer cells confer telomere dysfunction and this can be related to Shelterin proteins and their level of expression in breast cancer cell lines. This study investigates whether expression of Shelterin and Shelterin-associated proteins are altered, and influence the protection and maintenance of telomeres, in breast cancer cells. 5-aza-2′-deoxycytidine (5-aza-CdR) and trichostatin A (TSA) were used in an attempt to reactivate the expression of silenced genes. Our studies have shown that Shelterin and Shelterin-associated genes were down-regulated in breast cancer cell lines; this may be due to epigenetic modification of DNA as the promoter region of POT1 was found to be partially methylated. Shelterin genes expression was up-regulated upon treatment of 21NT breast cancer cells with 5-aza-CdR and TSA. The telomere length of treated 21NT cells was measured by q-PCR showed an increase in telomere length at different time points. Our studies have shown that down-regulation of Shelterin genes is partially due to methylation in some epithelial breast cancer cell lines. Removal of epigenetic silencing results in up-regulation of Shelterin and Shelterin-associated genes which can then lead to telomere length elongation and stability.", "corpus_id": 18793233, "score": 0 }, { "doc_id": "41816224", "title": "Gemcitabine causes telomere attrition by stabilizing TRF2.", "abstract": "Gemcitabine is an effective anti-cancer agent against solid tumors. The pharmacological mechanism of gemcitabine is known as incorporation into DNA and thereby inhibition of DNA synthesis. When used in metronomic chemotherapy of cancer, the agent may inhibit angiogenesis. It is still uncertain whether the agent can inhibit tumor growth by a mechanism other than DNA incorporation. In this report, we show that gemcitabine causes telomere shortening by stabilizing TRF2 that is required for XPF-dependent telomere loss. Overexpression of TRF2 in the absence of gemcitabine also causes telomere shortening with simultaneous association of TRF2 with XPF/ERCC1. Our study provides a new mechanism by which gemcitabine exerts its anti-tumor activity.", "corpus_id": 41816224, "score": 0 }, { "doc_id": "22831817", "title": "The antitumor enediyne C-1027 alters cell cycle progression and induces chromosomal aberrations and telomere dysfunction.", "abstract": "This study examined the extent of chromosome instability induced in cultured human colon carcinoma HCT116 cells by the antitumor radiomimetic enediyne antibiotic C-1027. Spectral karyotype analysis showed frequent intrachromosomal fusions and fragmentations 26 hours after addition of as little as 0.035 nmol/L C-1027. When the concentration was increased to 0.14 nmol/L C-1027, 92% of cells showed chromosomal aberrations compared with only 2.9% after treatment with an equivalent growth inhibitory dose of ionizing radiation (20 Gy). Thus, chromosome misrejoining was associated to a much greater extent with C-1027-induced than with ionizing radiation-induced cell growth inhibition. Despite these aberrations, a large fraction of C-1027-treated cells progressed into G1. Comet analysis showed that these extensive chromosomal anomalies were not due to increased induction or reduced repair of C-1027-induced compared with ionizing radiation-induced strand breaks. Fluorescence in situ hybridization analysis showed that misrejoining of telomere repeats (i.e., chromosomes joined end to end at their telomeres or fused together after complete loss of telomere sequences) was observed within 26 hours of C-1027 addition. The extreme cytotoxicity of C-1027 may reflect both induction and erroneous repair of DNA double-strand break in the whole genome and/or in subgenomic targets such as telomere sequences.", "corpus_id": 22831817, "score": 0 }, { "doc_id": "19031978", "title": "Topoisomerase II inhibition suppresses the proliferation of telomerase-negative cancers", "abstract": "Telomere maintenance is required for chromosome stability, and telomeres are typically elongated by telomerase following DNA replication. In both tumor and yeast cells that lack telomerase, telomeres are maintained via an alternative recombination mechanism. Previous studies have indicated that yeast Sgs1 and Top3 may work together to remove highly negative supercoils that are generated from recombination. However, the mechanism by which cells eradicate highly positive supercoils during recombination remains unclear. In the present study, we demonstrate that TOP2 is involved in telomere–telomere recombination. Disturbance of telomeric structure by RIF1 or RIF2 deletion alleviates the requirement for TOP2 in telomere–telomere recombination. In human telomerase-negative alternative lengthening of telomere (ALT) cells, TOP2α or TOP2β knockdown decreases ALT-associated PML bodies, increases telomere dysfunction-induced foci and triggers telomere shortening. Similar results were observed when ALT cells were treated with ICRF-193, a TOP2 inhibitor. Importantly, ICRF-193 treatment blocks ALT-associated phenotypes in vitro, causes telomere shortening, and inhibits ALT cell proliferation in mice. Taken together, these findings imply that TOP2 is involved in the ALT pathway, perhaps by resolving the highly positive supercoil structure at the front of the helicase. Inhibition of topoisomerase II may be a promising therapeutic approach that can be used to prevent cell proliferation in ALT-type cancer cells.", "corpus_id": 19031978, "score": 1 }, { "doc_id": "35827841", "title": "Chromosome aberrations and telomere length modulation in bone marrow and spleen cells of melphalan‐treated p53+/− mice", "abstract": "The p53 gene regulates cell cycle and apoptotic pathways after induction of DNA damage. Telomeres, capping chromosome ends, are involved in maintaining chromosome stability; alterations of their length have been related to increased levels of chromosomal aberrations. To study a possible interaction between chromosome aberrations, telomere dysfunction, and p53, we investigated via painting analysis the induction and persistence of chromosome aberrations in bone marrow and spleen cells of p53+/− (and wild type) mice exposed for 4, 13, or 26 weeks to 2 mg/kg melphalan (MLP), a chemotherapeutic agent with carcinogenic potential. In addition, telomere length was evaluated in bone marrow cells by quantitative fluorescence in situ hybridization (Q‐FISH). Chromosome aberrations were significantly increased in both tissues after MLP treatment. The p53 genotype did not influence the response of spleen cells, whereas a slight but significant increase of the aberration frequency was measured in the bone marrow of p53+/− mice exposed to MLP for 13 weeks with respect to the level detected in the matched wild‐type group. The main finding of our still preliminary results on telomere length modulation was again a difference between the two genotypes. In bone marrow cells of wild‐type mice, MLP treatment was associated with telomere shortening, while in p53+/− mice telomere elongation was the prevalent response to MLP exposure. In agreement with previous literature data, our in vivo study suggests that even the lack of a single functional copy of the p53 gene might have an impact on the quantity and quality of chromosome alterations induced in cycling cells by a clastogenic exposure. Environ. Mol. Mutagen., 2008. © 2008 Wiley‐Liss, Inc.", "corpus_id": 35827841, "score": 0 }, { "doc_id": "5786436", "title": "Long-term cultivation of colorectal carcinoma cells with anti-cancer drugs induces drug resistance and telomere elongation: an in vitro study", "abstract": "BackgroundThe role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood. Therefore, we investigated the relationships, among the telomerase activity, telomere length and the expression of multidrug resistance genes in colorectal cancer cell lines cultivated with anti-cancer drugs.MethodsLoVo and DLD-1 cells were continuously grown in the presence of both CDDP and 5-FU for up to 100 days. Cell proliferation, telomerase activity, telomere length and the expression of multidrug resistance genes were serially monitored as the PDL increased.ResultsThe expression of multidrug resistance genes tended to increase as the PDL increased. However, an abnormal aneuploid clone was not detected as far as the cells were monitored by a DNA histogram analysis. Tumor cells showing resistance to anti-cancer drugs revealed a higher cell proliferation rate. The telomere length gradually increased with a progressive PDL. The telomerase activity reached a maximum level at 15 PDL in LoVo cells and at 27 PDL in DLD-1 cells. An increase in the mRNA expression of the telomerase components, especially in hTERT and in hTR, was observed at the same PDLs.ConclusionsThese results suggest that a high telomerase activity and an elongation of telomeres both appear to help maintain and/or increase drug resistance in colorectal cancer cells. Cancer cells with long telomeres and a high proliferative activity may thus be able to better survive exposure to anti-cancer drugs. This is presumably due to an increased chromosome stability and a strong expression of both mdr-1 and MRP genes.", "corpus_id": 5786436, "score": 0 }, { "doc_id": "7199058", "title": "Chromosomal aberrations involving telomeres and interstitial telomeric sequences.", "abstract": "Telomeres are specialised nucleoproteic complexes localised at the physical ends of linear eukaryotic chromosomes that maintain their stability and integrity. In vertebrate chromosomes, the DNA component of telomeres is constituted by (TTAGGG)n repeats, which can be localised at the terminal regions of chromosomes (true telomeres) or at intrachromosomal sites (interstitial telomeric sequences or ITSs, located at the centromeric region or between the centromere and the telomere). In the past two decades, the use of molecular cytogenetic techniques has led to a new spectrum of spontaneous and clastogen-induced chromosomal aberrations being identified, involving telomeres and ITSs. Some aberrations involve the chromosome ends and, indirectly, the telomeric repeats located at the terminal regions of chromosomes (true telomeres). A second type of aberrations directly involves the telomeric sequences located at the chromosome ends. Finally, there is a third class of aberrations that specifically involves the ITSs. The aims of this review are to provide a detailed description of these aberrations and to summarise the available data regarding their induction by physical and chemical mutagens.", "corpus_id": 7199058, "score": 0 }, { "doc_id": "33584902", "title": "Bleomycins: towards better therapeutics", "abstract": "Bleomycins are a family of glycopeptide antibiotics that have potent antitumour activity against a range of lymphomas, head and neck cancers and germ-cell tumours. The therapeutic efficacy of the bleomycins is limited by development of lung fibrosis. The cytotoxic and mutagenic effects of the bleomycins are thought to be related to their ability to mediate both single-stranded and double-stranded DNA damage, which requires the presence of specific cofactors (a transition metal, oxygen and a one-electron reductant). Progress in understanding the mechanisms involved in the therapeutic efficacy of the bleomycins and the unwanted toxicity and elucidation of the biosynthetic pathway of the bleomycins sets the stage for developing a more potent, less toxic therapeutic agent.", "corpus_id": 33584902, "score": 0 }, { "doc_id": "35787732", "title": "Genotoxicity of streptozotocin.", "abstract": "Streptozotocin (Streptozocin, STZ, CAS No. 18883-66-4) is a monofunctional nitrosourea derivative isolated from Streptomyces achromogenes. It has broad spectrum antibiotic activity and antineoplastic properties and is often used to induce diabetes mellitus in experimental animals through its toxic effects on pancreatic beta cells. STZ is a potent alkylating agent known to directly methylate DNA and is highly genotoxic, producing DNA strand breaks, alkali-labile sites, unscheduled DNA synthesis, DNA adducts, chromosomal aberrations, micronuclei, sister chromatid exchanges, and cell death. This antibiotic was found to be mutagenic in bacterial assays and eukaryotic cells. STZ is also carcinogenic; a single administration induces tumors in rat kidney, liver, and pancreas. Several lines of evidence indicate that free radicals are involved in the production of DNA and chromosome damage by this compound. Because of the use of STZ as an antineoplastic agent, the study of its genotoxicity has considerable practical significance. The purpose of this review is to present our current knowledge regarding the genotoxicity of STZ.", "corpus_id": 35787732, "score": 0 }, { "doc_id": "12750916", "title": "Telomere instability is present in the progeny of mammalian cells exposed to bleomycin.", "abstract": "We analyzed the chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the radiomimetic compound bleomycin (BLM) in order to determine if this antineoplastic drug induces long-term telomere instability. To this end, rat cells (ADIPO-P2 cell line, derived from adipose cells from Sprague-Dawley rat) were treated with a single concentration of BLM (2.5 μg/ml), and chromosomal aberrations were analyzed 18 h and 10 days after treatment by using PNA-FISH with a pan-telomeric probe [(TTAGGG)n repeats]. Cytogenetic analysis revealed a higher frequency of aberrations at 18 h and 10 days after treatment in BLM-exposed cultures vs. untreated cultures, although the yield of BLM-induced aberrations 10 days after treatment decreased about 25% compared with the one at 18 h after treatment. Moreover, the level of telomerase activity in BLM-treated cells compared with that of untreated control cells was significantly higher at 10 days after treatment, but did not differ at 18 h after treatment. These data indicate that in terms of unstable aberrations, the in vitro clastogenic effect of BLM on ADIPO-P2 cells persists for at least 10 days after exposure. In addition, our data demonstrate, for the first time, that BLM-induced telomere instability in mammalian cells (cytogenetically detectable as incomplete chromosome elements and telomere FISH signal loss and duplication) persists for several generations after exposure. Moreover, the appearance of telomere fusions in BLM-exposed cells 10 days after treatment suggests that this compound can induce delayed telomere instability. The increase in telomerase activity in BLM-exposed cells 10 days after treatment is accompanied by the presence of aberrations directly related to telomere dysfunction. This fact suggests that telomerase is not directly involved in BLM-induced telomere instability.", "corpus_id": 12750916, "score": 0 }, { "doc_id": "11771354", "title": "The radiomimetic compound streptonigrin induces persistent telomere dysfunction in mammalian cells.", "abstract": "We analyzed the chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the radiomimetic compound streptonigrin (SN) in order to determine if this antineoplastic drug induces long-term telomere instability. To this end, rat cells (ADIPO-P2 cell line, derived from adipose cells from Sprague-Dawley rat) were treated with a single concentration of SN (100ng/ml), and chromosomal aberrations were analyzed 18h and 10 and 15 days after treatment by using PNA-FISH with a pan-telomeric probe [Cy3-(CCCTAA)3] to detect (TTAGGG)n repeats. Cytogenetic analysis revealed a higher frequency of telomere dysfunction-related aberrations (additional telomeric FISH signals, extra-chromosomal telomeric FISH signals, and telomere FISH signal loss and duplications) in SN-exposed cultures vs. untreated cultures at every time points analyzed. The yield of SN-induced aberrations remained very similar at 18h, 10 days as well as 15 days after treatment. Thus, our data demonstrate that SN induces persistent telomere dysfunction in mammalian cells. Moreover, we found that the level of telomerase activity in SN-treated cells was significantly lower (up to 77%) than that of untreated control cells at each time points analyzed. This fact suggests that telomerase could be involved in SN-induced telomere dysfunction.", "corpus_id": 11771354, "score": 0 }, { "doc_id": "23784788", "title": "Paclitaxel in cancer therapy", "abstract": "The last decade witnessed the introduction of exciting new chemotherapeutic agents. Among these, paclitaxel emerged as one of the most powerful compounds. Paclitaxel promotes the polymerisation of tubulin, thereby causing cell death by disrupting the normal microtubule dynamics required for cell division and vital interphase processes. Mechanisms of acquired resistance to paclitaxel include alterations of tubulin structure and the amplification of membrane phosphoglycoproteins that function as drug-efflux pumps. Toxicities associated with paclitaxel include hypersensitivity reaction, neurotoxicity and haematological toxicities. Toxicities may be both dose- and schedule-dependent. Paclitaxel has activity against a broad band of tumour types, including breast, ovarian, lung, head and neck cancers. Paclitaxel also has activity in other malignancies that are refractory to conventional chemotherapy, including previously-treated lymphoma and small cell lung cancers and oesophageal, gastric endometrial, bladder and germ cell tumours. Paclitaxel is also active against AIDS-associated Kaposi’s sarcoma.", "corpus_id": 23784788, "score": 0 }, { "doc_id": "1012041", "title": "New applications of old metal-binding drugs in the treatment of human cancer.", "abstract": "Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and ruthenium-based compounds are currently being investigated in clinical trials. Since the process of drug development can be expensive and cumbersome, finding new applications of existing drugs may provide effective means to expedite the regulatory process in bringing new drugs to the clinical setting. Encouraging findings from laboratory studies reveal significant anticancer activity from different classes of metal-chelating compounds, such as disulfiram, clioquinol, and dithiocarbamate derivatives that are currently approved for the treatment of various pathological disorders. Their use as coordination complexes with metals such as copper, zinc, and gold that target the ubiquitin-proteasome pathway have shown significant promise as potential anticancer agents. This review discusses the unique role of several selected metals in relation to their anti-cancer properties as well as the new therapeutic potential of several previously approved metal-chelating drugs. In vitro and in vivo experimental evidence along with mechanisms of action (e.g., via targeting the tumor proteasome) will also be discussed with anticipation of strengthening this exciting new concept.", "corpus_id": 1012041, "score": 0 }, { "doc_id": "20731055", "title": "5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy", "abstract": "5-Azacytidine was first synthesized almost 40 years ago. It was demonstrated to have a wide range of anti-metabolic activities when tested against cultured cancer cells and to be an effective chemotherapeutic agent for acute myelogenous leukemia. However, because of 5-azacytidine's general toxicity, other nucleoside analogs were favored as therapeutics. The finding that 5-azacytidine was incorporated into DNA and that, when present in DNA, it inhibited DNA methylation, led to widespread use of 5-azacytidine and 5-aza-2′-deoxycytidine (Decitabine) to demonstrate the correlation between loss of methylation in specific gene regions and activation of the associated genes. There is now a revived interest in the use of Decitabine as a therapeutic agent for cancers in which epigenetic silencing of critical regulatory genes has occurred. Here, the current status of our understanding of the mechanism(s) by which 5-azacytosine residues in DNA inhibit DNA methylation is reviewed with an emphasis on the interactions of these residues with bacterial and mammalian DNA (cytosine-C5) methyltransferases. The implications of these mechanistic studies for development of less toxic inhibitors of DNA methylation are discussed.", "corpus_id": 20731055, "score": 0 }, { "doc_id": "10135819", "title": "A new macromolecular antitumor antibiotic, C-1027. I. Discovery, taxonomy of producing organism, fermentation and biological activity.", "abstract": "Strain C-1027, an actinomycete isolated from a soil sample collected in China, was found to produce the new antibiotic, C-1027. From taxonomical studies on its morphological, cultural and physiological characteristics, this antibiotic-producing strain was identified as Streptomyces globisporus C-1027. Antibiotic C-1027 has antimicrobial activity against most Gram-positive bacteria but not against Mycobacterium sp. or Gram-negative bacteria. This antibiotic shows remarkable activity in spermatogonial assay and potent cytotoxicity against KB carcinoma cells in vitro, and exhibits inhibition on transplantable tumors in mice.", "corpus_id": 10135819, "score": 0 }, { "doc_id": "2539740", "title": "A new macromolecular antitumor antibiotic, C-1027. II. Isolation and physico-chemical properties.", "abstract": "A new macromolecular antibiotic C-1027 was obtained from the broth filtrate of Streptomyces globisporus C-1027 by precipitation with ammonium sulfate, DEAE-cellulose column chromatography and gel filtration chromatography on a Sephadex G-75 column. This antibiotic, prepared as a white powder, is an acidic polypeptide having an isoelectric point of pH 3.5-3.7 and a molecular weight of 15,000 as determined by SDS-polyacrylamide gel electrophoresis and gel filtration chromatography. The acid hydrolysate of the purified antibiotic C-1027 contained no methionine or tryptophan. From the physico-chemical data, it may be considered to possess a very labile non-protein chromophore.", "corpus_id": 2539740, "score": 0 }, { "doc_id": "1958729", "title": "A new macromolecular antitumor antibiotic, C-1027. III. Antitumor activity.", "abstract": "C-1027, a new macromolecular antitumor antibiotic produced by Streptomyces globisporus C-1027, showed extremely potent cytotoxicity toward cultured cancer cells. Compared in terms of IC50 values, antibiotic C-1027 showed much more potent cytotoxicity than doxorubicin, mitomycin C and neocarzinostatin. Spermatogonial assay, a prescreen for anticancer drugs, was highly sensitive for detection of C-1027. At tolerable doses, C-1027 exhibited marked inhibition on a panel of transplantable tumors in mice, which included leukemia L1210, P388, ascites hepatoma H22, sarcoma 180 and melanoma Harding-Passey.", "corpus_id": 1958729, "score": 0 }, { "doc_id": "24835445", "title": "Lidamycin inhibits tumor initiating cells of hepatocellular carcinoma Huh7 through GSK3β/β‐catenin pathway", "abstract": "Recently, tumor initiating cells are considered as the central role of tumorigenicity in hepatocellular carcinoma. Enediyne anticancer antibiotic lidamycin with great potential antitumor activity is currently evaluated in Phase II clinical trials. In this study, we evaluated the effect of lidamycin on tumor initiating cells of hepatocellular carcinoma Huh7 and identified the potential mechanism. Flow cytometry analysis and sorting assay, surface marker assay, sphere formation assay, and aldefluor assay were used to evaluate the effect of lidamycin on Huh7 tumor initiating cells in vitro. To investigate the potential mechanism, the activity of GSK3β/β‐catenin pathway was detected by Western blot and T cell factors transcriptional activity assay. Subcutaneous tumor model in nude mice was used to observe in vivo effect of lidamycin on Huh7 cells. Lidamycin decreased the proportion of EpCAM+ cells and the expression of EpCAM protein. Lidamycin inhibited sphere formation of sorted EpCAM+ cells in 7 d, and of parental cells in three serial passages. The population of aldehyde dehydrogenase‐positive cells was reduced by lidamycin. In addition, lidamycin restrained tumor volume and incidence in vivo. Lidamycin activated GSK3β, and degraded the activity of β‐catenin. Consequently, transcriptional activity of β‐catenin/T cell factors was decreased. In brief, these results suggest that lidamycin suppressed Huh7 tumor initiating cells via GSK3β/β‐catenin pathway. These findings reveal the potential mechanism of lidamycin on tumor initiating cells and the benefit for further clinical evaluation. © 2013 Wiley Periodicals, Inc.", "corpus_id": 24835445, "score": 0 }, { "doc_id": "4367111", "title": "A topoisomerase II-dependent G2 cycle checkpoint in mammalian cells", "abstract": "THE enzyme DNA topoisomerase II, which removes the caten-ations formed between the DNA molecules of sister chromatids during replication1 and is a structural component of chromosome cores2 , is needed for chromosome condensation in yeast3 and in Xenopus extracts4–6. Inhibitors of topoisomerase II arrest mam-malian cells before mitosis in the G2 phase of the cell cycle7, but also produce DNA damage, which causes arrest through established checkpoint controls8. It is open to question whether cells need topoisomerase II to leave G2, or control late-cycle progres-sion in response to its activity. Bisdioxopiperazines are topoisomerase II inhibitors that act without producing direct DNA damage9; the most potent, ICRF-193, blocks mammalian entry into but not exit from mitosis. Here we show that checkpoint-evading agents such as caffeine override this block to produce abortively condensed chromosomes, indicating that topoisomerase II is needed for complete condensation. We find that exit from G2 is regulated by a catenation-sensitive checkpoint mechanism which is distinct from the G2-damage checkpoint.", "corpus_id": 4367111, "score": 0 }, { "doc_id": "34063635", "title": "Repair of DNA interstrand cross-links.", "abstract": "DNA interstrand cross-links (ICLs) are very toxic to dividing cells, because they induce mutations, chromosomal rearrangements and cell death. Inducers of ICLs are important drugs in cancer treatment. We discuss the main properties of several classes of ICL agents and the types of damage they induce. The current insights in ICL repair in bacteria, yeast and mammalian cells are reviewed. An intriguing aspect of ICLs is that a number of multi-step DNA repair pathways including nucleotide excision repair, homologous recombination and post-replication/translesion repair all impinge on their repair. Furthermore, the breast cancer-associated proteins Brca1 and Brca2, the Fanconi anemia-associated FANC proteins, and cell cycle checkpoint proteins are involved in regulating the cellular response to ICLs. We depict several models that describe possible pathways for the repair or replicational bypass of ICLs.", "corpus_id": 34063635, "score": 0 }, { "doc_id": "16902273", "title": "Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): a review.", "abstract": "Although 5-fluorouracil (5-FU) was first introduced in 1957, it remains an essential part of the treatment of a wide range of solid tumors. 5-FU has antitumor activity against epithelial malignancies arising in the gastrointestinal tract and breast as well as the head and neck, with single-agent response rates of only 10%-30%. Although 5-FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than one-third of patients achieve objective responses. Recent research has focused on the biomodulation of 5-FU to improve the cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer agents, 5-FU leads to several toxicities. The toxicity profile of 5-FU is schedule dependent. Myelotoxicity is the major toxic effect in patients receiving bolus doses. Hand-foot syndrome (palmar-plantar erythrodysesthesia), stomatitis, and neuro- and cardiotoxicities are associated with continuous infusions. Other adverse effects associated with both bolus-dose and continuous-infusion regimens include nausea and vomiting, diarrhea, alopecia, and dermatitis. All these reasons explain the need for more effective and less toxic fluoropyrimidines. In the first part of this review, we briefly present the metabolic pathways of 5-FU responsible for the efficacy and toxicity of this drug. This knowledge is also necessary to understand the target(s) of biomodulation. The second part is devoted to a review of the literature on three recent prodrugs of 5-FU, i.e., capecitabine, UFT (ftorafur [FTO] plus uracil), and S-1 (FTO plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate). The pharmacological principles that have influenced the development of these new drugs and our current knowledge of the clinical pharmacology of these new agents, focusing on antitumor activity and toxicity, are presented. The literature was analyzed until March 2002. This review is intended to be as exhaustive as possible since it was conceived as a work tool for readers wanting to go further.", "corpus_id": 16902273, "score": 0 }, { "doc_id": "25381232", "title": "Prodrugs—from Serendipity to Rational Design", "abstract": "The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.", "corpus_id": 25381232, "score": 0 } ]

{ "doc_id": "7864691", "title": "A CURE for Noisy Magnetic Resonance Images: Chi-Square Unbiased Risk Estimation", "abstract": "In this paper, we derive an unbiased expression for the expected mean-squared error associated with continuously differentiable estimators of the noncentrality parameter of a chi-square random variable. We then consider the task of denoising squared-magnitude magnetic resonance (MR) image data, which are well modeled as independent noncentral chi-square random variables on two degrees of freedom. We consider two broad classes of linearly parameterized shrinkage estimators that can be optimized using our risk estimate, one in the general context of undecimated filterbank transforms, and the other in the specific case of the unnormalized Haar wavelet transform. The resultant algorithms are computationally tractable and improve upon most state-of-the-art methods for both simulated and actual MR image data.", "corpus_id": 7864691 }

[ { "doc_id": "44507394", "title": "Measurement of signal intensities in the presence of noise in MR images.", "abstract": "Power spectrum or magnitude images are frequently presented in magnetic resonance imaging. In such images, measurement of signal intensity at low signal levels is compounded with the noise. This report describes how to extract true intensity measurements in the presence of noise.", "corpus_id": 44507394, "score": 0 }, { "doc_id": "9825881", "title": "The rician distribution of noisy mri data", "abstract": "The image intensity in magnetic resonance magnitude images in the presence of noise is shown to be governed by a Rician distribution. Low signal intensities (SNR < 2) are therefore biased due to the noise. it is shown how the underlying noise can be estimated from the images and a simple correction scheme is provided to reduce the bias. the noise characteristics in phase images are also studied and shown to be very different from those of the magnitude images. Common to both, however, is that the noise distributions are nearly Gaussian for SNR larger than two.", "corpus_id": 9825881, "score": 0 }, { "doc_id": "10650720", "title": "A Nonlocal Maximum Likelihood Estimation Method for Rician Noise Reduction in MR Images", "abstract": "Postacquisition denoising of magnetic resonance (MR) images is of importance for clinical diagnosis and computerized analysis, such as tissue classification and segmentation. It has been shown that the noise in MR magnitude images follows a Rician distribution, which is signal-dependent when signal-to-noise ratio (SNR) is low. It is particularly difficult to remove the random fluctuations and bias introduced by Rician noise. The objective of this paper is to estimate the noise free signal from MR magnitude images. We model images as random fields and assume that pixels which have similar neighborhoods come from the same distribution. We propose a nonlocal maximum likelihood (NLML) estimation method for Rician noise reduction. Our method yields an optimal estimation result that is more accurate in recovering the true signal from Rician noise than NL means algorithm in the sense of SNR, contrast, and method error. We demonstrate that NLML performs better than the conventional local maximum likelihood (LML) estimation method in preserving and defining sharp tissue boundaries in terms of a well-defined sharpness metric while also having superior performance in method error.", "corpus_id": 10650720, "score": 0 }, { "doc_id": "11182238", "title": "Feature-Preserving MRI Denoising: A Nonparametric Empirical Bayes Approach", "abstract": "This paper presents a novel method for Bayesian denoising of magnetic resonance (MR) images that bootstraps itself by inferring the prior, i.e., the uncorrupted-image statistics, from the corrupted input data and the knowledge of the Rician noise model. The proposed method relies on principles from empirical Bayes (EB) estimation. It models the prior in a nonparametric Markov random field (MRF) framework and estimates this prior by optimizing an information-theoretic metric using the expectation-maximization algorithm. The generality and power of nonparametric modeling, coupled with the EB approach for prior estimation, avoids imposing ill-fitting prior models for denoising. The results demonstrate that, unlike typical denoising methods, the proposed method preserves most of the important features in brain MR images. Furthermore, this paper presents a novel Bayesian-inference algorithm on MRFs, namely iterated conditional entropy reduction (ICER). This paper also extends the application of the proposed method for denoising diffusion-weighted MR images. Validation results and quantitative comparisons with the state of the art in MR-image denoising clearly depict the advantages of the proposed method.", "corpus_id": 11182238, "score": 0 }, { "doc_id": "6623504", "title": "Noise estimation and removal in MR imaging: The variance-stabilization approach", "abstract": "We develop optimal forward and inverse variance-stabilizing transformations for the Rice distribution, in order to approach the problem of magnetic resonance (MR) image filtering by means of standard denoising algorithms designed for homoskedastic observations.", "corpus_id": 6623504, "score": 0 }, { "doc_id": "4683670", "title": "Restoration of DWI Data Using a Rician LMMSE Estimator", "abstract": "This paper introduces and analyzes a linear minimum mean square error (LMMSE) estimator using a Rician noise model and its recursive version (RLMMSE) for the restoration of diffusion weighted images. A method to estimate the noise level based on local estimations of mean or variance is used to automatically parametrize the estimator. The restoration performance is evaluated using quality indexes and compared to alternative estimation schemes. The overall scheme is simple, robust, fast, and improves estimations. Filtering diffusion weighted magnetic resonance imaging (DW-MRI) with the proposed methodology leads to more accurate tensor estimations. Real and synthetic datasets are analyzed.", "corpus_id": 4683670, "score": 0 }, { "doc_id": "7263571", "title": "Noise and Signal Estimation in Magnitude MRI and Rician Distributed Images: A LMMSE Approach", "abstract": "A new method for noise filtering in images that follow a Rician model-with particular attention to magnetic resonance imaging-is proposed. To that end, we have derived a (novel) closed-form solution of the linear minimum mean square error (LMMSE) estimator for this distribution. Additionally, a set of methods that automatically estimate the noise power are developed. These methods use information of the sample distribution of local statistics of the image, such as the local variance, the local mean, and the local mean square value. Accordingly, the dynamic estimation of noise leads to a recursive version of the LMMSE, which shows a good performance in both noise cleaning and feature preservation. This paper also includes the derivation of the probability density function of several local sample statistics for the Rayleigh and Rician model, upon which the estimators are built.", "corpus_id": 7263571, "score": 1 }, { "doc_id": "16606570", "title": "An Optimized Blockwise Non Local Means Denoising Filter for 3D Magnetic Resonance Images", "abstract": "A critical issue in image restoration is the problem of noise removal while keeping the integrity of relevant image information. Denoising is a crucial step to increase image quality and to improve the performance of all the tasks needed for quantitative imaging analysis. The method proposed in this paper is based on a 3D optimized blockwise version of the Non Local (NL) means filter [1]. The NL-means filter uses the redundancy of information in the image under study to remove the noise. The performance of the NL-means filter has been already demonstrated for 2D images, but reducing the computational burden is a critical aspect to extend the method to 3D images. To overcome this problem, we propose improvements to reduce the computational complexity. These different improvements allow to drastically divide the computational time while preserving the performances of the NL-means filter. A fully-automated and optimized version of the NL-means filter is then presented. Our contributions to the NL-means filter are: (a) an automatic tuning of the smoothing parameter, (b) a selection of the most relevant voxels, (c) a blockwise implementation and (d) a parallelized computation. Quantitative validation was carried out on synthetic datasets generated with BrainWeb [2]. The results show that our optimized NL-means filter outperforms the classical implementation of the NL-means filter, as well as two other classical denoising methods (Anisotropic Diffusion [3] and Total Variation minimization process [4]) in terms of accuracy (measured by the Peak Signal to Noise Ratio) with low computation time. Finally, qualitative results on real data are presented.", "corpus_id": 16606570, "score": 0 }, { "doc_id": "18390050", "title": "Denoising of Dynamic Contrast-Enhanced MR Images Using Dynamic Nonlocal Means", "abstract": "This paper presents a new algorithm for denoising dynamic contrast-enhanced (DCE) MR images. It is a novel variation on the nonlocal means (NLM) algorithm. The algorithm, called dynamic nonlocal means (DNLM), exploits the redundancy of information in the temporal sequence of images. Empirical evaluations of the performance of the DNLM algorithm relative to seven other denoising methods-simple Gaussian filtering, the original NLM algorithm, a trivial extension of NLM to include the temporal dimension, bilateral filtering, anisotropic diffusion filtering, wavelet adaptive multiscale products threshold, and traditional wavelet thresholding-are presented. The evaluations include quantitative evaluations using simulated data and real data (20 DCE-MRI data sets from routine clinical breast MRI examinations) as well as qualitative evaluations using the same real data (24 observers: 14 image/signal-processing specialists, 10 clinical breast MRI radiographers). The results of the quantitative evaluation using the simulated data show that the DNLM algorithm consistently yields the smallest MSE between the denoised image and its corresponding original noiseless version. The results of the quantitative evaluation using the real data provide evidence, at the ¿ = 0.05 level of significance, that the DNLM algorithm yields the smallest MSE between the denoised image and its corresponding original noiseless version. The results of the qualitative evaluation provide evidence, at the ¿ = 0.05 level of significance, that the DNLM algorithm performs visually better than all of the other algorithms. Collectively the qualitative and quantitative results suggest that the DNLM algorithm more effectively attenuates noise in DCE MR images than any of the other algorithms.", "corpus_id": 18390050, "score": 0 }, { "doc_id": "12475205", "title": "MRI denoising using Non-Local Means", "abstract": "Magnetic Resonance (MR) images are affected by random noise which limits the accuracy of any quantitative measurements from the data. In the present work, a recently proposed filter for random noise removal is analyzed and adapted to reduce this noise in MR magnitude images. This parametric filter, named Non-Local Means (NLM), is highly dependent on the setting of its parameters. The aim of this paper is to find the optimal parameter selection for MR magnitude image denoising. For this purpose, experiments have been conducted to find the optimum parameters for different noise levels. Besides, the filter has been adapted to fit with specific characteristics of the noise in MR image magnitude images (i.e. Rician noise). From the results over synthetic and real images we can conclude that this filter can be successfully used for automatic MR denoising.", "corpus_id": 12475205, "score": 1 }, { "doc_id": "37997080", "title": "An adaptive nonlocal means scheme for medical image denoising", "abstract": "Medical images often consist of low-contrast objects corrupted by random noise arising in the image acquisition process. Thus, image denoising is one of the fundamental tasks required by medical imaging analysis. In this work, we investigate an adaptive denoising scheme based on the nonlocal (NL)-means algorithm for medical imaging applications. In contrast with the traditional NL-means algorithm, the proposed adaptive NL-means (ANL-means) denoising scheme has three unique features. First, it employs the singular value decomposition (SVD) method and the K-means clustering (K-means) technique for robust classification of blocks in noisy images. Second, the local window is adaptively adjusted to match the local property of a block. Finally, a rotated block matching algorithm is adopted for better similarity matching. Experimental results from both additive white Gaussian noise (AWGN) and Rician noise are given to demonstrate the superior performance of the proposed ANL denoising technique over various image denoising benchmarks in term of both PSNR and perceptual quality comparison.", "corpus_id": 37997080, "score": 0 }, { "doc_id": "26608870", "title": "Filtering noise from images with wavelet transforms", "abstract": "A new method of filtering MR images is presented that uses wavelet transforms instead of Fourier transforms. The new filtering method does not reduce the sharpness of edges. However, the new method does eliminate any small structures that are similar in size to the noise eliminated. There are many possible extensions of the filter. © 1991 Academic Press, Inc.", "corpus_id": 26608870, "score": 0 }, { "doc_id": "16798253", "title": "Wavelet transform domain filters: a spatially selective noise filtration technique", "abstract": "Wavelet transforms are multiresolution decompositions that can be used to analyze signals and images. They describe a signal by the power at each scale and position. Edges can be located very effectively in the wavelet transform domain. A spatially selective noise filtration technique based on the direct spatial correlation of the wavelet transform at several adjacent scales is introduced. A high correlation is used to infer that there is a significant feature at the position that should be passed through the filter. The authors have tested the technique on simulated signals, phantom images, and real MR images. It is found that the technique can reduce noise contents in signals and images by more than 80% while maintaining at least 80% of the value of the gradient at most edges. The authors did not observe any Gibbs' ringing or significant resolution loss on the filtered images. Artifacts that arose from the filtration are very small and local. The noise filtration technique is quite robust. There are many possible extensions of the technique. The authors see its applications in spatially dependent noise filtration, edge detection and enhancement, image restoration, and motion artifact removal. They have compared the performance of the technique to that of the Weiner filter and found it to be superior.", "corpus_id": 16798253, "score": 0 }, { "doc_id": "17029533", "title": "Wavelet-based Rician noise removal for magnetic resonance imaging", "abstract": "It is well known that magnetic resonance magnitude image data obey a Rician distribution. Unlike additive Gaussian noise, Rician \"noise\" is signal-dependent, and separating signal from noise is a difficult task. Rician noise is especially problematic in low signal-to-noise ratio (SNR) regimes where it not only causes random fluctuations, but also introduces a signal-dependent bias to the data that reduces image contrast. This paper studies wavelet-domain filtering methods for Rician noise removal. We present a novel wavelet-domain filter that adapts to variations in both the signal and the noise.", "corpus_id": 17029533, "score": 1 }, { "doc_id": "14352579", "title": "A versatile wavelet domain noise filtration technique for medical imaging", "abstract": "We propose a robust wavelet domain method for noise filtering in medical images. The proposed method adapts itself to various types of image noise as well as to the preference of the medical expert; a single parameter can be used to balance the preservation of (expert-dependent) relevant details against the degree of noise reduction. The algorithm exploits generally valid knowledge about the correlation of significant image features across the resolution scales to perform a preliminary coefficient classification. This preliminary coefficient classification is used to empirically estimate the statistical distributions of the coefficients that represent useful image features on the one hand and mainly noise on the other. The adaptation to the spatial context in the image is achieved by using a wavelet domain indicator of the local spatial activity. The proposed method is of low complexity, both in its implementation and execution time. The results demonstrate its usefulness for noise suppression in medical ultrasound and magnetic resonance imaging. In these applications, the proposed method clearly outperforms single-resolution spatially adaptive algorithms, in terms of quantitative performance measures as well as in terms of visual quality of the images.", "corpus_id": 14352579, "score": 1 }, { "doc_id": "548723", "title": "Noise Reduction for Magnetic Resonance Images via Adaptive Multiscale Products Thresholding", "abstract": "Edge-preserving denoising is of great interest in medical image processing. This paper presents a wavelet-based multiscale products thresholding scheme for noise suppression of magnetic resonance images. A Canny edge detector-like dyadic wavelet transform is employed. This results in the significant features in images evolving with high magnitude across wavelet scales, while noise decays rapidly. To exploit the wavelet interscale dependencies we multiply the adjacent wavelet subbands to enhance edge structures while weakening noise. In the multiscale products, edges can be effectively distinguished from noise. Thereafter, an adaptive threshold is calculated and imposed on the products, instead of on the wavelet coefficients, to identify important features. Experiments show that the proposed scheme better suppresses noise and preserves edges than other wavelet-thresholding denoising methods.", "corpus_id": 548723, "score": 0 }, { "doc_id": "11637816", "title": "A New SURE Approach to Image Denoising: Interscale Orthonormal Wavelet Thresholding", "abstract": "This paper introduces a new approach to orthonormal wavelet image denoising. Instead of postulating a statistical model for the wavelet coefficients, we directly parametrize the denoising process as a sum of elementary nonlinear processes with unknown weights. We then minimize an estimate of the mean square error between the clean image and the denoised one. The key point is that we have at our disposal a very accurate, statistically unbiased, MSE estimate-Stein's unbiased risk estimate-that depends on the noisy image alone, not on the clean one. Like the MSE, this estimate is quadratic in the unknown weights, and its minimization amounts to solving a linear system of equations. The existence of this a priori estimate makes it unnecessary to devise a specific statistical model for the wavelet coefficients. Instead, and contrary to the custom in the literature, these coefficients are not considered random any more. We describe an interscale orthonormal wavelet thresholding algorithm based on this new approach and show its near-optimal performance-both regarding quality and CPU requirement-by comparing it with the results of three state-of-the-art nonredundant denoising algorithms on a large set of test images. An interesting fallout of this study is the development of a new, group-delay-based, parent-child prediction in a wavelet dyadic tree", "corpus_id": 11637816, "score": 0 }, { "doc_id": "2221107", "title": "The SURE-LET Approach to Image Denoising", "abstract": "We propose a new approach to image denoising, based on the image-domain minimization of an estimate of the mean squared error-Stein's unbiased risk estimate (SURE). Unlike most existing denoising algorithms, using the SURE makes it needless to hypothesize a statistical model for the noiseless image. A key point of our approach is that, although the (nonlinear) processing is performed in a transformed domain-typically, an undecimated discrete wavelet transform, but we also address nonorthonormal transforms-this minimization is performed in the image domain. Indeed, we demonstrate that, when the transform is a ldquotightrdquo frame (an undecimated wavelet transform using orthonormal filters), separate subband minimization yields substantially worse results. In order for our approach to be viable, we add another principle, that the denoising process can be expressed as a linear combination of elementary denoising processes-linear expansion of thresholds (LET). Armed with the SURE and LET principles, we show that a denoising algorithm merely amounts to solving a linear system of equations which is obviously fast and efficient. Quite remarkably, the very competitive results obtained by performing a simple threshold (image-domain SURE optimized) on the undecimated Haar wavelet coefficients show that the SURE-LET principle has a huge potential.", "corpus_id": 2221107, "score": 1 }, { "doc_id": "236129", "title": "Chi-square unbiased risk estimate for denoising magnitude MR images", "abstract": "In this article we develop Stein-type results for unbiased estimation of the risk associated with parametric estimators of the noncentrality parameter of chi-squared random variables on two degrees of freedom. These results allow for estimator adaptivity, and thus can be used to optimize the parameters of a broad class of typical denoising functions, subject only to weak smoothness assumptions. We show how to apply these results to the problem of enhancing magnitude magnetic resonance images, which are known to be corrupted by Rician noise. As an example, we propose a transform-domain point-wise estimator based on linear expansion of thresholds. Finally, we apply this estimator to synthetic and real image data in conjunction with the undecimated Haar wavelet transform, and conclude that it is able to outperform previous wavelet-based techniques and compares favorably with a more recent approach based on non-local means.", "corpus_id": 236129, "score": 0 }, { "doc_id": "16806403", "title": "Translation-Invariant De-Noising", "abstract": "De-Noising with the traditional (orthogonal, maximally-decimated) wavelet transform sometimes exhibits visual artifacts; we attribute some of these—for example, Gibbs phenomena in the neighborhood of discontinuities—to the lack of translation invariance of the wavelet basis. One method to suppress such artifacts, termed “cycle spinning” by Coifman, is to “average out” the translation dependence. For a range of shifts, one shifts the data (right or left as the case may be), De-Noises the shifted data, and then unshifts the de-noised data. Doing this for each of a range of shifts, and averaging the several results so obtained, produces a reconstruction subject to far weaker Gibbs phenomena than thresholding based De-Noising using the traditional orthogonal wavelet transform.", "corpus_id": 16806403, "score": 0 }, { "doc_id": "9403574", "title": "Image Denoising in Mixed Poisson–Gaussian Noise", "abstract": "We propose a general methodology (PURE-LET) to design and optimize a wide class of transform-domain thresholding algorithms for denoising images corrupted by mixed Poisson-Gaussian noise. We express the denoising process as a linear expansion of thresholds (LET) that we optimize by relying on a purely data-adaptive unbiased estimate of the mean-squared error (MSE), derived in a non-Bayesian framework (PURE: Poisson-Gaussian unbiased risk estimate). We provide a practical approximation of this theoretical MSE estimate for the tractable optimization of arbitrary transform-domain thresholding. We then propose a pointwise estimator for undecimated filterbank transforms, which consists of subband-adaptive thresholding functions with signal-dependent thresholds that are globally optimized in the image domain. We finally demonstrate the potential of the proposed approach through extensive comparisons with state-of-the-art techniques that are specifically tailored to the estimation of Poisson intensities. We also present denoising results obtained on real images of low-count fluorescence microscopy.", "corpus_id": 9403574, "score": 1 }, { "doc_id": "124660839", "title": "THE NON-CENTRAL χ2- AND F-DISTRIBUTIONS AND THEIR APPLICATIONS", "abstract": "In the Neyman-Pearson theory of testing statistical hypotheses, the efficiency of a statistical test is to be judged by its power of detecting departures from the null hypothesis. Thus besides knowing the random sampling distribution of a given statistic T under this hypothesis, say Ho, it is also necessary to know the distribution of T under admissible hypotheses alternative to Ho. Hence the power function of the test is obtained. In the case of the wellknown tests using X2, t and F, the evaluation of their power functions involves the use of what have been called non-central distributions. For example, if we are applying the t-test to examine if a sample has come from a normal population with mean # = 0(HO), we know that under Ho, t has a 5 % chance of exceeding the 5 % point of its distribution. But in order to compute the power of the test we wish to know the chance that t exceeds this point when M has alternative values, not equal to zero. This chance is given by the non-central t-integral. This distribution has been studied by Fisher (1931), Neyman (1935), Neyman & Tokarska (1936) and Johnson & Welch (1939). In a similar way, the non-central X2and F-distributions arise in consideration of the power functions of the X2and variance-ratio tests. The power function may be used either to determine the extent of the departures from Ho in a given direction, which will be detected as significant (at a prescribed level) with a given probability, or it may be used to determine in advance the size of experiment necessary to ensure that a worth-while difference will be established as significant, if it exists. But apart from its value in this connexion, the study of non-central distributions is of considerable interest. The mathematical forms of these distributions of t, x2 and F have been long known, but their use without extensive tabling has not been easy. The present paper is therefore concerned with two lines of investigation: (a) The derivation of certain approximations to the probability integrals of (i) non-central X2, and (ii) the ratio of non-central X2 to an independent central X2, which we have termed noncentral F. These approximations, depending on tabled functions, permit easy calculation. (b) Discussion of the ways in which these distributions may be used in connexion with the power functions of statistical tests.", "corpus_id": 124660839, "score": 0 }, { "doc_id": "149055", "title": "De-noising by soft-thresholding", "abstract": "Donoho and Johnstone (1994) proposed a method for reconstructing an unknown function f on [0,1] from noisy data d/sub i/=f(t/sub i/)+/spl sigma/z/sub i/, i=0, ..., n-1,t/sub i/=i/n, where the z/sub i/ are independent and identically distributed standard Gaussian random variables. The reconstruction f/spl circ/*/sub n/ is defined in the wavelet domain by translating all the empirical wavelet coefficients of d toward 0 by an amount /spl sigma//spl middot//spl radic/(2log (n)/n). The authors prove two results about this type of estimator. [Smooth]: with high probability f/spl circ/*/sub n/ is at least as smooth as f, in any of a wide variety of smoothness measures. [Adapt]: the estimator comes nearly as close in mean square to f as any measurable estimator can come, uniformly over balls in each of two broad scales of smoothness classes. These two properties are unprecedented in several ways. The present proof of these results develops new facts about abstract statistical inference and its connection with an optimal recovery model. >", "corpus_id": 149055, "score": 0 }, { "doc_id": "8872792", "title": "Wavelet-based Poisson rate estimation using the Skellam distribution", "abstract": "Owing to the stochastic nature of discrete processes such as photon counts in imaging, real-world data measurements often exhibit heteroscedastic behavior. In particular, time series components and other measurements may frequently be assumed to be non-iid Poisson random variables, whose rate parameter is proportional to the underlying signal of interest-witness literature in digital communications, signal processing, astronomy, and magnetic resonance imaging applications. In this work, we show that certain wavelet and filterbank transform coefficients corresponding to vector-valued measurements of this type are distributed as sums and differences of independent Poisson counts, taking the so-called Skellam distribution. While exact estimates rarely admit analytical forms, we present Skellam mean estimators under both frequentist and Bayes models, as well as computationally efficient approximations and shrinkage rules, that may be interpreted as Poisson rate estimation method performed in certain wavelet/filterbank transform domains. This indicates a promising potential approach for denoising of Poisson counts in the above-mentioned applications.", "corpus_id": 8872792, "score": 0 }, { "doc_id": "7222723", "title": "Fast interscale wavelet denoising of Poisson-corrupted images", "abstract": "We present a fast algorithm for image restoration in the presence of Poisson noise. Our approach is based on (1) the minimization of an unbiased estimate of the MSE for Poisson noise, (2) a linear parametrization of the denoising process and (3) the preservation of Poisson statistics across scales within the Haar DWT. The minimization of the MSE estimate is performed independently in each wavelet subband, but this is equivalent to a global image-domain MSE minimization, thanks to the orthogonality of Haar wavelets. This is an important difference with standard Poisson noise-removal methods, in particular those that rely on a non-linear preprocessing of the data to stabilize the variance. Our non-redundant interscale wavelet thresholding outperforms standard variance-stabilizing schemes, even when the latter are applied in a translation-invariant setting (cycle-spinning). It also achieves a quality similar to a state-of-the-art multiscale method that was specially developed for Poisson data. Considering that the computational complexity of our method is orders of magnitude lower, it is a very competitive alternative. The proposed approach is particularly promising in the context of low signal intensities and/or large data sets. This is illustrated experimentally with the denoising of low-count fluorescence micrographs of a biological sample.", "corpus_id": 7222723, "score": 0 }, { "doc_id": "11995267", "title": "Adapting to Unknown Smoothness via Wavelet Shrinkage", "abstract": "Abstract We attempt to recover a function of unknown smoothness from noisy sampled data. We introduce a procedure, SureShrink, that suppresses noise by thresholding the empirical wavelet coefficients. The thresholding is adaptive: A threshold level is assigned to each dyadic resolution level by the principle of minimizing the Stein unbiased estimate of risk (Sure) for threshold estimates. The computational effort of the overall procedure is order N · log(N) as a function of the sample size N. SureShrink is smoothness adaptive: If the unknown function contains jumps, then the reconstruction (essentially) does also; if the unknown function has a smooth piece, then the reconstruction is (essentially) as smooth as the mother wavelet will allow. The procedure is in a sense optimally smoothness adaptive: It is near minimax simultaneously over a whole interval of the Besov scale; the size of this interval depends on the choice of mother wavelet. We know from a previous paper by the authors that traditional smoot...", "corpus_id": 11995267, "score": 0 }, { "doc_id": "25386929", "title": "Spatially adaptive wavelet thresholding with context modeling for image denoising", "abstract": "The method of wavelet thresholding for removing noise, or denoising, has been researched extensively due to its effectiveness and simplicity. Much of the literature has focused on developing the best uniform threshold or best basis selection. However, not much has been done to make the threshold values adaptive to the spatially changing statistics of images. Such adaptivity can improve the wavelet thresholding performance because it allows additional local information of the image (such as the identification of smooth or edge regions) to be incorporated into the algorithm. This work proposes a spatially adaptive wavelet thresholding method based on context modeling, a common technique used in image compression to adapt the coder to changing image characteristics. Each wavelet coefficient is modeled as a random variable of a generalized Gaussian distribution with an unknown parameter. Context modeling is used to estimate the parameter for each coefficient, which is then used to adapt the thresholding strategy. This spatially adaptive thresholding is extended to the overcomplete wavelet expansion, which yields better results than the orthogonal transform. Experimental results show that spatially adaptive wavelet thresholding yields significantly superior image quality and lower MSE than the best uniform thresholding with the original image assumed known.", "corpus_id": 25386929, "score": 0 }, { "doc_id": "207761262", "title": "Image quality assessment: from error visibility to structural similarity", "abstract": "Objective methods for assessing perceptual image quality traditionally attempted to quantify the visibility of errors (differences) between a distorted image and a reference image using a variety of known properties of the human visual system. Under the assumption that human visual perception is highly adapted for extracting structural information from a scene, we introduce an alternative complementary framework for quality assessment based on the degradation of structural information. As a specific example of this concept, we develop a structural similarity index and demonstrate its promise through a set of intuitive examples, as well as comparison to both subjective ratings and state-of-the-art objective methods on a database of images compressed with JPEG and JPEG2000. A MATLAB implementation of the proposed algorithm is available online at http://www.cns.nyu.edu//spl sim/lcv/ssim/.", "corpus_id": 207761262, "score": 0 }, { "doc_id": "14400709", "title": "Automatic estimation of the noise variance from the histogram of a magnetic resonance image.", "abstract": "Estimation of the noise variance of a magnetic resonance (MR) image is important for various post-processing tasks. In the literature, various methods for noise variance estimation from MR images are available, most of which however require user interaction and/or multiple (perfectly aligned) images. In this paper, we focus on automatic histogram-based noise variance estimation techniques. Previously described methods are reviewed and a new method based on the maximum likelihood (ML) principle is presented. Using Monte Carlo simulation experiments as well as experimental MR data sets, the noise variance estimation methods are compared in terms of the root mean squared error (RMSE). The results show that the newly proposed method is superior in terms of the RMSE.", "corpus_id": 14400709, "score": 0 }, { "doc_id": "5827025", "title": "Noise measurement from magnitude MRI using local estimates of variance and skewness.", "abstract": "In this note, we address the estimation of the noise level in magnitude magnetic resonance (MR) images in the absence of background data. Most of the methods proposed earlier exploit the Rayleigh distributed background region in MR images to estimate the noise level. These methods, however, cannot be used for images where no background information is available. In this note, we propose two different approaches for noise level estimation in the absence of the image background. The first method is based on the local estimation of the noise variance using maximum likelihood estimation and the second method is based on the local estimation of the skewness of the magnitude data distribution. Experimental results on synthetic and real MR image datasets show that the proposed estimators accurately estimate the noise level in a magnitude MR image, even without background data.", "corpus_id": 5827025, "score": 0 }, { "doc_id": "1912619", "title": "K-SVD : An Algorithm for Designing of Overcomplete Dictionaries for Sparse Representation", "abstract": "In recent years there has been a growing interest in the study of sparse representation of signals. Using an overcomplete dictionary that contains prototype signal-atoms, signals are described by sparse linear combinations of these atoms. Applications that use sparse representation are many and include compression, regularization in inverse problems, feature extraction, and more. Recent activity in this field concentrated mainly on the study of pursuit algorithms that decompose signals with respect to a given dictionary. Designing dictionaries to better fit the above model can be done by either selecting one from a pre-specified set of linear transforms, or by adapting the dictionary to a set of training signals. Both these techniques have been considered, but this topic is largely still open. In this paper we propose a novel algorithm for adapting dictionaries in order to achieve sparse signal representations. Given a set of training signals, we seek the dictionary that leads to the best representation for each member in this set, under strict sparsity constraints. We present a new method – the K-SVD algorithm – generalizing the K-Means clustering process. K-SVD is an iterative method that alternates between sparse coding of the examples based on the current dictionary, and a process of updating the dictionary atoms to better fit the data. The update of the dictionary columns is combined with an update of the sparse representations, thereby accelerating convergence. The K-SVD algorithm is flexible and can work with any pursuit method (e.g., basis pursuit, FOCUSS, or matching pursuit). We analyze this algorithm and demonstrate its results on both synthetic tests and in applications on real image data.", "corpus_id": 1912619, "score": 0 } ]

{ "doc_id": "53533191", "title": "Nonparametric frequency domain analysis of nonstationary multivariate time series", "abstract": "We analyse the properties of nonparametric spectral estimates when applied to long memory and trending nonstationary multiple time series. We show that they estimate consistently a generalized or pseudo-spectral density matrix at frequencies both close and away from the origin and we obtain the asymptotic distribution of the estimates. Using adequate data tapers this technique is consistent for observations with any degree of nonstationarity, including polynomial trends. We propose an estimate of the degree of fractional cointegration for possibly nonstationary series based on coherence estimates around zero frequency and analyse its finite sample properties in comparison with residual-based inference. We apply this new semiparametric estimate to an example vector time series.", "corpus_id": 53533191 }

[ { "doc_id": "123348002", "title": "Time series - data analysis and theory", "abstract": "This book will be most useful to applied mathematicians, communication engineers, signal processors, statisticians, and time series researchers, both applied and theoretical. Readers should have some background in complex function theory and matrix algebra and should have successfully completed the equivalent of an upper division course in statistics.", "corpus_id": 123348002, "score": 0 }, { "doc_id": "123467908", "title": "ESTIMATION OF THE MEMORY PARAMETER FOR NONSTATIONARY OR NONINVERTIBLE FRACTIONALLY INTEGRATED PROCESSES", "abstract": ". We consider the asymptotic characteristics of the periodogram ordinates of a fractionally integrated process having memory parameter d≥ 0.5, for which the process is nonstationary, or d≤ -.5, for which the process is noninvertible. Series having d outside the range (-.5,.5) may arise in practice when a raw series is modeled without preliminary consideration of the stationarity and invertibility of the series or when a wrong decision is made concerning the stationarity and invertibility of the series. We find that the periodogram of a nonstationary or noninvertible fractionally integrated process at the jth Fourier frequency ωj= 2πj/n, where n is the sample size, suffers from an asymptotic relative bias which depends on j. We also examine the impact of periodogram bias on the regression estimator of d proposed by Geweke and Porter-Hudak (1983) in finite samples. The results indicate that the bias in the periodogram ordinates can strongly affect the GPH estimator even when the number of Fourier frequencies used in the regression is allowed to depend on the length of the series. We find that data tapering and elimination of the first periodogram ordinate in the regression can reduce this bias, at the cost of an increase in variance for nonstationary series. Additionally, we find for nonstationary series that the GPH estimator is more nearly invariant to first-differencing when a data taper is used.", "corpus_id": 123467908, "score": 1 }, { "doc_id": "122340330", "title": "Semiparametric Analysis of Long-Memory Time Series", "abstract": "We study problems of semiparametric statistical inference connected with long-memory covariance stationary time series, having spectrum which varies regularly at the origin: There is an unknown self-similarity parameter, but elsewhere the spectrum satisfies no parametric or smoothness conditions, it need not be in $L_p$, for any $p > 1$, and in some circumstances the slowly varying factor can be of unknown form. The basic statistic of interest is the discretely averaged periodogram, based on a degenerating band of frequencies around the origin. We establish some consistency properties under mild conditions. These are applied to show consistency of new estimates of the self-similarity parameter and scale factor. We also indicate applications of our results to standard errors of least squares estimates of polynomial regression with long-memory errors, to generalized least squares estimates of this model and to estimates of a \"cointegrating\" relationship between long-memory time series", "corpus_id": 122340330, "score": 0 }, { "doc_id": "121918124", "title": "Band Spectrum Regression for Cointegrated Time Series with Long Memory Innovations", "abstract": "Band spectrum regression is considered for cointegrated time series with long memory innovations. The estimates we advocate are shown to be consistent when cointegrating relationships among stationary variables are investigated, while OLS are inconsistent due to correlation between the regressor and the cointegrating residuals; in the presence of unit roots, these estimates share the same asymptotic distribution as OLS. As a corollary of the main result, we provide a functional central limit theorem for quadratic forms in nonstationary fractionally integrated processes.", "corpus_id": 121918124, "score": 1 }, { "doc_id": "122793370", "title": "Asymptotic normality of spectral estimates", "abstract": "The asymptotic normality of some spectral estimates, including a functional central limit theorem for an estimate of the spectral distribution function, is proved for fourth-order stationary processes. In contrast to known results it is not assumed that all moments exist or that the process is linear. The data are allowed to be tapered. Using some recent results on the central limit theorem for stationary processes, corollaries are obtained for strong and [phi]-mixing sequences and linear transformations of martingale differences.", "corpus_id": 122793370, "score": 0 }, { "doc_id": "120459238", "title": "On the errors-in-variables problem for time series", "abstract": "The usual assumption in the classical errors-in-variables problem of independent measurement errors cannot necessarily be maintained when the data are time series; errors may be strongly serially correlated, possibly containing seasonal effects and trends. When it is possible to identify frequency bands over which the signal-to-noise ratio is large, an approximate solution to the errors-in-variables problem is to omit the remaining frequencies from a time series regression. We draw attention to the danger of \"leakage\" from the omitted frequencies, and show that the consequent bias can be reduced by means of tapering.", "corpus_id": 120459238, "score": 0 }, { "doc_id": "18184838", "title": "Narrow-Band Analysis of Nonstationary Processes", "abstract": "The behaviour of averaged periodograms and cross-periodograms of a broad class of nonstationary processes is studied. The processes include nonstationary ones that are fractional of any order, as well as asymptotically stationary fractional ones. The cross-periodogram can involve two nonstationary processes of possibly different orders, or a nonstationary and an asymptotically stationary one. The averaging takes place either over the whole frequency band, or over one that degenerates slowly to zero frequency as sample size increases. In some cases it is found to make no asymptotic difference, and in particular we indicate how the behaviour of the mean and variance changes across the two-dimensional space of integration orders. The results employ only local-to-zero assumptions on the spectra of the underlying weakly stationary sequences. It is shown how the results can be applied in fractional cointegration with unknown integration orders.", "corpus_id": 18184838, "score": 1 }, { "doc_id": "55160770", "title": "THE NONSTATIONARY FRACTIONAL UNIT ROOT", "abstract": "This paper deals with a scalar I(d) process {yj}, where the integration order d is any real number. Under this setting, we first explore asymptotic properties of various statistics associated with {yj}, assuming that d is known and is greater than or equal to ½. Note that {yj} becomes stationary when d ½. We then consider, under the normality assumption, testing and estimation for d, allowing for any value of d. The tests suggested here are asymptotically uniformly most powerful invariant, whereas the maximum likelihood estimator is asymptotically efficient. The asymptotic theory for these results will not assume normality. Unlike in the usual unit root problem based on autoregressive models, standard asymptotic results hold for test statistics and estimators, where d need not be restricted to d ≥ ½. Simulation experiments are conducted to examine the finite sample performance of both the tests and estimators.", "corpus_id": 55160770, "score": 0 }, { "doc_id": "120400298", "title": "CONSISTENCY OF THE AVERAGED CROSS‐PERIODOGRAM IN LONG MEMORY SERIES", "abstract": "Several aspects of inference with long memory series in a multivariate framework are examined. The main result of this paper is to prove the consistency of the averaged cross‐ periodogram evaluated in a degenerating neighbourhood of zero frequency. We also illustrate several applications of that result and consider some specification issues.", "corpus_id": 120400298, "score": 0 }, { "doc_id": "56339472", "title": "Non-stationary log-periodogram regression", "abstract": "Abstract We study asymptotic properties of the log-periodogram semiparametric estimate of the memory parameter d for non-stationary ( d⩾ 1 2 ) time series with Gaussian increments, extending the results of Robinson (1995) for stationary and invertible Gaussian processes. We generalize the definition of the memory parameter d for non-stationary processes in terms of the (successively) differentiated series. We obtain that the log-periodogram estimate is asymptotically normal for d∈[ 1 2 , 3 4 ) and still consistent for d∈[ 1 2 , 1) . We show that with adequate data tapers, a modified estimate is consistent and asymptotically normal distributed for any d, including both non-stationary and non-invertible processes. The estimates are invariant to the presence of certain deterministic trends, without any need of estimation.", "corpus_id": 56339472, "score": 0 }, { "doc_id": "153937008", "title": "Long Memory in Stock-Market Trading Volume", "abstract": "This article examines consistent estimation of the long-memory parameters of stock-market trading volume and volatility. The analysis is carried out in the frequency domain by tapering the data instead of detrending them. The main theoretical contribution of the article is to prove a central limit theorem for a multivariate two-step estimator of the memory parameters of a nonstationary vector process. Using robust semiparametric procedures, the long-memory properties of trading volume for the 30 stocks in the Dow Jones Industrial Average index are analyzed. Two empirical results are found. First, there is strong evidence that stock-market trading volume exhibits long memory. Second, although it is found that volatility and volume exhibit the same degree of long memory for most of the stocks, there is no evidence that both processes share the same long-memory component.", "corpus_id": 153937008, "score": 0 }, { "doc_id": "18652080", "title": "Log-Periodogram Regression Of Time Series With Long Range Dependence", "abstract": "This paper discusses the use of fractional exponential models (Robinson (1990), Beran (1994)) to model the spectral density f(x) of a covariance stationary process when f(x) may be decomposed as f(x) = x ?2d f (x), where f (x) is bounded and bounded away from zero. A form of log-periodogram regression technique is presented both in the parametric context (i.e. f (x) is a nite order exponential model in the sense of Bloommeld (1973)) and the semi-parametric context (f (x) is regarded as a nuisance parameter). Assuming gaussianity and additional conditions on the regularity of f (x) which seem mild, asymptotic normality of the parameter estimates in the parametric and the semi-parametric context is established. As a by-product, some improvements over the results presented by Robinson (1994) have been obtained for the large sample distribution of log-periodogram ordinates for Gaussian processes.", "corpus_id": 18652080, "score": 1 }, { "doc_id": "122259513", "title": "Gaussian Semiparametric Estimation of Long Range Dependence", "abstract": "Assuming the model f(A) GA1- 2H, as A -- 0 +, for the spectral densityo f a covariances tationaryp rocess,w e considera n estimateo f H E (0, 1) which maximizes an approximate form of frequency domain Gaussian likelihood, where discrete averaging is carried out over a neighbourhood of zero frequency which degenerates slowly to zero as sample size tends to infinityT. he estimate has several advantages. It is shown to be consistent under mild conditions. Under conditions which are not greatly stronger, it is shown to be asymptotically normal and more efficientt han previous estimates. Gaussianity is nowhere assumed in the asymptotict heory,t he limitingn ormal distributioni s of very simple form, involving a variance which is not dependent on unknown parameters, and the theory covers simultaneously the cases f(A) -x oc, f(A) -+ 0 and f(A) -+ C E (0, oc), as A -* 0. Monte Carlo evidence on finite-sample performance is reported, along with an application to a historical series of minimum levels of the River Nile.", "corpus_id": 122259513, "score": 1 }, { "doc_id": "121785356", "title": "A semiparametric two-step estimator in a multivariate long memory model", "abstract": "This paper analyzes a two-step estimator of the long memory parameters of a vector process. The objective function considered is a semiparametric version of the multivariate Gaussian likelihood function in the frequency domain. In our context, semiparametric refers to the fact that only periodogram ordinates evaluated in a degenerating neighborhood of zero frequency are employed in the estimation procedure. Asymptotic normality is established under mild conditions that do not include Gaussianity. Furthermore, the simplicity of the form of the covariance matrix of the estimates facilitates statistical inference. We include an application of these estimates to exchange rate data.", "corpus_id": 121785356, "score": 0 }, { "doc_id": "120186925", "title": "REGRESSION OF SPECTRAL ESTIMATORS WITH FRACTIONALLY INTEGRATED TIME SERIES", "abstract": ". Assuming a normal distribution we supplement the proof of periodogram regression suggested by Geweke and Porter-Hudak (J. Time Ser. Anal. 4 (1983) 221–38) in order to estimate and test the difference parameter of fractionally integrated autoregressive moving-average models. The procedure proposed by Kashyap and Eom (J. Time Ser. Anal. 9 (1988) 35–41) arises as a special case and is found to be correct if the true parameter value is negative. Regression of the smoothed periodogram yields estimators for the difference parameter with much faster vanishing variance; no asymptotic distribution can be derived, however. In computer experiments we find that the smoothed periodogram regression may be superior to pure periodogram regression when we have to discriminate between autoregression and fractional integration", "corpus_id": 120186925, "score": 0 }, { "doc_id": "121479524", "title": "LAG WINDOW ESTIMATION OF THE DEGREE OF DIFFERENCING IN FRACTIONALLY INTEGRATED TIME SERIES MODELS", "abstract": ". In this paper we consider the estimation of the degree of differencing d in the fractionally integrated autoregressive moving-average time series model ARFIMA (p, d, q). Using lag window spectral density estimators we develop a regression type estimator of d which is easy to calculate and does not require prior knowledge of p and q. Some large sample properties of the estimator are studied and the performance of the estimator for small samples is investigated using the simulation method for a range of commonly used lag windows. Some practical recommendations on the choice of lag windows and the choice of the window parameters are provided.", "corpus_id": 121479524, "score": 0 }, { "doc_id": "123179190", "title": "ESTIMATION OF THE FRACTIONAL DIFFERENCE PARAMETER IN THE ARIMA(p, d, q) MODEL USING THE SMOOTHED PERIODOGRAM", "abstract": ". In recent work on time series analysis considerable interest has been focused on series having the property of long memory. Long memory is a characteristic of time series in which the dependence between distant observations is not negligible. The model that has been most frequently studied, which in some situations shows properties of long memory, is based on the autoregressive integrated moving-average ARIMA(p, d, q) process. Hosking (Fractional differencing, Biometrika 68 (1) (1981), 165–76) generalized this model by permitting the degree of differencing d to take fractional values. He then demonstrated that for d in the range 0 < d < 0.5 the process is stationary and possesses the long memory property. Our study is based on the ARIMA(p, d, q) model when d takes any real non-integer value in the interval (-0.5, 0.5). The main aim of our study is to examine methods for estimating the parameters of this model. For estimating d we suggest an estimator based on the smoothed periodogram. Using an empirical approach we compare this estimator with other which are well known in the literature of long memory models, e.g. the raw periodogram regression method and the Hurst coefficient method.", "corpus_id": 123179190, "score": 0 }, { "doc_id": "121226929", "title": "Time series regression with long-range dependence", "abstract": "A central limit theorem is established for time series regression estimates which include generalized least squares, in the presence of long-range dependence in both errors and stochastic regressors. The setting and results differ significantly from earlier work on regression withlong-range-dependent errors. Spectral singularities are permitted at any frequency. When sufficiently strong spectral singularities in the error and a regressor coincide at the same frequency, least squares need no longer be $n^{1/2}$-consistent, where n is the sample size. However, we show that our class of estimates is $n^{1/2}$-consistent and asymptotically normal. In the generalized least squares case, we show that efficient estimation is still possible when the error autocorrelation is known only up to finitely many parameters. We include a Monte Carlo study of finite-sample performance and provide an extension to nonlinear least squares.", "corpus_id": 121226929, "score": 0 }, { "doc_id": "11330076", "title": "Residual Log-Periodogram Inference for Long-Run-Relationships", "abstract": "We assume that some consistent estimator of an equilibrium relation between non-stationary fractionally integrated series is used in a first step to compute residuals (or differences thereof). We propose to apply the semiparametric log-periodogram regression to the (differenced) residuals in order to estimate and test the degree of persistence of the equilibrium deviation. Provided the first step estimator converges fast enough, we describe simple semiparametric conditions around zero frequency that guarantee consistent estimation of persistence from residuals. At the same time limiting normality is derived, which allows to construct approximate confidence intervals to test hypotheses on the persistence. Our assumptions allow for stationary deviations with long memory as well as for non-stationary but transitory equilibrium errors. In particular, in case of several regressors we consider the joint estimation of the memory parameters of the observed series and of the equilibrium deviation. Wald statistics to test for parameter restrictions of the system have a limiting chi-squared distribution. We also analyze the benefits of a pooled version of the estimate. The empirical applicability of our general cointegration test is investigated by means of Monte Carlo experiments and illustrated with a study of exchange rate dynamics.", "corpus_id": 11330076, "score": 0 }, { "doc_id": "119752825", "title": "THE ESTIMATION AND APPLICATION OF LONG MEMORY TIME SERIES MODELS", "abstract": "Abstract. The definitions of fractional Gaussian noise and integrated (or fractionally differenced) series are generalized, and it is shown that the two concepts are equivalent. A new estimator of the long memory parameter in these models is proposed, based on the simple linear regression of the log periodogram on a deterministic regressor. The estimator is the ordinary least squares estimator of the slope parameter in this regression, formed using only the lowest frequency ordinates of the log periodogram. Its asymptotic distribution is derived, from which it is evident that the conventional interpretation of these least squares statistics is justified in large samples. Using synthetic data the asymptotic theory proves to be reliable in samples of 50 observations or more. For three postwar monthly economic time series, the estimated integrated series model provides more reliable out-of-sample forecasts than do more conventional procedures.", "corpus_id": 119752825, "score": 0 }, { "doc_id": "14065938", "title": "Maximum-Likelihood Estimation of Fractional Cointegration with an Application to U.S. and Canadian Bond Rates", "abstract": "We estimate a multivariate ARFIMA model to illustrate a cointegration testing methodology based on joint estimates of the fractional orders of integration of a cointegrating vector and its parent series. Previous cointegration tests relied on a two-step testing procedure and maintained the assumption in the second step that the parent series were known to have a unit root. In our empirical example of fractional cointegration, we illustrate how uncertainty regarding the order of integration of the parent series can be even more important than uncertainty regarding the order of integration of the cointegrating vector when testing for cointegration.", "corpus_id": 14065938, "score": 0 } ]

{ "doc_id": "3032926", "title": "The Future of Deforestation in the Brazilian Amazon", "abstract": "Abstract Concern about the future of Amazonian forests is growing as both the extent and rate of primary forest destruction increase. We combine spatial information on various biophysical, demographic and infrastructural factors in the Brazilian Amazon with satellite data on deforestation to evaluate the relative importance of each factor to deforestation in the region. We assess the sensitivity of results to alternative sampling methodologies, and compare our results to those of previous empirical studies of Amazonian deforestation. Our findings, in concert with those of previous studies, send a clear message to planners: both paved and unpaved roads are key drivers of the deforestation process. Proximity to previous clearings, high population densities, low annual rainfall, and long dry seasons also increase the likelihood that a site will be deforested; however, roads are consistently important and are the factors most amenable to policymaking. We argue that there is ample evidence to justify a fundamental change in current Amazonian development priorities if additional large-scale losses of forests and environmental services are to be avoided.", "corpus_id": 3032926 }

[ { "doc_id": "154136134", "title": "Environmental services as a strategy for sustainable development in rural Amazonia", "abstract": "Abstract Rural Amazonians, especially Indians, extractivists and other forest dwellers, desperately need something that they can sell. Sale of material commodities taken from the rainforest is the focus of most attempts to encourage ‘sustainable development’ for these populations, but the mother lode waiting to be tapped is not a material commodity, but rather the forest's environmental services. Converting services like biodiversity maintenance, carbon storage and water cycling into monetary flows that can support a population of forest guardians requires crossing a series of hurdles. Reliable quantification of the magnitude of services being offered is a first necessity. How to convert forest environmental services into an income stream, and how to convert this stream into a foundation for sustainable development in rural Amazonia is a great challenge. Effort should be focused on tapping environmental services as a long-term strategy for maintaining both rainforest and its population. In addition to progressing toward long-term goals, immediate measures are needed to support the population and to avoid further loss of forest.", "corpus_id": 154136134, "score": 0 }, { "doc_id": "153481315", "title": "Deforestation and land use in the Brazilian Amazon", "abstract": "Deforestation in the Brazilian Amazon was less than 1% before 1975. Between 1975 and 1987 the rate increased exponentially. By 1985, world opinion and attention to the destruction of the richest biome on earth led to elimination of some of the major incentives that had fueled deforestation. Favorable credit policies for cattle ranchers, rather than population growth, explains the process of deforestation in the Brazilian Amazon. The paper suggests other actions that may be taken to reduce deforestation, and examines the rapid growth rates of secondary successional species in a colonization area.", "corpus_id": 153481315, "score": 1 }, { "doc_id": "21872130", "title": "A crisis in the making: responses of Amazonian forests to land use and climate change.", "abstract": "At least three global-change phenomena are having major impacts on Amazonian forests: (1) accelerating deforestation and logging; (2) rapidly changing patterns of forest loss; and (3) interactions between human land-use and climatic variability. Additional alterations caused by climatic change, rising concentrations of atmospheric carbon dioxide, mining, overhunting and other large-scale phenomena could also have important effects on the Amazon ecosystem. Consequently, decisions regarding Amazon forest use in the next decade are crucial to its future existence.", "corpus_id": 21872130, "score": 0 }, { "doc_id": "84971077", "title": "Road paving, fire regime feedbacks, and the future of Amazon forests", "abstract": "Abstract Fire poses the greatest threat to the forests of Amazonia. The magnitude of this threat is amplified by three positive feedback loops that drive the expansion of forest fire in the region: (1) Fire promotes drought, and therefore more fire, by releasing smoke into the atmosphere, thus reducing rainfall. Fire-assisted conversion of forests to pastures may also promote drought by increasing albedo and decreasing water vapor flux to the atmosphere, further inhibiting rainfall. (2) Fire increases the susceptibility of forests to recurrent burning by killing trees, thereby allowing sunlight to penetrate the forest interior, and increasing the fuel load on the forest floor. (3) Finally, fires also self-perpetuate by burning agricultural and forestry systems, discouraging landholders from making those fire-sensitive investments in their land that would allow them to move beyond their dependence upon fire as a management tool. The long-term reduction of Amazon fire, and its substantial costs to society, is most likely to emerge through investments and policy change that stimulate permanent agricultural and forestry production systems within existing frontiers while slowing the rate of frontier expansion. But the Brazilian government’s plan to pave, recuperate or construct 6245 km of roads in the Amazon may have the opposite effect. We present research findings that the government plan would nearly double the area of forestland that is accessible by paved highways, including 192,000 km2 of fire-prone forest. Our analysis finds that these roads will stimulate 120,000–270,000 km2 of additional deforestation, and forest impoverishment through logging and understory fire, if the historical relationship between road paving and forest alteration by humans continues. Infrastructural investments are urgently needed in Amazonia to help integrate isolated urban centers into the market economy, to improve the quality of life for millions of rural Amazonians, and to improve the profitability of agribusiness in Brazil’s agricultural belt. But as currently planned, these investments will have the ancillary effects of accelerating deforestation, logging, forest fire, smoke-related illness, and the displacement of small-scale farmers.", "corpus_id": 84971077, "score": 1 }, { "doc_id": "126819814", "title": "Predominant land uses in Brazilian Amazonia.", "abstract": "Please cite as: Fearnside, P.M. 1990. Predominant land uses in the Brazilian Amazon. pp. 235-251 In: A.B. Anderson (compilador) Alternatives to Deforestation: Towards Sustainable Use of the Amazon Rain Forest. Columbia University Press, New York, U.S.A. 281 pp. Copyright: Columbia University Press, New York, U.S.A. The original publication is available from: Columbia University Press, New York, U.S.A.", "corpus_id": 126819814, "score": 1 }, { "doc_id": "87460056", "title": "Deforestation in Brazilian Amazonia: the effect of population and land tenure", "abstract": "LANDSAT data for 1978, 1988, 1989, 1990 and 1991 indicate that by 1991 the area of forest cleared had reached 426.000 km2 (10.5 of the 4 million Km2 originally forested portion of Brazil's 5 million km2 legal Amazon Region). Over the 1978-1988 period, forest was lost at a rate of 22.000 km2 yr-1 (including hydroelectric flooding), while the rate was 19.000 km2 yr-1 for 1988-1989, 14.000 km2 yr-1 for 1989-1990 and 11.000 yr-1 for 1990-1991. The reduction in the rate since 1987 has mostly been due to Brazil's economic recession rather than to any policy changes. The number of properties censured in each size class explains 74 of the variation in deforestation rate among the 9 Amazonian states. Multiple regressions indicate that 30 of the clearing in 1991 can be attributed to small farmers (properties", "corpus_id": 87460056, "score": 0 }, { "doc_id": "44770405", "title": "Soybean cultivation as a threat to the environment in Brazil", "abstract": "Soybeans represent a recent and powerful threat to tropical biodiversity in Brazil. Developing effective strategies to contain and minimize the environmental impact of soybean cultivation requires understanding of both the forces that drive the soybean advance and the many ways that soybeans and their associated infrastructure catalyse destructive processes. The present paper presents an up-to-date review of the advance of soybeans in Brazil, its environmental and social costs and implications for development policy. Soybeans are driven by global market forces, making them different from many of the land-use changes that have dominated the scene in Brazil so far, particularly in Amazonia. Soybeans are much more damaging than other crops because they justify massive transportation infrastructure projects that unleash a chain of events leading to destruction of natural habitats over wide areas in addition to what is directly cultivated for soybeans. The capacity of global markets to absorb additional production represents the most likely limit to the spread of soybeans, although Brazil may someday come to see the need for discouraging rather than subsidizing this crop because many of its effects are unfavourable to national interests, including severe concentration of land tenure and income, expulsion of population to Amazonian frontier, and gold-mining, as well as urban areas, and the opportunity cost of substantial drains on government resources. The multiple impacts of soybean expansion on biodiversity and other development considerations have several implications for policy: (1) protected areas need to be created in advance of soybean frontiers, (2) elimination of the many subsidies that speed soybean expansion beyond what would occur otherwise from market forces is to be encouraged, (3) studies to assess the costs of social and environmental impacts associated with soybean expansion are urgently required, and (4) the environmental-impact regulatory system requires strengthening, including mechanisms for commitments not to implant specific infrastructure projects that are judged to have excessive impacts.", "corpus_id": 44770405, "score": 1 }, { "doc_id": "154543908", "title": "Crossing spatial analyses and livestock economics to understand deforestation processes in the Brazilian Amazon: the case of Sao Felix do Xingu in South Para", "abstract": "The Amazon is the largest tropical forest area on Earth, and has been undergoing rapid deforestation for the last four decades. In the Brazilian Amazon, large-scale pasture for cattle ranching and soybean production are the main land uses, leading to a yearly deforestation rate of 0.5%. These conversions are mostly located in frontier areas distributed along the so-called \"arc of deforestation\". Within this large zone, various land use change processes are interacting through several modes of land valuation and organisation. From several case studies in the State of Para (Brazil), the current project aims at analysing how landscape dynamics are related to infrastructure development, ecological conditions, zoning policies and to the evolution and the organisation of the production, consumption and marketing chains of livestock products. This paper presents the results for one test site, the region of Sao Felix do Xingu, South of Para. This region is the focus of land speculation, cattle expansion, and deforestation. Road construction, investments in electrical energy, financial credit for cattle, and the land reform policies have all fuelled this process. All these factors make this region one of the most dynamic agricultural frontiers in the Brazilian Amazon. The main objective of the paper is to improve our understanding of deforestation processes by crossing spatial analyses and livestock economics studies, and to characterise the role and impact of various natural and anthropic factors in the location and development of the main types of farmers, and their policy implications. © 2002 Elsevier Science B.V. All rights reserved.", "corpus_id": 154543908, "score": 1 }, { "doc_id": "154543908", "title": "Crossing spatial analyses and livestock economics to understand deforestation processes in the Brazilian Amazon: the case of Sao Felix do Xingu in South Para", "abstract": "The Amazon is the largest tropical forest area on Earth, and has been undergoing rapid deforestation for the last four decades. In the Brazilian Amazon, large-scale pasture for cattle ranching and soybean production are the main land uses, leading to a yearly deforestation rate of 0.5%. These conversions are mostly located in frontier areas distributed along the so-called \"arc of deforestation\". Within this large zone, various land use change processes are interacting through several modes of land valuation and organisation. From several case studies in the State of Para (Brazil), the current project aims at analysing how landscape dynamics are related to infrastructure development, ecological conditions, zoning policies and to the evolution and the organisation of the production, consumption and marketing chains of livestock products. This paper presents the results for one test site, the region of Sao Felix do Xingu, South of Para. This region is the focus of land speculation, cattle expansion, and deforestation. Road construction, investments in electrical energy, financial credit for cattle, and the land reform policies have all fuelled this process. All these factors make this region one of the most dynamic agricultural frontiers in the Brazilian Amazon. The main objective of the paper is to improve our understanding of deforestation processes by crossing spatial analyses and livestock economics studies, and to characterise the role and impact of various natural and anthropic factors in the location and development of the main types of farmers, and their policy implications. © 2002 Elsevier Science B.V. All rights reserved.", "corpus_id": 154543908, "score": 0 }, { "doc_id": "73600837", "title": "Deforestation and Cattle Ranching in the Brazilian Amazon: External Capital and Household Processes", "abstract": "This paper decomposes recent deforestation in four study areas in the Brazilian Amazon into components associated with large ranches and small producers. It then assesses in an inferential framework small producer deforestation with respect to the proximate causes of their farming systems, and the household drivers of their farming system choices. It is shown that, for areas with substantial in-migration of small producers, forest clearance at the household level is mainly attributable to the availability of hired labor, and not to household labor force or the physical capital at their disposal. The paper conducts the inferential analysis of small producer deforestation using measures of forest clearance taken from satellite image classification and directly from field surveys. A substantial discrepancy in the measures is identified, which has implications for household level research on land cover change.", "corpus_id": 73600837, "score": 0 }, { "doc_id": "204992349", "title": "Large-scale impoverishment of Amazonian forests by logging and fire", "abstract": "Amazonian deforestation rates are used to determine human effects on the global carbon cycle and to measure Brazil's progress in curbing forest impoverishment,,. But this widely used measure of tropical land use tells only part of the story. Here we present field surveys of wood mills and forest burning across Brazilian Amazonia which show that logging crews severely damage 10,000 to 15,000 km2 yr−1 of forest that are not included in deforestation mapping programmes. Moreover, we find that surface fires burn additional large areas of standing forest, the destruction of which is normally not documented. Forest impoverishment due to such fires may increase dramatically when severe droughts provoke forest leaf-shedding and greater flammability; our regional water-balance model indicates that an estimated 270,000 km2 of forest became vulnerable to fire in the 1998 dry season. Overall, we find that present estimates of annual deforestation for Brazilian Amazonia capture less than half of the forest area that is impoverished each year, and even less during years of severe drought. Both logging and fire increase forest vulnerability to future burning, and release forest carbon stocks to the atmosphere, potentially doubling net carbon emissions from regional land-use during severe El Niño episodes. If this forest impoverishment is to be controlled, then logging activities need to be restricted or replaced with low-impact timber harvest techniques, and more effective strategies to prevent accidental forest fires need to be implemented.", "corpus_id": 204992349, "score": 0 }, { "doc_id": "154754052", "title": "The effects of structural adjustment on deforestation and forest degradation in lowland Bolivia", "abstract": "Bolivia's structural adjustment policies, initiated in 1985, increased poverty among certain groups, but this did not lead to widespread migration to the agricultural frontier. Nor did adjustment greatly affect the average area planted in annual crops by small lowland farmers. Structural adjustment contributed to large-scale forest clearing for soybean production for export and, to a lesser extent, forest degradation by lumber companies. The economic benefits generated by soybean and timber expansion may have outweighed the environmental costs, but alternative policies might have reduced those costs and improved the distribution of the benefits.", "corpus_id": 154754052, "score": 0 }, { "doc_id": "126901754", "title": "National Forests in the Amazon", "abstract": "Brazil9s government is currently implementing a policy for sustainable forest production within an expanded system of National Forests (Flonas). By 2010, 50 million hectares of new Flonas will be created. The scale of this initiative is equivalent to the 1908 establishment of the U.S. National Forest system and is unprecedented in the tropics. The resultant mosaic of conservation areas, combining Flonas with fully protected parks and indigenous reservations, will enhance biodiversity conservation and economic stability throughout the Amazon. Establishment of these Flonas will foster development of large-scale sustainable forestry and make Brazil a world leader in conserving natural resources.", "corpus_id": 126901754, "score": 0 }, { "doc_id": "55507873", "title": "Extent of nontimber resource extraction in tropical forests: Accessibility to game vertebrates by hunters in the Amazon Basin", "abstract": "Abstract: Extractive activities targeting a wide range of nontimber forest products ( NTFPs ) are ubiquitous in tropical forests, yet the extent of structurally intact forests in a given region affected by this form of cryptic disturbance is poorly documented. We conducted a basin-wide geographic information system analysis of the nonmotorized accessibility of Amazonian NTFP extraction and estimated the proportion of the Amazon drainage basin within Brazil ( 3.74 million km 2 ) that can be accessed on foot from the nearest navigable river or functional road. We use a long-term series of standardized line-transect vertebrate censuses conducted throughout the region to illustrate the effects of physical accessibility on wildlife densities in terms of hunting pressure as a function of distance from the nearest point of access. Population abundance in large-bodied, prime-target species preferred by game hunters tended to increase at greater distances from the access matrix, whereas small-bodied species ignored by hunters usually showed the reverse trend. In addition, we estimated the proportion of presumably inviolate core areas within nature, extractive, and indigenous reserves of Brazilian Amazonia that are prohibitively remote and unlikely to be overhunted; for instance, only 1.16% of the basin-wide area is strictly protected on paper and is reasonably safe from extractive activities targeted to game vertebrates and other valuable NTFPs. Finally, we discuss the concept of truly undisturbed wildlands in the last major tropical forest regions by distinguishing potentially overharvested areas from those that remain largely or entirely pristine and that maintain viable populations of a full complement of harvest-sensitive species.", "corpus_id": 55507873, "score": 0 }, { "doc_id": "153411014", "title": "Deforestation in the Brazilian Amazon: Comparing the Impacts of Macroeconomic Shocks, Land Tenure, and Technological Change", "abstract": "The paper examines the current relevance of the set of variables reported in the literature as driving deforestation in the Brazilian Amazon. The analysis uses a computable general equilibrium (CGE)model adapted to capture regional economic structures and the environmental processes specific to tropical areas. The paper compares the impact on deforestation in the Brazilian Amazon of: changes in real exchange rate; modifications in agricultural tax and support policies; reductions in transportation costs arising from investment in infrastructure in the Amazon; changes in land tenure regimes; and technological change in agriculture affecting productivity and agronomic sustainability. (JEL Q15, Q23)", "corpus_id": 153411014, "score": 0 }, { "doc_id": "86646661", "title": "Biodiversity as an environmental service in Brazil's Amazonian forests: risks, value and conservation", "abstract": "The environmental service provided by the great biodiversity of Amazonian forests is one of several factors leading to the conclusion that much greater efforts are warranted to reduce the destruction of these forests. Risks to biodiversity in Amazonian forests include deforestation, logging, fires, fragmentation, depletion of fauna, invasion by exotic species, and climate change. Financial values assigned to biodiversity depend strongly on the purposes of valuation. Utilitarian benefits include the values of presently-marketed and presently-unexploited forest products, and the monetary value of environmental benefits. Non-monetary values of Amazonian forests are also essential components of decision-making on conservation. Measures of ‘willingness to pay’ and ‘willingness to accept’ can be useful as indicators of potential financial flows, but should not be confused with the true values of the forests to society. Valuation for the purpose of setting penalties for destruction of biodiversity is an important legal question in Brazil and must take into consideration additional factors. Conservation of biodiversity in Brazil includes creation of various types of protected areas. The status of these areas varies greatly, with practice frequently deviating from official requirements. Creating reserves that include human occupants has a variety of pros and cons. Although the effect of humans is not always benign, much larger areas can be brought under protection regimes if human occupants are included. Additional considerations apply to buffer zones around protected areas. The choice and design of reserves depends on the financial costs and biodiversity benefits of different strategies. In Brazil, rapid creation of lightly-protected ‘paper parks’ has been a means of keeping ahead of the advance of barriers to establishment of new conservation units, but emphasis must eventually shift to better protection of existing reserves. Indigenous peoples have the best record of maintaining forest, but negotiation with these peoples is essential in order to ensure maintenance of the large areas of forest they inhabit. The benefits of environmental services provided by the forest must accrue to those who maintain these forests. Development of mechanisms to capture the value of these services will be a key factor affecting the long-term prospects of Amazonian forests. However, many effective measures to discourage deforestation could be taken immediately through government action, including levying and collecting taxes that discourage land speculation, changing land tenure establishment procedures so as not to reward deforestation, revoking remaining incentives, restricting road building and improvement, strengthening requirements for environmental impact statements (RIMAs) for proposed development projects, and creating employment alternatives.", "corpus_id": 86646661, "score": 0 }, { "doc_id": "31032936", "title": "Predictors of Deforestation in the Brazilian Amazon", "abstract": "Aim and Location \n \nWe assessed the effects of biophysical and anthropogenic predictors on deforestation in Brazilian Amazonia. This region has the world's highest absolute rates of forest destruction and fragmentation. \n \n \n \nMethods \n \nUsing a GIS, spatial data coverages were developed for deforestation and for three types of potential predictors: (1) human-demographic factors (rural-population density, urban-population size); (2) factors that affect physical accessibility to forests (linear distances to the nearest paved highway, unpaved road and navigable river), and (3) factors that may affect land-use suitability for human occupation and agriculture (annual rainfall, dry-season severity, soil fertility, soil waterlogging, soil depth). To reduce the effects of spatial autocorrelation among variables, the basin was subdivided into >1900 quadrats of 50 × 50 km, and a random subset of 120 quadrats was selected that was stratified on deforestation intensity. A robust ordination analysis (non-metric multidimensional scaling) was then used to identify key orthogonal gradients among the ten original predictor variables. \n \n \n \nResults \n \nThe ordination revealed two major environmental gradients in the study area. Axis 1 discriminated among areas with relatively dense human populations and highways, and areas with sparse populations and no highways; whereas axis 2 described a gradient between wet sites having low dry-season severity, many navigable rivers and few roads, and those with opposite values. A multiple regression analysis revealed that both factors were highly significant predictors, collectively explaining nearly 60% of the total variation in deforestation intensity (F2,117=85.46, P < 0.0001). Simple correlations of the original variables were highly concordant with the multiple regression model and suggested that highway density and rural-population size were the most important correlates of deforestation. \n \n \n \nMainconclusions \n \nThese trends suggest that deforestation in the Brazilian Amazon is being largely determined by three proximate factors: human population density, highways and dry-season severity, all of which increase deforestation. At least at the spatial scale of this analysis, soil fertility and waterlogging had little influence on deforestation activity, and soil depth was only marginally significant. Our findings suggest that current policy initiatives designed to increase immigration and dramatically expand highway and infrastructure networks in the Brazilian Amazon are likely to have important impacts on deforestation activity. Deforestation will be greatest in relatively seasonal, south-easterly areas of the basin, which are most accessible to major population centres and where large-scale cattle ranching and slash-and-burn farming are most easily implemented.", "corpus_id": 31032936, "score": 1 }, { "doc_id": "129365978", "title": "Rainforest Cities: Urbanization, Development, and Globalization of the Brazilian Amazon", "abstract": "Amazonia has undergone a significant urban transformation since the late 1970s. This is the first comprehensive analysis of urbanization in the Brazilian Amazon. Drawing on comparative household and sectoral survey research, the authors find that the growth of Amazon cities fits no single current theory of urbanization; instead they propose a pluralistic theory of \"disarticulated urbanization\" to explain the region's varied and volatile settlement patterns.", "corpus_id": 129365978, "score": 0 }, { "doc_id": "25782542", "title": "Spatial and temporal patterns of Amazon rainfall. Consequences for the planning of agricultural occupation and the protection of primary forests.", "abstract": "The spatial and temporal pattern of annual rainfall and the strength of the dry season within the Amazon region are poorly known. Existing rainfall maps are based on the data from full-scale, long-term meteorological stations, operated by national organizations linked to the World Meteorological Organisation, such as INMET in Brazil. Stations with 30 or more years of uninterrupted and reliable recordings are very few, considering the size of the region, and most of them are located along the major rivers. It has been suggested that rainfall conditions away from these rivers are substantially different. An analysis has been made of the records of a network of simple pluviometric sites in the Brazilian part of the region as maintained by the National Agency for Electric Energy (ANEEL) since 1970. The latter data sets were used to draw more detailed maps on annual rainfall, and on the strength of the dry season in particular; average number of consecutive months with less than 100 mm, 50 mm, and 10 mm, respectively. Also, some data were obtained on the spatial expression of El Niño events within the region. Subregional differences are large, and it is argued that they are important for the success or failure of agricultural settlements; for the hazard of large-scale fire damage of the still existing primary forest vegetation; for the functioning of this land cover as stock and sink of CO2, and for the likelihood that secondary forests on abandoned agricultural lands will have less biomass. The effects of past El Niño rainfall anomalies on the biodiversity of the natural savannahs within the forest region are discussed.", "corpus_id": 25782542, "score": 0 }, { "doc_id": "19353141", "title": "\nAvança Brasil: Environmental and Social Consequences of Brazil's Planned Infrastructure in Amazonia", "abstract": "Abstract\n“Avança Brasil” (Forward Brazil) is a package of 338 projects throughout Brazil; the portion of the plan to be carried out in Brazil's Legal Amazon region totals US$43 billion over 8 years, US$20 billion of which would be for infrastructure causing environmental damage. Brazil's environmental impact assessment system is not yet capable of coping with the challenge presented by Avança Brasil. Generic problems with the licensing process include stimulation of a lobby in favor of construction before decisions are made on the advisability of the projects, the “dragging effect” of third parties, whereby economic activity is attracted to the infrastructure but escapes the environmental impact assessment system, a tendency for consulting firms to produce favorable reports, a bureaucratic emphasis on the existence of steps without regard to the content of what is said, and the inability to take account of the chain of events unleashed when a given project is undertaken.The environmental and social costs of forest loss are high; among them is loss of opportunities for sustainable use of the forest, including loss of environmental services such as biodiversity maintenance, water cycling, and carbon storage. The benefits of export infrastructure are meager, especially from the point of view of generating employment. Much of the transportation infrastructure is for soybeans, while the hydroelectric dams contribute to processing aluminum. The example of Avança Brasil makes clear the need to rethink how major development decisions are made and to reconsider a number of the plan's component projects.", "corpus_id": 19353141, "score": 0 }, { "doc_id": "32234602", "title": "Is deforestation accelerating in the Brazilian Amazon?", "abstract": "Recent studies suggest that deforestation rates in the Brazilian Amazon could increase sharply in the future as a result of over US$ 40 billion in planned investments in highway paving and major new infrastructure projects in the region. These studies have been challenged by several Brazilian ministries, which assert that recent improvements in environmental laws, enforcement and public attitudes have fundamentally reduced the threat posed to forests by such projects. The notion that hazards to Amazonian forests have declined over the last decade was assessed using available data on deforestation rates from 1978 to 2000. Although the alarmingly high rate of forest loss during 1978–1989 (1.98 million ha yr−1) declined somewhat in 1990–1994 (1.38 million ha yr−1), it rebounded to a high level in the period 1995–2000 (1.90 million ha yr−1). Moreover, correlation and regression analyses reveal that both absolute and per caput rates of forest loss accelerated significantly over the last decade. These trends fail to support the assertion that deforestation pressure in Amazonian forests has been brought under control. Poor enforcement of existing environmental laws, rapidly expanding logging and mining industries, increasing population pressure and other challenges are greatly hindering efforts to limit the environmental impacts of development activities in Brazilian Amazonia.", "corpus_id": 32234602, "score": 0 }, { "doc_id": "5396247", "title": "Development of the Brazilian Amazon", "abstract": "In their discussion of “the future of the Brazilian Amazon” ( Science 's Compass, Policy Forum, 19 Jan., p. [438][1]), W. F. Laurance and his co-authors offer a serious contribution to a very serious subject. Nevertheless, we reject their projections of extensive deforestation in the Brazilian", "corpus_id": 5396247, "score": 0 }, { "doc_id": "154427057", "title": "Conservation Policy in Brazilian Amazonia: Understanding the Dilemmas", "abstract": "Abstract Conservation policy in Brazilian Amazonia is rapidly evolving. The dynamics of different interest groups affect the political economy of land use. Choices include allocation of effort between completely and partially protected areas and between creation of new conservation units versus consolidation of existing units. Tensions between different levels of government, different groups of nongovernmental organizations, and between the public versus private sectors are evident. While the conflicting interests of such groups present many barriers, they also offer conservation opportunities. Negotiation with indigenous peoples represents one of the most critical areas for the long-term future of natural ecosystems in the region.", "corpus_id": 154427057, "score": 0 }, { "doc_id": "96889198", "title": "Forests and global warming mitigation in Brazil: opportunities in the Brazilian forest sector for responses to global warming under the ''clean development mechanism''", "abstract": "Abstract The Kyoto Protocol created global warming response opportunities through the clean development mechanism that allow countries like Brazil to receive investments from companies and governments wishing to offset their emissions of greenhouse gases. Brazil has a special place in strategies for combating global warming because its vast areas of tropical forest represent a potentially large source of emissions if deforested. A number of issues need to be settled to properly assign credit for carbon in the types of options presented by the Brazilian forest sector. These include definition of the units of carbon (permanent sequestration versus carbon-ton-years, the latter being most appropriate for forest options), the means of crediting forest reserve establishment, adoption of discounting or other time-preference weighting for carbon, definition of the accounting method (avoided emissions versus stock maintenance), and mechanisms to allow program contributions to be counted, rather than restricting consideration to free-standing projects. Silvicultural plantations offer opportunities for carbon benefits, but these depend heavily on the end use of the products. Plantations for charcoal have the greatest carbon benefits, but have high social impacts in the Brazilian context. Plantations also inherently compete with deforestation reduction options for funds. Forest management has been proposed as a global warming response option, but the assignment of any value to time makes this unattractive in terms of carbon benefits. However, reduced-impact logging can substantially reduce emissions over those from traditional logging practices. Slowing deforestation is the major opportunity offered by Brazil. Slowing deforestation will require understanding its causes and creating functional models capable of generating land-use change scenarios with and without different policy changes and other activities. Brazil already has a number of programs designed to slow deforestation, but the continued rapid loss of forest highlights the vast gulf that exists between the magnitude of the problem and the efforts to address it. The ups and downs of Brazil’s deforestation rate have so far had little to do with deliberate programs to control or influence the process. Achieving this control will require a major effort in which contributions from the private sector will be needed. Mechanisms are needed to make contributions to such programs eligible for carbon credit.", "corpus_id": 96889198, "score": 0 }, { "doc_id": "84500075", "title": "NET CARBON FLUXES FROM FOREST CLEARANCE AND REGROWTH IN THE AMAZON", "abstract": "Estimates of net carbon exchange resulting from forest clearance and re- growth were made for three areas in the Brazilian and Bolivian Amazon. The study areas, ranging in size from 600 to 10 000 km 2 , include communities that practice a range of land uses from small-scale, rotational agriculture to long-term pasture. Carbon emissions from deforestation were estimated based on rates of deforestation derived from Landsat satellite data and published estimates of mature forest biomass. Estimates of carbon uptake by secondary forest regrowth were based on area estimates from the satellite data and biomass estimates from field surveys. Estimates of carbon emissions from the clearance of secondary forest were included. The total carbon emissions were partitioned into that immediately released by biomass burning during clearance and that from subsequent decomposition and burning of felled biomass. A range of net carbon fluxes from secondary forest regrowth and clearance was estimated by extrapolating land-use patterns in each study area to the entire area of deforested landscape in Amazonian Brazil and Bolivia, and by varying average biomass accumulation rate of regrowing forest and fallow period. Over 60 km 2 of forest were cleared from 1988 to 1995 in each of the Brazilian study areas, and over 940 km 2 were cleared from 1986 to 1996 in the Bolivian study area. This resulted in 30-200 Mg C/yr emitted from biomass burning during deforestation. If the carbon that is committed to subsequent burning and decomposition of felled biomass is included, total committed emissions of 75-650 Mg C/yr resulted from deforestation in each study area. The carbon uptake by secondary forests was 33-435 Mg C/yr. However, emis- sions from the reclearance of secondary forests were nearly as large: 17-365 Mg C/yr. Extrapolation of these results to the Brazilian and Bolivian Amazon suggests that, at the national level, carbon uptake by secondary forests offset less than one-fifth of the carbon emissions from deforestation. Despite differences in land-use pattern, average fallow period, and rate of biomass accumulation used in the extrapolation, net carbon uptake by secondary forests was consistently small when compared to the total emissions from deforestation.", "corpus_id": 84500075, "score": 0 }, { "doc_id": "44007989", "title": "The faint promise of a distant market: a survey of Belém's trade in non-timber forest products", "abstract": "Increased trade in non-timber forest products (NTFPs) has been promoted as one possible means to slow tropical deforestation by increasing the economic value of intact forest. A market survey of NTFPs occurring in the Capim River basin in eastern Amazonia, Brazil demonstrated that the reality for many smallholder communities in frontier and remote regions includes chronic transportation difficulties, high variability in fruit production, perishable products and lack of market expertise. In some communities, declining abundance of NTFPs due to logging and fire has resulted in a lack of forest products to even meet subsistence needs. In areas close to cities where transportation is assured and where forest clearing has eroded the natural occurrence of some valuable native NTFPs, smallholders who manage and successfully market native fruit and medicinal species are overcoming these obstacles. In frontier regions undergoing rapid transformation, however, decline in locally used and regionally marketed NTFPs currently pose detrimental consequences for communities. Findings suggest that an overemphasis on NTFP marketing has diverted attention from local livelihood, resource access and subsistence issues.", "corpus_id": 44007989, "score": 0 }, { "doc_id": "55860248", "title": "Experiments in Forest-Based Development in Western Amazonia", "abstract": "The state government of Acre, Brazil, has integrated ecological, cultural, social, and economic forest values into a comprehensive forest policy to manage Acre's abundance of comparatively pristine forests, while couching specific goals and the processes for achieving them within a broader sustainable development framework. Inspired by the rubber tapper culture and social movement, policy implementation has been advanced with broad support from national and international allies. While these experiments in forest-based development serve as a hopeful alternative to the steady deforestation observed in Amazonia, many long-term ecological, economic, cultural, and political challenges remain for sustaining and adapting these policy initiatives.", "corpus_id": 55860248, "score": 0 } ]

{ "doc_id": "58948201", "title": "Breast Cancer and Exposure to Organochlorines in the CECILE Study: Associations with Plasma Levels Measured at the Time of Diagnosis and Estimated during Adolescence", "abstract": "Exposure to environmental chemicals with hormonal effects, such as organochlorine compounds (OCs), during developmental periods of breast cells may have an impact on the incidence of breast cancer later in life. However, the assessment of exposure to these chemicals that occurred in early life at the time of breast cancer development in adult women is a difficult challenge in epidemiological studies. Plasma levels of the OCs p,p’-dichlorodiphenyl dichloroethene (DDE) and polychlorinated biphenyl congener 153 (PCB153) were measured in 695 cases and 1055 controls of a population-based case-control study conducted in France (CECILE study). Based on these values, we used a physiologically-based pharmacokinetic (PBPK) model to estimate PCB153 levels at age 11–20 years when the women were adolescents. Overall, there was no clear association between breast cancer risk and measured levels of DDE and PCB153 at the time of diagnosis, but there was a trend of decreasing odds ratios of breast cancer with increasing DDE and PCB153 levels in women aged 50 years and over. The PBPK model revealed that PCB153 concentrations estimated during adolescence were highest in the youngest women born after 1960 who reached adolescence at a time when environmental contamination was maximum, and very low in the oldest women who attained adolescence before the contamination peak. Negative associations between breast cancer and PCB153 estimates during adolescence were also found. The negative associations between DDE and PCB153 levels measured at the time of diagnosis or estimated during adolescence in our study were unexplained. Further investigations are needed to clarify whether this finding is real or related to study artifacts. However, this study suggests that using PBPK models in epidemiological studies to back-estimate OC exposures during early life stages may be useful to address critical questions on cancer development.", "corpus_id": 58948201 }

[ { "doc_id": "4788711", "title": "Environmental chemicals and breast cancer: An updated review of epidemiological literature informed by biological mechanisms", "abstract": "Background Many common environmental chemicals are mammary gland carcinogens in animal studies, activate relevant hormonal pathways, or enhance mammary gland susceptibility to carcinogenesis. Breast cancer’s long latency and multifactorial etiology make evaluation of these chemicals in humans challenging. Objective For chemicals previously identified as mammary gland toxicants, we evaluated epidemiologic studies published since our 2007 review. We assessed whether study designs captured relevant exposures and disease features suggested by toxicological and biological evidence of genotoxicity, endocrine disruption, tumor promotion, or disruption of mammary gland development. Methods We systematically searched the PubMed database for articles with breast cancer outcomes published in 2006–2016 using terms for 134 environmental chemicals, sources, or biomarkers of exposure. We critically reviewed the articles. Results We identified 158 articles. Consistent with experimental evidence, a few key studies suggested higher risk for exposures during breast development to dichlorodiphenyltrichloroethane (DDT), dioxins, perfluorooctane‐sulfonamide (PFOSA), and air pollution (risk estimates ranged from 2.14 to 5.0), and for occupational exposure to solvents and other mammary carcinogens, such as gasoline components (risk estimates ranged from 1.42 to 3.31). Notably, one 50‐year cohort study captured exposure to DDT during several critical windows for breast development (in utero, adolescence, pregnancy) and when this chemical was still in use. Most other studies did not assess exposure during a biologically relevant window or specify the timing of exposure. Few studies considered genetic variation, but the Long Island Breast Cancer Study Project reported higher breast cancer risk for polycyclic aromatic hydrocarbons (PAHs) in women with certain genetic variations, especially in DNA repair genes. Conclusions New studies that targeted toxicologically relevant chemicals and captured biological hypotheses about genetic variants or windows of breast susceptibility added to evidence of links between environmental chemicals and breast cancer. However, many biologically relevant chemicals, including current‐use consumer product chemicals, have not been adequately studied in humans. Studies are challenged to reconstruct exposures that occurred decades before diagnosis or access biological samples stored that long. Other problems include measuring rapidly metabolized chemicals and evaluating exposure to mixtures. HighlightsChemicals that cause mammary tumors in animals also influence breast cancer risk.Few studies assessed exposure in biologically relevant times of breast development.Studies of early life exposure show risk for some OCPs, air pollution and solvents.Genetic variants may modify breast cancer risk associated with PAH exposure.", "corpus_id": 4788711, "score": 1 }, { "doc_id": "4547833", "title": "Environmental Determinants of Breast Cancer.", "abstract": "In the United States, breast cancer is the most common invasive malignancy and the second most common cause of death from cancer in women. Reproductive factors, estrogen, and progesterone have major causal roles, but concerns about other potential causes in the external environment continue to drive research inquiries and stimulate calls for action at the policy level. The environment is defined as anything that is not genetic and includes social, built, and chemical toxicant aspects. This review covers the scope of known and suspected environmental factors that have been associated with breast cancer and illustrates how epidemiology, toxicology, and mechanistic studies work together to create the full picture of environmental effects on this malignancy. Newer approaches to risk-related evaluations may allow this field to move forward and more clearly delineate actionable environmental causes of this most common of cancers in women.", "corpus_id": 4547833, "score": 0 }, { "doc_id": "33011537", "title": "Polychlorobiphenyls in freshwater fish: a new strategy to set maximum contamination limits", "abstract": "ABSTRACT Polychlorinated biphenyls (PCBs) are persistent organic pollutants accumulating along the food chain, and particularly in fish. Consequently, the European Commission has set regulatory limits for PCBs in both sea- and freshwater fish. Focusing on freshwater fish, the French Agency for Food Environmental and Occupational Health & Safety has developed a method to determine the areas in France where the consumption of locally caught freshwater fish is not recommended due to PCB contamination. To determine these areas of potential health concern, an existing statistical model of the relationship between the consumption of local fish by freshwater anglers and their PCB body burden is linked to a newly determined critical PCB body burden threshold for the population. The main conclusions of this study are that the consumption of two freshwater fish per week from rivers in the areas of France where the median contamination level in fish is greater than 250 ng g–1 could lead to some exceedance of the critical body burden threshold.", "corpus_id": 33011537, "score": 0 }, { "doc_id": "15131948", "title": "Environmental Exposures and Mammary Gland Development: State of the Science, Public Health Implications, and Research Recommendations", "abstract": "Objectives: Perturbations in mammary gland (MG) development may increase risk for later adverse effects, including lactation impairment, gynecomastia (in males), and breast cancer. Animal studies indicate that exposure to hormonally active agents leads to this type of developmental effect and related later life susceptibilities. In this review we describe current science, public health issues, and research recommendations for evaluating MG development. Data sources: The Mammary Gland Evaluation and Risk Assessment Workshop was convened in Oakland, California, USA, 16–17 November 2009, to integrate the expertise and perspectives of scientists, risk assessors, and public health advocates. Interviews were conducted with 18 experts, and seven laboratories conducted an MG slide evaluation exercise. Workshop participants discussed effects of gestational and early life exposures to hormonally active agents on MG development, the relationship of these developmental effects to lactation and cancer, the relative sensitivity of MG and other developmental end points, the relevance of animal models to humans, and methods for evaluating MG effects. Synthesis: Normal MG development and MG carcinogenesis demonstrate temporal, morphological, and mechanistic similarities among test animal species and humans. Diverse chemicals, including many not considered primarily estrogenic, alter MG development in rodents. Inconsistent reporting methods hinder comparison across studies, and relationships between altered development and effects on lactation or carcinogenesis are still being defined. In some studies, altered MG development is the most sensitive endocrine end point. Conclusions: Early life environmental exposures can alter MG development, disrupt lactation, and increase susceptibility to breast cancer. Assessment of MG development should be incorporated in chemical test guidelines and risk assessment.", "corpus_id": 15131948, "score": 0 }, { "doc_id": "2425300", "title": "Endocrine-disrupting compounds and mammary gland development: early exposure and later life consequences.", "abstract": "Breast cancer is the most common non-skin cancer among women in this country. Breast cancer risk is significantly influenced by genetics, but over 70% of the women that are diagnosed have noninherited or sporadic cancer. The risk of breast cancer is thought to be modified by lifestyle and environment. Exposures to certain chemicals and hormone-mimicking or endocrine-disrupting compounds (EDCs) are suspected of contributing to increased breast cancer incidence as well as precocious puberty in the United States. Studies of EDC effects in rodents indicate that multiple toxicants can alter mammary gland development, with or without changing other markers of puberty. EDCs can cause transient and persistent effects on mammary gland development depending on dose, exposure parameters, and whether exposure was during critical periods of gland growth or differentiation. Adverse effects from these abnormal developmental patterns include the presence of carcinogen-sensitive structures in greater numbers or for longer periods in the gland and inhibited functional differentiation leading to malnutrition or increased mortality of their offspring. Developmental toxicants of the mammary gland could lead to an increase in the incidence of mammary tumors if they alter circulating or tissue-localized hormone levels, gland receptor expression patterns, hormone transport, or metabolism that results in altered response to endogenous hormones or growth factors. Environmental disruptors of rodent mammary gland development must be identified for informed decisions in epidemiological studies aimed at identification of environmental factors contributing to breast cancer risk, altered breast development during puberty, or inability to produce sufficient breast milk.", "corpus_id": 2425300, "score": 0 }, { "doc_id": "15470625", "title": "Carcinogenicity of lindane, DDT, and 2,4-dichlorophenoxyacetic acid.", "abstract": "Lancet Oncology, The - In Press.Proof corrected by the author Available online since mercredi 24 juin 2015", "corpus_id": 15470625, "score": 1 }, { "doc_id": "2372155", "title": "Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50", "abstract": "Discrete windows of susceptibility to toxicants have been identified for the breast, including in utero, puberty, pregnancy, and postpartum. We tested the hypothesis that polychlorinated biphenyls (PCBs) measured during the early postpartum predict increased risk of maternal breast cancer diagnosed before age 50. We analyzed archived early postpartum serum samples collected from 1959 to 1967, an average of 17 years before diagnosis (mean diagnosis age 43 years) for 16 PCB congeners in a nested case–control study in the Child Health and Development Studies cohort (N = 112 cases matched to controls on birth year). We used conditional logistic regression to adjust for lipids, race, year, lactation, and body mass. We observed strong breast cancer associations with three congeners. PCB 167 was associated with a lower risk (odds ratio (OR), 75th vs. 25th percentile = 0.2, 95 % confidence interval (95 % CI) 0.1, 0.8) as was PCB 187 (OR, 75th vs. 25th percentile = 0.4, 95 % CI 0.1, 1.1). In contrast, PCB 203 was associated with a sixfold increased risk (OR, 75th vs. 25th percentile = 6.3, 95 % CI 1.9, 21.7). The net association of PCB exposure, estimated by a post-hoc score, was nearly a threefold increase in risk (OR, 75th vs. 25th percentile = 2.8, 95 % CI 1.1, 7.1) among women with a higher proportion of PCB 203 in relation to the sum of PCBs 167 and 187. Postpartum PCB exposure likely also represents pregnancy exposure, and may predict increased risk for early breast cancer depending on the mixture that represents internal dose. It remains unclear whether individual differences in exposure, response to exposure, or both explain risk patterns observed.", "corpus_id": 2372155, "score": 1 }, { "doc_id": "14712837", "title": "Physiologically Based Pharmacokinetic Modeling of Persistent Organic Pollutants for Lifetime Exposure Assessment: A New Tool in Breast Cancer Epidemiologic Studies", "abstract": "Background Despite experimental evidence, most epidemiologic studies to date have not supported an association between exposure to persistent organic pollutants (POP) and breast cancer incidence in humans. This may be attributable to difficulties in estimating blood/tissue POP concentration at critical time periods of carcinogenesis. Objectives In this work we aimed to develop a tool to estimate lifetime POP blood/tissue exposure and levels during any hypothesized time window of susceptibility in breast cancer development. Methods We developed a physiologically based pharmacokinetic (PBPK) model that can account for any given physiologic lifetime history. Using data on pregnancies, height, weight, and age, the model estimates the values of physiologic parameters (e.g., organ volume, composition, and blood flow) throughout a woman’s entire life. We assessed the lifetime toxicokinetic profile (LTP) for various exposure scenarios and physiologic factors (i.e., breast-feeding, growth, pregnancy, lactation, and weight changes). Results Simulations for three POPs [hexachlorobenzene, polychlorinated biphenyl (PCB)-153, PCB-180] using different lifetime physiologic profiles showed that the same blood concentration at 55 years of age can be reached despite totally different LTP. Aside from exposure levels, lactation periods and weight profile history were shown to be the factors that had the greatest impact on the LTP. Conclusions This new lifetime PBPK model, which showed the limitations of using a single sample value obtained around the time of diagnosis for lifetime exposure assessment, will enable researchers conducting environmental epidemiology studies to reduce uncertainty linked to past POP exposure estimation and to consider exposure during time windows that are hypothesized to be mechanistically critical in carcinogenesis.", "corpus_id": 14712837, "score": 1 }, { "doc_id": "35629984", "title": "Determinants of serum concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene and polychlorinated biphenyls among French women in the CECILE study.", "abstract": "BACKGROUND\nDichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) are persistent organochlorine compounds bioaccumulating in human tissues. Body burden of organochlorines may be influenced by individual characteristics such as age, weight variations, breastfeeding, dietary habits and place of residence.\n\n\nOBJECTIVES\nTo assess the current serum concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), the main DDT breakdown product, and of PCBs in women from two French administrative areas (Ille-et-Vilaine and Côte d'Or). To identify determinants of the current serum levels among individual characteristics related to intake, metabolism, and excretion of organochlorines.\n\n\nMETHODS\nWe measured serum p,p'-DDE and PCB levels in 1055 general population women who were recruited in 2005-2007 to serve as controls in a case-control study on breast cancer. Associations between organochlorine levels and age, current body mass index (BMI), BMI change during the last 10 years, dietary habits, breastfeeding history, residence area and education were assessed in multivariate analyses.\n\n\nRESULTS\nMedian concentrations of p,p'-DDE and total PCBs were 85 and 240ng/g lipid, respectively. Based on multivariate analyses, the main predictors of high p,p'-DDE levels included age and frequent consumption of saltwater fish in women below 50 years, and high BMI in older women. Total PCB levels increased markedly with age. Among older women, other important predictors of high PCB levels included frequent consumption of saltwater fish and low BMI. Our results are also suggestive of an inverse association between PCB levels and BMI gain during the last ten years. Women in Côte d'Or had significantly higher PCB levels than women in Ille-et-Vilaine.\n\n\nCONCLUSION\nThe patterns of associations between determinants and serum organochlorine concentrations suggest that human PCB contamination is still ongoing in France. The most important predictors of serum p,p'-DDE and PCB concentrations among French women include age, body mass index, dietary habits, and place of residence.", "corpus_id": 35629984, "score": 1 }, { "doc_id": "11786822", "title": "Chlorinated hydrocarbon levels in human serum: Effects of fasting and feeding", "abstract": "Twenty healthy adult humans had serum samples drawn on four occasions within a 24-hr period: after a 12 hr overnight fast, 4–5 hr after a high fat breakfast, at midafternoon, and the next morning after another 12 hr fast. Nonfasting samples had 22% to 29% higher mean concentrations (p < 0.05) than did fasting samples for polychlorinated biphenyls (PCBs, 4.81 vs 3.74 ng/g serum wt), hexachlorobenzene (HCB, 0.163 vs 0.134 ng/g serum wt), andp,p′-dichlorodiphenyldichloroethylene (p,p′-DDE, 6.74 vs 5.37 ng/g serum wt) measured by electron capture gas liquid chromatography. Total serum lipids were estimated from measurements of total cholesterol, free cholesterol, triglycerides, and phospholipids and were 20% higher in nonfasting samples than in fasting samples (7.05 g/L vs 5.86 g/L). When PCBs, HCB, andp,p′-DDE concentrations were corrected by total serum lipids, results from fasting and nonfasting samples were not statistically different. Because of the differences in these chlorinated hydrocarbon concentrations observed with different sample collection regimens, meaningful comparison of analytical results requires standardizing collection procedures or correcting by total serum lipid levels.", "corpus_id": 11786822, "score": 0 }, { "doc_id": "11587287", "title": "A Case Study Addressing the Reliability of Polychlorinated Biphenyl Levels Measured at the Time of Breast Cancer Diagnosis in Representing Early-Life Exposure", "abstract": "Background: To date, breast cancer epidemiologic studies have relied on blood or tissue specimens sampled at the time of diagnosis or a few years prior to assess lifetime exposure to polychlorinated biphenyls (PCB). In this study, we evaluated whether such PCB measurements are indicative of early-life levels by reconstructing lifetime toxicokinetic profiles for women included in the CECILE case–control study, using a physiologically based pharmacokinetic (PBPK) model. Methods: We simulated lifetime toxicokinetic profiles of PCB-153 for 2,134 French women by incorporating information on body weight history, height, pregnancies, and breast-feeding in the PBPK model. Oral dose was calculated by considering measured blood PCB-153 and the temporal trend of environmental contamination. Area under the concentration versus time curve (AUC) for each decade of life and maximum blood concentration (Cmax) were compiled and compared with measured levels, using Pearson partial correlation analyses adjusting for age at diagnosis. Results: When considering all individuals, simulated AUCs correlated with measured PCBs, with coefficients ranging from 0.735 to 0.981. The weakest correlations were obtained with AUCs for the first decades of life. Stratified analyses suggested that breast-feeding reduces the reliability of late-life blood levels in representing lifetime exposure. Conclusion: Results of this study suggest that PCB levels measured at the time of diagnosis do not fully represent early-life exposures. Impact: PBPK-derived estimates of early-life levels circumvent the limitations of current approaches in assessing PCB lifetime exposure and may be used to address hypothesized windows of breast vulnerability (e.g., puberty) in this population. Cancer Epidemiol Biomarkers Prev; 20(2); 281–6. ©2010 AACR.", "corpus_id": 11587287, "score": 1 }, { "doc_id": "45871418", "title": "Dioxins, dioxin-like PCBs and non-dioxin-like PCBs in foodstuffs: occurrence and dietary intake in The Netherlands.", "abstract": "Data on occurrence of dioxins (polychlorinated dibenzo-p-dioxins [PCDDs] and dibenzofurans [PCDFs]), dioxin-like PCBs (polychlorinated non-ortho and mono-ortho biphenyls) and non-dioxin-like PCBs (as represented by the so-called indicator-PCBs: congeners 28, 52, 101, 118, 138, 153 and 180) in food products consumed in The Netherlands that were collected in measurement programs carried out during 1998 and 1999, and combined with food consumption data to assess the dietary intake of these persistent food contaminants. The estimated median life-long-averaged intake of the sum of dioxins and dioxin-like PCBs in the population is 1.2 pg WHO-TEQ (toxic equivalents) per kg body weight (bw) per day, while the estimated median life-long-averaged intake of indicator-PCBs is 5.6 ng per kg bw per day. The contribution of different food groups to the total intake of both dioxins + dioxin-like PCBs and non-dioxin-like PCBs is fairly uniformly distributed over the foods consumed: meat products (23% and 27%, respectively), dairy products (27% and 17%, respectively), fish (16% and 26%, respectively), eggs (4% and 5%, respectively), vegetable products (13% and 7%, respectively), and industrial oils and fats (17% and 18%, respectively). Compared with earlier intake estimations the present estimation shows a continued reduction in the intake of dioxins as well as PCBs. This reduction is related to the decrease in the concentration of these substances in the majority of foodstuffs. Nevertheless, a small part of the population still has a rather high life-long averaged intake: 8% of the population is exposed to intake levels above the tolerable weekly intake for dioxins and dioxin-like PCBs of 14 pg WHO-TEQ per kg bw per week, as recently derived by the Scientific Committee on Food of the European Commission. For the non-dioxin-like PCBs an internationally accepted maximum intake level is still lacking. However, to provide risk managers with a health-based guideline to prevent health effects of exposure to non-dioxin-like PCBs, the (international) derivation of a tolerable daily intake is recommended. Monitoring the dietary intake of PCBs is just as important as monitoring the intake of dioxins and dioxin-like PCBs, and attempts to decrease the exposure to both compound classes need continuous attention.", "corpus_id": 45871418, "score": 0 }, { "doc_id": "94783861", "title": "Serum polychlorinated biphenyl and organochlorine insecticide concentrations in a Faroese birth cohort.", "abstract": "A prospective birth cohort of 1022 participants was established in the Faroe Islands over a 21-month period during 1986-1987. We collected questionnaire data on potential persistent organic pollutant (POP) concentration predictors, such as duration of breastfeeding and blubber consumption. To assess the participants' exposure from in utero to 14 years of age to polychlorinated biphenyls (PCBs) and the insecticide p,p'-DDT and its primary degradate p,p'-DDE, we measured 37 PCB congeners and pesticides in 316 umbilical cord samples taken from participants at birth, in 124 serum samples collected from participants at approximately 7 years of age, and in 795 serum samples collected from participants at 14 years of age. Measurements of higher chlorination PCB congeners made on individuals' serum samples collected at 7 years and 14 years were highly correlated (typically r > 0.5, p > 0.01), although their concentrations at 7 years were generally two to three times higher than at 14 years. Similarly, umbilical cord PCB concentrations were correlated with PCB concentrations in both 7- and 14-year serum samples. Sex-specific differences in higher chlorination PCB and p,p'-DDE concentrations were found at 14 years but not at 7 years, although a sex interaction with blubber consumption and nursing duration was observed at both ages. Both duration of breastfeeding and consumption of blubber were significant predictors of serum summationPCB concentrations at 7 and 14 years. Multivariate analyses showed that breastfeeding duration was the primary contributor to serum summationPCB concentrations at 7 years, and blubber consumption was the primary contributor at 14 years. These data suggest that infant exposures from breastfeeding were sufficiently large so that continued exposures to PCBs, p,p'-DDT, and p,p'-DDE through the diet have not fully diluted their contribution to the summationPCB and p,p'-DDE body burden of the children.", "corpus_id": 94783861, "score": 0 }, { "doc_id": "25400380", "title": "Temporal trends in concentrations and total serum burdens of organochlorine compounds from birth until adolescence and the role of breastfeeding.", "abstract": "INTRODUCTION\nThe aims of the present study are to assess the temporal trends of organochlorine compounds (OCs) concentrations and total serum burdens from birth until adolescence and the influence of breastfeeding in these temporal trends.\n\n\nMETHODS\nIn 1997 two birth cohort studies were set up in Ribera d'Ebre (N=102) and the island of Menorca (N=482), Spain. Concentrations (ng/mL) of OCs [pentachlorobenzene (PeCB), four isomers of hexachlorocyclohexane (HCH), hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (4,4'-DDT), dichlorodiphenyldichloroethylene (4,4'-DDE) and seven polychlorobiphenyl congeners (Σ7PCBs)] were measured in cord blood and at the age of 4 and 14years. The total serum burdens (ng) of these compounds were estimated based on the total blood volume (mL) of children at the different ages. We compared median concentrations and total serum burdens of these OCs at the different time-points of follow-up between children of Ribera d'Ebre and Menorca and between breastfed and non-breastfed children.\n\n\nRESULTS\nFrom birth until adolescence concentrations of all OCs drastically reduced. These reductions were mainly derived from the dilution of OCs, associated to an increase in total blood volume of children at the age of 4 and 14years. Despite the reduction in OCs concentrations, the total serum burdens of 4,4'-DDE and Σ7PCBs, were higher in adolescents than at birth. Increases in OCs total serum burden occurred both in breastfed and non-breastfed children, but were significantly higher in the first.\n\n\nCONCLUSIONS\nEven after decades of banning OCs production and use, current young generations in westernized countries are still bioaccumulating these compounds. Given the potential health effects of OCs, especial attention should be paid in the control of secondary emissions in the environment and in the control of food production and contamination. In countries with endemic malaria it is important to work towards effective alternatives to the use of DDT.", "corpus_id": 25400380, "score": 0 }, { "doc_id": "25259593", "title": "DDT/DDE and breast cancer: a meta-analysis.", "abstract": "The biological basis for investigating dichlorodiphenyltrichloroethane (DDT) exposure and breast cancer risk stems from in vitro and animal studies indicating that DDT has estrogenic properties. The objective of this study was to update a meta-analysis from 2004 which found no association between dichlorodiphenyldichloroethylene (DDE) and breast cancer. We searched PubMed and Web of Science for studies published through June 2012 assessing DDT/DDE exposure and breast cancer. Summary Odds Ratios (ORs) with 95% confidence intervals (CIs) were calculated for the prevalence of breast cancer in the highest versus the lowest exposed groups for DDT and DDE. Difference of means of exposure for cases versus controls was analyzed for DDT and DDE. From the 500 studies screened, 46 were included in the meta-analysis. Slightly elevated, but not statistically significant summary ORs were found for DDE (1.05; 95% CI: 0.93-1.18) and DDT (1.02; 95% CI: 0.92-1.13). Lipid adjusted difference of means analysis found a significantly higher DDE concentration in cases versus controls (11.30 ng/g lipid; p=0.01). No other difference of means analysis found significant relationships. The existing information does not support the hypothesis that exposure to DDT/DDE increases the risk of breast cancer in humans.", "corpus_id": 25259593, "score": 0 }, { "doc_id": "16510119", "title": "Exposure to Dichlorodiphenyltrichloroethane and the Risk of Breast Cancer: A Systematic Review and Meta-analysis", "abstract": "Objectives This study extended and updated a meta-analysis of the association between exposure to dichlorodiphenyltrichloroethane (DDT) and the risk of breast cancer. Methods We reviewed the published literature on exposure to DDE and breast cancer risk to update a meta-analysis from 2004. The total of 35 studies included 16 hospital-based case–control studies, 11 population-based case–control studies, and 10 nested case–control studies identified through keyword searches in the PubMed and EMBASE databases. Results The summary odds ratio (OR) for the identified studies was 1.03 (95% confidence interval 0.95–1.12) and the overall heterogeneity in the OR was observed (I2 = 40.9; p = 0.006). Subgroup meta-analyses indicated no significant association between exposure to DDE and breast cancer risk by the type of design, study years, biological specimen, and geographical region of the study, except from population-based case–control studies with estimated DDE levels in serum published in 1990s. Conclusion Existing studies do not support the view that DDE increases the risk of breast cancer in humans. However, further studies incorporating more detailed information on DDT exposure and other potential risk factors for breast cancer are needed.", "corpus_id": 16510119, "score": 0 }, { "doc_id": "5502076", "title": "Polychlorinated biphenyls and breast cancer: A congener-specific meta-analysis.", "abstract": "The incidence of breast cancer is related to various risk factors, especially that the environmental and lifestyle factors account for major contribution at the rate of 70% to 95% over all. However, there still remains some controversy over the epidemiological evidence regarding the effects of environmental carcinogens on the risk of breast cancer. We conducted a quantitative meta-analysis aiming at full evaluation of the effects of polychlorinated biphenyls (PCBs) on breast cancer in a congener-specific fashion. Four online literature databases were systematically searched before 1st January 2015, for studies stating correlation between PCB congeners and breast cancer. The Newcastle-Ottawa Scale was used to evaluate the quality of the studies that were included in our analysis. Sixteen studies were included in our final meta-analysis after screening based on the priori inclusion criteria. Nine PCB congeners were reported by more than two studies and they were presented in detail. The pooled Odds Ratios (ORs) showed a significant increase in the risk of breast cancer in individuals with higher plasma/fat levels of PCB 99 (OR: 1.36; 95% CI: 1.02 to 1.80), PCB 183 (OR: 1.56; 95% CI: 1.25 to 1.95) and PCB 187 (OR: 1.18; 95% CI: 1.01 to 1.39). Besides, the outcomes did not support a relationship between dioxin-like PCB congeners and the risk of breast cancer. The results of our meta-analysis imply that PCB 99, PCB 183 and PCB 187 would increase the risk of breast cancer. The mechanism of this increased risk may be by the induction of the CYP2B family in cytochrome P450 enzymes.", "corpus_id": 5502076, "score": 0 }, { "doc_id": "25926681", "title": "Serum levels of environmental pollutants is a risk factor for breast cancer in Inuit: a case control study", "abstract": "BackgroundEnvironmental Persistent Organic Pollutants (POPs) can alter the hormone homeostasis by mimicking, interfering or blocking the function of hormones; moreover POPs are hypothesized to modify the risk of breast cancer. The association between POPs and breast cancer has been widely studied but the conclusions are inconsistent. The present study examined the associations between serum levels of POPs and breast cancer with focus on the highly exposed Greenlandic Inuit population.MethodsThe study design was a case-control study of Inuit women from Greenland. The participants were asked to complete a questionnaire with information on reproductive history and lifestyle and to provide a blood sample. The sampling was carried out in two time periods (2000–2003 and 2011–2014). The serum levels were determined of 14 polychlorinated biphenyls (PCBs), 11 organochlorine pesticides (OCPs), 16 perfluoroalkyl acids (PFAAs), 1 polybrominated biphenyl (PBB), and 9 polybrominated diphenyl ethers (PBDEs). Independent samples t-test was used to compare differences between cases and controls and odds ratios (OR) adjusted for identified confounders were obtained using logistic regression.ResultsThe study population included 77 breast cancer cases and 84 controls. The majority of the measured compounds declined significantly from 2000 – 2003 to 2011–2014. However, for the perfluorinated carboxylic acids (PFCAs) an increase was observed. The serum levels were significantly higher in cases compared to controls for the majority of the compounds, and after adjusting for age the difference was maintained for ∑OCP, dichlorodiphenyldichloroethylene (p,p′-DDE), ∑PFAA, ∑perfluorinated sulfonic acids (PFSA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS). For the lipophilic POPs, high serum levels (middel/highest vs. lowest tertile) of ∑PCB, ∑estrgoenicPCB, PCB99, PCB138, PCB153, PCB170, PCB170, and PCB183 was associated with breast cancer risk; for the amphiphilic PFAAs, high serum levels of ∑PFAA, ∑PFCA, ∑PFSA, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), PFHxS, and PFOS were associated with breast cancer risk.ConclusionSignificant, positive associations between breast cancer risk and PCBs and PFAAs were observed. The associations indicate that environmental exposure to POPs can be a factor increasing the risk for breast cancer in Inuit women.", "corpus_id": 25926681, "score": 0 }, { "doc_id": "13270431", "title": "Correlations among polychlorinated biphenyls, dioxins, and furans in humans.", "abstract": "BACKGROUND\nCorrelations among human levels of polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans potentially complicate interpretation of studies of their individual health effects. Outcomes attributed to one may, in fact, be due to another.\n\n\nMETHODS\nWe present correlations among dioxins, furans, and PCBs in blood collected in 1991-1992 from 44 American Vietnam veterans from Michigan.\n\n\nRESULTS\nCorrelations among specific dioxins and furans ranged from 0.26 to 0.80, with the higher-chlorinated congeners being more highly correlated. Correlations among PCBs ranged from 0.06 to 0.94, with those occurring at highest concentrations being more highly correlated. Correlations of PCBs with dioxins and furans ranged from -0.09 to 0.59. Correlations of individual chemicals with total dioxin toxic equivalents ranged from 0.31 to 0.76.\n\n\nDISCUSSION/CONCLUSIONS\nIf confirmed in other populations, such correlations may allow the use of simpler assays but may also raise issues of confounding and calibration.", "corpus_id": 13270431, "score": 0 }, { "doc_id": "22661780", "title": "Serum organochlorines and breast cancer risk in Japanese women: a case–control study", "abstract": "ObjectiveMost epidemiological studies of the association between breast cancer risk and exposure to organochlorine pesticides or polychlorinated biphenyls (PCBs), which are suspected endocrine disrupters and potential risk factors for human breast cancer, have been conducted in western countries, and the majority of results have been null and the rest inconsistent. Here, we examined these associations in Japanese women in the largest study in Asian women to date.MethodsThe study was a matched case–control study of breast cancer with 403 eligible matched pairs from May 2001 to September 2005 at four hospitals in Nagano Prefecture, Japan.MeasurementsSerum samples were measured for PCBs and nine pesticide-related organochlorines, including dichlorodiphenyltrichloroethane (DDT). Odds ratios of breast cancer or its hormone-receptor-defined subtypes according to serum organochlorines were calculated.ResultsNo increase in the risk of breast cancer was seen among women with higher serum concentrations of any organochlorine: o,p′-DDT, p,p′-DDT, p,p′-dichlorodiphenyldichloroethylene, hexachlorobenzene, β-hexachlorocyclohexane, trans-nonachlor, cis-nonachlor, oxychlordane, mirex, or PCBs. Rather, higher serum levels of cis-nonachlor, mirex, or total PCBs were associated with a decreased risk of breast cancerConclusionsOverall, these results suggest that breast cancer risk in Japan, a low-incidence country, is similar to that in western countries in terms of organochlorine exposure.", "corpus_id": 22661780, "score": 0 }, { "doc_id": "29862752", "title": "Risk of female breast cancer and serum concentrations of organochlorine pesticides and polychlorinated biphenyls: a case-control study in Tunisia.", "abstract": "The aim of this study was to investigate the association between serum concentrations of a group of organochlorine pesticides/polychlorinated biphenyls with xenoestrogenic potential and the risk of breast cancer in a female population from Tunisia. The relationship between serum levels of the pollutants and the risk of cancer was assessed using logistic regression analyses. In the unadjusted models, β-hexachlorocyclohexane (β-HCH), hexachlorobenzene, heptachlor, polychlorinated biphenyl congeners 138, 153, and 180, and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were positively associated with breast cancer risk. However, when the models were further adjusted for the selected covariates, only β-HCH and p,p'-DDE remained statistically significant, and heptachlor was borderline significant. In addition, analyses using POP concentration tertiles corroborated a positive dose-response relationship that was significant for p,p'-DDE (p-trend=0.020) and borderline significant for heptachlor (p-trend=0.078). A similar trend was also confirmed for β-HCH, in which concentrations≥limit of detection were positively associated with breast cancer risk (vs. concentrations<limit of detection, OR=3.44, p<0.05). Finally, the relative influence of each chemical in the presence of the others was assessed by entering the three chemicals in a single model with all covariates, and only β-HCH remained positively associated with the risk of cancer (OR:1.18, 95%CI: 1.05-1.34). Our findings suggest a potential association between exposure to at least one organochlorine pesticide and breast cancer risk. However, our results should be interpreted with caution, and further research is warranted to confirm these findings.", "corpus_id": 29862752, "score": 0 }, { "doc_id": "15296365", "title": "Joint effects of nine polychlorinated biphenyl (PCB) congeners on breast cancer risk.", "abstract": "BACKGROUND\nPolychlorinated biphenyls (PCB) have been a major environmental health concern because of their wide distribution and persistence in the environment. Estimating joint effects of all congeners in a single analysis is complicated by correlation among exposure levels, and the resulting collinearity makes the results difficult to interpret.\n\n\nMETHODS\nPatients with breast-related surgery at Yale-New Haven Hospital were interviewed using a standardized questionnaire, and breast adipose tissue samples were analysed for nine PCB congeners (74, 118, 138, 153, 156, 170, 180, 183, 187). The study recruited 490 women (304 cases and 186 controls) between 1994 and 1997. Logistic ridge regression was used to analyse the instability caused by collinearity.\n\n\nRESULTS\nAlthough total PCB did not appear to be associated with breast cancer risk, significant differences in effect were observed among the nine congeners. Logistic ridge regression demonstrated a protective effect on breast cancer risk for a potentially anti-oestrogenic and dioxin-like congener, 156, while two phenobarbital, CYP1A and CYP2B inducers had an adverse effect, 180 and 183. This analysis also suggested that a protective effect for another phenobarbital congener, 153, was largely explained by instability caused by collinearity.\n\n\nCONCLUSIONS\nThese results indicate that studies of PCB congeners and health require an in-depth statistical analysis in order to better understand the complex issues related to their collinearity.", "corpus_id": 15296365, "score": 0 }, { "doc_id": "19614218", "title": "Breast cancer risk associated with congeners of polychlorinated biphenyls.", "abstract": "Experimental studies show that hormonal and nonhormonal activities of polychlorinated biphenyls (PCBs) are structure dependent, suggesting that the breast cancer risk associated with PCBs may vary according to specific PCB congeners. In 1994-1997, the authors conducted a case-control study of Connecticut women to investigate whether breast cancer risk is associated with body burden of PCBs and varies by PCB congeners. A total of 304 breast cancer cases and 186 controls aged 40-79 years were recruited into the study. Fresh breast adipose tissue was analyzed for PCBs. The age- and lipid-adjusted geometric mean tissue levels of total PCBs were not significantly different (p = 0.46) for the cases (478.6 parts per billion) and controls (494.1 parts per billion). The covariate-adjusted odds ratio was 0.7 (95% confidence interval: 0.4, 1.1) for all study participants when the third tertile was compared with the lowest tertile. No individual congeners or groups of congeners were associated with a significantly increased risk of breast cancer. Further stratification by type of breast disease; menopausal, parity, and lactation status; and body size also showed no significant association with body levels of PCBs. These results suggest that environmental exposure to PCBs may not substantially affect breast cancer risk.", "corpus_id": 19614218, "score": 0 }, { "doc_id": "1466442", "title": "Polychlorinated biphenyls and risk of testicular germ cell tumors.", "abstract": "Exposure to endocrine-disrupting chemicals, such as polychlorinated biphenyls (PCB), may alter hormonal balance and thereby increase risk of testicular germ cell tumors (TGCT). To study the relationship of PCBs to TGCT, prediagnostic serum samples from 736 cases and 913 controls in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants study were analyzed. Adjusted odds ratios and 95% confidence intervals were estimated using logistic regression. PCB levels were examined in association with all TGCT and, separately, with each histologic type (seminoma and nonseminoma). Risks associated with seven functional groupings of PCBs, as well as sum of PCBs, were also examined. There were significantly decreased risks of TGCT in association with eight PCBs (PCB-118, PCB-138, PCB-153, PCB-156, PCB-163, PCB-170, PCB-180, and PCB-187) and no association with the remaining three (PCB-99, PCB-101, and PCB-183). The same eight congeners were significantly associated with decreased risk of nonseminoma, whereas five (PCB-138, PCB-153, PCB-156, PCB-163, and PCB-170) were associated with decreased risk of seminoma. All functional groupings of PCBs were also associated with decreased risk of TGCT and of nonseminoma, whereas six of the seven functional groups were associated with decreased risk of seminoma. Sum of PCBs was significantly associated with decreased risk of TGCT (P(trend) = 0.006), nonseminoma (P(trend) = 0.007), and seminoma (P(trend) = 0.05). Overall, these data do not support the hypothesis that PCB exposure increases the risk of TGCT.", "corpus_id": 1466442, "score": 0 }, { "doc_id": "36083258", "title": "Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity.", "abstract": "Polychlorinated biphenyls (PCBs) are ubiquitous environmental persistent contaminants giving rise to potential health hazard. Some PCBs exert dioxin-like activities mediated through the aryl hydrocarbon receptor. Although reports on interaction with other nuclear receptors are sparce, some congeners are hypothesized to possess endocrine disruptive potential. Here we present evidence that the three PCBs most abundant in biological extracts, 2,2',3'4,4',5-hexachlorobiphenyl (PCB#138), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB#153), and 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB#180) have pleiotropic effects on the estrogen- and androgen-receptor. In MCF-7 cells a slightly increased cell proliferation was observed at low concentrations (1-10 nM) in cells co-treated with 0.01 nM 17beta-Estradiol, whereas the compounds inhibited cell growth significantly at 1 and 10 microM. In reporter gene (ERE-tk-CAT) analysis the three congeners exhibited a significantly estrogen receptor-ligand mediated decrease of the chloramphenicol transferase activity in both control and 10 nM 17beta-estradiol induced MCF-7 cells. In addition, PCB#138 elicited a dose-dependent antagonistic effect on androgen receptor activity in transiently co-transfected Chinese Hamster Ovary cells with an IC(50), of 6.2 microM. In summary, this study indicate that the di-ortho, multiple-chloro substituted biphenyls, PCB#138, PCB#153 and PCB#180, can compete with the binding of the natural ligand to two nuclear receptors and thus possess the ability to interfere with sexual hormone regulated processes.", "corpus_id": 36083258, "score": 0 }, { "doc_id": "29060764", "title": "Antiestrogenic potentials of ortho-PCB congeners by single or complex exposure", "abstract": "Di-ortho PCB congeners 52, 138, 153 and 180, and the mono-ortho coplanar congener 118 have been detected as a complex mixture in human tissue in Korea. This study examined the antiestrogenic effects of samples exposed to single or combination treatment of the ortho-PCB congeners. In order to determined the combined toxicity, a sample mixture (M1, M2, M3, M4, and M5) was designed based on the ortho-PCB congeners found in Korean human tissue. With the exception of PCB 52, the ortho-PCB congeners (PCB 118, 138, 153, and 180) showed weak antiestrogenic activity. The antiestrogenic activity of di-ortho PCB congeners (PCB 138, 153, and 180) was induced by the depletion of endogenous E2 as well as through the ER-dependent pathway, whereas the antiestrogenic activity of mono-ortho PCB 118 was only induced through the depletion of endogenous E2. When the MCF7-BUS cells were treated with mixtures containing the no effective concentration (10-6 M) of the PCB congeners, M3 (PCB 118 + PCB 138 + PCB 180) and M4 (PCB 118 + PCB 138) had an antiestrogenic effect but the other mixtures (M1; PCB 52 + PCB 118 + PCB 138 + PCB 180, M2; PCB 118 + PCB 138 + PCB 153 + PCB 180, M5; PCB 118 + PCB 180) did not. Although the mechanism for the interaction between the PCB congeners is not completely understood, it was presumed that exposure to a mixture of the PCB congeners might have synergistic effects on their antiestrogenicity through the ER-independent pathway.", "corpus_id": 29060764, "score": 0 }, { "doc_id": "18662557", "title": "Impact of Polychlorinated Biphenyls Contamination on Estrogenic Activity in Human Male Serum", "abstract": "Polychlorinated biphenyls (PCBs) are thought to cause numerous adverse health effects, but their impact on estrogen signaling is still not fully understood. In the present study, we used the ER-CALUX bioassay to determine estrogenic/antiestrogenic activities of the prevalent PCB congeners and PCB mixtures isolated from human male serum. The samples were collected from residents of an area with an extensive environmental contamination from a former PCB production site as well as from a neighboring background region in eastern Slovakia. We found that the lower-chlorinated PCBs were estrogenic, whereas the prevalent higher-chlorinated PCB congeners 138, 153, 170, 180, 187, 194, 199, and 203, as well as major PCB metabolites, behaved as anti-estrogens. Coplanar PCBs had no direct effect on estrogen receptor (ER) activation in this in vitro model. In human male serum samples, high levels of PCBs were associated with a decreased ER-mediated activity and an increased dioxin-like activity, as determined by the DR-CALUX assay. 17β-Estradiol (E2) was responsible for a major part of estrogenic activity identified in total serum extracts. Significant negative correlations were found between dioxin-like activity, as well as mRNA levels of cytochromes P450 1A1 and 1B1 in lymphocytes, and total estrogenic activity. For sample fractions containing only persistent organic pollutants (POPs), the increased frequency of anti-estrogenic samples was associated with a higher sum of PCBs. This suggests that the prevalent non-dioxin-like PCBs were responsible for the weak antiestrogenic activity of some POPs fractions. Our data also suggest that it might be important to pay attention to direct effects of PCBs on steroid hormone levels in heavily exposed subjects.", "corpus_id": 18662557, "score": 0 }, { "doc_id": "23375534", "title": "Activation of the aryl hydrocarbon receptor by TCDD inhibits mammary tumor metastasis in a syngeneic mouse model of breast cancer.", "abstract": "Treatment with aryl hydrocarbon receptor (AhR) agonists can slow or reverse the growth of primary mammary tumors in rodents, which has fostered interest in developing selective AhR modulators for treatment of breast cancer. However, the major goal of breast cancer therapy is to inhibit metastasis, the primary cause of mortality in women with this disease. Studies conducted using breast cancer cell lines have demonstrated that AhR agonists suppress proliferation, invasiveness, and colony formation in vitro; however, further exploration using in vivo models of metastasis is warranted. To test the effect of AhR activation on metastasis, 4T1.2 mammary tumor cells were injected into the mammary gland fat pad of syngeneic Balb/c mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Primary tumor growth was monitored for 4 weeks, at which time metastasis was determined. TCDD treatment suppressed metastasis by approximately 50%, as measured both in the lung and in mammary glands at sites distant from the primary tumor. Primary tumor growth was not suppressed by TCDD exposure nor was proliferation of 4T1.2 cells affected by TCDD treatment in vitro. Taken together, these results suggest that the protective effect of AhR activation was selective for the metastatic process and not simply the result of a direct decrease in tumor cell proliferation or survival at the primary site. These observations in immunologically intact animals warrant further investigation into the mechanism of the protective effects of AhR activation and support the promise for use of AhR modulators to treat breast cancer.", "corpus_id": 23375534, "score": 0 }, { "doc_id": "15076950", "title": "Dioxin emissions from a municipal solid waste incinerator and risk of invasive breast cancer: a population-based case-control study with GIS-derived exposure", "abstract": "BackgroundTo date, few epidemiologic studies have examined the relationship between environmental PCDD/F exposure and breast cancer in human populations. Dioxin emissions from municipal solid waste incinerators (MSWIs) are one of the major sources of environmental dioxins and are therefore an exposure source of public concern. The purpose of this study was to examine the association between dioxins emitted from a polluting MSWI and invasive breast cancer risk among women residing in the area under direct influence of the facility.MethodsWe compared 434 incident cases of invasive breast cancer diagnosed between 1996 and 2002, and 2170 controls randomly selected from the 1999 population census. A validated dispersion model was used as a proxy for dioxin exposure, yielding four exposure categories. The latter were linked to individual places of residence, using Geographic Information System technology.ResultsThe age distribution at diagnosis for all cases combined showed a bimodal pattern with incidence peaks near 50 and 70 years old. This prompted us to run models separately for women aged 20–59 years, and women aged 60 years or older. Among women younger than 60 years old, no increased or decreased risk was found for any dioxin exposure category. Conversely, women over 60 years old living in the highest exposed zone were 0.31 time less likely (95% confidence interval, 0.08–0.89) to develop invasive breast cancer.ConclusionBefore speculating that this decreased risk reflects a dioxin anti-estrogenic activity with greater effect on late-onset acquired breast cancer, some residual confounding must be envisaged.", "corpus_id": 15076950, "score": 0 }, { "doc_id": "22937247", "title": "Body weight loss increases plasma and adipose tissue concentrations of potentially toxic pollutants in obese individuals", "abstract": "BACKGROUND: While there appears to be a consensus among scientists and clinicians that body weight loss reduces the risk of several chronic diseases, these apparently favourable effects should be balanced against any potentially harmful side effect of weight loss. In this regard, weight loss has been shown to produce an increase in blood concentration of potentially toxic organochlorine pollutants in animals that can cause prejudice to health, but human data are lacking.METHODS: Thirty-nine obese individuals were subjected to a hypocaloric diet during 15 weeks. Blood and subcutaneous adipose tissue samples were analysed before and after treatment for 26 organochlorine compounds. A control group consisting of 57 women of similar mean age was also formed in order to compare plasma concentrations.RESULTS: Organochlorine pollutants were found in every subject and all 19 compounds detected had their plasma concentration increased following treatment (mean body weight loss 9.5 kg), 15 of which were statistically significant. When compared with a control group, five compounds increased significantly. These observations persisted after an 18 week low-fat diet/exercise program follow-up. Increases were correlated with body weight loss (−0.3 ≥ r ≥−0.6, P<0.05) and adipose tissue analyses yielded similar results, as their concentration of organochlorine compounds increased following treatment.CONCLUSION: Body weight loss increases plasma and subcutaneous adipose tissue concentrations of organochlorine pesticides and PCBs in obese subjects. These results raise concerns about an undesired and potentially harmful side effect of weight loss in some obese patients who seem to be at greater risk of health problems than leaner subjects since they show higher organochlorine body burden.", "corpus_id": 22937247, "score": 0 } ]

{ "doc_id": "15159859", "title": "On decidability of monadic logic of order over the naturals extended by monadic predicates", "abstract": "A fundamental result of Buchi states that the set of monadic second-order formulas true in the structure (Nat, <) is decidable. A natural question is: what monadic predicates (sets) can be added to (Nat, <) while preserving decidability? Elgot and Rabin found many interesting predicates P for which the monadic theory of is decidable. The Elgot and Rabin automata theoretical method has been generalized and sharpened over the years and their results were extended to a variety of unary predicates. We give a sufficient and necessary model-theoretical condition for the decidability of the monadic theory of (Nat,<,P\"1,...,P\"n).We reformulate this condition in an algebraic framework and show that a sufficient condition proposed previously by O. Carton and W.Thomas is actually necessary. A crucial argument in the proof is that monadic second-order logic has the selection and the uniformization properties over the extensions of (Nat,<) by monadic predicates. We provide a self-contained proof of this result.", "corpus_id": 15159859 }

[ { "doc_id": "122199984", "title": "Restricted set-theoretical definitions in arithmetic", "abstract": "Notice that sets of ordered pairs of natural numbers are used in this definition. Here and throughout this paper the logical symbols A (and), v (or), -* (if * * * then * * * ), -+ (if and only if), A (for every), and V (there exists) are used; negation does not occur explicitly. The concepts just mentioned, together with identity, are considered as the logical notions. On the other hand, it is known that it is not possible to give an explicit arithmetical definition of addition in terms of successor, that is, a definition using only the concepts of logic, and excluding the concepts of set theory. In fact, from a formula containing (besides parentheses and variables ranging over the natural numbers) only logical symbols and the symbol for successor, we can eliminate all quantifiers, if we allow the symbol 0 to be introduced.' From this, it follows that the only sets of natural numbers which are definable are the finite sets and their complements. In particular, the set of even numbers is not definable. It is then clear that addition also is not definable in this way. Alfred Tarski has proposed (in lectures) consideration of an intermediate type of definition, in which sets of natural numbers but no other sets are allowed. Thus we will have variables a, b, c, * * * which represent natural numbers, and variables A, B, C, * * * which repre-", "corpus_id": 122199984, "score": 0 }, { "doc_id": "45785189", "title": "Decidability and Undecidability of Extensions of Second (First) Order Theory of (Generalized) Successor", "abstract": "We study certain first and second order theories which are semantically defined as the sets of all sentences true in certain given structures. Let be a structure where A is a non-empty set, λ is an ordinal, and P α is an n ( α )-ary relation or function 4 on A . With we associate a language L appropriate for which may be a first or higher order calculus. L has an n ( α )-place predicate or function constant P for each α A ; (3) restricted (weak) second-order calculi which contain monadic predicate variables ranging over finite subsets of A .", "corpus_id": 45785189, "score": 0 }, { "doc_id": "204013692", "title": "LOGICAL THEORIES OF ONE-PLACE FUNCTIONS ON THE SET OF NATURAL NUMBERS", "abstract": "In this paper the author studies the decision problem for logical languages intended to describe the properties of one-place functions on the set of natural numbers. For functions taking a finite number of values a criterion for decidability of the monadic theory of the structure is obtained. For a large class of monotone functions , conditions are found under which the elementary theory of the structure is decidable; corresponding conditions are also found for structures of the form .Bibliography: 20 titles.", "corpus_id": 204013692, "score": 1 }, { "doc_id": "44456626", "title": "The Monadic Theory of Morphic Infinite Words and Generalizations", "abstract": "We present new examples of infinite words which have a decidable monadic theory. Formally, we consider structures ?N, <, P? which expand the ordering ?N, <? of the natural numbers by a unary predicate P; the corresponding infinite word is the characteristic 0-1-sequence xP of P. We show that for a morphic predicate P the associated monadic second-order theory MTh?N, <, P? is decidable, thus extending results of Elgot and Rabin (1966) and Maes (1999). The solution is obtained in the framework of semigroup theory, which is then connected to the known automata theoretic approach of Elgot and Rabin. Finally, a large class of predicates P is exhibited such that the monadic theory MTh?N, <, P? is decidable, which unifies and extends the previously known examples.", "corpus_id": 44456626, "score": 1 }, { "doc_id": "16225689", "title": "Decidable Theories of the Ordering of Natural Numbers with Unary Predicates", "abstract": "Expansions of the natural number ordering by unary predicates are studied, using logics which in expressive power are located between first-order and monadic second-order logic. Building on the model-theoretic composition method of Shelah, we give two characterizations of the decidable theories of this form, in terms of effectiveness conditions on two types of “homogeneous sets”. We discuss the significance of these characterizations, show that the first-order theory of successor with extra predicates is not covered by this approach, and indicate how analogous results are obtained in the semigroup theoretic and the automata theoretic framework.", "corpus_id": 16225689, "score": 1 }, { "doc_id": "1566485", "title": "Uniformization and Skolem Functions in the Class of Trees", "abstract": "The monadic second-order theory of trees allows quantification over elements and over arbitrary subsets. We classify the class of trees with respect to the question: does a tree T have definable Skolem functions (by a monadic formula with parameters)? This continues [LiSh539] where the question was asked only with respect to choice functions. Here we define a subclass of the class of tame trees (trees with a definable choice function) and prove that this is exactly the class (actually set) of trees with definable Skolem functions.", "corpus_id": 1566485, "score": 1 }, { "doc_id": "122129926", "title": "The monadic theory of order", "abstract": "We deal with the monadic (second-order) theory of order. We prove all known results in a unified way, show a general way of reduction, prove more results and show the limitation on extending them. We prove (CH) that the monadic theory of the real order is undecidable. Our methods are modeltheoretic, and we do not use automaton theory.", "corpus_id": 122129926, "score": 0 }, { "doc_id": "18297522", "title": "Monadic Second-Order Theories", "abstract": "In the present chapter we will make a case for the monadic second-order logic (that is to say, for the extension of first-order logic allowing quantification over monadic predicates) as a good source of theories that are both expressive and manageable. We will illustrate two powerful decidability techniques here—the one makes use of automata and games while the other uses generalized products a la Feferman-Vaught. The latter is, of course, particularly relevant, since monadic logic definitely appears to be the proper framework for examining generalized products. Undecidability proofs must be thought out anew in this area; for, whereas true first-order arithmetic is reducible to the monadic theory of the real line R, it is nevertheless not interpretable in the monadic theory of R. Thus, the examination of a quite unusual undecidability method is another subject that will be explained in this chapter. In the last section we will briefly review the history of the methods thus far developed and give a description of some further results. Monadic (second-order) logic is the extension of the first-order logic that allows quantification over monadic (unary) predicates. Thus, although binary, ternary, and other predicates, as well as functions, may appear in monadic (second-order) languages, they may nevertheless not be quantified over. 1.1. Formal Languages for Mathematical Theories We are interested less in monadic (second-order) logic itself than in the applications of this logic to mathematical theories. We are interested in the monadic formalization of the language of a mathematical theory and in monadic theories of corresponding mathematical objects. Before we explore this line of thought in more detail, let us argue that formalizing a mathematical language—not necessarily in monadic logic, but rather in first-order logic or in any other formal logic for that matter—can be useful.", "corpus_id": 18297522, "score": 0 }, { "doc_id": "4568478", "title": "Solving sequential conditions by finite-state strategies", "abstract": "Our main purpose is to present an algorithm which decides whether or not a condition 𝕮(X, Y) stated in sequential calculus admits a finite automata solution, and produces one if it exists. This solves a problem stated in [4] and contains, as a very special case, the answer to Case 4 left open in [6]. In an equally appealing form the result can be restated in the terminology of [7], [10], [15]: Every ω-game definable in sequential calculus is determined. Moreover the player who has a winning strategy, in fact, has a winning finite-state strategy, that is one which can effectively be played in a strong sense. The main proof, that of the central Theorem 1, will be presented at the end. We begin with a discussion of its consequences.", "corpus_id": 4568478, "score": 1 } ]

{ "doc_id": "27705568", "title": "Emerging role of adipose tissue hypoxia in obesity and insulin resistance", "abstract": "Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.", "corpus_id": 27705568 }

[ { "doc_id": "4424156", "title": "Inflammation and metabolic disorders", "abstract": "Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.", "corpus_id": 4424156, "score": 0 }, { "doc_id": "13038542", "title": "TNF-alpha and insulin resistance: summary and future prospects.", "abstract": "While the causes of obesity remain elusive, the relationship between obesity and insulin resistance is a well-established fact [1]. Insulin resistance is defined as a smaller than normal response to a certain dose of insulin, and contributes to several pathological problems of obese patients such as hyperlipidemia, arteriosclerosis and hypertension. Several pieces of evidence indicate that the cytokine tumor necrosis factor a (TNF-alpha) is an important player in the state of insulin resistance observed during obesity. In this review we will try to summarize what is known about the function of TNF-alpha in insulin resistance during obesity and how TNF-alpha interferes with insulin signaling.", "corpus_id": 13038542, "score": 0 }, { "doc_id": "28347489", "title": "Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkβ", "abstract": "We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IκB kinase β (IKKβ) attenuated insulin signaling in cultured cells, whereas IKKβ inhibition reversed insulin resistance. Thus, IKKβ, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkβ +/−) protected against the development of insulin resistance during high-fat feeding and in obese Lepob/ob mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKβ pathway as a target for insulin sensitization.", "corpus_id": 28347489, "score": 0 }, { "doc_id": "8914559", "title": "Prevention of fat-induced insulin resistance by salicylate.", "abstract": "Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may involve fat-induced activation of a serine kinase cascade involving IKK-beta. To test this hypothesis, we first examined insulin action and signaling in awake rats during hyperinsulinemic-euglycemic clamps after a lipid infusion with or without pretreatment with salicylate, a known inhibitor of IKK-beta. Whole-body glucose uptake and metabolism were estimated using [3-(3)H]glucose infusion, and glucose uptake in individual tissues was estimated using [1-(14)C]2-deoxyglucose injection during the clamp. Here we show that lipid infusion decreased insulin-stimulated glucose uptake and activation of IRS-1-associated PI 3-kinase in skeletal muscle but that salicylate pretreatment prevented these lipid-induced effects. To examine the mechanism of salicylate action, we studied the effects of lipid infusion on insulin action and signaling during the clamp in awake mice lacking IKK-beta. Unlike the response in wild-type mice, IKK-beta knockout mice did not exhibit altered skeletal muscle insulin signaling and action following lipid infusion. In summary, high-dose salicylate and inactivation of IKK-beta prevent fat-induced insulin resistance in skeletal muscle by blocking fat-induced defects in insulin signaling and action and represent a potentially novel class of therapeutic agents for type 2 diabetes.", "corpus_id": 8914559, "score": 0 }, { "doc_id": "38247018", "title": "Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha.", "abstract": "The possibility that lipid-induced insulin resistance in human muscle is related to alterations in diacylglycerol (DAG)/protein kinase C (PKC) signaling was investigated in normal volunteers during euglycemic-hyperinsulinemic clamping in which plasma free fatty acid (FFA) levels were increased by a lipid/heparin infusion. In keeping with previous reports, rates of insulin-stimulated glucose disappearance (G(Rd)) were normal after 2 h but were reduced by 43% (from 52.7 +/- 8.2 to 30.0 +/- 5.3 micromol. kg(-1). min(-1), P < 0.05) after 6 h of lipid infusion. No changes in PKC activity or DAG mass were seen in muscle biopsy samples after 2 h of lipid infusion; however, at approximately 6 h, PKC activity and DAG mass were increased approximately fourfold, as were the abundance of membrane-associated PKC-betaII and -delta. A threefold increase in membrane-associated PKC-betaII was also observed at approximately 2 h but was not statistically significant (P = 0.058). Ceramide mass was not changed at either time point. To evaluate whether the fatty acid-induced insulin activation of PKC was associated with a change in the IkB kinase (IKK)/nuclear factor (NF)-kappaB pathway, we determined the abundance in muscle of IkappaB-alpha, an inhibitor of NF-kappaB that is degraded after its phosphorylation by IKK. In parallel with the changes in DAG/PKC, no change in IkappaB-alpha mass was observed after 2 h of lipid infusion, but at approximately 6 h, IkappaB-alpha was diminished by 70%. In summary, the results indicated that the insulin resistance observed in human muscle when plasma FFA levels were elevated during euglycemic-hyperinsulinemic clamping was associated with increases in DAG mass and membrane-associated PKC-betaII and -delta and a decrease in IkappaB-alpha. Whether acute FFA-induced insulin resistance in human skeletal muscle is caused by the activation of these specific PKC isoforms and the IKK-beta/IkappaB/NFkappaB pathway remains to be established.", "corpus_id": 38247018, "score": 0 }, { "doc_id": "35441661", "title": "Reciprocal Modulation of Toll-like Receptor-4 Signaling Pathways Involving MyD88 and Phosphatidylinositol 3-Kinase/AKT by Saturated and Polyunsaturated Fatty Acids*", "abstract": "Toll-like receptor-4 (TLR4) can be activated by nonbacterial agonists, including saturated fatty acids. However, downstream signaling pathways activated by nonbacterial agonists are not known. Thus, we determined the downstream signaling pathways derived from saturated fatty acid-induced TLR4 activation. Saturated fatty acid (lauric acid)-induced NFκB activation was inhibited by a dominant-negative mutant of TLR4, MyD88, IRAK-1, TRAF6, or IκBα in macrophages (RAW264.7) and 293T cells transfected with TLR4 and MD2. Lauric acid induced the transient phosphorylation of AKT. LY294002, dominant-negative (DN) phosphatidylinositol 3-kinase (PI3K), or AKT(DN) inhibited NFκB activation, p65 transactivation, and cyclooxygenase-2 (COX-2) expression induced by lauric acid or constitutively active (CA) TLR4. AKT(DN) blocked MyD88-induced NFκB activation, suggesting that AKT is a MyD88-dependent downstream signaling component of TLR4. AKT(CA) was sufficient to induce NFκB activation and COX-2 expression. These results demonstrate that NFκB activation and COX-2 expression induced by lauric acid are at least partly mediated through the TLR4/PI3K/AKT signaling pathway. In contrast, docosahexaenoic acid (DHA) inhibited the phosphorylation of AKT induced by lipopolysaccharide or lauric acid. DHA also suppressed NFκB activation induced by TLR4(CA), but not MyD88(CA) or AKT(CA), suggesting that the molecular targets of DHA are signaling components upstream of MyD88 and AKT. Together, these results suggest that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4 and its downstream signaling pathways involving MyD88/IRAK/TRAF6 and PI3K/AKT and further suggest the possibility that TLR4-mediated target gene expression and cellular responses are also differentially modulated by saturated and unsaturated fatty acids.", "corpus_id": 35441661, "score": 0 }, { "doc_id": "22024234", "title": "TLR4 links innate immunity and fatty acid-induced insulin resistance.", "abstract": "TLR4 is the receptor for LPS and plays a critical role in innate immunity. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. Inflammatory pathways are activated in tissues of obese animals and humans and play an important role in obesity-associated insulin resistance. Here we show that nutritional fatty acids, whose circulating levels are often increased in obesity, activate TLR4 signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4. Moreover, mice lacking TLR4 are substantially protected from the ability of systemic lipid infusion to (a) suppress insulin signaling in muscle and (b) reduce insulin-mediated changes in systemic glucose metabolism. Finally, female C57BL/6 mice lacking TLR4 have increased obesity but are partially protected against high fat diet-induced insulin resistance, possibly due to reduced inflammatory gene expression in liver and fat. Taken together, these data suggest that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.", "corpus_id": 22024234, "score": 0 }, { "doc_id": "12846469", "title": "Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance", "abstract": "Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor (TLR)4 has an important role in inflammation and immunity, and its expression has been reported in most tissues of the body, including the insulin-sensitive ones. Because it is activated by lipopolysaccharide and saturated fatty acids, which are inducers of insulin resistance, TLR4 may be a candidate for participation in the cross-talk between inflammatory and metabolic signals. Here, we show that C3H/HeJ mice, which have a loss-of-function mutation in TLR4, are protected against the development of diet-induced obesity. In addition, these mice demonstrate decreased adiposity, increased oxygen consumption, a decreased respiratory exchange ratio, improved insulin sensitivity, and enhanced insulin-signaling capacity in adipose tissue, muscle, and liver compared with control mice during high-fat feeding. Moreover, in these tissues, control mice fed a high-fat diet show an increase in IκB kinase complex and c-Jun NH2-terminal kinase activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/HeJ mice, protection from saturated fatty acid–induced insulin resistance is observed. Thus, TLR4 appears to be an important mediator of obesity and insulin resistance and a potential target for the therapy of these highly prevalent medical conditions.", "corpus_id": 12846469, "score": 0 }, { "doc_id": "29927260", "title": "Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle*", "abstract": "Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase). To examine the mechanism by which fatty acids mediate this effect, rats were infused with either a lipid emulsion (consisting mostly of 18:2 fatty acids) or glycerol. Intracellular C18:2 CoA increased in a time-dependent fashion, reaching an ∼6-fold elevation by 5 h, whereas there was no change in the concentration of any other fatty acyl-CoAs. Diacylglycerol (DAG) also increased transiently after 3–4 h of lipid infusion. In contrast there was no increase in intracellular ceramide or triglyceride concentrations during the lipid infusion. Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)-θ activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser307 phosphorylation. These data support the hypothesis that an increase in plasma fatty acid concentration results in an increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-θ leading to increased IRS-1 Ser307 phosphorylation. This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity.", "corpus_id": 29927260, "score": 0 }, { "doc_id": "26170399", "title": "Inhibition of ceramide production reverses TNF-induced insulin resistance.", "abstract": "Ceramide has been implicated as a mediator of insulin resistance induced by tumor necrosis factor-alpha (TNF) in adipocytes. Adipocytes contain numerous caveolae, sphingolipid and cholesterol-enriched lipid microdomains, that are also enriched in insulin receptor (IR). Since caveolae may be important sites for crosstalk between tyrosine kinase and sphingolipid signaling pathways, we examined the role of increased caveolar pools of ceramide in regulating tyrosine phosphorylation of the IR and its main substrate, insulin receptor substrate-1 (IRS-1). Neither exogenous short-chain ceramide analogs nor pharmacologic increases in endogenous caveolar pools of ceramide inhibited insulin-induced tyrosine phosphorylation of the IR and IRS-1. However, inhibition of TNF-induced caveolar ceramide production reversed the decrease in IR tyrosine phosphorylation in response to TNF. These results suggest that TNF-independent increases in caveolar pools of ceramide are not sufficient to inhibit insulin signaling but that in conjunction with other TNF-dependent signals, caveolar pools of ceramide are a critical component for insulin resistance by TNF.", "corpus_id": 26170399, "score": 0 }, { "doc_id": "608906", "title": "Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state.", "abstract": "Tumor necrosis factor (TNF)-alpha causes insulin resistance on glucose uptake in fetal brown adipocytes. We explored the hypothesis that some effects of TNF-alpha could be mediated by the generation of ceramide, given that TNF-alpha treatment induced the production of ceramide in these primary cells. A short-chain ceramide analog, C2-ceramide, completely precluded insulin-stimulated glucose uptake and insulin-induced GLUT4 translocation to plasma membrane, as determined by Western blot or immunofluorescent localization of GLUT4. These effects were not produced in the presence of a biologically inactive ceramide analog, C2-dihydroceramide. Analysis of the phosphatidylinositol (PI) 3-kinase signaling pathway indicated that C2-ceramide precluded insulin stimulation of Akt kinase activity, but not of PI-3 kinase or protein kinase C-zeta activity. C2-ceramide completely abolished insulin-stimulated Akt/protein kinase B phosphorylation on regulatory residues Thr 308 and Ser 473, as did TNF-alpha, and inhibited insulin-induced mobility shift in Akt1 and Akt2 separated in PAGE. Moreover, C2-ceramide seemed to activate a protein phosphatase (PP) involved in dephosphorylating Akt because 1) PP2A activity was increased in C2-ceramide- and TNF-alpha-treated cells, 2) treatment with okadaic acid concomitantly with C2-ceramide completely restored Akt phosphorylation by insulin, and 3) transient transfection of a constitutively active form of Akt did not restore Akt activity. Our results indicate that ceramide produced by TNF-alpha induces insulin resistance in brown adipocytes by maintaining Akt in an inactive dephosphorylated state.", "corpus_id": 608906, "score": 0 }, { "doc_id": "21632295", "title": "Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance.", "abstract": "Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.", "corpus_id": 21632295, "score": 0 }, { "doc_id": "20731552", "title": "Involvement of Endoplasmic Reticulum Stress in Insulin Resistance and Diabetes*", "abstract": "Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic β-cell dysfunction are the hallmarks of the disease. In this study, we have shown that endoplasmic reticulum (ER) stress, which is provoked under diabetic conditions, plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress. Sense ORP overexpression in the liver of obese diabetic mice significantly improved insulin resistance and markedly ameliorated glucose tolerance. Conversely, expression of antisense ORP150 in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of IRS-1 and Akt, which are key molecules for insulin signaling, and the expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were also altered by ORP150 overexpression. This is the first report showing that ER stress plays a crucial role in the insulin resistance found in diabetes and thus could be a potential therapeutic target for diabetes.", "corpus_id": 20731552, "score": 0 }, { "doc_id": "7096877", "title": "Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase", "abstract": "Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative stress. However, the role of reactive oxygen species or specific antioxidant enzymes in its development has not been tested under physiological conditions. The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide (H2O2) in vivo, on glucose metabolism and insulin function. The GPX1-overexpressing (OE) and WT male mice (n = 80) were fed a selenium-adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE mice developed (P < 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of age. Meanwhile, these mice were heavier (37 vs. 27 g, P < 0.001) and fatter (37% vs. 17% fat, P < 0.01) than the WT mice. At 30–60 min after an insulin challenge, the OE mice had 25% less (P < 0.05) of a decrease in blood glucose than the WT mice. Their insulin resistance was associated with a 30–70% reduction (P < 0.05) in the insulin-stimulated phosphorylations of insulin receptor (β-subunit) in liver and Akt (Ser473 and Thr308) in liver and soleus muscle. Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing.", "corpus_id": 7096877, "score": 0 }, { "doc_id": "23208425", "title": "Reactive oxygen species have a causal role in multiple forms of insulin resistance", "abstract": "Insulin resistance is a cardinal feature of type 2 diabetes and is characteristic of a wide range of other clinical and experimental settings. Little is known about why insulin resistance occurs in so many contexts. Do the various insults that trigger insulin resistance act through a common mechanism? Or, as has been suggested, do they use distinct cellular pathways? Here we report a genomic analysis of two cellular models of insulin resistance, one induced by treatment with the cytokine tumour-necrosis factor-α and the other with the glucocorticoid dexamethasone. Gene expression analysis suggests that reactive oxygen species (ROS) levels are increased in both models, and we confirmed this through measures of cellular redox state. ROS have previously been proposed to be involved in insulin resistance, although evidence for a causal role has been scant. We tested this hypothesis in cell culture using six treatments designed to alter ROS levels, including two small molecules and four transgenes; all ameliorated insulin resistance to varying degrees. One of these treatments was tested in obese, insulin-resistant mice and was shown to improve insulin sensitivity and glucose homeostasis. Together, our findings suggest that increased ROS levels are an important trigger for insulin resistance in numerous settings.", "corpus_id": 23208425, "score": 0 }, { "doc_id": "7406768", "title": "Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500294-JLR200", "abstract": "Macrophage infiltration of white adipose tissue (WAT) is implicated in the metabolic complications of obesity. The precipitating event(s) and function(s) of macrophage infiltration into WAT are unknown. We demonstrate that >90% of all macrophages in WAT of obese mice and humans are localized to dead adipocytes, where they fuse to form syncytia that sequester and scavenge the residual “free” adipocyte lipid droplet and ultimately form multinucleate giant cells, a hallmark of chronic inflammation. Adipocyte death increases in obese (db/db) mice (30-fold) and humans and exhibits ultrastructural features of necrosis (but not apoptosis). These observations identify necrotic-like adipocyte death as a pathologic hallmark of obesity and suggest that scavenging of adipocyte debris is an important function of WAT macrophages in obese individuals. The frequency of adipocyte death is positively correlated with increased adipocyte size in obese mice and humans and in hormone-sensitive lipase-deficient (HSL−/−) mice, a model of adipocyte hypertrophy without increased adipose mass. WAT of HSL−/− mice exhibited a 15-fold increase in necrotic-like adipocyte death and formation of macrophage syncytia, coincident with increased tumor necrosis factor-α gene expression. These results provide a novel framework for understanding macrophage recruitment, function, and persistence in WAT of obese individuals.", "corpus_id": 7406768, "score": 0 }, { "doc_id": "15816847", "title": "Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications", "abstract": "OBJECTIVE—We sought to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications. RESEARCH DESIGN AND METHODS—Male C57BL/6 mice were fed a high-fat diet for 20 weeks to induce obesity. Every 4 weeks, insulin resistance was assessed by intraperitoneal insulin tolerance tests, and epididymal (eAT) and inguinal subcutaneous AT (iAT) and livers were harvested for histological, immunohistochemical, and gene expression analyses. RESULTS—Frequency of adipocyte death in eAT increased from <0.1% at baseline to 16% at week 12, coincident with increases in 1) depot weight; 2) AT macrophages (ATMΦs) expressing F4/80 and CD11c; 3) mRNA for tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, and interleukin (IL)-10; and 4) insulin resistance. ATMΦs in crown-like structures surrounding dead adipocytes expressed TNF-α and IL-6 proteins. Adipocyte number began to decline at week 12. At week 16, adipocyte death reached ∼80%, coincident with maximal expression of CD11c and inflammatory genes, loss (40%) of eAT mass, widespread collagen deposition, and accelerated hepatic macrosteatosis. By week 20, adipocyte number was restored with small adipocytes, coincident with reduced adipocyte death (fourfold), CD11c and MCP-1 gene expression (twofold), and insulin resistance (35%). eAT weight did not increase at week 20 and was inversely correlated with liver weight after week 12 (r = −0. 85, P < 0.001). In iAT, adipocyte death was first detected at week 12 and remained ≤3%. CONCLUSIONS—These results implicate depot-selective adipocyte death and MΦ-mediated AT remodeling in inflammatory and metabolic complications of murine obesity.", "corpus_id": 15816847, "score": 0 }, { "doc_id": "29520280", "title": "Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice.", "abstract": "Chronic inflammation and reduced adiponectin are widely observed in the white adipose tissue in obesity. However, the cause of the changes remains to be identified. In this study, we provide experimental evidence that hypoxia occurs in adipose tissue in obese mice and that adipose hypoxia may contribute to the endocrine alterations. The adipose hypoxia was demonstrated by a reduction in the interstitial partial oxygen pressure (Po(2)), an increase in the hypoxia probe signal, and an elevation in expression of the hypoxia response genes in ob/ob mice. The adipose hypoxia was confirmed in dietary obese mice by expression of hypoxia response genes. In the adipose tissue, hypoxia was associated with an increased expression of inflammatory genes and decreased expression of adiponectin. In dietary obese mice, reduction in body weight by calorie restriction was associated with an improvement of oxygenation and a reduction in inflammation. In cell culture, inflammatory cytokines were induced by hypoxia in primary adipocytes and primary macrophages of lean mice. The transcription factor NF-kappaB and the TNF-alpha gene promoter were activated by hypoxia in 3T3-L1 adipocytes and NIH3T3 fibroblasts. In addition, adiponectin expression was reduced by hypoxia, and the reduction was observed in the gene promoter in adipocytes. These data suggest a potential role of hypoxia in the induction of chronic inflammation and inhibition of adiponectin in the adipose tissue in obesity.", "corpus_id": 29520280, "score": 1 }, { "doc_id": "21078120", "title": "Adipose Tissue Hypoxia in Obesity and Its Impact on Adipocytokine Dysregulation", "abstract": "Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker. Moreover, local tissue hypoperfusion (measured by colored microspheres) was confirmed in adipose tissue of obese mice. Adiponectin mRNA expression was decreased, and mRNA of C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress–mediated protein, was significantly increased in adipose tissue of obese mice. In 3T3-L1 adipocytes, hypoxia dysregulated the expression of adipocytokines, such as adiponectin and plasminogen activator inhibitor type-1, and increased the mRNAs of ER stress marker genes, CHOP and GRP78 (glucose-regulated protein, 78 kD). Expression of CHOP attenuated adiponectin promoter activity, and RNA interference of CHOP partly reversed hypoxia-induced suppression of adiponectin mRNA expression in adipocytes. Hypoxia also increased instability of adiponectin mRNA. Our results suggest that hypoperfusion and hypoxia in adipose tissues underlie the dysregulated production of adipocytokines and metabolic syndrome in obesity.", "corpus_id": 21078120, "score": 1 }, { "doc_id": "45602142", "title": "How Obesity Causes Diabetes: Not a Tall Tale", "abstract": "The epidemic of obesity-associated diabetes is a major crisis in modern societies, in which food is plentiful and exercise is optional. The biological basis of this problem has been explored from evolutionary and mechanistic perspectives. Evolutionary theories, focusing on the potential survival advantages of “thrifty” genes that are now maladaptive, are of great interest but are inherently speculative and difficult to prove. Mechanistic studies have revealed numerous fat-derived molecules and a link to inflammation that, together, are hypothesized to underlie the obesity-diabetes connection and thereby represent prospective targets for therapeutic intervention.", "corpus_id": 45602142, "score": 0 }, { "doc_id": "23975963", "title": "Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.", "abstract": "Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.", "corpus_id": 23975963, "score": 0 }, { "doc_id": "46109528", "title": "Obesity and insulin resistance.", "abstract": "The association of obesity with type 2 diabetes has been recognized for decades, and the major basis for this link is the ability of obesity to engender insulin resistance. Insulin resistance is a fundamental aspect of the etiology of type 2 diabetes and is also linked to a wide array of other pathophysiologic sequelae including hypertension, hyperlipidemia, atherosclerosis (i.e., the metabolic syndrome, or syndrome X), and polycystic ovarian disease (1). Although many details of the mechanisms by which the enlarged adipose tissue mass that defines obesity causes systemic insulin resistance remain unknown, the past several years have witnessed an explosive increase in our understanding of what may now be referred to as the adipo-insulin axis. There are also grounds for considering the related possibility that insulin resistance and hyperinsulinemia, in addition to being caused by obesity, can contribute to the development of obesity. In this Perspective, we will review recent progress, highlight areas of controversy or uncertainty, and suggest approaches to clarifying the unresolved issues.", "corpus_id": 46109528, "score": 0 }, { "doc_id": "17236229", "title": "Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.", "abstract": "Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.", "corpus_id": 17236229, "score": 0 }, { "doc_id": "24044009", "title": "Obesity is associated with macrophage accumulation in adipose tissue.", "abstract": "Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.", "corpus_id": 24044009, "score": 0 }, { "doc_id": "40522851", "title": "Adiposity Elevates Plasma MCP-1 Levels Leading to the Increased CD11b-positive Monocytes in Mice*", "abstract": "Obesity is currently considered as an epidemic in the western world, and it represents a major risk factor for life-threatening diseases such as heart attack, stroke, diabetes, and cancer. Taking advantage of DNA microarray technology, we tried to identify the molecules explaining the relationship between obesity and vascular disorders, comparing mRNA expression of about 12,000 genes in white adipose tissue between normal, high fat diet-induced obesity (DIO) and d-Trp34 neuropeptide Y-induced obesity in mice. Expression of monocyte chemoattractant protein-1 (MCP-1) mRNA displayed a 7.2-fold increase in obese mice as compared with normal mice, leading to substantially elevated MCP-1 protein levels in adipocytes. MCP-1 levels in plasma were also increased in DIO mice, and a strong correlation between plasma MCP-1 levels and body weight was identified. We also showed that elevated MCP-1 protein levels in plasma increased the CD11b-positive monocyte/macrophage population in DIO mice. Furthermore, infusion of MCP-1 into lean mice increased the CD11b-positive monocyte population without inducing changes in body weight. Given the importance of MCP-1 in activation of monocytes and subsequent atherosclerotic development, these results suggest a novel role of adiposity in the development of vascular disorders.", "corpus_id": 40522851, "score": 0 }, { "doc_id": "1119157", "title": "Insulin signalling and the regulation of glucose and lipid metabolism", "abstract": "The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.", "corpus_id": 1119157, "score": 0 }, { "doc_id": "13389359", "title": "Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways.", "abstract": "Serine/threonine phosphorylation of IRS-1 might inhibit insulin signaling, but the relevant phosphorylation sites are difficult to identify in cultured cells and to validate in isolated tissues. Recently, we discovered that recombinant NH2-terminal Jun kinase phosphorylates IRS-1 at Ser307, which inhibits insulin-stimulated tyrosine phosphorylation of IRS-1. To monitor phosphorylation of Ser307 in various cell and tissue backgrounds, we prepared a phosphospecific polyclonal antibody designated alphapSer307. This antibody revealed that TNF-alpha, IGF-1, or insulin stimulated phosphorylation of IRS-1 at Ser307 in 3T3-L1 preadipocytes and adipocytes. Insulin injected into mice or rats also stimulated phosphorylation of Ser307 on IRS-1 immunoprecipitated from muscle; moreover, Ser307 was phosphorylated in human muscle during the hyperinsulinemic euglycemic clamp. Experiments in 3T3-L1 preadipocytes and adipocytes revealed that insulin-stimulated phosphorylation of Ser307 was inhibited by LY294002 or wortmannin, whereas TNF-alpha-stimulated phosphorylation was inhibited by PD98059. Thus, distinct kinase pathways might converge at Ser307 to mediate feedback or heterologous inhibition of IRS-1 signaling to counterregulate the insulin response.", "corpus_id": 13389359, "score": 0 }, { "doc_id": "39382438", "title": "Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes.", "abstract": "Insulin receptor substrate (IRS) has been suggested as a molecular target of free fatty acids (FFAs) for insulin resistance. However, the signaling pathways by which FFAs lead to the inhibition of IRS function remain to be established. In this study, we explored the FFA-signaling pathway that contributes to serine phosphorylation and degradation of IRS-1 in adipocytes and in dietary obese mice. Linoleic acid, an FFA used in this study, resulted in a reduction in insulin-induced glucose uptake in 3T3-L1 adipocytes. This mimics insulin resistance induced by high-fat diet in C57BL/6J mice. The reduction in glucose uptake is associated with a decrease in IRS-1, but not IRS-2 or GLUT4 protein abundance. Decrease in IRS-1 protein was proceeded by IRS-1 (serine 307) phosphorylation that was catalyzed by serine kinases inhibitor kappaB kinase (IKK) and c-JUN NH2-terminal kinase (JNK). IKK and JNK were activated by linoleic acid and inhibition of the two kinases led to prevention of IRS-1 reduction. We demonstrate that protein kinase C (PKC) theta is expressed in adipocytes. In 3T3-L1 adipocytes and fat tissue, PKCtheta was activated by fatty acids as indicated by its phosphorylation status, and by its protein level, respectively. Activation of PKCtheta contributes to IKK and JNK activation as inhibition of PKCtheta by calphostin C blocked activation of the latter kinases. Inhibition of either PKCtheta or IKK plus JNK by chemical inhibitors resulted in protection of IRS-1 function and insulin sensitivity in 3T3-L1 adipocytes. These data suggest that: 1) activation of PKCtheta contributes to IKK and JNK activation by FFAs; 2) IKK and JNK mediate PKCtheta signals for IRS-1 serine phosphorylation and degradation; and 3) this molecular mechanism may be responsible for insulin resistance associated with hyperlipidemia.", "corpus_id": 39382438, "score": 0 }, { "doc_id": "8342351", "title": "JNK and Tumor Necrosis Factor-α Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes*", "abstract": "Lipid infusion and high fat feeding are established causes of systemic and adipose tissue insulin resistance. In this study, we treated 3T3-L1 adipocytes with a mixture of free fatty acids (FFAs) to investigate the molecular mechanisms underlying fat-induced insulin resistance. FFA treatment impaired insulin receptor-mediated signal transduction and decreased insulin-stimulated GLUT4 translocation and glucose transport. FFAs activated the stress/inflammatory kinases c-Jun N-terminal kinase (JNK) and IKKβ, and the suppressor of cytokine signaling protein 3, increased secretion of the inflammatory cytokine tumor necrosis factor (TNF)-α, and decreased secretion of adiponectin into the medium. RNA interference-mediated down-regulation of JNK blocked JNK activation and prevented most of the FFA-induced defects in insulin action. Blockade of TNF-α signaling with neutralizing antibodies to TNF-α or its receptors or with a dominant negative TNF-α peptide had a partial effect to inhibit FFA-induced cellular insulin resistance. We found that JNK activation by FFAs was not inhibited by blocking TNF-α signaling, whereas the FFA-induced increase in TNF-α secretion was inhibited by RNA interference-mediated JNK knockdown. Together, these results indicate that 1) JNK can be activated by FFAs through TNF-α-independent mechanisms, 2) activated JNK is a major contributor to FFA-induced cellular insulin resistance, and 3) TNF-α is an autocrine/paracrine downstream effector of activated JNK that can also mediate insulin resistance.", "corpus_id": 8342351, "score": 0 }, { "doc_id": "46312669", "title": "Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade.", "abstract": "Pluripotent mesenchymal stem cells in bone marrow differentiate into adipocytes, osteoblasts and other cells. Balanced cytodifferentiation of stem cells is essential for the formation and maintenance of bone marrow; however, the mechanisms that control this balance remain largely unknown. Whereas cytokines such as interleukin-1 (IL-1) and tumour-necrosis factor-alpha (TNF-alpha) inhibit adipogenesis, the ligand-induced transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), is a key inducer of adipogenesis. Therefore, regulatory coupling between cytokine- and PPAR-gamma-mediated signals might occur during adipogenesis. Here we show that the ligand-induced transactivation function of PPAR-gamma is suppressed by IL-1 and TNF-alpha, and that this suppression is mediated through NF-kappaB activated by the TAK1/TAB1/NF-kappaB-inducing kinase (NIK) cascade, a downstream cascade associated with IL-1 and TNF-alpha signalling. Unlike suppression of the PPAR-gamma transactivation function by mitogen-activated protein kinase-induced growth factor signalling through phosphorylation of the A/B domain, NF-kappaB blocks PPAR-gamma binding to DNA by forming a complex with PPAR-gamma and its AF-1-specific co-activator PGC-2. Our results suggest that expression of IL-1 and TNF-alpha in bone marrow may alter the fate of pluripotent mesenchymal stem cells, directing cellular differentiation towards osteoblasts rather than adipocytes by suppressing PPAR-gamma function through NF-kappaB activated by the TAK1/TAB1/NIK cascade.", "corpus_id": 46312669, "score": 0 }, { "doc_id": "25142490", "title": "PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.", "abstract": "The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, a member of the nuclear hormone receptor superfamily. PPAR-gamma has also been recently identified as the major functional receptor for the thiazolidinedione class of insulin-sensitizing drugs. This review examines the evidence that has implicated this transcription factor in the processes of adipogenesis and systemic insulin action. In addition, several models are discussed that may explain how a single protein can be involved in these related but distinct physiological actions. I also point out several important areas where our knowledge is incomplete and more research is needed. Finally, I discuss how advances in our understanding of nuclear receptor function, particularly the docking of cofactors in a ligand-dependent fashion, should lead to improved drugs that utilize the PPAR-gamma system for the treatment of insulin resistance.", "corpus_id": 25142490, "score": 0 }, { "doc_id": "11459441", "title": "The mechanisms of action of PPARs.", "abstract": "The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR gamma, PPAR alpha, and PPAR delta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.", "corpus_id": 11459441, "score": 0 }, { "doc_id": "46118093", "title": "Progress in cardiovascular biology: PPAR for the course", "abstract": "Studies on mice lacking the peroxisome proliferator-activated receptor (PPAR) suggest that PPAR ligands reduce lipid accumulation in foamy macrophages, and may target other receptors. These findings warrant an in-depth investigation into the gene regulatory mechanisms of PPAR ligands, which are currently being developed as drugs to treat atherosclerosis and diabetes. (pages 41–47)", "corpus_id": 46118093, "score": 0 }, { "doc_id": "21600178", "title": "Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia.", "abstract": "Cellular differentiation involves transcriptional responses to environmental stimuli. Adipocyte differentiation is inhibited under hypoxic conditions, indicating that oxygen (O(2)) is an important physiological regulator of adipogenesis. Hypoxia inhibits PPAR gamma 2 nuclear hormone receptor transcription, and overexpression of PPAR gamma 2 or C/EBP beta stimulates adipogenesis under hypoxia. Mouse embryonic fibroblasts deficient in hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) are refractory to hypoxia-mediated inhibition of adipogenesis. The HIF-1-regulated gene DEC1/Stra13, a member of the Drosophila hairy/Enhancer of split transcription repressor family, represses PPAR gamma 2 promoter activation and functions as an effector of hypoxia-mediated inhibition of adipogenesis. These data indicate that an O(2)-sensitive signaling mechanism regulates adipogenesis. Thus, agents that regulate HIF-1 activity or O(2) sensing may be used to inhibit adipogenesis and control obesity.", "corpus_id": 21600178, "score": 0 }, { "doc_id": "1413809", "title": "Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes.", "abstract": "Low plasma levels of adiponectin (hypoadiponectinemia) and elevated circulating concentrations of plasminogen activator inhibitor (PAI)-1 are causally associated with obesity-related insulin resistance and cardiovascular disease. However, the mechanism that mediates the aberrant production of these two adipokines in obesity remains poorly understood. In this study, we investigated the effects of hypoxia and reactive oxygen species (ROS) on production of adiponectin and PAI-1 in 3T3-L1 adipocytes. Quantitative PCR and immunoassays showed that ambient hypoxia markedly suppressed adiponectin mRNA expression and its protein secretion, and increased PAI-1 production in mature adipocytes. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1alpha (HIF-1alpha), mimicked the hypoxia-mediated modulations of these two adipokines. Hypoxia caused a modest elevation of ROS in adipocytes. However, ablation of intracellular ROS by antioxidants failed to alleviate hypoxia-induced aberrant production of adiponectin and PAI-1. On the other hand, the antioxidants could reverse hydrogen peroxide (H2O2)-induced dysregulation of adiponectin and PAI-1 production. H2O2 treatment decreased the expression levels of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein (C/EBPalpha), but had no effect on HIF-1alpha, whereas hypoxia stabilized HIF-1alpha and decreased expression of C/EBPalpha, but not PPARgamma. Taken together, these data suggest that hypoxia and ROS decrease adiponectin production and augment PAI-1 expression in adipocytes via distinct signaling pathways. These effects may contribute to hypoadiponectinemia and elevated PAI-1 levels in obesity, type 2 diabetes, and cardiovascular diseases.", "corpus_id": 1413809, "score": 0 }, { "doc_id": "10043114", "title": "Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes", "abstract": "The effect of hypoxia, induced by incubation under low (1%) oxygen tension or by exposure to CoCl2, on the expression and secretion of inflammation-related adipokines was examined in human adipocytes. Hypoxia led to a rapid and substantial increase (greater than sevenfold by 4 h of exposure to 1% O2) in the hypoxia-sensitive transcription factor, HIF-1α, in human adipocytes. This was accompanied by a major increase (up to 14-fold) in GLUT1 transporter mRNA level. Hypoxia (1% O2 or CoCl2) led to a reduction (up to threefold over 24 h) in adiponectin and haptoglobin mRNA levels; adiponectin secretion also decreased. No changes were observed in TNFα expression. In contrast, hypoxia resulted in substantial increases in FIAF/angiopoietin-like protein 4, IL-6, leptin, MIF, PAI-1 and vascular endothelial growth factor (VEGF) mRNA levels. The largest increases were with FIAF (maximum 210-fold), leptin (maximum 29-fold) and VEGF (maximum 23-fold); these were reversed on return to normoxia. The secretion of IL-6, leptin, MIF and VEGF from the adipocytes was also stimulated by exposure to 1% O2. These results demonstrate that hypoxia induces extensive changes in human adipocytes in the expression and release of inflammation-related adipokines. Hypoxia may underlie the development of the inflammatory response in adipocytes, leading to obesity-associated diseases.", "corpus_id": 10043114, "score": 0 }, { "doc_id": "206213395", "title": "Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?", "abstract": "White adipose tissue is a key endocrine and secretory organ, releasing multiple adipokines, many of which are linked to inflammation and immunity. During the expansion of adipose tissue mass in obesity there is a major inflammatory response in the tissue with increased expression and release of inflammation-related adipokines, including IL-6, leptin, monocyte chemoattractant protein-1 and TNF-α, together with decreased adiponectin production. We proposed in 2004 (Trayhurn & Wood, Br J Nutr92, 347–355) that inflammation in adipose tissue in obesity is a response to hypoxia in enlarged adipocytes distant from the vasculature. Hypoxia has now been directly demonstrated in adipose tissue of several obese mouse models (ob/ob, KKAy, diet-induced) and molecular studies indicate that the level of the hypoxia-inducible transcription factor, hypoxia-inducible factor-1α, is increased, as is expression of the hypoxia-sensitive marker gene, GLUT1. Cell- culture studies on murine and human adipocytes show that hypoxia (induced by low O2 or chemically) leads to stimulation of the expression and secretion of a number of inflammation-related adipokines, including angiopoietin-like protein 4, IL-6, leptin, macrophage migration inhibitory factor and vascular endothelial growth factor. Hypoxia also stimulates the inflammatory response of macrophages and inhibits adipocyte differentiation from preadipocytes. GLUT1 gene expression, protein level and glucose transport by human adipocytes are markedly increased by hypoxia, indicating that low O2 tension stimulates glucose utilisation. It is suggested that hypoxia has a pervasive effect on adipocyte metabolism and on overall adipose tissue function, underpinning the inflammatory response in the tissue in obesity and the subsequent development of obesity-associated diseases, particularly type 2 diabetes and the metabolic syndrome.", "corpus_id": 206213395, "score": 0 }, { "doc_id": "4683757", "title": "Adipokines: inflammation and the pleiotropic role of white adipose tissue", "abstract": "White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name ‘adipocytokines’ or ‘adipokines’. However, since most are neither ‘cytokines’ nor ‘cytokine-like’, it is recommended that the term ‘adipokine’ be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fatty acids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFα, IL-1β, IL-6, IL-8, IL-10, transforming growth factor-β, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.", "corpus_id": 4683757, "score": 0 }, { "doc_id": "19941810", "title": "Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration", "abstract": "Background:Obesity is currently viewed as a state of chronic low-grade inflammation in which there is a pro-inflammatory alteration in the serum adipocytokine profile as well as an infiltration of white adipose tissue by activated macrophages. The etiology of this inflammation, however, is poorly understood.Methods:Hypothesizing that local hypoxia within expanding white adipose tissue depots may contribute to obesity-related inflammation, we compared body composition, serum inflammatory marker concentrations and the expression of several hypoxia-regulated genes in white adipose tissue derived from lean, dietary-induced obese (DIO) and ob/ob male C57BL/6J mice. We also examined white adipose tissue for the presence of hypoxia using both a pimonidazole-based antibody system and a fiberoptic sensor for real-time pO2 quantification in vivo. Finally, using cell-specific leukocyte antibodies, we performed immunohistochemistry and flow cytometric analyses to further characterize the cellular nature of adipose inflammation.Results:We determined that obesity in male C57BL/6J mice is associated with increased expression of HIF (hypoxia-inducible factor) isoforms and GLUT-1, and that white adipose tissue hypoxia was present in the obese mice. Immunohistochemistry revealed hypoxic areas to colocalize predominantly with F4/80+ macrophages. Interestingly, CD3+ T cells were present in large numbers within the adipose of both DIO and ob/ob obese mice, and flow cytometry revealed their adipose to possess significantly more CD8+ T cells than their lean cohort.Conclusions:White adipose hypoxia and cytotoxic T-cell invasion are features of obesity in C57BL/6J mice and are potential contributors to their local and generalized inflammatory state.", "corpus_id": 19941810, "score": 1 }, { "doc_id": "11109646", "title": "Obesity Decreases Perioperative Tissue Oxygenation", "abstract": "BackgroundObesity is an important risk factor for surgical site infections. The incidence of surgical wound infections is directly related to tissue perfusion and oxygenation. Fat tissue mass expands without a concomitant increase in blood flow per cell, which might result in a relative hypoperfusion with decreased tissue oxygenation. Consequently, the authors tested the hypotheses that perioperative tissue oxygen tension is reduced in obese surgical patients. Furthermore, they compared the effect of supplemental oxygen administration on tissue oxygenation in obese and nonobese patients. MethodsForty-six patients undergoing major abdominal surgery were assigned to one of two groups according to their body mass index: body mass index less than 30 kg/m2 (nonobese) or 30 kg/m2 or greater (obese). Intraoperative oxygen administration was adjusted to arterial oxygen tensions of approximately 150 mmHg and approximately 300 mmHg in random order. Anesthesia technique and perioperative fluid management were standardized. Subcutaneous tissue oxygen tension was measured with a polarographic electrode positioned within a subcutaneous tonometer in the lateral upper arm during surgery, in the recovery room, and on the first postoperative day. Postoperative tissue oxygen was also measured adjacent to the wound. Data were compared with unpaired two-tailed t tests and Wilcoxon rank sum test; P < 0.05 was considered statistically significant. ResultsIntraoperative subcutaneous tissue oxygen tension was significantly less in the obese patients at baseline (36 vs. 57 mmHg; P = 0.002) and with supplemental oxygen administration (47 vs. 76 mmHg; P = 0.014). Immediate postoperative tissue oxygen tension was also significantly less in subcutaneous tissue of the upper arm (43 vs. 54 mmHg; P = 0.011) as well as near the incision (42 vs. 62 mmHg; P = 0.012) in obese patients. In contrast, tissue oxygen tension was comparable in each group on the first postoperative morning. ConclusionWound and tissue hypoxia were common in obese patients in the perioperative period and most pronounced during surgery. Even with supplemental oxygen tissue, oxygen tension in obese patients was reduced to levels that are associated with a substantial increase in infection risk.", "corpus_id": 11109646, "score": 0 }, { "doc_id": "11095883", "title": "Tissue Oxygenation in Obese and Non-obese Patients During Laparoscopy", "abstract": "Background: Wound infection risk is inversely related to subcutaneous tissue oxygenation, which is reduced in obese patients and may be reduced even more during laparoscopic procedures. Methods: We evaluated subcutaneous tissue oxygenation (PsqO2) in 20 patients with a body mass index (BMI) ≥40 kg/m2 (obese group) and 15 patients with BMI <30 kg/m2 (non-obese group) undergoing laparoscopic surgery with standardized anaesthesia technique and fluid administration. Arterial oxygen tension was maintained near 150 mmHg. PsqO2 was measured from a surrogate wound on the upper arm. Results: A mean FIO2 of 51% (13%) was required in obese patients to reach an arterial oxygen tension of 150 mmHg; however, a mean FIO2 of only 40% (7%) was required to reach the same oxygen tension in non-obese patients (P=0.007). PsqO2 was significantly less in obese patients: 41 (10) vs 57 (15) mmHg (P<0.001). Conclusion: Obese patients having laparoscopic surgery require a significantly greater FIO2 to reach an arterial oxygen tension of about 150 mmHg than non-obese patients; they also have significantly lower subcutaneous oxygen tensions. Both factors probably contribute to an increased infection risk in obese patients.", "corpus_id": 11095883, "score": 0 }, { "doc_id": "706044", "title": "A novel technique for measuring human tissue pO2 at the cellular level.", "abstract": "Some electron-affinic drugs, developed as hypoxic cell radiosensitizers, become selectively bound to the molecules of hypoxic cells by metabolism. This technique has been used to identify zones of chronically hypoxic cells in multicellular spheroids and animal tumours. Tritiated-misonidazole was administered to a patient with advanced melanoma 22 h prior to the surgical resection of a large metastatic s.c. lesion growing on the face. Autoradiographic analysis of histological sections revealed zones of intense labelling by the radioactive drug, indicative of tumour cells which were chronically hypoxic. This technique appears to provide an indirect measurement of tissue pO2 at the cellular level from which estimates of the tumour hypoxic fraction can be made. These data are encouraging as regards the development of 'sensitizer-adduct' procedures for the invasive and non-invasive measurement of hypoxia in both tumours and normal tissues.", "corpus_id": 706044, "score": 0 }, { "doc_id": "11801631", "title": "Signal transduction to hypoxia-inducible factor 1.", "abstract": "Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator that functions as a master regulator of O2 homeostasis. HIF-1 target genes encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. HIF-1 activity is regulated by the cellular O2 concentration and by the major growth factor-stimulated signal transduction pathways. In human cancer cells, both intratumoral hypoxia and genetic alterations affecting signal transduction pathways lead to increased HIF-1 activity, which promotes angiogenesis, metabolic adaptation, and other critical aspects of tumor progression.", "corpus_id": 11801631, "score": 1 }, { "doc_id": "23956651", "title": "HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption.", "abstract": "The HIF-1 transcription factor drives hypoxic gene expression changes that are thought to be adaptive for cells exposed to a reduced-oxygen environment. For example, HIF-1 induces the expression of glycolytic genes. It is presumed that increased glycolysis is necessary to produce energy when low oxygen will not support oxidative phosphorylation at the mitochondria. However, we find that while HIF-1 stimulates glycolysis, it also actively represses mitochondrial function and oxygen consumption by inducing pyruvate dehydrogenase kinase 1 (PDK1). PDK1 phosphorylates and inhibits pyruvate dehydrogenase from using pyruvate to fuel the mitochondrial TCA cycle. This causes a drop in mitochondrial oxygen consumption and results in a relative increase in intracellular oxygen tension. We show by genetic means that HIF-1-dependent block to oxygen utilization results in increased oxygen availability, decreased cell death when total oxygen is limiting, and reduced cell death in response to the hypoxic cytotoxin tirapazamine.", "corpus_id": 23956651, "score": 0 }, { "doc_id": "36959452", "title": "Insulin Stimulates Hypoxia-inducible Factor 1 through a Phosphatidylinositol 3-Kinase/Target of Rapamycin-dependent Signaling Pathway*", "abstract": "Hypoxia-inducible factor 1 (HIF-1) is a transcription factor involved in normal mammalian development and in the pathogenesis of several disease states. It consists of two subunits, HIF-1α, which is degraded during normoxia, and HIF-1β, which is constitutively expressed. Activated HIF-1 induces the expression of genes involved in angiogenesis, erythropoiesis, and glucose metabolism. We have previously reported that insulin stimulates vascular endothelial growth factor (VEGF) expression (1). In this study, we show that insulin activates HIF-1, leading to VEGF expression in retinal epithelial cells. Insulin activates HIF-1α protein expression in a dose-dependent manner with a maximum reached within 6 h. The expression of HIF-1α is correlated with the activation of HIF-1 DNA binding activity and the transactivation of a HIF-1-dependent reporter gene. Insulin does not appear to affect HIF-1α mRNA transcription but regulates HIF-1α protein expression through a translation-dependent pathway. The expression of an active form of protein kinase B and treatment of cells with specific inhibitors of phosphatidylinositol 3-kinase (PI3K), MAPK, and target of rapamycin (TOR) show that mainly PI3K and to a lesser extent TOR are required for insulin-induced HIF-1α expression. HIF-1 activity and VEGF expression are also dependent on PI3K- and TOR-dependent signaling. In conclusion, we show here that insulin regulates HIF-1 action through a PI3K/TOR-dependent pathway, resulting in increased VEGF expression.", "corpus_id": 36959452, "score": 0 }, { "doc_id": "1107868", "title": "Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.", "abstract": "Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine), whereas cycloheximide blocked induction of glycolytic RNAs and HIF-1 activity. Oligonucleotides from the ALDA, PGK1, enolase 1, lactate dehydrogenase A, and phosphofructokinase L (PFKL) genes, containing sequences similar to the HIF-1 binding site in the erythropoietin enhancer, specifically bound HIF-1 present in crude nuclear extracts or affinity-purified preparations. Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. These results support the role of HIF-1 as a mediator of adaptive responses to hypoxia that underlie cellular and systemic oxygen homeostasis.", "corpus_id": 1107868, "score": 0 }, { "doc_id": "28854226", "title": "Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.", "abstract": "Hypoxia is an essential developmental and physiological stimulus that plays a key role in the pathophysiology of cancer, heart attack, stroke, and other major causes of mortality. Hypoxia-inducible factor 1 (HIF-1) is the only known mammalian transcription factor expressed uniquely in response to physiologically relevant levels of hypoxia. We now report that in Hif1a-/- embryonic stem cells that did not express the O2-regulated HIF-1alpha subunit, levels of mRNAs encoding glucose transporters and glycolytic enzymes were reduced, and cellular proliferation was impaired. Vascular endothelial growth factor mRNA expression was also markedly decreased in hypoxic Hif1a-/- embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF-1alpha resulted in developmental arrest and lethality by E11 of Hif1a-/- embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme. In Hif1a+/+ embryos, HIF-1alpha expression increased between E8.5 and E9.5, coincident with the onset of developmental defects and cell death in Hif1a-/- embryos. These results demonstrate that HIF-1alpha is a master regulator of cellular and developmental O2 homeostasis.", "corpus_id": 28854226, "score": 0 }, { "doc_id": "26031453", "title": "Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss.", "abstract": "In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of scWAT-infiltrating macrophages before surgery was higher in obese than in lean subjects (HAM56+/CD68+; 22.6 +/- 4.3 vs. 1.4 +/- 0.6%, P < 0.001). Typical \"crowns\" of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant decrease in macrophage number (-11.63 +/- 2.3%, P < 0.001), and remaining macrophages stained positive for the anti-inflammatory protein interleukin 10. Genes involved in macrophage attraction (monocyte chemotactic protein [MCP]-1, plasminogen activator urokinase receptor [PLAUR], and colony-stimulating factor [CSF]-3) and hypoxia (hypoxia-inducible factor-1alpha [HIF-1alpha]), expression of which increases in obesity and decreases after surgery, were predominantly expressed in the SVF. We show that improvement of the inflammatory profile after weight loss is related to a reduced number of macrophages in scWAT. MCP-1, PLAUR, CSF-3, and HIF-1alpha may play roles in the attraction of macrophages in scWAT.", "corpus_id": 26031453, "score": 0 }, { "doc_id": "4444781", "title": "Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue.", "abstract": "Using high-density oligonucleotide microarrays, we examined the actions of energy restriction (ER) on the expression of >11,000 genes in epididymal white adipose tissue (WAT) of 10- to 11-mo-old male C57Bl6 mice. Four groups were studied: controls not subjected to food restriction (CO), food-restricted 18 h before being killed (FR), short-term ER for 23 d (SER), and long-term ER for 9 mo (LER). As we reported previously, compared with CO mice, FR and SER minimally influenced the gene expression profiles; however, 345 transcripts of 6,266 genes determined to be expressed in WAT were significantly altered by LER. We focus here on the 109 (31%) of these genes that were involved in either inflammation (56 genes), cytoskeleton (16 genes), extracellular matrix (23 genes), or angiogenesis (14 genes). Among these 109 genes, 104 transcripts (95%) were down regulated by LER. Western blotting for heat shock protein 47 and osteonectin, and immunohistochemical staining for hypoxia inducible factor (HIF)-1alpha), supported the microarray data that LER down regulated the expressions of these genes. Additionally, a 75% reduction in adipocyte size with LER reflected the change in the expression of genes involved in cell morphology. Our findings provide evidence that LER suppresses the expression of genes encoding inflammatory molecules in WAT while promoting structural remodeling of the cytoskeleton, extracellular matrix, and vasculature. These alterations may play an important role in the protection against WAT-derived inflammation and in lifespan extension by LER.", "corpus_id": 4444781, "score": 0 }, { "doc_id": "26434952", "title": "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.", "abstract": "Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells. We show that both HIF-1 subunits are basic-helix-loop-helix proteins containing a PAS domain, defined by its presence in the Drosophila Per and Sim proteins and in the mammalian ARNT and AHR proteins. HIF-1 alpha is most closely related to Sim. HIF-1 beta is a series of ARNT gene products, which can thus heterodimerize with either HIF-1 alpha or AHR. HIF-1 alpha and HIF-1 beta (ARNT) RNA and protein levels were induced in cells exposed to 1% O2 and decayed rapidly upon return of the cells to 20% O2, consistent with the role of HIF-1 as a mediator of transcriptional responses to hypoxia.", "corpus_id": 26434952, "score": 0 }, { "doc_id": "41659164", "title": "Purification and Characterization of Hypoxia-inducible Factor 1 (*)", "abstract": "Hypoxia-inducible factor 1 (HIF-1) is a DNA-binding protein that activates erythropoietin (Epo) gene transcription in Hep3B cells subjected to hypoxia or cobalt chloride treatment. HIF-1 DNA binding activity is also induced by hypoxia or cobalt in non-Epo-producing cells, suggesting a general role for HIF-1 in hypoxia signal transduction and transcriptional regulation. Here we report the biochemical purification of HIF-1 from Epo-producing Hep3B cells and non-Epo-producing HeLa S3 cells. HIF-1 protein was purified 11,250-fold by DEAE ion-exchange and DNA affinity chromatography. Analysis of HIF-1 isolated from a preparative gel shift assay revealed four polypeptides. Peptide mapping of these HIF-1 components demonstrated that 91-, 93-, and 94-kDa polypeptides had similar tryptic maps, whereas the 120-kDa polypeptide had a distinct profile. Glycerol gradient sedimentation analysis suggested that HIF-1 exists predominantly in a heterodimeric form and to a lesser extent as a heterotetramer. Partially purified HIF-1 bound specifically to the wild-type HIF-1 binding site from the EPO enhancer but not to a mutant sequence that lacks hypoxia-inducible enhancer activity. UV cross-linking analysis with purified HIF-1 indicated that both subunits of HIF-1 contact DNA directly. We conclude that in both cobalt chloride-treated HeLa cells and hypoxic Hep3B cells HIF-1 is composed of two different subunits: 120-kDa HIF-1α and 91-94-kDa HIF-1β.", "corpus_id": 41659164, "score": 0 }, { "doc_id": "20759604", "title": "Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung.", "abstract": "Hypoxia-inducible factor (HIF)-1 is a basic helix-loop-helix transcription factor that transactivates genes encoding proteins that participate in homeostatic responses to hypoxia. Several of these downstream gene products, such as erythropoietin, vascular endothelial growth factor, heme oxygenase-1, and inducible nitric oxide synthase, may contribute to the pathogenesis of pulmonary hypertension. Previous studies demonstrated increased HIF-1 mRNA levels in rats and mice subjected to hypoxia. In this study, we have demonstrated spatial, temporal, and O2-dependent expression of HIF-1 protein. Immunoblot analysis revealed hypoxic induction of HIF-1 in all cultured pulmonary cell types assayed, including those derived from pulmonary arterial endothelium and smooth muscle, bronchial epithelium, alveolar macrophages, alveolar epithelium, and microvascular endothelium. In contrast to all other cell types, pulmonary arterial smooth muscle cells expressed HIF-1 under nonhypoxic conditions. Immunohistochemistry and immunoblot analysis of ferret lungs demonstrated pulmonary expression of HIF-1 in vivo. HIF-1 protein expression was induced maximally when lungs were ventilated with 0 or 1% O2 for 4 h. On reoxygenation, HIF-1 was rapidly degraded, with a half-life of <1 min. These findings demonstrate that HIF-1 expression is tightly coupled to O2 concentration in vivo and are consistent with the involvement of HIF-1 in the physiological and pathophysiological responses to hypoxia in the lung.", "corpus_id": 20759604, "score": 0 }, { "doc_id": "25369564", "title": "Induction of hypoxia‐inducible factor‐1 (HIF‐1) and its target genes following focal ischaemia in rat brain", "abstract": "HIF‐1 is a heterodimeric transcription factor, induced by hypoxia, that is composed of HIF‐1α and HIF‐1β protein subunits. It binds to promoter/enhancer elements and stimulates the transcription of hypoxia‐inducible target genes, including glucose transporter‐1 and the glycolytic enzymes. Because HIF‐1 activation might promote cell survival in hypoxic tissues, we studied the effect of permanent middle cerebral artery occlusion on the expression of HIF‐1α, HIF‐1β and several HIF‐1 target genes in adult rat brain. After focal ischaemia, mRNAs encoding HIF‐1α, glucose transporter‐1 and several glycolytic enzymes were up‐regulated in the peri‐infarct penumbra. This was observed by 7.5 h after the onset of ischaemia and increased further at 19 and 24 h. Regional cerebral blood flow was moderately decreased at 1 and 24 h after the ischaemia in areas of HIF‐1 and HIF‐1 target gene induction. Because hypoxia induces HIF‐1 in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown to increase HIF‐1α protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF‐1 and its target genes. This is the first study to show induction of HIF‐1 after focal ischaemia in brain. Increased expression of HIF‐1 target genes as a result of HIF‐1 activation by hypoxia may contribute to tissue viability in the hypoxic/ischaemic penumbra by increasing glucose transport and glycolysis.", "corpus_id": 25369564, "score": 0 }, { "doc_id": "45063736", "title": "Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation.", "abstract": "Hypoxia-Inducible Factor-1 (HIF-1) is a transcription factor which is activated by hypoxia and involved in the adaptative response of the cell to oxygen deprivation. During hypoxic stress, HIF-1 triggers the overexpression of genes coding for glycolytic enzymes and angiogenic factors. To be active HIF-1 must be phosphorylated. HIF-1 is a substrate for various kinase pathways including PI-3K and the MAP kinases ERK and p38. Several transduction pathways have been proposed which act downstream of putative oxygen sensors and lead to the activation of these kinases. In this review, we summarize some of the latest advances describing the possible signaling pathways leading to HIF-1 phosphorylation and subsequent activation. The physiological relevance of these regulations is also discussed.", "corpus_id": 45063736, "score": 0 }, { "doc_id": "5902740", "title": "Ischemia-Reperfusion Injury of Adipofascial Tissue: An Experimental Study Evaluating Early Histologic and Biochemical Alterations in Rats", "abstract": "Fat necrosis remains a serious complication in reconstructive flaps. In clinical setting, it is well known that fat tissue is more susceptible to ischemic events. We aimed to evaluate early histological and biochemical changes of adipofascial tissue in an experimantal model. An epigastric flap model in rats was used to evaluate the effect of ischemia-reperfusion (I-R) injury on adipofascial tissue. Two groups of animals (one with ischemia alone and other ischemia-reperfusion group) were used to evaluate the degree of histological edema, congestion and extravascular bleeding, and early biochemical alterations within the adipofascial flaps. The biochemical parameters included glutathione (GSH) and malondialdehyde (MDA). In each group, contralateral groin subcutaneous adipose tissue served as control. These evaluations were compared to normal unmanipulated, contralateral abdominal subcutaneous adipose tissue. The ischemia-reperfused flap group showed histologically significantly much edema congestion and bleeding than the control groups (P < .0001). The control group showed less edema in fat tissue than the ischemia-alone group (P < .05). All of the flaps in the ischemia-only group showed significantly less bleeding and edema than I-R group (P < .001). The ratio of MDA/GSH was 33 in control, 37 in ischemia alone, and 82 in ischemia-reperfusion groups, respectively. This study confirms that significant histologic and biochemical alteration occurs after ischemia and ischemia-reperfusion events in adipose tissue. Marked drop in adipose tissue antioxidant levels after I-R suggested that preemptive measures to this decrease should be undertaken in clinical settings.", "corpus_id": 5902740, "score": 0 }, { "doc_id": "40037106", "title": "Hypoxia Regulates Macrophage Functions in Inflammation1", "abstract": "The presence of areas of hypoxia is a prominent feature of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of joints with rheumatoid arthritis, healing wounds, and sites of bacterial infection. These areas form when the blood supply is occluded and/or unable to keep pace with the growth and/or infiltration of inflammatory cells in a given area. Macrophages are present in all tissues of the body where they normally assist in guarding against invading pathogens and regulate normal cell turnover and tissue remodeling. However, they are also known to accumulate in large numbers in such ischemic/hypoxic sites. Recent studies show that macrophages then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. In the present study, we outline and compare the phenotypic responses of macrophages to hypoxia in different diseased states and the implications of these for their progression and treatment.", "corpus_id": 40037106, "score": 0 }, { "doc_id": "15215617", "title": "Macrophage responses to hypoxia: relevance to disease mechanisms", "abstract": "Macrophages are ubiquitous in the stromal compartment of tissues under normal physiological conditions and the number of these cells increases markedly with the onset and progression of many pathological states. The mechanisms underlying this response are well described in such conditions as wound healing and malignant tumors, where tissue‐specific signals enhance the extravasation of blood monocytes and their subsequent differentiation into macrophages. Recent evidence suggests that macrophages may also be stimulated by microenvironmental factors present in diseased tissues to perform distinct, tissue‐specific activities. One such factor, hypoxia (low oxygen tension), results from insufficient vascular perfusion of a given tissue. Various studies have shown that experimental hypoxia alters the morphology, expression of cell surface markers, viability, phagocytosis, metabolic activity, and release of cytokines by macrophages. Here we review the evidence for these macrophage responses to hypoxia, the involvement of co‐stimuli, and their implications for the role of macrophages in various disease processes. Because the intracellular mechanisms mediating the effects of hypoxia on gene expression in other cell types have been characterized recently, we discuss their possible involvement in the effects of hypoxia on gene expression in macrophages. J. Leukoc. Biol. 66: 889–900; 1999.", "corpus_id": 15215617, "score": 0 }, { "doc_id": "4302092", "title": "Hypoxia signalling in cancer and approaches to enforce tumour regression", "abstract": "Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pHi) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pHi-control systems.", "corpus_id": 4302092, "score": 0 }, { "doc_id": "16880360", "title": "Science review: Redox and oxygen-sensitive transcription factors in the regulation of oxidant-mediated lung injury: role for hypoxia-inducible factor-1α", "abstract": "A progressive rise of oxidative stress due to altered reduction–oxidation (redox) homeostasis appears to be one of the hallmarks of the processes that regulate gene transcription in physiology and pathophysiology. Reactive oxygen species and reactive nitrogen species serve as signaling messengers for the evolution and perpetuation of the inflammatory process that is often associated with the condition of oxidative stress, which involves genetic regulation. Changes in the pattern of gene expression through reactive oxygen species/reactive nitrogen species-sensitive regulatory transcription factors are crucial components of the machinery that determines cellular responses to oxidative/redox conditions. The present review describes the basic components of the intracellular oxidative/redox control machinery and its crucial regulation of oxygen-sensitive and redox-sensitive transcription factors within the context of lung injury. Particularly, the review discusses mechanical ventilation and NF-κB-mediated lung injury, ischemia-reperfusion and transplantation, compromised host defense and inflammatory stimuli, and hypoxemia and the crucial role of hypoxia-inducible factor in mediating lung injury. Changes in the pattern of gene expression through regulatory transcription factors are therefore crucial components of the machinery that determines cellular responses to oxidative/redox stress.", "corpus_id": 16880360, "score": 0 }, { "doc_id": "36606698", "title": "Nuclear factor-kappaB in cancer development and progression.", "abstract": "Nuclear factor-kappaB (NF-kappaB) transcription factors and the signalling pathways that activate them are central coordinators of innate and adaptive immune responses. More recently, it has become clear that NF-kappaB signalling also has a critical role in cancer development and progression. NF-kappaB provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both pre-neoplastic and malignant cells to resist apoptosis-based tumour-surveillance mechanisms. NF-kappaB might also regulate tumour angiogenesis and invasiveness, and the signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic approaches.", "corpus_id": 36606698, "score": 0 }, { "doc_id": "10513523", "title": "The NF-kappa B and I kappa B proteins: new discoveries and insights.", "abstract": "The transcription factor NF-kappa B has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-kappa B is through interactions with an inhibitor protein called I kappa B. Recent evidence confirms the existence of multiple forms of I kappa B that appear to regulate NF-kappa B by distinct mechanisms. NF-kappa B can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-kappa B to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of I kappa B. Exciting new research has elaborated several important and unexpected findings that explain mechanisms involved in the activation of NF-kappa B. In the nucleus, NF-kappa B dimers bind to target DNA elements and activate transcription of genes encoding proteins involved with immune or inflammation responses and with cell growth control. Recent data provide evidence that NF-kappa B is constitutively active in several cell types, potentially playing unexpected roles in regulation of gene expression. In addition to advances in describing the mechanisms of NF-kappa B activation, excitement in NF-kappa B research has been generated by the first report of a crystal structure for one form of NF-kappa B, the first gene knockout studies for different forms of NF-kB and of I kappa B, and the implications for therapies of diseases thought to involve the inappropriate activation of NF-kappa B.", "corpus_id": 10513523, "score": 0 }, { "doc_id": "40174944", "title": "NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses.", "abstract": "The transcription factor NF-kappa B, more than a decade after its discovery, remains an exciting and active area of study. The involvement of NF-kappa B in the expression of numerous cytokines and adhesion molecules has supported its role as an evolutionarily conserved coordinating element in the organism's response to situations of infection, stress, and injury. Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-kappa B:I kappa B complex in the cytosol. The field now awaits the discovery and characterization of the kinase responsible for the inducible phosphorylation of I kappa B proteins. Another exciting development has been the demonstration that in certain situations NF-kappa B acts as an anti-apoptotic protein; therefore, elucidation of the mechanism by which NF-kappa B protects against cell death is an important goal. Finally, the generation of knockouts of members of the NF-kappa B/I kappa B family has allowed the study of the roles of these proteins in normal development and physiology. In this review, we discuss some of these recent findings and their implications for the study of NF-kappa B.", "corpus_id": 40174944, "score": 0 }, { "doc_id": "205211222", "title": "Adipocytes as regulators of energy balance and glucose homeostasis", "abstract": "Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions.", "corpus_id": 205211222, "score": 0 }, { "doc_id": "4347293", "title": "Macrophage-specific PPARγ controls alternative activation and improves insulin resistance", "abstract": "Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-γ (PPARγ), we show here that PPARγ is required for maturation of alternatively activated macrophages. Disruption of PPARγ in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.", "corpus_id": 4347293, "score": 0 }, { "doc_id": "558637", "title": "Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones.", "abstract": "PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.", "corpus_id": 558637, "score": 0 }, { "doc_id": "16161078", "title": "Absence of CC Chemokine Ligand 2 Does Not Limit Obesity-Associated Infiltration of Macrophages Into Adipose Tissue", "abstract": "Macrophage recruitment to adipose tissue in obesity contributes to enhanced adipose tissue inflammatory activity and thus may underlie obesity-associated metabolic dysfunction. Obese adipose tissue exhibits increases in CC chemokine ligand 2 (CCL2, or monocyte chemoattractant protein-1), an important macrophage-recruiting factor. We therefore hypothesized that elevated CCL2 may contribute to obesity-associated adipose tissue macrophage recruitment. Male 6-week-old CCL2−/− and wild-type mice (n = 11–14 per group) were fed standard and high-fat diets until 34 weeks of age. At 12–16 and 25–29 weeks of age, blood was collected for plasma glucose and hormone measurements, and glucose tolerance and insulin tolerance tests were performed. Adipose tissue was collected at 34 weeks for analysis of macrophage infiltration. Surprisingly, CCL2−/− mice on high-fat diet showed no reductions in adipose tissue macrophages. CCL2−/− mice on standard and high-fat diet were also glucose intolerant and had mildly increased plasma glucose and decreased serum adiponectin levels compared with wild-type mice. On high-fat diet, CCL2−/− mice also gained slightly more weight and were hyperinsulinemic compared with wild-type mice. Because macrophage levels were unchanged in CCL2−/− mice, the phenotype appears to be caused by lack of CCL2 itself. The fact that metabolic function was altered in CCL2−/− mice, despite no changes in adipose tissue macrophage levels, suggests that CCL2 has effects on metabolism that are independent of its macrophage-recruiting capabilities. Importantly, we conclude that CCL2 is not critical for adipose tissue macrophage recruitment. The dominant factor for recruiting macrophages in adipose tissue during obesity therefore remains to be identified.", "corpus_id": 16161078, "score": 0 }, { "doc_id": "9680955", "title": "Angiogenic Role of LYVE-1–Positive Macrophages in Adipose Tissue", "abstract": "Here we report the discovery of a characteristic dense vascular network (DVN) in the tip portion of epididymal adipose tissue in adult mice. The DVN is formed by angiogenesis rather than by vasculogenesis, and has functional blood circulation. This DVN and its subsequent branching may provide a new functional route for adipogenesis. The recruitment, infiltration, and accumulation of bone marrow-derived LYVE-1+ macrophages in the tip region are crucial for the formation of the DVN. Matrix metalloproteinases (MMPs) and the VEGF-VEGFR2 system are responsible not only for the formation of the DVN, but also for the recruitment and infiltration of LYVE-1+ macrophages into the epididymal adipose tissue tip region. SDF-1, but not the MCP-1-CCR2 system, is a critical factor in recruitment and ongoing retention of macrophages in this area. We also demonstrate that the tip region of epididymal adipose tissue is highly hypoxic, and thus provides a microenvironment conducive to the high expression and enhanced activities of VEGF, VEGFR2, MMPs, and SDF-1 in autocrine and paracrine manners, to create an ideal niche for the recruitment, retention, and angiogenic action of macrophages. These findings shed light on the complex interplay between macrophage infiltration, angiogenesis, and adipogenesis in the tip region of adult epididymal adipose tissue, and provide novel insight into the regulation of alternative outgrowth of adipose tissue.", "corpus_id": 9680955, "score": 0 }, { "doc_id": "13772164", "title": "Hypoxia inhibits macrophage migration", "abstract": "The chemokine monocyte chemoattractant protein (MCP)‐1 plays a role in regulating the lymphocyte and macrophage infiltrate in ovarian cancer, but macrophages also accumulate in necrotic areas of the tumors where there is little MCP‐1 expression (Negus, R. P. M. et al., Am. J. Pathol. 1997. 150: 1723 – 1734). Necrotic regions are likely to be hypoxic. In this study we show that hypoxia inhibits MCP‐1‐induced migration of THP‐1 monocytic cells and human macrophages. In contrast, lymphocytes from peripheral blood migrate normally to an MCP‐1 gradient in hypoxic conditions. The inhibition of monocyte migration by hypoxia is rapid and reversible. At the exposure times studied (30 – 90 min) hypoxia does not affect expression of the MCP‐1 receptor CCR2B and cells exposed to hypoxia still respond to MCP‐1 with an elevation of intracellular calcium. Although hypoxia is known to modulate gene expression, the inhibition of migration reported here was not due to the production of soluble factors, and mRNA expression of macrophage migration inhibitory factor was unchanged. Hypoxia‐induced inhibition of chemotaxis was not limited to MCP‐1. Hypoxia also inhibited the chemotactic response to macrophage inflammatory protein‐1α, RANTES and the chemoattractant N‐formyl‐met‐leu‐phe, but hypoxic cells were still able to phagocytose opsonized red blood cells. We suggest that inhibition of migration by hypoxia is not due to gene regulation but is a reflection of metabolic changes in the cell. Transient hypoxia may regulate the distribution of macrophages in tumors and other inflammatory conditions.", "corpus_id": 13772164, "score": 0 }, { "doc_id": "6383094", "title": "Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue.", "abstract": "Recent studies suggest that adipose tissue hypoxia (ATH) may contribute to endocrine dysfunction in adipose tissue of obese mice. In this study, we examined hypoxia's effects on metabolism in adipocytes. We determined the dynamic relationship of ATH and adiposity in ob/ob mice. The interstitial oxygen pressure (Po(2)) was monitored in the epididymal fat pads for ATH. During weight gain from 39.5 to 55.5 g, Po(2) declined from 34.8 to 20.1 mmHg, which are 40-60% lower than those in the lean mice. Insulin receptor-beta (IRbeta) and insulin receptor substrate-1 (IRS-1) were decreased in the adipose tissue of obese mice, and the alteration was observed in 3T3-L1 adipocytes after hypoxia (1% oxygen) treatment. Insulin-induced glucose uptake and Akt Ser(473) phosphorylation was blocked by hypoxia in the adipocytes. This effect of hypoxia exhibited cell type specificity, as it was not observed in L6 myotubes and betaTC6 cells. In response to hypoxia, free fatty acid (FFA) uptake was reduced and lipolysis was increased in 3T3-L1 adipocytes. The molecular mechanism of decreased fatty acid uptake may be related to inhibition of fatty acid transporters (FATP1 and CD36) and transcription factors (PPARgamma and C/EBPalpha) by hypoxia. The hypoxia-induced lipolysis was observed in vivo after femoral arterial clamp. Necrosis and apoptosis were induced by hypoxia in 3T3-L1 adipocytes. These data suggest that ATH may promote FFA release and inhibit glucose uptake in adipocytes by inhibition of the insulin-signaling pathway and induction of cell death.", "corpus_id": 6383094, "score": 1 }, { "doc_id": "45457149", "title": "A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes (*)", "abstract": "We describe a novel 30-kDa secretory protein, Acrp30 (adipocyte complement-related protein of 30 kDa), that is made exclusively in adipocytes and whose mRNA is induced over 100-fold during adipocyte differentiation. Acrp30 is structurally similar to complement factor C1q and to a hibernation-specific protein isolated from the plasma of Siberian chipmunks; it forms large homo-oligomers that undergo a series of post-translational modifications. Like adipsin, secretion of Acrp30 is enhanced by insulin, and Acrp30 is an abundant serum protein. Acrp30 may be a factor that participates in the delicately balanced system of energy homeostasis involving food intake and carbohydrate and lipid catabolism. Our experiments also further corroborate the existence of an insulin-regulated secretory pathway in adipocytes.", "corpus_id": 45457149, "score": 0 }, { "doc_id": "19084145", "title": "cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1).", "abstract": "Abstract We isolated a novel adipose-specific gene, apM1, the transcript of which is the most abundant in the mRNA population from human adipose tissue. Northern blotting revealed that the human apM1 gene transcript is exclusively expressed in adipose tissue. The apM1 gene encodes a 244 amino acid open reading frame containing a putative signal sequence and G-X-Y repeats (66 amino acids) followed by a cluster of aromatic residues near the C terminus having high local similarity with collagens X and VIII and complement factor C1q. Thus, apM1 is likely to be a novel collagen-like secretory protein exclusively produced by adipose tissue.", "corpus_id": 19084145, "score": 0 }, { "doc_id": "634943", "title": "AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity (*)", "abstract": "Adipose differentiation is accompanied by changes in cellular morphology, a dramatic accumulation of intracellular lipid and activation of a specific program of gene expression. Using an mRNA differential display technique, we have isolated a novel adipose cDNA, termed adipoQ. The adipoQ cDNA encodes a polypeptide of 247 amino acids with a secretory signal sequence at the amino terminus, a collagenous region (Gly-X-Y repeats), and a globular domain. The globular domain of adipoQ shares significant homology with subunits of complement factor C1q, collagen α1(X), and the brain-specific factor cerebellin. The expression of adipoQ is highly specific to adipose tissue in both mouse and rat. Expression of adipoQ is observed exclusively in mature fat cells as the stromal-vascular fraction of fat tissue does not contain adipoQ mRNA. In cultured 3T3-F442A and 3T3-L1 preadipocytes, hormone-induced differentiation dramatically increases the level of expression for adipoQ. Furthermore, the expression of adipoQ mRNA is significantly reduced in the adipose tissues from obese mice and humans. Whereas the biological function of this polypeptide is presently unknown, the tissue-specific expression of a putative secreted protein suggests that this factor may function as a novel signaling molecule for adipose tissue.", "corpus_id": 634943, "score": 0 }, { "doc_id": "22381685", "title": "Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma.", "abstract": "By use of its affinity to gelatin-Cellulofine, a novel protein, GBP28 (gelatin-binding protein of 28 kDa), was obtained from human plasma. GBP28 bound to gelatin-Cellulofine could be eluted with 1 M NaCl. By analysis of its amino-terminal amino acid sequences and the peptides obtained by protease digestion, GBP28 was identified as a novel protein. After repeated gel chromatography of the 1 M NaCl eluate from gelatin-Cellulofine, about 50 micrograms of GBP28 was purified from 500 ml of human plasma. On gel chromatography, the protein migrated as a molecule of about 420 kDa. On SDS-PAGE, its molecular mass was 28 kDa under reducing conditions and 68 kDa under nonreducing conditions. Recently, human mRNA specific to adipose tissue, cDNA clone apM1, has been registered [Maeda, K., Okubo, K., Shimomura, I., Funahashi, T., Matsuzawa, Y., and Matsubara, K. (1996) Biochem. Biophys. Res. Commun. 221, 286-289]. The assumed amino acid sequence of cDNA clone apM1 contained all the sequences of GBP28 and its peptides. Therefore, it is evident that the cDNA clone apM1 encodes GBP28 and the protein is specific to adipose tissue. The clone encodes a polypeptide of 244 amino acids with a secretory signal sequence at the amino terminus, a small non-helical region, a stretch of 22 collagen repeats and a globular domain. Thus, GBP28 appears to belong to a family of proteins possessing a collagen-like domain through which they form homo-trimers, which further combine to make oligomeric complexes. Although its biological function is presently unclear, its adipocyte-specific expression suggests that GBP28 may function as an endogenous factor involved in lipid catabolism and storage or whole body metabolism.", "corpus_id": 22381685, "score": 0 }, { "doc_id": "26320659", "title": "ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism", "abstract": "In recent years, we have learned that adipocytes are not merely inert storage depots for triglycerides but rather highly active cells with potent autocrine, paracrine and endocrine functions. Adipose tissue secretes a large number of physiologically active polypeptides. Although leptin remains one of the best-studied examples of an adipocyte-specific secretory factor, recent reports describe potent physiological activities for another adipocyte-specific secreted protein, adipocyte complement-related protein of 30 kDa (Acrp30). Full-length versions of Acrp30 or its proteolytic fragments decrease the postprandial rise of plasma free fatty acids and improve postabsorptive insulin-mediated suppression of hepatic glucose output. A strong correlation between plasma Acrp30 levels and systemic insulin sensitivity is well established and the protein has putative anti-atherogenic properties that are relevant for the prevention of formation of atherosclerotic plaques. The current challenge is to understand the molecular mechanisms through which the protein exerts its multiple functions.", "corpus_id": 26320659, "score": 0 }, { "doc_id": "6663675", "title": "Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.", "abstract": "Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)-matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6+/-0.4 versus 7.9+/-0.5 microg/mL in men, 7.6+/-0.7 versus 11.7+/-1.0 microg/mL in women; P<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0+/-0.4 versus 6.6+/-0.4 microg/mL, P<0.001 in men; 6.3+/-0.8 versus 7.6+/-0. 7 microg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (r=-0.18, P<0.01) and glucose (r=-0.26, P<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.", "corpus_id": 6663675, "score": 0 }, { "doc_id": "39541832", "title": "Adiponectin and development of type 2 diabetes in the Pima Indian population", "abstract": "Adiponectin is a collagen-like circulating protein secreted by adipocytes that is proposed to mediate obesity-related resistance to insulin. In a case-control series, we assessed the role of adiponectin in later development of type 2 diabetes in 70 patients who later developed type 2 diabetes and 70 controls, matched for body-mass index, age, and sex. Cases and controls were taken from the longitudinal study of health in the Pima Indian population. At baseline, the concentration of adiponectin was lower in cases than in controls (p=0.01) and individuals with high concentrations of this protein were less likely to develop type 2 diabetes than those with low concentrations (incidence rate ratio 0.63 [95% CI 0.43-0.92]; p=0.02).", "corpus_id": 39541832, "score": 0 }, { "doc_id": "14674961", "title": "A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome.", "abstract": "Adiponectin is a protein secreted by adipocytes that modulates insulin action. To assess whether variants of this gene contribute to the prevalence of insulin resistance in Caucasians, we genotyped 413 nondiabetic individuals for two single nucleotide polymorphisms (SNPs) at this locus. The two SNPs (45T-->G and 276G-->T) were chosen because of their association with type 2 diabetes in Japanese. Whereas each polymorphism was significantly associated with some correlate of insulin resistance, the haplotype defined by the two together was strongly associated with many components of the insulin resistance syndrome. Homozygotes for the risk haplotype had higher body weight (P = 0.03), waist circumference (P = 0.004), systolic (P = 0.01) and diastolic (P = 0.003) blood pressure, fasting glucose (P = 0.02) and insulin (P = 0.005) levels, homeostasis model assessment (HOMA) for insulin resistance (P = 0.003), and total to HDL cholesterol ratio (P = 0.01). Homozygotes also had significantly lower plasma levels of adiponectin (P = 0.03), independent of sex, age, and body weight. In an independent study group of 614 Caucasians, including 310 with type 2 diabetes, the risk haplotype was confirmed to be associated with increased body weight (P = 0.03) but not with type 2 diabetes per se. We conclude that variability at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome, but given the nature of the two SNPs, the risk haplotype is most probably a marker in linkage disequilibrium with an as yet unidentified polymorphism that affects plasma adiponectin levels and insulin sensitivity.", "corpus_id": 14674961, "score": 0 }, { "doc_id": "13180335", "title": "Decreased plasma adiponectin concentrations in women with dyslipidemia.", "abstract": "Adiponectin, the gene product of the adipose most abundant gene transcript 1, is a novel adipocyte-derived peptide that has been considered to have antiinflammatory and antiatherogenic effects. To characterize the relationship between adiponectin and lipids metabolism, we measured fasting plasma adiponectin concentration by ELISA, serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and apolipoprotein (apo) levels in 352 nondiabetic women, 16-86 yr old, with a wide range of body weight [body mass index (BMI), 14.8-36.3 kg/m(2)]. Plasma adiponectin concentrations in women with the highest tertile of TG (1.69 mM < or approximately) were decreased, compared with the middle (1.13 < or = approximately < 1.69) or lowest tertile of TG (approximately < 1.13) (5.9 +/- 0.5 vs. 7.5 +/- 0.3, 9.2 +/- 0.2 microg/ml; P < 0.005, 0.001). Plasma adiponectin with the lowest tertile of HDL-C (approximately < 1.16 mM) was decreased, compared with the middle (1.16 < or = approximately < 1.81) or highest tertile of HDL-C (1.81 < or approximately ) (5.7 +/- 0.5 vs. 7.8 +/- 0.2, 10.1 +/- 0.4 microg/ml; both P < 0.001). These relationships had similar tendencies after adjustment for BMI, body fat mass, age, or diastolic blood pressure. Adiponectin was negatively correlated with serum TG (r = -0.33, P < 0.0001), atherogenic index [(total cholesterol - HDL-C)/HDL-C] (r = -0.34, P < 0.0001), apo B (r = -0.45, P < 0.0001), or apo E (r = -0.29, P < 0.05), and positively correlated with serum HDL-C (r = 0.39, P < 0.0001) or apo A-I levels (r = 0.42, P < 0.002). Those negative relationships became stronger after adjusting for BMI or body fat mass. The slightly positive correlation between adiponectin and age, blood urea nitrogen, or creatinine levels was also observed (all P < 0.001). These results indicate that high-TGnemia and low-HDL-Cnemia are associated with low plasma adiponectin concentrations in nondiabetic women. Further efforts must now be targeted to determine whether adiponectin causes these lipid abnormalities and thus whether it is partly responsible for the atherogenic risk seen in the metabolic syndrome.", "corpus_id": 13180335, "score": 0 }, { "doc_id": "2435944", "title": "Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans.", "abstract": "Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. Moreover, adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity (insulin-stimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 +/- 8 years, body fat 29 +/- 8% [mean +/- SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). Group 1 (19 subjects) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR (stimulated by 100 nmol/l insulin). The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation. Group 2 (38 subjects) had follow-up measurements of insulin-stimulated glucose disposal. Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r = 0.58, P < 0.0001) and negatively associated with percent body fat (r = -0.62, P < 0.0001) in the whole group. In group 1 plasma adiponectin was negatively associated with the basal (r = -0.65, P = 0.003) and positively associated with the fold increase in IR tyrosine phosphorylation (r = 0.69, P = 0.001) before and after the adjustment for percent body fat (r = -0.58, P = 0.01 and r = 0.54, P = 0.02, respectively). Longitudinally, after adjustment for age, sex, and percent body fat, low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity (P = 0.04). In conclusion, our cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation. Prospectively, low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity. Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans.", "corpus_id": 2435944, "score": 0 }, { "doc_id": "38469282", "title": "Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes.", "abstract": "Recently, it has been demonstrated that the fat-derived protein adiponectin is an important insulin-sensitizing adipocytokine which is downregulated in insulin resistance and obesity and replenishment of which in adiponectin-deficient states improves insulin sensitivity. To clarify the regulation of adiponectin gene expression, 3T3-L1 adipocytes were treated with various hormones known to induce insulin resistance in vivo and adiponectin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, treatment of 3T3-L1 cells with 100 nM insulin, 10 ng/ml tumor necrosis factor (TNF) alpha, or 100 nM dexamethasone for 16 h suppressed adiponectin gene expression by about 50 to 85% while angiotensin 2, growth hormone, and triiodothyronine did not have any effect. Furthermore, insulin reduced the level of adiponectin mRNA in a dose- and time-dependent fashion with inhibition detectable at concentrations as low as 10 nM insulin and as early as 4 h after effector addition. The inhibitory effect of insulin was partially reversed by pretreatment of 3T3-L1 cells with pharmacological inhibitors of p44/42 mitogen-activated protein (MAP) kinase, phosphatidylinositol (PI) 3-kinase, and p70S6 kinase. Moreover, the negative effects of insulin, TNFalpha, and dexamethasone on adiponectin gene expression could be completely reversed by withdrawal of the hormones for 24 h. Taken together, our results suggest that adiponectin gene expression is reversibly downregulated by insulin, TNFalpha, and dexamethasone. The data support the concept of adiponectin being an important selectively controlled modulator of insulin sensitivity.", "corpus_id": 38469282, "score": 0 }, { "doc_id": "24858119", "title": "Adiponectin and inflammation: consensus and controversy.", "abstract": "Circulating levels of adiponectin decrease with increasing visceral obesity and are lower in patients with type 2 diabetes, the metabolic syndrome, and cardiovascular disease compared with controls matched by body mass index. Several reports demonstrated anti-inflammatory effects of adiponectin. Because increased adipose tissue is associated with low-grade chronic inflammation and proinflammatory factors inhibit adiponectin production, the current hypothesis states that chronic inflammation associated with visceral obesity inhibits production of adiponectin, perpetuating inflammation. The negative correlation between adiponectin and markers of inflammation in the aforementioned conditions supports this hypothesis. In contrast with disorders typically associated with excess adiposity and positive energy balance, adiponectin levels are elevated--rather than decreased--in classic chronic inflammatory/autoimmune diseases that are unrelated to increased adipose tissue, such as rheumatoid arthritis, SLE, inflammatory bowel disease, type 1 diabetes, and cystic fibrosis. In these patients, adiponectin levels positively--rather than negatively--correlate with inflammatory markers. Furthermore, proinflammatory effects of adiponectin have been reported in tissues such as joint synovium and colonic epithelium. Thus, adiponectin is regulated in the opposite direction and may exert differential functions in classic versus obesity-associated inflammatory conditions. This article discusses this apparent paradox and presents possible alternative and/or complementary explanations.", "corpus_id": 24858119, "score": 0 }, { "doc_id": "21590164", "title": "Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors.", "abstract": "Adiponectin is a fat-derived hormone with antidiabetic and antiatherogenic properties. Hypoadiponectinemia seen in obesity is associated with insulin-resistant diabetes and atherosclerosis. Thiazolidinediones, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, have been shown to increase plasma adiponectin levels by the transcriptional induction in adipose tissues. However, the precise mechanism of such action is unknown. In this study, we have identified a functional PPAR-responsive element (PPRE) in human adiponectin promoter. PPAR-gamma/retinoid X receptor (RXR) heterodimer directly bound to the PPRE and increased the promoter activity in cells. In adipocytes, point mutation of the PPRE markedly reduced the basal transcriptional activity and completely blocked thiazolidinedione-induced transactivation of adiponectin promoter. We have also identified a responsive element of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in adiponectin promoter. LRH-1 was expressed in 3T3-L1 cells and rat adipocytes. LRH-1 bound specifically to the identified responsive element (LRH-RE). LRH-1 augmented PPAR-gamma-induced transactivation of adiponectin promoter, and point mutation of the LRH-RE significantly decreased the basal and thiazolidinedione-induced activities of adiponectin promoter. Our results indicate that PPAR-gamma and LRH-1 play significant roles in the transcriptional activation of adiponectin gene via the PPRE and the LRH-RE in its promoter.", "corpus_id": 21590164, "score": 0 }, { "doc_id": "37047519", "title": "Adipocyte Determination- and Differentiation-dependent Factor 1/Sterol Regulatory Element-binding Protein 1c Regulates Mouse Adiponectin Expression*", "abstract": "Adiponectin is exclusively expressed in differentiated adipocytes and plays an important role in regulating energy homeostasis, including the glucose and lipid metabolism associated with increased insulin sensitivity. However, the control of adiponectin gene expression in adipocytes is poorly understood. We show here that levels of adiponectin mRNA and protein are reduced in the white adipose tissue of ob/ob and db/db mice and that there is a concomitant reduction of the adipocyte determination- and differentiation-dependent factor 1 (ADD1)/sterol regulatory element-binding protein 1c (SREBP1c) transcription factor. To determine whether ADD1/SREBP1c regulates adiponectin gene expression, we isolated and characterized the mouse adiponectin promoter. Analysis of the adiponectin promoter revealed putative binding sites for the adipogenic transcription factors ADD1/SREBP1c, peroxisomal proliferator-activated receptor γ and CCAAT enhancer-binding proteins. DNase I footprinting and chromatin immunoprecipitation analyses revealed that ADD1/SREBP1c binds in vitro and in vivo to the proximal promoter containing sterol regulatory element (SRE) motifs. A luciferase reporter containing the promoter was transactivated by ADD1/SREBP1c, and introduction of SRE mutations into the construct abolished transactivation. Adenoviral overexpression of ADD1/SREBP1c also elevated adiponectin mRNA and protein levels in 3T3-L1 adipocytes. Furthermore, insulin stimulated adiponectin mRNA expression in adipocytes and augmented transactivation of the adiponectin promoter by ADD1/SREBP1c. Taken together, these data indicate that ADD1/SREBP1c controls adiponectin gene expression in differentiated adipocytes.", "corpus_id": 37047519, "score": 0 }, { "doc_id": "10192743", "title": "SIRT1 Regulates Adiponectin Gene Expression through Foxo1-C/Enhancer-binding Protein α Transcriptional Complex*", "abstract": "Adiponectin is an adipose-derived hormone that plays an important role in maintaining energy homeostasis. Adiponectin gene expression is diminished in both obesity and type 2 diabetes. However, the mechanism underlying the impaired adiponectin gene expression remains poorly understood. Recent studies have indicated that forkhead transcription factor O1 (Foxo1) and silent information regulator 2 mammalian ortholog SIRT1 are involved in adipogenesis. Here we have shown that Foxo1 up-regulates adiponectin gene transcription through a Foxo1-responsive region in the mouse adiponectin promoter that contains two adjacent Foxo1 binding sites. Foxo1 interacts with CCAAT/enhancer-binding protein α (C/EBPα) to form a transcription complex at the mouse adiponectin promoter and up-regulates adiponectin gene transcription. Our study has revealed that C/EBPα accesses the adiponectin promoter through two Foxo1 binding sites and acts as a co-activator. Further, SIRT1 increases adiponectin transcription in adipocytes by activating Foxo1 and enhancing Foxo1 and C/EBPα interaction. Importantly, both Foxo1 and SIRT1 protein levels were significantly lower in epididymal fat tissues from db/db and high fat diet-induced obese mice compared with normal mice. We propose that low expression of SIRT1 and Foxo1 leads to impaired Foxo1-C/EBPα complex formation, which contributes to the diminished adiponectin expression in obesity and type 2 diabetes.", "corpus_id": 10192743, "score": 0 }, { "doc_id": "26084640", "title": "Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1.", "abstract": "The phosphatidylinositol 3-kinase (PI3K) signaling pathway has inherent oncogenic potential. It is up-regulated in diverse human cancers by either a gain of function in PI3K itself or in its downstream target Akt or by a loss of function in the negative regulator PTEN. However, the complete consequences of this up-regulation are not known. Here we show that insulin and epidermal growth factor or an inactivating mutation in the tumor suppressor PTEN specifically increase the protein levels of hypoxia-inducible factor (HIF) 1alpha but not of HIF-1beta in human cancer cell lines. This specific elevation of HIF-1alpha protein expression requires PI3K signaling. In the prostate carcinoma-derived cell lines PC-3 and DU145, insulin- and epidermal growth factor-induced expression of HIF-1alpha was inhibited by the PI3K-specific inhibitors LY294002 and wortmannin in a dose-dependent manner. HIF-1beta expression was not affected by these inhibitors. Introduction of wild-type PTEN into the PTEN-negative PC-3 cell line specifically inhibited the expression of HIF-1alpha but not that of HIF-1beta. In contrast to the HIF-1alpha protein, the level of HIF-1alpha mRNA was not significantly affected by PI3K signaling. Vascular endothelial growth factor reporter gene activity was induced by insulin in PC-3 cells and was inhibited by the PI3K inhibitor LY294002 and by the coexpression of a HIF-1 dominant negative construct. Vascular endothelial growth factor reporter gene activity was also inhibited by expression of a dominant negative PI3K construct and by the tumor suppressor PTEN.", "corpus_id": 26084640, "score": 0 }, { "doc_id": "9063138", "title": "FoxOs at the Crossroads of Cellular Metabolism, Differentiation, and Transformation", "abstract": "Forkhead transcription factors of the FoxO subfamily are emerging as a shared component among pathways regulating diverse cellular functions, such as differentiation, metabolism, proliferation, and survival. Their transcriptional output is controlled via a two-tiered mechanism of phosphorylation and acetylation. Modest alterations of this balance can result in profound effects. The gamut of phenotypes runs from protection against diabetes and predisposition to neoplasia, conferred by FoxO loss of function, to increased cellular survival and a marked catabolic response associated with gain of function.", "corpus_id": 9063138, "score": 0 }, { "doc_id": "2006355", "title": "Insulin and leptin as adiposity signals.", "abstract": "There is now considerable consensus that the adipocyte hormone leptin and the pancreatic hormone insulin are important regulators of food intake and energy balance. Leptin and insulin fulfill many of the requirements to be putative adiposity signals to the brain. Plasma leptin and insulin levels are positively correlated with body weight and with adipose mass in particular. Furthermore, both leptin and insulin enter the brain from the plasma. The brain expresses both insulin and leptin receptors in areas important in the control of food intake and energy balance. Consistent with their roles as adiposity signals, exogenous leptin and insulin both reduce food intake when administered locally into the brain in a number of species under different experimental paradigms. Additionally, central administration of insulin antibodies increases food intake and body weight. Recent studies have demonstrated that both insulin and leptin have additive effects when administered simultaneously. Finally, we recently have demonstrated that leptin and insulin share downstream neuropeptide signaling pathways. Hence, insulin and leptin provide important negative feedback signals to the central nervous system, proportional to peripheral energy stores and coupled with catabolic circuits.", "corpus_id": 2006355, "score": 0 }, { "doc_id": "24913035", "title": "The beta 3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes.", "abstract": "Various model systems have been used to study the expression of the recently cloned ob gene, leptin. Here we report that freshly isolated rat white adipocytes incubated with insulin release leptin in a rapid and concentration-dependent manner (EC50 of 0.221 +/- .075 nM). Insulin-stimulated leptin release could be detected as early as 30 min and a maximal 2-3 fold effect was produced by 10 nM insulin. The effect of insulin was completely blocked by simultaneous activation of cAMP-dependent protein kinase. Using the activation of lipolysis as an index of cAMP-dependent protein kinase activity, we show that inhibition of leptin release by norepinephrine or the selective beta 3-adrenergic receptor agonist, CL316,243, occurred in parallel to activation of cAMP-dependent protein kinase. In addition, beta 1- and beta 2-adrenergic receptor antagonists did not impair the ability of norepinephrine or CL316,243 to inhibit leptin release from the adipocytes. These findings suggest that the beta 3-adrenergic receptor plays a central role in regulating the release of leptin from the adipocyte.", "corpus_id": 24913035, "score": 0 }, { "doc_id": "39422623", "title": "Transcriptional Activation of the Human Leptin Gene in Response to Hypoxia", "abstract": "In addition to having a major role in energy homeostasis, leptin is emerging as a pleiotropic cytokine with multiple physiological effector functions. The recently discovered proangiogenic activity of leptin suggested the hypothesis that its production might be regulated by hypoxia, as are other angiogenic factors. To examine this proposal, the expression of leptin protein and mRNA was measured and found to be markedly up-regulated in response to ambient or chemical hypoxia (upon exposure to desferrioxamine or cobalt chloride), an effect that requires intact RNA synthesis, suggesting a transcriptional mechanism. Transient transfection of cultured cells with deletion constructs of the leptin gene promoter linked to a reporter gene revealed a functional hypoxiaresponse element (HRE) located at position –116 within the proximal upstream region. This putative HRE harbors a characteristic 5′-RCGTG-3′ core motif, a hallmark of hypoxia-sensitive genes and recognized by the hypoxia-induciblefactor 1 (HIF1), which consists of a HIF1α/HIFβ heterodimer. Constructs harboring this –116/HRE supported reporter gene expression in response to hypoxia but not when mutated. Expression of HIF1α cDNA in normoxic cells mimicked hypoxia-induced reporter gene expression in cells cotransfected with the wild type leptin –116/HRE construct but not with the mutant. Gel shift assays with a32P-labeled leptin promoter –116/HRE probe and nuclear extracts from hypoxia-treated cells indicated binding of the HIF1α/β heterodimer, which was blocked with an excess of unlabeled –116/HRE probe or a HIF1-binding probe from the erythropoietin gene enhancer. Taken together, these observations demonstrate that the leptin gene is actively engaged by hypoxia through a transcriptional pathway commonly utilized by hypoxia-sensitive genes.", "corpus_id": 39422623, "score": 0 }, { "doc_id": "23546441", "title": "Hypoxia-inducible Factor 1 Transactivates the Human Leptin Gene Promoter*", "abstract": "Increased placental leptin has been demonstrated in preeclampsia, a pregnancy disorder associated with placental hypoxia. This suggests that leptin gene expression is enhanced in response to oxygen deficiency in this organ. In support of this hypothesis, we have previously shown that hypoxia activates the leptin promoter in trophoblast-derived BeWo cells. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric HIF-1α/HIF-1β complex that regulates the transcription of hypoxia-responsive genes. To test whether this factor is involved in hypoxia-induced leptin promoter activation, BeWo cells were transiently transfected with a HIF-1α expression vector. Exogenous HIF-1α markedly increased luciferase reporter activity driven by the leptin promoter when HIF-1β was co-expressed in the same cells. This effect was similar to that elicited by CoCl2, an agent known to stabilize endogenous HIF-1α. These data suggest that HIF-1α/HIF-1β dimers are involved in the effect of CoCl2 to activate the leptin promoter. To confirm the implication of HIF-1, the cells were transfected with a dominant negative form of HIF-1α producing transcriptionally inactive HIF-1β/HIF-1α dimers. This mutant HIF-1α protein abolished CoCl2 activation of the leptin promoter, providing direct evidence that the effect of CoCl2 is mediated by endogenous HIF-1α. Deletion analysis and site-specific mutagenesis demonstrated that a HIF-1 consensus binding site (HRE) spanning −120 to −116 bp relative to the start site was required for CoCl2 and exogenous HIF-1α induction of leptin promoter activity. Electrophoretic mobility shift assays performed with in vitro-translated HIF-1α and HIF-1β proteins demonstrated binding to this HRE and not to mutated sequences only when both subunits were used together. These data demonstrate that leptin is a new hypoxia-inducible gene, which is stimulated in a placental cell line through HIF-1 interaction with a consensus HRE site located at −116 in the proximal promoter.", "corpus_id": 23546441, "score": 0 }, { "doc_id": "22366947", "title": "Hypoxia increases leptin expression in human PAZ6 adipose cells", "abstract": "HeadingAbstract\n Aims/hypothesis. Leptin, an adipose tissue-derived cytokine involved in the control of body weight, also participates in a variety of biological functions, including angiogenesis. Because reduced oxygen availability is a major inducer of angiogenesis, we hypothesized that low cellular oxygen tension could regulate leptin expression in adipose cells.\n Methods. Differentiated PAZ6 adipocytes were cultured for 48 h in the presence of chemical inducers of cellular hypoxia (cobalt chloride or desferrioxamine) or in an atmosphere containing only 6% oxygen. The effect of hypoxia on the expression of leptin and several adipose genes was assessed by semi-quantitative RT-PCR. The effect of hypoxia on leptin promoter activity was tested in PAZ6 cells transiently transfected with a luciferase reporter construct, containing 1.87 kb of the human leptin promoter. Leptin secretion in the culture medium was determined by radioimmunoassay.\n Results. Hypoxia increased leptin mRNA expression, leptin promoter activity and leptin secretion in the culture medium by two- to threefold (p<0.05). The expression of the glucose transporter isoform 1 (GLUT-1) mRNA, a well known hypoxia inducible gene, was also increased. In contrast, glucose transporter isoform 4 (GLUT-4), hormone sensitive lipase (HSL), fatty acid binding protein (aP2) and uncoupling protein 2 (UCP2) mRNAs were markedly reduced by hypoxia. In addition, a similar hypoxia-induced increase in leptin mRNA and secretion was observed in primary rat adipose cells.\n Conclusion/interpretation. Hypoxia markedly and specifically increased leptin gene expression through activation of the leptin gene promoter, and this resulted in an increased leptin production by human PAZ6 adipocytes.", "corpus_id": 22366947, "score": 0 }, { "doc_id": "17564774", "title": "Hypoxia-induced leptin production in human trophoblasts does not protect from apoptosis.", "abstract": "OBJECTIVE\nThe ob-gene product, leptin, is an important regulator of placental and fetal development during pregnancy. Leptin, being induced by hypoxia in the placenta, is a known pro-apoptotic molecule in adipose tissue but is also known to inhibit apoptosis in other tissues like neuroblastoma cells. Based on these findings, we investigated if leptin has a pro- or anti-apoptotic effect on a trophoblastic cell line (JAr cells) in the presence or absence of oxygen.\n\n\nMETHODS AND RESULTS\nMeasurement of leptin in the supernatant by using ELISA showed hypoxia-induced leptin production in JAr cells in vitro. This could be confirmed by a leptin-specific RT-PCR. By analyzing leptin and/or hypoxia exposed cells with FACS cytometry we found that JAr cells can cope with hypoxia down to oxygen tensions of 1%. At this level, only a small number of cells underwent apoptosis. Interestingly, leptin added to the culture medium in high concentrations was not able to interfere with the rate of proliferation or apoptosis in these cells independent of the oxygen tension. Finally, an anti-caspase-3 and anti-caspase-9 Western blot was performed. Again, no difference in the expression of caspase-3 and -9 under the conditions tested was seen.\n\n\nCONCLUSIONS\nThese results show that leptin, produced by placental cells after hypoxia in vitro, has no influence on the rate of proliferation of these cells. Furthermore, it does not influence apoptotic pathways in the trophoblastic cell line tested under hypoxic and non-hypoxic conditions.", "corpus_id": 17564774, "score": 0 }, { "doc_id": "15867561", "title": "Mechanisms of leptin secretion from white adipocytes.", "abstract": "The mechanisms regulating leptin secretion were investigated in isolated rat white adipocytes. Insulin (1-100 nM) linearly stimulated leptin secretion from incubated adipocytes for at least 2 h. The adrenergic agonists norepinephrine, isoproterenol (two nonselective beta-agonists), or CL-316243 (potent beta3) all inhibited insulin (10 nM)-stimulated leptin release. The inhibitory effects of norepinephrine and isoproterenol could be reversed not only by the nonselective antagonist propranolol but also by the selective antagonists ICI-89406 (beta1) or ICI-118551 (beta2), the beta2-antagonist being less effective than the beta1. Insulin-stimulated leptin secretion could also be inhibited by a series of agents increasing intracellular cAMP levels, such as lipolytic hormones (ACTH and thyrotropin-stimulating hormone), various nonhydrolyzable cAMP analogs, pertussis toxin, forskolin, methylxanthines (caffeine, theophylline, IBMX), and specific inhibitors of phosphodiesterase III (imazodan, milrinone, and amrinone). Significantly, antilipolytic agents other than insulin (adenosine, nicotinic acid, acipimox, and orthovanadate) did not mimic the acute stimulatory effects of insulin on leptin secretion under these conditions. We conclude that norepinephrine specifically inhibits insulin-stimulated leptin secretion not only via the low-affinity beta3-adrenoceptors but also via the high-affinity beta1/beta2-adrenoceptors. Moreover, it is suggested that 1) activation of phosphodiesterase III by insulin represents an important metabolic step in stimulation of leptin secretion, and 2) lipolytic hormones competitively counterregulate the stimulatory effects of insulin by activating the adenylate cyclase system.", "corpus_id": 15867561, "score": 0 }, { "doc_id": "207255894", "title": "Hypoxia induces leptin gene expression and secretion in human preadipocytes: differential effects of hypoxia on adipokine expression by preadipocytes.", "abstract": "The effect of hypoxia on the expression and secretion of major adipokines by human preadipocytes has been examined. Hypoxia (1% O(2)) led to an increase in the HIF-1 alpha transcription factor subunit in cultured preadipocytes, as did incubation with the hypoxia mimetic CoCl(2). Leptin mRNA was essentially undetectable in preadipocytes incubated under normoxia (21% O(2)), but exposure to 1% O(2), or CoCl(2), for 4 or 24 h resulted in an induction of leptin gene expression (measured by real-time PCR). Immunoreactive leptin was not detected in the medium from normoxic preadipocytes, but was present in the medium from the hypoxic cells. Hypoxia stimulated expression of the GLUT-1 facilitative glucose transporter gene and the vascular endothelial growth factor (VEGF) gene in preadipocytes, as in adipocytes. PPAR gamma and aP2 mRNA levels, markers of adipocyte differentiation, were reduced by hypoxia in both cell types. In marked contrast to adipocytes, interleukin-6 (IL-6), angiopoietin-like protein 4, and plasminogen activator inhibitor-1 expression by preadipocytes was not stimulated by low O(2) tension. Consistent with the gene expression results, VEGF release into the medium from preadipocytes was increased by hypoxia, but there was no change in IL-6 secretion. It is concluded that hypoxia induces human preadipocytes to synthesize and secrete leptin. Preadipocytes and adipocytes differ in their responsiveness to low O(2) tension, maturation of the response to hypoxia developing on differentiation.", "corpus_id": 207255894, "score": 0 }, { "doc_id": "43439323", "title": "Effects of Perinatal Hypoxia on Serum Unbound Free Fatty Acids and Lung Inflammatory Mediators", "abstract": "Cellular injury during tissue hypoxia is due, in part, to reactive intermediates released by activated leukocytes. We found that the inflammatory mediators tumor necrosis factor (TNF)-α, IL-6, and IL-1β are elevated in situ in lung macrophages on day 14 following exposure of rats to intermittent or chronic hypoxia from birth. Because inflammatory mediators can increase lipolysis in adipocytes, we also measured serum unbound free fatty acids (FFAu) – the biologically active compartment of FFA – in rat pups exposed to intermittent or chronic hypoxia. FFAu values were markedly elevated during the first 2 days of life in all rats, displaying an approximately 3-fold decrease from day 2 to day 3. Exposure to chronic hypoxia significantly increased FFAu levels measured on day 13. Since elevated serum FFAu are known to suppress leukocyte activation, we speculate that increased FFAu levels represent a mechanism for attenuating inflammation and tissue injury following sublethal hypoxia in the perinatal period, either physiologically in the immediate newborn period, or as a late response to ongoing hypoxic insult.", "corpus_id": 43439323, "score": 0 }, { "doc_id": "23961036", "title": "The role of free radicals in cerebral hypoxia and ischemia.", "abstract": "This review focuses on the effects that ischemia and hypoxia have on the cerebral cortex and the cerebellum during different periods of life. The acute interruption or reduction of cerebral blood flow, that can be induced by several factors and clinical pathologies, reduces available oxygen to the nervous system and this causes either focal or global brain damage, with characteristic biochemical and molecular alterations that can result in permanent or transitory neurological sequelae or even death. Under these circumstances, an increase in the activity of different isoforms of nitric oxide synthase occurs and nitric oxide is produced. This excess of nitric oxide reacts with cellular proteins yielding nitrotyrosine, thus contributing to cerebral damage. This phenomenon has been studied at different stages of perinatal and postnatal development, including aging animals. Both the duration and the intensity of the ischemic injury were evaluated. In all cases there is overproduction of nitric oxide in ischemia, which may represent an effort to reestablish normal blood flow. Unfortunately, in many cases this response becomes excessive and it triggers a cascade of free-radical reactions, leading to modifications of cerebral plasticity and overt injury.", "corpus_id": 23961036, "score": 0 }, { "doc_id": "5761117", "title": "Insulin resistance in adipocytes of obese women: effects of body fat distribution and race.", "abstract": "Upper-body obesity (UBO) in white women is associated with increased fatty acid turnover and resistance to the effects of insulin on systemic glucose metabolism. The present study determined whether the abilities of insulin to stimulate glucose transport and suppress lipolysis are impaired in adipocytes from white UBO (W-UBO) women. Because the clinical risks associated with UBO are attenuated in black women, the effects of race on adipocyte insulin sensitivity were assessed. Forty-two healthy, equally obese women were selected for study on the basis of race (black or white) and body fat distribution (UBO or lower-body obesity [LBO]). In white women, both abdominal and gluteal fat cells from the UBO versus LBO group were less responsive to the stimulatory effects of insulin on glucose uptake and less sensitive to the antilipolytic effects of insulin and the adenosine analog, phenylisopropyladenosine (PIA). In contrast, in black women, fat cells from UBO and LBO groups were equally sensitive to the stimulatory effects of insulin on glucose transport and the suppressive effects of insulin and PIA on lipolysis. These in vitro data correlate well with previous clinical findings that UBO in white women but not in black women is associated with insulin resistance and dyslipidemia. Thus, resistance to the antilipolytic effects of insulin and adenosine at the level of adipose tissue may increase systemic lipolysis and play a role in the development or maintenance of peripheral insulin resistance associated with UBO in white women, but not in black women.", "corpus_id": 5761117, "score": 0 }, { "doc_id": "23533121", "title": "Visceral adiposity, increased adipocyte lipolysis, and metabolic dysfunction in obese postmenopausal women.", "abstract": "This study determines whether there are regional differences in lipolysis and whether adipocyte lipolysis is associated with the degree of visceral adiposity and its metabolic complications in 32 obese (28-37 kg/m2), nondiabetic, postmenopausal women. In vitro lipolysis was measured in the basal state and after addition of epinephrine (Epi), Epi plus yohimbine, Epi plus propranolol, and N6,2'-O-dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) in abdominal (ABD) and gluteal (GLT) adipocytes. Upper body obese [UBO, waist-to-hip ratio (WHR) > or = 0.80, n = 19] women had a greater intra-abdominal fat area (IA, 199 +/- 50 vs. 142 +/- 28 cm2) and Epi-stimulated lipolysis (ABD: 1.60 +/- 1.10 vs. 0.95 +/- 0.54 mumol glycerol.10(6) cells-1.2h; GLT: 1.14 +/- 0.70 vs. 0.66 +/- 0.42 mumol glycerol.10(6) cells-1.2 h) than lower body obese (LBO, WHR < 0.80, n = 13) women. The UBO women also had lower high-density lipoprotein cholesterol (1.39 +/- 0.40 vs. 1.64 +/- 0.39 mmol/l, P < 0.05), higher plasma triglycerides (1.89 +/- 0.48 vs. 1.44 +/- 0.56 mmol/l, P < 0.05), and higher fasting insulin levels (154 +/- 57 vs. 118 +/- 33 pmol/l, P < 0.05) than LBO women. Basal, adrenergic receptor-mediated, and DBcAMP-stimulated lipolytic rates in ABD and GLT adipocytes were positively correlated with IA (r = 0.44-0.76, P < 0.05, n = 28). In both UBO and LBO women, Epi-stimulated lipolysis was higher (+30%, P < 0.05) in ABD than GLT adipocytes. These results show that, in postmenopausal women, visceral obesity is associated with increased rates of lipolysis in both ABD and GLT subcutaneous adipocytes. The findings also indicate that Epi-stimulated lipolysis is greater in ABD than GLT adipocytes regardless of fat distribution.", "corpus_id": 23533121, "score": 0 }, { "doc_id": "15291508", "title": "Extreme insulin resistance of the central adipose depot in vivo.", "abstract": "Despite the well-described association between obesity and insulin resistance, the physiologic mechanisms that link these two states are poorly understood. The present study was performed to elucidate the role of visceral adipose tissue in whole-body glucose homeostasis. Dogs made abdominally obese with a moderately elevated fat diet had catheters placed into the superior mesenteric artery so that the visceral adipose bed could be insulinized discretely. Omental insulin infusion was extracted at approximately 27%, such that systemic insulin levels were lower than in control (portal vein) insulin infusions. Omental infusion did not lower systemic free fatty acid levels further than control infusion, likely because of the resistance of the omental adipose tissue to insulin suppression and the confounding lower systemic insulin levels. The arteriovenous difference technique showed that local infusion of insulin did suppress omental lipolysis, but only at extremely high insulin concentrations. The median effective dose for suppression of lipolysis was almost fourfold higher in the visceral adipose bed than for whole-body suppression of lipolysis. Thus, the omental adipose bed represents a highly insulin-resistant depot that drains directly into the portal vein. Increased free fatty acid flux to the liver may account for hepatic insulin resistance in the moderately obese state.", "corpus_id": 15291508, "score": 0 }, { "doc_id": "42008837", "title": "Oxygen Tension Regulates the Stability of Insulin Receptor Substrate-1 (IRS-1) through Caspase-mediated Cleavage*", "abstract": "The insulin and insulin-like growth factor-1 (IGF-1) receptors mediate signaling for energy uptake and growth through insulin receptor substrates (IRSs), which interact with these receptors as well as with downstream effectors. Oxygen is essential not only for ATP production through oxidative phosphorylation but also for many cellular processes, particularly those involved in energy homeostasis. The oxygen tension in vivo is significantly lower than that in the air and can vary widely depending on the tissue as well as on perfusion and oxygen consumption. How oxygen tension affects IRSs and their functions is poorly understood. Our findings indicate that transient hypoxia (1% oxygen) leads to caspase-mediated cleavage of IRS-1 without inducing cell death. The IRS-1 protein level rebounds rapidly upon return to normoxia. Protein tyrosine phosphatases (PTPs) appear to be important for the IRS-1 cleavage because tyrosine phosphorylation of the insulin receptor was decreased in hypoxia and IRS-1 cleavage could be blocked either with H2O2 or with vanadate, each of which inhibits PTPs. Activity of Akt, a downstream effector of insulin and IGF-1 signaling that is known to suppress caspase activation, was suppressed in hypoxia. Overexpression of dominant-negative Akt led to IRS-1 cleavage even in normoxia, and overexpression of constitutively active Akt partially suppressed IRS-1 cleavage in hypoxia, suggesting that hypoxia-mediated suppression of Akt may induce caspase-mediated IRS-1 cleavage. In conclusion, our study elucidates a mechanism by which insulin and IGF-1 signaling can be matched to the oxygen level that is available to support growth and energy metabolism.", "corpus_id": 42008837, "score": 0 }, { "doc_id": "16331402", "title": "Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue.", "abstract": "Triacylglycerol (TAG) stored in adipose tissue can be rapidly mobilized by the hydrolytic action of lipases, with the release of fatty acids (FA) that are used by other tissues during times of energy deprivation. Unlike synthesis of TAG, which occurs not only in adipose tissue but also in other tissues such as liver for very-low-density lipoprotein formation, hydrolysis of TAG, lipolysis, predominantly occurs in adipose tissue. Until recently, hormone-sensitive lipase was considered to be the key rate-limiting enzyme responsible for regulating TAG mobilization. However, recent studies on hormone-sensitive lipase-null mice have challenged such a concept. A novel lipase named desnutrin/ATGL has been recently discovered to play a key role in lipolysis in adipocytes. Lipolysis is under tight hormonal regulation. Although opposing regulation of lipolysis in adipose tissue by insulin and catecholamines is well understood, autocrine/paracrine factors may also participate in its regulation. Intricate cooperation of these endocrine and autocrine/paracrine factors leads to a fine regulation of lipolysis in adipocytes, needed for energy homeostasis. In this review, we summarize and discuss the recent progress made in the regulation of adipocyte lipolysis.", "corpus_id": 16331402, "score": 0 }, { "doc_id": "7324798", "title": "PPARs and the complex journey to obesity", "abstract": "Obesity and the related disorders of dyslipidemia and diabetes (components of syndrome X) have become global health epidemics. Over the past decade, the elucidation of key regulators of energy balance and insulin signaling have revolutionized our understanding of fat and sugar metabolism and their intimate link. The three 'lipid-sensing' peroxisome proliferator–activated receptors (PPAR-α, PPAR-γ and PPAR-δ) exemplify this connection, regulating diverse aspects of lipid and glucose homeostasis, and serving as bona fide therapeutic targets. With molecular underpinnings now in place, new pharmacologic approaches to metabolic disease and new questions are emerging.", "corpus_id": 7324798, "score": 0 }, { "doc_id": "38770643", "title": "AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism.", "abstract": "The AMP-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status, and recent data demonstrate that it also plays a critical role in systemic energy balance. AMPK integrates nutritional and hormonal signals in peripheral tissues and the hypothalamus. It mediates effects of adipokines (leptin, adiponectin, and possibly resistin) in regulating food intake, body weight, and glucose and lipid homeostasis. AMPK is regulated by upstream kinases of which the tumor suppressor, LKB1, is the first to be identified. Complex signaling networks suggest that AMPK may prevent insulin resistance, in part by inhibiting pathways that antagonize insulin signaling. Through signaling, metabolic, and gene expression effects, AMPK enhances insulin sensitivity and fosters a metabolic milieu that may reduce the risk for obesity and type 2 diabetes.", "corpus_id": 38770643, "score": 0 }, { "doc_id": "14874811", "title": "Hypoxia-induced energy stress regulates mRNA translation and cell growth.", "abstract": "Oxygen (O2) deprivation, or hypoxia, has profound effects on cell metabolism and growth. Cells can adapt to low O2 in part through activation of hypoxia-inducible factor (HIF). We report here that hypoxia inhibits mRNA translation by suppressing multiple key regulators, including eIF2alpha, eEF2, and the mammalian target of rapamycin (mTOR) effectors 4EBP1, p70S6K, and rpS6, independent of HIF. Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic AMP-activated protein kinase (AMPK) activation also leads to eEF2 inhibition. Moreover, hypoxic effects on cellular bioenergetics and mTOR inhibition increase over time. Mutation of the TSC2 tumor suppressor gene confers a growth advantage to cells by repressing hypoxic mTOR inhibition and hypoxia-induced G1 arrest. Together, eIF2alpha, eEF2, and mTOR inhibition represent important HIF-independent mechanisms of energy conservation that promote survival under low O2 conditions.", "corpus_id": 14874811, "score": 0 }, { "doc_id": "1659156", "title": "A central role for JNK in obesity and insulin resistance", "abstract": "Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.", "corpus_id": 1659156, "score": 0 }, { "doc_id": "13163931", "title": "Modulation of the JNK Pathway in Liver Affects Insulin Resistance Status*", "abstract": "The c-Jun N-terminal kinase (JNK) pathway is known to be activated under diabetic conditions and to possibly be involved in the progression of insulin resistance. In this study, we examined the effects of modulation of the JNK pathway in liver on insulin resistance and glucose tolerance. Overexpression of dominant-negative type JNK in the liver of obese diabetic mice dramatically improved insulin resistance and markedly decreased blood glucose levels. Conversely, expression of wild type JNK in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of crucial molecules for insulin signaling was altered upon modification of the JNK pathway. Furthermore, suppression of the JNK pathway resulted in a dramatic decrease in the expression levels of the key gluconeogenic enzymes, and endogenous hepatic glucose production was also greatly reduced. Similar effects were observed in high fat, high sucrose diet-induced diabetic mice. Taken together, these findings suggest that suppression of the JNK pathway in liver exerts greatly beneficial effects on insulin resistance status and glucose tolerance in both genetic and dietary models of diabetes.", "corpus_id": 13163931, "score": 0 }, { "doc_id": "27934014", "title": "An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue.", "abstract": "The c-Jun NH2-terminal kinase (JNK) is activated during obesity. One consequence of obesity is that JNK phosphorylates the adapter protein insulin receptor substrate 1 (IRS-1) on Ser 307 and inhibits signaling by the insulin receptor. JNK can therefore cause peripheral insulin resistance during obesity and may contribute to the development of type 2 diabetes. Here we report that the JNK-interacting protein 1 (JIP1) scaffold protein, which binds components of the JNK signaling module, is essential for JNK activation in the adipose tissue of obese mice. These data identify JIP1 as a novel molecular target for therapeutic intervention in the development of obesity.", "corpus_id": 27934014, "score": 0 }, { "doc_id": "16238092", "title": "The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 *", "abstract": "Tumor necrosis factor α (TNFα) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. TNFα promotes multipotential signal transduction cascades, including the activation of the Jun NH2-terminal kinase (JNK). Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. Serine 307 is a major site of JNK phosphorylation in IRS-1. Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFα on insulin-stimulated tyrosine phosphorylation of IRS-1. These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFα on IRS-1 function.", "corpus_id": 16238092, "score": 0 }, { "doc_id": "18452867", "title": "The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes.", "abstract": "To determine the role of the endoplasmic reticulum (ER) in diabetes, Akita mice, a mouse model of type 2 diabetes, were mated with either heterozygous knockout mice or two types of transgenic mice of 150-kDa oxygen-regulated protein (ORP150), a molecular chaperone located in the ER. Systemic expression of ORP150 in Akita mice improves insulin intolerance, whereas the exclusive overexpression of ORP150 in pancreatic beta-cells of Akita mice did not change their glucose tolerance. Both an insulin tolerance test and hyperinsulinemic-euglycemic clamp revealed that ORP150 enhanced glucose uptake, accompanied by suppression of oxidized protein. Furthermore, ORP150 enhanced the insulin sensitivity of myoblast cells treated with hydrogen peroxide. These data suggest that ORP150 plays an important role in insulin sensitivity and is a potential target for the treatment of diabetes.", "corpus_id": 18452867, "score": 0 }, { "doc_id": "44000760", "title": "Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes", "abstract": "Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.", "corpus_id": 44000760, "score": 0 }, { "doc_id": "23533957", "title": "Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2α", "abstract": "ABSTRACT Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little is known about the mechanism by which hypoxia induces a global downregulation of protein synthesis. A critical step in the regulation of protein synthesis in response to stress is the phosphorylation of translation initiation factor eIF2α on Ser51, which leads to inhibition of new protein synthesis. Here we report that exposure of human diploid fibroblasts and transformed cells to hypoxia led to phosphorylation of eIF2α, a modification that was readily reversed upon reoxygenation. Expression of a transdominant, nonphosphorylatable mutant allele of eIF2α attenuated the repression of protein synthesis under hypoxia. The endoplasmic reticulum (ER)-resident eIF2α kinase PERK was hyperphosphorylated upon hypoxic stress, and overexpression of wild-type PERK increased the levels of hypoxia-induced phosphorylation of eIF2α. Cells stably expressing a dominant-negative PERK allele and mouse embryonic fibroblasts with a homozygous deletion of PERK exhibited attenuated phosphorylation of eIF2α and reduced inhibition of protein synthesis in response to hypoxia. PERK−/− mouse embryo fibroblasts failed to phosphorylate eIF2α and exhibited lower survival after prolonged exposure to hypoxia than did wild-type fibroblasts. These results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2α and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.", "corpus_id": 23533957, "score": 0 }, { "doc_id": "4711204", "title": "Mitochondrial Reactive Oxygen Species Control the Transcription Factor CHOP-10/GADD153 and Adipocyte Differentiation", "abstract": "Recent reports emphasize the importance of mitochondria in white adipose tissue biology. In addition to their crucial role in energy homeostasis, mitochondria are the main site of reactive oxygen species generation. When moderately produced, they function as physiological signaling molecules. Thus, mitochondrial reactive oxygen species trigger hypoxia-dependent gene expression. Therefore the present study tested the implication of mitochondrial reactive oxygen species in adipocyte differentiation and their putative role in the hypoxia-dependent effect on this differentiation. Pharmacological manipulations of mitochondrial reactive oxygen species generation demonstrate a very strong and negative correlation between changes in mitochondrial reactive oxygen species and adipocyte differentiation of 3T3-F442A preadipocytes. Moreover, mitochondrial reactive oxygen species positively and specifically control expression of the adipogenic repressor CHOP-10/GADD153. Hypoxia (1% O2) strongly increased reactive oxygen species generation, hypoxia-inducible factor-1 and CHOP-10/GADD153 expression, and inhibited adipocyte differentiation. All of these hypoxia-dependent effects were partly prevented by antioxidants. By using hypoxia-inducible factor-1α (HIF-1α)-deficient mouse embryonic fibroblasts, HIF-1α was shown not to be required for hypoxia-mediated CHOP-10/GADD153 induction. Moreover, the comparison of hypoxia and CoCl2 effects on adipocyte differentiation of wild type or HIF-1α deficient mouse embryonic fibroblasts suggests the existence of at least two pathways dependent or not on the presence of HIF-1α. Together, these data demonstrate that mitochondrial reactive oxygen species control CHOP-10/GADD153 expression, are antiadipogenic signaling molecules, and trigger hypoxia-dependent inhibition of adipocyte differentiation.", "corpus_id": 4711204, "score": 0 }, { "doc_id": "10969174", "title": "Adipose tissue failure and mitochondria as a possible target for improvement by bioactive food components", "abstract": "Purpose of review Adipose tissue is an essential, highly dynamic and metabolically active tissue that vigorously communicates to support its primary function: the storage of lipids. It performs this function to secure energy supply and prevent lipotoxicity. Adipose tissue is essential for maintaining a healthy glucose and lipid homeostasis and failure results in disease. This review discusses causes of adipose tissue failure and four categories of bioactive food components that may help to prevent this. Recent findings Based on recent findings, it is argued that initial adipose failure following long-term excess energy intake may be the result of reduced mitochondrial capacity associated with altered mitochondrial reactive oxygen species signaling and adipose tissue hypoxia. Current data suggest that different classes of bioactive food components, including vitamin B3, retinoids, fatty acids and polyphenols, may have the potential to modulate mitochondrial function and consequently prevent adipose dysfunction in obesity. Summary It seems most attractive to aim nutritional intervention at the prevention of initial adipose dysfunction and hence to target dietary intervention at improvement of mitochondrial function.", "corpus_id": 10969174, "score": 0 }, { "doc_id": "25585703", "title": "HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.", "abstract": "Many cancer cells are characterized by increased glycolysis and decreased respiration, even under aerobic conditions. The molecular mechanisms underlying this metabolic reprogramming are unclear. Here we show that hypoxia-inducible factor 1 (HIF-1) negatively regulates mitochondrial biogenesis and O(2) consumption in renal carcinoma cells lacking the von Hippel-Lindau tumor suppressor (VHL). HIF-1 mediates these effects by inhibiting C-MYC activity via two mechanisms. First, HIF-1 binds to and activates transcription of the MXI1 gene, which encodes a repressor of C-MYC transcriptional activity. Second, HIF-1 promotes MXI-1-independent, proteasome-dependent degradation of C-MYC. We demonstrate that transcription of the gene encoding the coactivator PGC-1beta is C-MYC dependent and that loss of PGC-1beta expression is a major factor contributing to reduced respiration in VHL-deficient renal carcinoma cells.", "corpus_id": 25585703, "score": 0 }, { "doc_id": "31964306", "title": "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.", "abstract": "Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1alpha null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.", "corpus_id": 31964306, "score": 0 }, { "doc_id": "8632604", "title": "Subcutaneous abdominal adipose tissue blood flow: variation within and between subjects and relationship to obesity.", "abstract": "1. We assessed the variation in subcutaneous abdominal adipose tissue blood flow within and between subjects and investigated whether it is correlated with body mass index. 2. We measured body mass index and subcutaneous abdominal adipose tissue blood flow in 38 fasting subjects on the same day and on different days and, in a subgroup of 16 subjects, after a mixed meal. 3. In 190 measurements in the fasted state, subcutaneous abdominal adipose tissue blood flow was significantly more variable between subjects than could be accounted for by the within-subject variation alone. Subcutaneous abdominal adipose tissue blood flow was also significantly more variable between days within subjects than could be accounted for by within-day variation alone. Fasting and post-prandial subcutaneous abdominal adipose tissue blood flow were negatively correlated with body mass index, as was the post-prandial rise in subcutaneous abdominal adipose tissue blood flow. Multiple regression analysis showed that fasting blood flow was not dependent on insulin concentration after allowing for body mass index. There was no correlation between post-prandial subcutaneous abdominal adipose tissue blood flow and insulin concentration. 4. Insulin does not appear to have a direct vasodilatory effect in subcutaneous adipose tissue. Obese subjects have lower fasting and post-prandial subcutaneous abdominal adipose tissue blood flow. This may be because of a blunted response to sympathetic stimulation, or it may be another aspect of the insulin-resistant state.", "corpus_id": 8632604, "score": 0 }, { "doc_id": "20200107", "title": "Relationship between blood pressure, metabolic variables and blood flow in obese subjects with or without non‐insulin‐dependent diabetes mellitus", "abstract": "To assess the relationship between systemic blood pressure, metabolic variables and adipose tissue blood flow, we studied 55 subjects before and 36 subjects after an oral glucose load (100 g).", "corpus_id": 20200107, "score": 0 }, { "doc_id": "26397111", "title": "Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity.", "abstract": "Obesity has been associated with dysfunctional postprandial adipose tissue blood flow (ATBF), but it has also been recognized that the interindividual response is highly variable. The present work aimed at characterizing this variability. Fifteen subjects were given 75 g oral glucose, and abdominal subcutaneous ATBF was monitored by the (133)Xe washout method. Determinants of insulin sensitivity based on nonesterified fatty acid (NEFA) suppression after oral glucose administration [ISI(NEFA)] were higher in the top tertile ATBF response group (1.29 +/- 0.09 vs. 0.90 +/- 0.08 in the lower tertiles, P = 0.01). ISI(NEFA) was related to ATBF response (r(s) = 0.73, P < 0.002) as well as insulin sensitivity based on postprandial glycemia [ISI(gly), r(s) = 0.58, P < 0.05], whereas the homeostasis model assessment (HOMA) index (r(s) = -0.39, P = 0.16) was not. The relationship between increase in ATBF and ISI(NEFA) was independent of BMI (P = 0.015) in multivariate analysis. Subjects with a high ATBF response had significantly higher increase of plasma norepinephrine (P < 0.05), indicating a link between postprandial insulinemia, sympathetic activation, and ATBF response. There is a close relationship between insulin sensitivity and the regulation of postprandial ATBF, independent of adiposity. Impaired regulation of ATBF seems to be another facet of the insulin resistance syndrome.", "corpus_id": 26397111, "score": 0 }, { "doc_id": "147859", "title": "Adipocyte blood flow is decreased in obese Zucker rats.", "abstract": "Blood flow to five adipose tissue depots and five other organs was measured in unanesthetized free-moving obese and lean male Zucker rats using the radiolabeled microsphere technique. Cardiac output and blood pressure were also measured. Obese rats were significantly heavier and had larger fat depots characterized by more and larger adipocytes. Cardiac output and blood pressure were similar in lean and obese rats. Blood flow to adipose tissue was substantially reduced in all five depots of obese rats when expressed per square millimeter of cell surface. When blood flow was expressed per cell, it was reduced in obese rats in the dorsal subcutaneous and inguinal depots and significantly elevated in the obese mesenteric adipose depot. Significant interdepot differences in blood flow were observed in both lean and obese rats. Nonadipose organ blood flow was not different between obese and lean rats, but when expressed on a per gram basis, blood flow through triceps surae muscle, epididymis, and testis was elevated in obese rats. These findings suggest that there is a substantial alteration of hemodynamics in obesity that may contribute to or reflect the altered metabolism of adipose tissue in obese rats. Furthermore, interdepot differences of adipose tissue blood flow also parallel reported interdepot differences in metabolism.", "corpus_id": 147859, "score": 0 }, { "doc_id": "14666249", "title": "Rates of skeletal muscle and adipose tissue glycerol release in nonobese and obese subjects.", "abstract": "Skeletal muscle and adipose tissue lipolysis rates were quantitatively compared in 12 healthy nonobese and 14 insulin-resistant obese subjects for 3.5 h after an oral glucose load using microdialysis measurements of interstitial glycerol concentrations and determinations of local blood flow with 133Xe clearance in the gastrocnemius muscle and in abdominal subcutaneous adipose tissue. Together with measurements of arterialized venous plasma glycerol, the absolute rates of glycerol mobilization were estimated. In the basal state, skeletal muscle and adipose tissue glycerol levels were 50% higher (P < 0.05-0.01) and adipose tissue blood flow (ATBF) and muscle blood flow (MBF) rates were 30-40% lower (P < 0.02-0.05) in obese versus nonobese subjects. After glucose ingestion, adipose tissue glycerol levels were rapidly and transiently reduced, whereas in muscle, a progressive and less pronounced fall in glycerol levels was evident. MBF remained unchanged in both study groups, whereas ATBF increased more markedly (P < 0.01) in the nonobese versus obese subjects after the oral glucose load. The fasting rates of glycerol release per unit of tissue weight from skeletal muscle were between 20 and 25% of that from adipose tissue in both groups. After glucose ingestion, the rates of glycerol release from skeletal muscle and from adipose tissue were almost identical in nonobese and obese subjects. However, the kinetic patterns differed markedly between tissues; in adipose tissue, the rate of glycerol mobilization was suppressed by 25-30% (P < 0.05) after glucose ingestion, whereas no significant reduction was registered in skeletal muscle. We conclude that significant amounts of glycerol are released from skeletal muscle, which suggests that muscle lipolysis provides an important endogenous energy source in humans. In response to glucose ingestion, the regulation of skeletal muscle glycerol release differs from that in adipose tissue; although the rate of glycerol release from adipose tissue is clearly suppressed, the rate of glycerol mobilization from skeletal muscle remains unaltered. In quantitative terms, the rate of glycerol release per unit of tissue weight in adipose tissue and in skeletal muscle is similar in nonobese and obese subjects in both the postabsorptive state and after glucose ingestion.", "corpus_id": 14666249, "score": 0 }, { "doc_id": "12546516", "title": "Marked increase in white adipose tissue blood perfusion in the type 2 diabetic GK rat.", "abstract": "The aim of the present study was to evaluate and cor-relate islet to brown and white adipose tissue (WAT) blood perfusion in one obese rat and one nonobese rat with type 2 diabetes (obese Zucker [OZ] and GK rats, respectively). We measured blood perfusion with a microsphere technique in anesthetized animals and subsequently estimated the blood flow to seven different WAT depots and brown adipose tissue, in addition to the whole pancreas and pancreatic islets. Both GK and OZ rats had higher islet blood perfusion than their respective control strains. Adipose tissue blood flow (ATBF) was similar to or lower than that of controls in the normoglycemic OZ rats. GK rats, however, had 5-10 times higher blood perfusion than control Wistar rats in most WAT depots. Vascular density and macrophage numbers in WAT did not differ between the different strains. The discrepancy in ATBF between the obese-normoglycemic and type 2 diabetic rats opens the intriguing possibility that changes in this blood perfusion may influence and/or modulate the beta-cell dysfunction in type 2 diabetes.", "corpus_id": 12546516, "score": 0 }, { "doc_id": "8465266", "title": "Adipocyte blood flow: influence of age, anatomic location, and dietary manipulation.", "abstract": "Adipocyte blood flow in four distinct adipose tissue depots has been measured in conscious, unrestrained, male Sprague-Dawley rats by using the microsphere technique together with cellularity determinations. Blood flow was determined in young rats (90 days old, 387 g mean body wt), spontaneously obese rats (450 days old, 713 g mean body wt), and long-term calorically restricted rats (450 days old, 390 g mean body wt), therefore allowing the comparison of the relative effects of age and fat mass on adipose tissue blood flow. Results of these experiments indicate that while cardiac index remained constant, cardiac output increased in only the obese group, concomitant with increased body fat mass. Spontaneously obese rats exhibited increased adipose tissue depot weight, fat cell lipid, and fat cell size compared with young and restricted groups. Despite significant differences in cell volume, blood flow per cell was remarkably similar between young and obese rats. Long-term caloric restriction, however, was associated with decreased flow per cell. Interdepot comparisons of flow per unit surface area (mm2) or per unit volume (pl) indicate that mesenteric cells receive significantly more blood than cells of the other depots. Our results suggest that adipocyte blood flow is dependent in part on anatomic location, may be further influenced by age or dietary manipulation, and is not a limiting factor in the enlargement of adipocytes during the development of spontaneous obesity.", "corpus_id": 8465266, "score": 0 }, { "doc_id": "6465674", "title": "Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity.", "abstract": "The biological role of macrophage infiltration into adipose tissue in obesity remains to be fully understood. We hypothesize that macrophages may act to stimulate angiogenesis in the adipose tissue. This possibility was examined by determining macrophage expression of angiogenic factor PDGF (platelet-derived growth factor) and regulation of tube formation of endothelial cells by PDGF. The data suggest that endothelial cell density was reduced in the adipose tissue of ob/ob mice. Expression of endothelial marker CD31 was decreased in protein and mRNA. The reduction was associated with an increase in macrophage infiltration. In the obese mice, PDGF concentration was elevated in the plasma, and its mRNA expression was increased in adipose tissue. Macrophages were found to be a major source of PDGF in adipose tissue, as deletion of macrophages led to a significant reduction in PDGF mRNA. In cell culture, PDGF expression was induced by hypoxia, and tube formation of endothelial cells was induced by PDGF. The PDGF activity was dependent on S6K, as inhibition of S6K in endothelial cells led to inhibition of the PDGF activity. We conclude that, in response to the reduced vascular density, macrophages may express PDGF in adipose tissue to facilitate capillary formation in obesity. Although the PDGF level is elevated in adipose tissue, its activity in angiogenesis is dependent on the availability of sufficient endothelial cells. The study suggests a new function of macrophages in the adipose tissue in obesity.", "corpus_id": 6465674, "score": 0 }, { "doc_id": "6088997", "title": "Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation.", "abstract": "The renin-angiotensin system (RAS) is a coordinated hormonal cascade in the control of cardiovascular, renal, and adrenal function that governs body fluid and electrolyte balance, as well as arterial pressure. The classical RAS consists of a circulating endocrine system in which the principal effector hormone is angiotensin (ANG) II. ANG is produced by the action of renin on angiotensinogen to form ANG I and its subsequent conversion to the biologically active octapeptide by ANG-converting enzyme. ANG II actions are mediated via the ANG type 1 receptor. Here, we discuss recent advances in our understanding of the components and actions of the RAS, including local tissue RASs, a renin receptor, ANG-converting enzyme-2, ANG (1-7), the function of the ANG type 2 receptor, and ANG receptor heterodimerization. The role of the RAS in the regulation of cardiovascular and renal function is reviewed and discussed in light of these newly recognized components.", "corpus_id": 6088997, "score": 0 }, { "doc_id": "16078693", "title": "Physiology and pathophysiology of the adipose tissue renin-angiotensin system.", "abstract": "The renin-angiotensin system has long been recognized as an important regulator of systemic blood pressure and renal electrolyte homeostasis, and local renin-angiotensin systems have also been implicated in pathological changes of organ structure and function by modulation of gene expression, growth, fibrosis, and inflammatory response. Recently, substantial data have been accumulated in support of the notion that adipose tissue, besides other endocrine functions, also hosts a local renin-angiotensin system. In the first part of this review, we describe the components of the adipose tissue renin-angiotensin system in human and rodent animal models with respect to regulation of angiotensinogen expression and secretion, formation of angiotensin peptides, and the existence of angiotensin II receptors. In the second part, we describe the role of the adipose tissue renin-angiotensin system in the process of adipogenic differentiation and in the regulation of body weight. We also detail the differential regulation of the adipose tissue renin-angiotensin system in obesity and hypertension and thereby also speculate on its possible role in the development of obesity-associated hypertension. Although some findings on the adipose tissue renin-angiotensin system appear to be confusing, its involvement in the physiology and pathophysiology of adipose tissue has been confirmed by several functional studies. Nevertheless, future studies with more carefully described phenotypes are necessary to conclude whether obesity (by stimulation of adipogenic differentiation) and hypertension are associated with changes of renin-angiotensin system activity in adipose tissue. If so, the physiological relevance of this system in animal models and humans may warrant further interest.", "corpus_id": 16078693, "score": 0 }, { "doc_id": "80854413", "title": "Adipose Tissue as an Endocrine Organ", "abstract": "In recent years, there has been an explosion in our understanding of adipose tissue biology. Fat tissue is no longer regarded as a tissue the sole function of which is to store energy in the form of triglycerides. Adipose tissue is now regarded as an endocrine organ that controls whole body glucose and lipid homeostasis by secreting numerous factors (free fatty acids, proteins) that exert specific functions in target tissues. Adipose tissue is broadly classified into white (WAT) and brown (BAT). WAT is largely responsible for the synthesis and storage of triglycerides, whereas BAT is important for heat production and energy expenditure due to its high content of uncoupling protein 1 (UCP1). Adipose tissue plays a key role in the pathogenesis of cardiometabolic diseases associated with obesity by promoting the development of a pro-inflammatory state. As we understand better the molecular and cellular mechanisms that control adipocyte biology and how fat tissue affects other organs, novel strategies to prevent and treat metabolic diseases by targeting the adipose tissue and its products will be developed.", "corpus_id": 80854413, "score": 0 }, { "doc_id": "2124292", "title": "Angiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans", "abstract": "We investigated the functional roles of circulating and locally produced angiotensin II (Ang II) in fasting and postprandial adipose tissue blood flow (ATBF) regulation and examined the interaction between Ang II and nitric oxide (NO) in ATBF regulation. Local effects of the pharmacological agents (or contralateral saline) on ATBF, measured with 133Xe wash‐out, were assessed using the recently developed microinfusion technique. Fasting and postprandial (75 g glucose challenge) ATBF regulation was investigated in nine lean healthy subjects (age, 29 ± 3 years; BMI, 23.4 ± 0.7 kg m−2) using local Ang II stimulation, Ang II type 1 (AT1) receptor blockade, and angiotensin‐converting enzyme (ACE) inhibition. Furthermore, NO synthase (NOS) blockade alone and in combination with AT1 receptor blockade was used to examine the interaction between Ang II and NO. Ang II induced a dose‐dependent decrease in ATBF (10−9m: −16%, P= 0.04; 10−7m: −33%, P < 0.01; 10−5m: −53%P < 0.01). Fasting ATBF was not affected by ACE inhibition, but was increased by ∼55% (P < 0.01) by AT1 receptor blockade. NOS blockade induced a ∼30% (P= 0.001) decrease in fasting ATBF. Combined AT1 receptor and NOS blockade increased ATBF by ∼40% (P= 0.003). ACE inhibition and AT1 receptor blockade did not affect the postprandial increase in ATBF. We therefore conclude that circulating Ang II is a major regulator of fasting ATBF, and a major proportion of the Ang II‐induced decrease in ATBF is NO independent. Locally produced Ang II does not appear to regulate ATBF. Ang II appears to have no major effect on the postprandial enhancement of ATBF.", "corpus_id": 2124292, "score": 0 }, { "doc_id": "9192937", "title": "Selective Angiotensin II Receptor Antagonism Reduces Insulin Resistance in Obese Zucker Rats", "abstract": "Effects of oral administration of the angiotensin II receptor antagonist (selective AT1-subtype) irbesartan on glucose tolerance and insulin action on skeletal-muscle glucose transport were assessed in the insulin-resistant obese Zucker rat. In the acute study, obese rats received either vehicle (water) or irbesartan 1 hour before the experiment. Although irbesartan had no effect on glucose transport (2-deoxyglucose uptake) in the epitrochlearis muscle, which consists mainly of type IIb fibers, acute angiotensin II receptor antagonism led to a dose-dependent increase in insulin action in the predominantly type I soleus muscle. Irbesartan at 25 and 50 mg/kg induced significant increases (41% and 50%, respectively;P <0.05) in insulin-mediated glucose transport. Moreover, these acute irbesartan-induced improvements in soleus-muscle glucose transport were associated with enhancements in whole-body insulin sensitivity (r =−0.732;P <0.05), as assessed during an oral glucose tolerance test. After chronic administration of irbesartan (21 days at 50 mg · kg−1 · d−1), glucose tolerance was enhanced further, and insulin-mediated glucose transport was significantly elevated in both epitrochlearis (32%) and soleus (73%) muscle. Chronic angiotensin II receptor antagonism was associated with significant increases in glucose transporter-4 (GLUT-4) protein expression in soleus (22%) and plantaris (20%) muscle and myocardium (15%). Chronic irbesartan-induced increases in whole-body insulin sensitivity were associated with increased insulin-mediated glucose transport in both epitrochlearis (r =−0.677;P <0.05) and soleus (r =−0.892;P <0.05) muscle. In summary, angiotensin II receptor (AT1-subtype) antagonism, either acutely or chronically, improves glucose tolerance, at least in part because of an enhancement in skeletal-muscle glucose transport, and the effect of chronic angiotensin II receptor antagonism on type I skeletal-muscle glucose uptake is associated with an increase in GLUT-4 protein expression.", "corpus_id": 9192937, "score": 0 }, { "doc_id": "28260896", "title": "Noninvasive measurement of microvascular and interstitial oxygen profiles in a human tumor in SCID mice.", "abstract": "Simultaneous measurements of intravascular and interstitial oxygen partial pressure (PO2) in any tissue have not previously been reported, despite the importance of oxygen in health and in disease. This is due to the limitations of current techniques, both invasive and noninvasive. We have optically measured microscopic profiles of PO2 with high spatial resolution in subcutaneous tissue and transplanted tumors in mice by combining an oxygen-dependent phosphorescence quenching method and a transparent tissue preparation. The strengths of our approach include the ability to follow PO2 in the same location for several weeks and to relate these measurements to local blood flow and vascular architecture. Our results show that (i) PO2 values in blood vessels in well-vascularized regions of a human colon adenocarcinoma xenograft are comparable to those in surrounding arterioles and venules, (ii) carbogen (95% O2/5% CO2) breathing increases microvascular PO2 in tumors, and (iii) in unanesthetized and anesthetized mice PO2 drops to hypoxic values at < 200 microns from isolated vessels but drops by < 5 mmHg (1 mmHg = 133 Pa) in highly vascularized tumor regions. Our method should permit noninvasive evaluations of oxygen-modifying agents and offer further mechanistic information about tumor pathophysiology in tissue preparations where the surface of the tissue can be observed.", "corpus_id": 28260896, "score": 0 }, { "doc_id": "44349603", "title": "Role of Insulin Action and Cell Size on Protein Expression Patterns in Adipocytes*", "abstract": "Mice with a fat-specific insulin receptor knock-out (FIRKO) exhibit a polarization of white adipose tissue into two populations of cells, one small (diameter <50 μm) and one large (diameter >100 μm), accompanied by changes in insulin-stimulated glucose uptake, triglyceride synthesis, and lipolysis. To characterize these subclasses of adipocytes, we have used a proteomics approach in which isolated adipocytes from FIRKO and control (IR lox/lox) mice were separated by size, fractionated into cytosolic and membrane subfractions, and analyzed by sucrose gradient, SDS-PAGE, and mass spectrometry. A total of 27 alterations in protein expression at key steps in lipid and energy metabolism could be defined, which were coordinately regulated by adipocyte cell size, impaired insulin signaling, or both. Nine proteins, including vimentin, EH-domain-containing protein 2, elongation factor 2, glucose-regulated protein 78, transketolase, and succinyl-CoA transferase were primarily affected by presence or absence of insulin signaling, whereas 21 proteins, including myosin non-muscle form A, annexin 2, annexin A6, and Hsp47 were regulated in relation to adipocyte size. Of these 27 alterations in protein expression, 14 changes correlated with altered levels of mRNA, whereas the remaining 13 were the result of changes in protein translation or turnover. These data suggest an intrinsic heterogeneity in adipocytes with differences in protein expression patterns caused by transcriptional and post-transcriptional alterations related to insulin action and cellular lipid accumulation.", "corpus_id": 44349603, "score": 0 }, { "doc_id": "14076719", "title": "Adipogenesis in Obesity Requires Close Interplay Between Differentiating Adipocytes, Stromal Cells, and Blood Vessels", "abstract": "OBJECTIVE—The expansion of adipose tissue mass seen in obesity involves both hyperplasia and hypertrophy of adipocytes. However, little is known about how adipocytes, adipocyte precursors, blood vessels, and stromal cells interact with one another to achieve adipogenesis. RESEARCH DESIGN AND METHODS—We have developed a confocal microscopy-based method of three-dimensional visualization of intact living adipose tissue that enabled us to simultaneously evaluate angiogenesis and adipogenesis in db/db mice. RESULTS—We found that adipocyte differentiation takes place within cell clusters (which we designated adipogenic/angiogenic cell clusters) that contain multiple cell types, including endothelial cells and stromal cells that express CD34 and CD68 and bind lectin. There were close spatial and temporal interrelationships between blood vessel formation and adipogenesis, and the sprouting of new blood vessels from preexisting vasculature was coupled to adipocyte differentiation. CD34+ CD68+ lectin-binding cells could clearly be distinguished from CD34− CD68+ macrophages, which were scattered in the stroma and did not bind lectin. Adipogenic/angiogenic cell clusters can morphologically and immunohistochemically be distinguished from crown-like structures frequently seen in the late stages of adipose tissue obesity. Administration of anti–vascular endothelial growth factor (VEGF) antibodies inhibited not only angiogenesis but also the formation of adipogenic/angiogenic cell clusters, indicating that the coupling of adipogenesis and angiogenesis is essential for differentiation of adipocytes in obesity and that VEGF is a key mediator of that process. CONCLUSIONS—Living tissue imaging techniques provide novel evidence of the dynamic interactions between differentiating adipocytes, stromal cells, and angiogenesis in living obese adipose tissue.", "corpus_id": 14076719, "score": 0 }, { "doc_id": "4358727", "title": "Retinal angiogenesis in development and disease", "abstract": "The retina has long been regarded as ‘an approachable part of the brain’ for investigating neurosensory processes. Cell biologists are now capitalizing on the accessibility of the retina to investigate important aspects of developmental angiogenesis, including how it relates to neuronal and glial development, morphogenesis, oxygen sensing and progenitor cells. Pathological angiogenesis also occurs in the retina and is a major feature of leading blinding diseases, particularly diabetic retinopathy. The retina and its clinical disorders have a pivotal role in angiogenesis research and provide model systems in which to investigate neurovascular relationships and angiogenic diseases.", "corpus_id": 4358727, "score": 0 }, { "doc_id": "22122686", "title": "Angiogenesis modulates adipogenesis and obesity.", "abstract": "Substantial evidence shows that neoplastic and nonneoplastic tissue growth is dependent on angiogenesis. Neovascularization and adipogenesis are temporally and spatially coupled processes during prenatal life and they continue to reciprocally interact via paracrine signaling systems throughout adult life. Activated adipocytes produce multiple angiogenic factors including leptin, angiopoietins, HGF, GM-CSF, VEGF, FGF-2, and TGF-beta, which either alone or collectively stimulate neovascularization during fat mass expansion. Thus antiangiogenic agents provide a novel therapeutic option for prevention and treatment of human obesity and its related disorders.", "corpus_id": 22122686, "score": 0 }, { "doc_id": "4302296", "title": "Angiogenesis in life, disease and medicine", "abstract": "The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.", "corpus_id": 4302296, "score": 0 }, { "doc_id": "4405580", "title": "Angiogenesis in cancer and other diseases", "abstract": "Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials. The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated. This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases. But owing to several unanswered questions, caution is needed.", "corpus_id": 4405580, "score": 0 }, { "doc_id": "4302834", "title": "From angiogenesis to neuropathology", "abstract": "Angiogenesis — the growth of new blood vessels — is a crucial force for shaping the nervous system and protecting it from disease. Recent advances have improved our understanding of how the brain and other tissues grow new blood vessels under normal and pathological conditions. Angiogenesis factors, especially vascular endothelial growth factor, are now known to have roles in the birth of new neurons (neurogenesis), the prevention or mitigation of neuronal injury (neuroprotection), and the pathogenesis of stroke, Alzheimer's disease and motor neuron disease. As our understanding of pathophysiology grows, these developments may point the way towards new molecular and cell-based therapies.", "corpus_id": 4302834, "score": 0 }, { "doc_id": "37957089", "title": "Adipose tissue angiogenesis.", "abstract": "A review of adipose tissue angiogenesis includes the morphological and cytochemical development of adipose tissue vasculature and the concept of primitive fat organs. Spatial and temporal relationships between fetal vascular and fat cell development are discussed, including depot- and genetic-dependent arteriolar differentiation. The relationship between connective tissue deposition and elaboration of adipose tissue vasculature is discussed with respect to regulating adipocyte development in a depot-dependent manner. In vitro studies indicated that depot-dependent vascular traits may be attributable to intrinsic growth characteristics of adipose tissue endothelial cells. These studies indicate that adipogenesis may be regulated by factors that drive angiogenesis. Fundamental aspects of angiogenesis, including basement membrane breakdown, vasculogenesis, angiogenic remodeling, vessel stabilization, and vascular permeability were reviewed. Critical angiogenic factors include vascular endothelial growth factor (VEGF), VEGF receptors, angiopoietins (Ang), ephrins, matrix metalloproteinases, and the plasminogen enzymatic system. Vascular endothelial growth factor is the most critical factor because it initiates the formation of immature vessels and disruption of a single VEGF allele leads to embryonic lethality in mice. Expression of VEGF is influenced by hypoxia, insulin, growth factors, and several cytokines. Angiogenic factors secreted and/or produced by adipocytes or preadipocytes are discussed. Vascular endothelial growth factor expression and secretion by adipocytes is regulated by insulin and hypoxia, and is associated with adipose tissue accretion. Vascular endothelial growth factor accounts for most of the angiogenic activity of adipose tissue. The proposed role of leptin as an adipogenic factor is reviewed with respect to efficacy on various aspects of angiogenesis relative to other angiogenic factors. The VEGF and leptin genes are both hypoxia inducible, but potential links between VEGF and leptin gene expression have not been examined. Finally, several studies including a study of mice treated with antiangiogenic factors indicate that adipose tissue accretion can be controlled through the vasculature per se.", "corpus_id": 37957089, "score": 0 }, { "doc_id": "37158454", "title": "Biological action of leptin as an angiogenic factor.", "abstract": "Leptin is a hormone that regulates food intake, and its receptor (OB-Rb) is expressed primarily in the hypothalamus. Here, it is shown that OB-Rb is also expressed in human vasculature and in primary cultures of human endothelial cells. In vitro and in vivo assays revealed that leptin has angiogenic activity. In vivo, leptin induced neovascularization in corneas from normal rats but not in corneas from fa/fa Zucker rats, which lack functional leptin receptors. These observations indicate that the vascular endothelium is a target for leptin and suggest a physiological mechanism whereby leptin-induced angiogenesis may facilitate increased energy expenditure.", "corpus_id": 37158454, "score": 0 }, { "doc_id": "21973028", "title": "Adiponectin Stimulates Angiogenesis in Response to Tissue Ischemia through Stimulation of AMP-activated Protein Kinase Signaling*", "abstract": "Obesity is a risk factor for the development of cardiovascular diseases that are associated with impaired angiogenesis. Adiponectin is an adipocyte-specific adipocytokine with anti-atherogenic and anti-diabetic properties, and its plasma levels are reduced in association with obesity-linked diseases. Here, we investigated whether adiponectin regulates angiogenesis in response to tissue ischemia using adiponectin knock-out (KO) mice. Angiogenic repair of ischemic hind limbs was impaired in adiponectin-KO mice compared with wild-type (WT) mice as evaluated by laser Doppler flow method and capillary density analyses. Adenovirus-mediated supplement of adiponectin accelerated angiogenic repair in both adiponectin-KO and WT mice. Intramuscular injection of an adenovirus encoding dominant-negative AMP-activated kinase diminished the improvement in limb perfusion seen in WT mice and abolished the adiponectin-induced enhancement of perfusion. These data indicate that adiponectin can function to stimulate angiogenesis in response to ischemic stress by promoting AMP-activated kinase signaling. Therefore, adiponectin may be useful in the treatment for obesity-related vascular deficiency diseases.", "corpus_id": 21973028, "score": 0 }, { "doc_id": "1183610", "title": "Angiogenesis as a therapeutic target", "abstract": "Inhibiting angiogenesis is a promising strategy for treatment of cancer and several other disorders, including age-related macular degeneration. Major progress towards a treatment has been achieved over the past few years, and the first antiangiogenic agents have been recently approved for use in several countries. Therapeutic angiogenesis (promoting new vessel growth to treat ischaemic disorders) is an exciting frontier of cardiovascular medicine, but further understanding of the mechanisms of vascular morphogenesis is needed first.", "corpus_id": 1183610, "score": 0 }, { "doc_id": "19462302", "title": "Angiogenesis in an in vivo model of adipose tissue development", "abstract": "Obesity is associated with an increased risk for cardiovascular disease and cancer. Angiogenesis is a critical component of these pathological processes, and expanding adipose tissue represents one of the few sites of active angiogenesis in the adult. Despite the potential importance of angiogenesis in obesity, little is known about underlying mechanisms. This problem is magnified by the absence of useful quantitative model systems. In this report, we examine the angiogenic process using the 3T3‐F442A model of adipose tissue development. In this model, 3T3‐F442A preadipocytes are implanted subcutaneously into athymic Balb/c nude mice. We show that these cells develop into highly vascularized fat pads over the next 14–21 days, and that these fat pads are morphologically similar to normal subcutaneous adipose tissue. Histological studies demonstrate that a new microvasculature is evident as early as 5 days after cell implantation, and real‐time quantitative RT‐PCR analyses show that the expression of endothelial cell markers and adipogenesis markers increase in parallel during fat pad development. Finally, these preliminary studies suggest that the neovasculature originates by sprouting from larger, host‐derived blood vessels that run parallel to peripheral nerves and that endothelial progenitor cells play little, if any, role in this process.", "corpus_id": 19462302, "score": 0 }, { "doc_id": "19369938", "title": "Reversal of obesity by targeted ablation of adipose tissue", "abstract": "Obesity is an increasingly prevalent human condition in developed societies. Despite major progress in the understanding of the molecular mechanisms leading to obesity, no safe and effective treatment has yet been found. Here, we report an antiobesity therapy based on targeted induction of apoptosis in the vasculature of adipose tissue. We used in vivo phage display to isolate a peptide motif (sequence CKGGRAKDC) that homes to white fat vasculature. We show that the CKGGRAKDC peptide associates with prohibitin, a multifunctional membrane protein, and establish prohibitin as a vascular marker of adipose tissue. Targeting a proapoptotic peptide to prohibitin in the adipose vasculature caused ablation of white fat. Resorption of established white adipose tissue and normalization of metabolism resulted in rapid obesity reversal without detectable adverse effects. Because prohibitin is also expressed in blood vessels of human white fat, this work may lead to the development of targeted drugs for treatment of obese patients.", "corpus_id": 19369938, "score": 0 }, { "doc_id": "35575643", "title": "Adipose tissue mass can be regulated through the vasculature", "abstract": "Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.", "corpus_id": 35575643, "score": 0 }, { "doc_id": "25855084", "title": "Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediated angiogenesis.", "abstract": "Omentum has been used clinically to promote wound healing and to stimulate the revascularization of ischemic tissues. The biologic mechanism responsible for these effects has, however, not yet been defined. A number of polypeptide growth factors that possess potent angiogenic properties have recently been identified, and we therefore sought to determine whether one of these growth factors might be responsible for the angiogenic properties of the omentum. The levels of vascular endothelial growth factor (VEGF) protein in a number of rat tissues and organs were analyzed by Western and enzyme immunoassay analysis. Because omentum was found to have the greatest VEGF concentrations of the tissues examined, antibody neutralization, transcription inhibition assays, and Northern blot analysis were performed under hypoxic and normoxic conditions on tissues extractions and primary tissue cultures of omentum to further characterize the functional significance of VEGF expression in these tissues. The omentum demonstrated the highest VEGF secretion rate as well as the highest concentration of VEGF protein of the various rat tissues and organs examined. Fractionation studies of the omentum furthermore demonstrated that omental adipocytes, rather than the stromal-vascular cells, were the primary source of VEGF protein. An endothelial cell mitogenic assay showed that a major portion of the mitogenic activity of heparin-binding proteins and conditioned media derived from omentum was abolished by VEGF antibody. Additional studies with the transcription inhibitor actinomycin-D furthermore demonstrated that the VEGF gene was continuously transcribed in the rat omental adipocytes. Incubation of the omental adipocytes under hypoxic conditions induced approximately a 1.7-fold increase in VEGF protein expression, which was abolished by actinomycin-D. Northern blot analysis demonstrated that hypoxia resulted in upregulation of the VEGF mRNA in the hypoxia-cultured omental adipocytes, suggesting that the augmentation of VEGF expression in omental adipocytes by hypoxia occurs at the transcriptional level. These data suggest that VEGF is the major angiogenic factor produced by omentum and possibly underlies the mechanism of omentum-induced angiogenesis. Augmented expression of VEGF by omental cells under hypoxic conditions may furthermore reflect the mechanism responsible for enhancing the angiogenic activity of omentum in the setting of ischemia.", "corpus_id": 25855084, "score": 0 }, { "doc_id": "38884657", "title": "Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects", "abstract": "Aims/hypothesisAdipose tissue expresses some bioactive molecules, which may be involved in the development of obesity-associated metabolic disorders and cardiovascular diseases. Vascular endothelial growth factor (VEGF) an important angiogenic factor is implicated in normal and pathological vessel formation. The aim of this study is to investigate clinically the association between blood serum VEGF concentrations and body fat accumulation as well as distribution. The study also aims to show the effect of serum VEGF protein on gene expression of transcriptional factor E26 transformation-specific-1 (Ets-1) and matrix metalloproteinase (MMP)-3.MethodsSerum VEGF concentrations were measured in 38 overweight or obese subjects. Fat distribution in the abdominal subcutaneous as well as visceral fat areas was assessed by computed tomography scans at umbilical level. Furthermore, the changes of serum VEGF concentrations following body weight reduction therapy were analyzed in eight subjects recruited from the original pool of subjects. Semi-purified circulating VEGF proteins were obtained by heparin-sepharose and its biological activities were shown to alter gene expressions in human aortic endothelial cells.ResultsSerum VEGF concentrations were positively correlated with BMI (r=0.433, p=0.007) and visceral fat area (r=0.488, p=0.002). Stepwise regression analysis showed the visceral fat area as the most important determinant factor for VEGF circulating levels. Following body weight reduction therapy, VEGF concentrations as well as visceral fat area were decreased. The serum semi-purified VEGF protein enhanced expressions of Ets-1 and MMP-3 in human aortic endothelial cells.Conclusion/interpretationIncreased serum VEGF concentrations associated with visceral fat accumulation could influence vascular endothelial function.", "corpus_id": 38884657, "score": 0 }, { "doc_id": "7220658", "title": "Roles of degree of fat deposition and its localization on VEGF expression in adipocytes.", "abstract": "Vascular endothelial growth factor (VEGF) is an important angiogenic factor and is expressed in wide variety of cell types. In this study, we investigated the mechanism of VEGF production in adipocytes in three sets of experiments. First, to clarify the relation between plasma VEGF concentrations and their expressions in adipose tissues, we investigated the genetically obese db/db and KK-Ay mice. Plasma VEGF concentrations in obese mice were significantly higher than in control and were related to adiposity. VEGF expressions in visceral fat were enhanced during growth and were related to fat deposition. Next, to demonstrate the relation between VEGF production and lipid accumulation in adipocytes, we analyzed VEGF mRNA expression and its protein secretion in 3T3-L1 cells. VEGF production was enhanced during lipid accumulation in 3T3-L1 cells after adipocyte conversion. Next, to clarify the role of anatomic localization on VEGF expression in adipocytes, we implanted 3T3-L1 cells into visceral or subcutaneous fat in athymic mice. 3T3-L1 cells implanted into the mesenteric area expressed more VEGF mRNA than that into the subcutaneous area. Plasma VEGF concentration in the mice implanted in visceral fat was higher than in controls. These results suggest that both the anatomic localization and the lipid accumulation are important for the VEGF production in adipocytes.", "corpus_id": 7220658, "score": 0 }, { "doc_id": "31105178", "title": "Insulin levels, blood pressure and sleep apnea.", "abstract": "This report concerns the relative contributions of body weight and sleep apnea to the following cardiovascular risk factors: blood pressure, fasting insulin and fasting glucose. We cross-sectionally examined the relationship of various levels of apneic activity [apnea-hypopnea index (AHI)] and a measure of obesity [body mass index (BMI)] to mean morning blood pressure and fasting serum insulin and fasting blood glucose concentrations sampled the morning after polysomnography. Subjects were 261 males (age 47 +/- 13 years, mean +/- SD), who were referred to a sleep laboratory for symptoms of sleep-disordered breathing. The dependent variables, mean morning blood pressure, insulin and fasting blood glucose (FBG) levels, were significantly related to both AHI (eta'2 = 0.10) and BMI (eta'2 = 0.18). AHI and BMI combined to account for approximately 30% of the variability in the best linear combination of these three factors. Further analysis indicated that mean morning blood pressure and fasting insulin levels each correlated positively with BMI and AHI, whereas FBG correlated only with BMI. We conclude that, although these data do not prove a causal relationship, there is evidence for an independent association between sleep apnea and not only blood pressure, but also fasting insulin levels.", "corpus_id": 31105178, "score": 0 }, { "doc_id": "21186965", "title": "Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia.", "abstract": "Sleep apnea and associated daytime sleepiness and fatigue are common manifestations of mainly obese middle-aged men. The onset of sleep apnea peaks in middle age, and its morbid and mortal sequelae include complications from accidents and cardiovascular events. The pathophysiology of sleep apnea remains obscure. The purpose of this study was to test three separate, albeit closely related, hypotheses. 1) Does sleep apnea contribute to the previously reported changes of plasma cytokine (tumor necrosis factor-alpha and interleukin-6) and leptin levels independently of obesity? 2) Among obese patients, is it generalized or visceral obesity that predisposes to sleep apnea? 3) Is apnea a factor independent from obesity in the development of insulin resistance? Obese middle-aged men with sleep apnea were first compared with nonapneic age- and body mass index (BMI)-matched obese and age-matched lean men. All subjects were monitored in the sleep laboratory for 4 consecutive nights. We obtained simultaneous indexes of sleep, sleep stages, and sleep apnea, including apnea/hypopnea index and percent minimum oxygen saturation. The sleep apneic men had higher plasma concentrations of the adipose tissue-derived hormone, leptin, and of the inflammatory, fatigue-causing, and insulin resistance-producing cytokines tumor necrosis factor-alpha and interleukin-6 than nonapneic obese men, who had intermediate values, or lean men, who had the lowest values. Because these findings suggested that sleep apneics might have a higher degree of insulin resistance than the BMI-matched controls, we studied groups of sleep-apneic obese and age- and BMI-matched nonapneic controls in whom we obtained computed tomographic scan measures of total, sc, and visceral abdominal fat, and additional biochemical indexes of insulin resistance, including fasting plasma glucose and insulin. The sleep apnea patients had a significantly greater amount of visceral fat compared to obese controls (<0.05) and indexes of sleep disordered breathing were positively correlated with visceral fat, but not with BMI or total or sc fat. Furthermore, the biochemical data confirmed a higher degree of insulin resistance in the group of apneics than in BMI-matched nonapneic controls. We conclude that there is a strong independent association among sleep apnea, visceral obesity, insulin resistance and hypercytokinemia, which may contribute to the pathological manifestations and somatic sequelae of this condition.", "corpus_id": 21186965, "score": 0 }, { "doc_id": "1019674", "title": "Obstructive sleep apnea is independently associated with insulin resistance.", "abstract": "Epidemiological studies have implicated obstructive sleep apnea (OSA) as an independent comorbid factor in cardiovascular and cerebrovascular diseases. It is postulated that recurrent episodes of occlusion of upper airways during sleep result in pathophysiological changes that may predispose to vascular diseases. Insulin resistance is a known risk factor for atherosclerosis, and we postulate that OSA represents a stress that promotes insulin resistance, hence atherogenesis. This study investigated the relationship between sleep-disordered breathing and insulin resistance, indicated by fasting serum insulin level and insulin resistance index based on the homeostasis model assessment method (HOMA-IR). A total of 270 consecutive subjects (197 male) who were referred for polysomnography and who did not have known diabetes mellitus were included, and 185 were documented to have OSA defined as an apnea-hypopnea index (AHI) > or =5. OSA subjects were more insulin resistant, as indicated by higher levels of fasting serum insulin (p = 0.001) and HOMA-IR (p < 0.001); they were also older and more obese. Stepwise multiple linear regression analysis showed that obesity was the major determinant of insulin resistance but sleep-disordered breathing parameters (AHI and minimum oxygen saturation) were also independent determinants of insulin resistance (fasting insulin: AHI, p = 0.02, minimum O(2), p = 0.041; HOMA-IR: AHI, p = 0.044, minimum O(2), p = 0.022); this association between OSA and insulin resistance was seen in both obese and nonobese subjects. Each additional apnea or hypopnea per sleep hour increased the fasting insulin level and HOMA-IR by about 0.5%. Further analysis of the relationship of insulin resistance and hypertension confirmed that insulin resistance was a significant factor for hypertension in this cohort. Our findings suggest that OSA is independently associated with insulin resistance, and its role in the atherogenic potential of sleep disordered breathing is worthy of further exploration.", "corpus_id": 1019674, "score": 0 }, { "doc_id": "907790", "title": "Sleep-disordered breathing and insulin resistance in middle-aged and overweight men.", "abstract": "Sleep-disordered breathing is a prevalent condition associated with impairment of daytime function and may predispose individuals to metabolic abnormalities independent of obesity. The primary objective of this study was to determine the metabolic consequences and community prevalence of sleep-disordered breathing in mildly obese, but otherwise healthy, individuals. One hundred and fifty healthy men, without diabetes or cardiopulmonary disease, were recruited from the community. Measurements included polysomnography, a multiple sleep latency test, an oral glucose tolerance test, determination of body fat by hydrodensitometry, and fasting insulin and lipids. The prevalence of sleep-disordered breathing, depending on the apnea-hypopnea index (AHI) cutoff, ranged from 40 to 60%. After adjusting for body mass index (BMI) and percent body fat, an AHI gt-or-equal, slanted 5 events/h was associated with an increased risk of having impaired or diabetic glucose tolerance (odds ratio, 2.15; 95% CI, 1.05-4.38). The impairment in glucose tolerance was related to the severity of oxygen desaturation (DeltaSa(O(2))) associated with sleep-disordered breathing. For a 4% decrease in oxygen saturation, the associated odds ratio for worsening glucose tolerance was 1.99 (95% CI, 1.11 to 3.56) after adjusting for percent body fat, BMI, and AHI. Multivariable linear regression analyses revealed that increasing AHI was associated with worsening insulin resistance independent of obesity. Thus, sleep-disordered breathing is a prevalent condition in mildly obese men and is independently associated with glucose intolerance and insulin resistance.", "corpus_id": 907790, "score": 0 }, { "doc_id": "34665531", "title": "Polygraphic study of the episodic diurnal and nocturnal (hypnic and respiratory) manifestations of the Pickwick syndrome.", "abstract": "Summary In a patient showing a typical pickwickian syndrome a study was made of respiratory functions and arterial gasometry, with polygraphic registrations carried out during the day and at night in an attempt to evaluate sleep, respiration, blood oxyhaemoglobin and CO2 concentration of the expiratory air. It was demonstrated that, at the onset of an authentic pickwickian syndrome, the symptomatology may be confined to obesity and diurnal drowsing episodes of the type described by Dickens in his novel. This means that the permanent alveolar hypoventilation regarded by some authors as an indispensable feature of the syndrome, In the patient under discussion, the numerous episodes of diurnal slumber which characterized his condition and occurred while the blood oxyhaemoglobin saturation and alveolar CO2 concentration were entirely normal, cannot be explained on the basis of hypoxia and hypercapnia as suggested by a majority of authors. One must resort to other hypotheses, bearing in mind that the one does not necessarily exclude the other. A first hypothesis suggests that the subject drowses during the day as a result of a primary disturbance of centres in the brain stem which regulate wakefulness and sleep by a mechanism not yet understood. According to this hypothesis, we are confronted with some sort of narcolepsy. A second hypothesis holds that the subject drowses during the day because he does not sleep sufficiently at night as a result of an exaggeration of the physiological phenomenon of hypnic hypoventilation. Nocturnal polygraphic registrations disclosed respiratory pauses which occurred in the initial phase of sleep, quite apart from hypotonia of the muscles of the floor of the mouth, so rapid and pronounced that the tongue moves back and causes the obstructive apnoea responsible for a hypoxia which arouses the subject, who returns to sleep after a short while. The cyclic repetition of arousal and slumber reduces nocturnal sleep to 2–3 h a night. This loss of nocturnal sleep is held responsible for the diurnal somnolence. Unfortunately the subject's diurnal sleep is disturbed even more than his nocturnal sleep because the slightest slumber immediately produces episodes of central or obstructive apnoea. Regardless of the respective values of these two hypotheses, the authors are convinced that the majority of individuals suffering from the pickwickian syndrome drowse during the day and sleep badly at night because of a primary disturbance in the wakefulness-sleep regulation which as such is based on their obesity. This affords an obvious explanation of the established fact that the only way to suppress hypnic disturbances in pickwickian patients is to have them lose weight.", "corpus_id": 34665531, "score": 0 }, { "doc_id": "25436717", "title": "The effect of altitude hypoxia on glucose homeostasis in men", "abstract": "1 Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia. Insulin action on glucose uptake has never been investigated during altitude hypoxia. 2 In eight healthy, sea level resident men (27 ± 1 years (mean ± S.E.M.); weight, 72 ± 2 kg; height, 182 ± 2 cm) hyperinsulinaemic (50 mU min−1 m−2), euglycaemic clamps were carried out at sea level, and subsequently on days 2 and 7 after a rapid passive ascent to an altitude of 4559 m. 3 Acute mountain sickness scores increased in the first days of altitude exposure, with a peak on day 2. Basal HGP did not change with the transition from sea level (2.2 ± 0.2 mg min− kg−1) to altitude (2.0 ± 0.1 and 2.1 ± 0.2 mg min−1 kg−1, days 2 and 7, respectively). Insulin‐stimulated glucose uptake rate was halved on day two compared with sea level (4.5 ± 0.6 and 9.8 ± 1.1 mg min−1 kg−1, respectively; P < 0.05), and was partly restored on day 7 (7.4 ± 1.4 mg min−1 kg−1; P < 0.05vs. day two and sea level). Concentrations of glucagon and growth hormone remained unchanged, whereas glucose, C‐peptide and cortisol increased on day 2. Noradrenaline concentrations increased during the stay at altitude, while adrenaline concentrations remained unchanged. In response to insulin infusion, catecholamines increased on day 2 (noradrenaline and adrenaline) and day 7 (adrenaline), but not at sea level. 4 In conclusion, insulin action decreases markedly in response to two days of altitude hypoxia, but improves with more prolonged exposure. HGP is always unchanged. The changes in insulin action may in part be explained by the changes in counter‐regulatory hormones.", "corpus_id": 25436717, "score": 0 }, { "doc_id": "246609", "title": "Women at altitude: short-term exposure to hypoxia and/or alpha(1)-adrenergic blockade reduces insulin sensitivity.", "abstract": "After short-term exposure to high altitude (HA), men appear to be less sensitive to insulin than at sea level (SL). We hypothesized that the same would be true in women, that reduced insulin sensitivity would be directly related to the rise in plasma epinephrine concentrations at altitude, and that the addition of alpha-adrenergic blockade would potentiate the reduction. To test the hypotheses, 12 women consumed a high-carbohydrate meal at SL and after 16 h at simulated 4,300-m elevation (HA). Subjects were studied twice at each elevation: once with prazosin (Prz), an alpha(1)-adrenergic antagonist, and once with placebo (Pla). Mathematical models were used to assess insulin resistance based on fasting [homeostasis model assessment of insulin resistance (HOMA-IR)] and postprandial [composite model insulin sensitivity index (C-ISI)] glucose and insulin concentrations. Relative to SL-Pla (HOMA-IR: 1.86 +/- 0.35), insulin resistance was greater in HA-Pla (3.00 +/- 0.45; P < 0.05), SL-Prz (3.46 +/- 0.51; P < 0.01), and HA-Prz (2.82 +/- 0.43; P < 0.05). Insulin sensitivity was reduced in HA-Pla (C-ISI: 4.41 +/- 1.03; P < 0.01), SL-Prz (5.73 +/- 1.01; P < 0.05), and HA-Prz (4.18 +/- 0.99; P < 0.01) relative to SL-Pla (8.02 +/- 0.92). Plasma epinephrine was significantly elevated in HA-Pla (0.57 +/- 0.08 ng/ml; P < 0.01), SL-Prz (0.42 +/- 0.07; P < 0.05), and HA-Prz (0.82 +/- 0.07; P < 0.01) relative to SL-Pla (0.28 +/- 0.04), but correlations with HOMA-IR, HOMA-beta-cell function, and C-ISI were weak. In women, short-term exposure to simulated HA reduced insulin sensitivity compared with SL. The change does not appear to be directly mediated by a concurrent rise in plasma epinephrine concentrations.", "corpus_id": 246609, "score": 0 }, { "doc_id": "20350249", "title": "Intermittent Hypoxia Increases Insulin Resistance in Genetically Obese Mice", "abstract": "Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin‐deficient obese (C57BL/6J−Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 ± 11 mg dl−1 on day 0 to 138 ± 10 mg dl−1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 ± 0.3 vs. 1.7 ± 0.2 ng ml−1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short‐term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 ± 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time‐dependent increase in fasting serum insulin levels (from 3.6 ± 1.1 ng ml−1 at baseline to 9.8 ± 1.8 ng ml−1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.", "corpus_id": 20350249, "score": 0 }, { "doc_id": "40426905", "title": "Intravenous Glucose Tolerance Test in Pregnancy in Women Living in Chronic Hypoxia", "abstract": "Rapid intravenous glucose tolerance tests have been performed in women living at high altitude in an environment of chronic hypoxia (average values: barometric pressure 445 mm. Hg, alveolar p02 46.0 mm. Hg, arterial p02 45.1 mm. Hg). The hypoxic group had a curve of the same shape but with lower values when compared with that of women born and living at sea level. At sea level pregnancy modified the curve obtained when compared with that of nonpregnant women, but at high altitude pregnancy did not modify the curve. As a possible explanation a higher basal level of insulin in the high altitude group is suggested.", "corpus_id": 40426905, "score": 0 }, { "doc_id": "36867070", "title": "Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity.", "abstract": "RATIONALE AND OBJECTIVES\nAlthough many clinical physiology and epidemiology studies show an association between obstructive sleep apnea (OSA) and markers of insulin resistance, no causal pathway has been established. The purpose of the current study was to determine if the intermittent hypoxia (IH) stimulus that characterizes OSA causes insulin resistance in the absence of obesity. Furthermore, we assessed the impact of IH on specific metabolic function in liver and muscle. Finally, we examined the potential mechanistic role of the autonomic nervous system (ANS) in mediating insulin resistance in response to IH.\n\n\nMETHODS AND RESULTS\nHyperinsulinemic euglycemic clamps were conducted and whole-body insulin sensitivity, hepatic glucose output, and muscle-specific glucose utilization assessed in conscious, chronically instrumented adult male C57BL/6J mice exposed to (1) IH (achieving a nadir of Fi(O(2)) = 5-6% at 60 cycles/h for 9 h), (2) intermittent air as a control, (3) IH with ANS blockade (hexamethonium), or (4) IA with ANS blockade. IH decreased whole-body insulin sensitivity compared with intermittent air (38.8 +/- 2.7 vs. 49.4 +/- 1.5 mg/kg/min, p < 0.005) and reduced glucose utilization in oxidative muscle fibers, but did not cause a change in hepatic glucose output. Furthermore, the reduction in whole-body insulin sensitivity during IH was not restored by ANS blockade.\n\n\nCONCLUSION\nWe conclude that IH can cause acute insulin resistance in otherwise lean, healthy animals, and that the response is associated with decreased glucose utilization of oxidative muscle fibers, but that it occurs independently of activation of the ANS.", "corpus_id": 36867070, "score": 0 }, { "doc_id": "23967889", "title": "Adipose tissue blood flow during prolonged, heavy exercise", "abstract": "SummarySubcutaneous adipose tissue blood flow (ATBF) was examined in 8 subjects during 6 h exercise on a bicycle ergometer. The initial work load was 118 W corresponding to about 50% of maximal work capacity. The oxygen uptake increased from 0.26 l ·min−1 at rest to about 1.6l·min−1 during work. In 7 subjects ATBF increased, in 1 it remained constant. After 3 h exercise ATBF at an average reached values 3–4 times the control value. This increase was maintained for the remaining work periods. The increase was significant at the 5% level. Plasma free fatty acids increased 7-, plasma glycerol 10-fold during work.", "corpus_id": 23967889, "score": 0 }, { "doc_id": "24487533", "title": "Post‐exercise adipose tissue and skeletal muscle lipid metabolism in humans: the effects of exercise intensity", "abstract": "1 One purpose of the present experiments was to examine whether the relative workload or the absolute work performed is the major determinant of the lipid mobilization from adipose tissue during exercise. A second purpose was to determine the co‐ordination of skeletal muscle and adipose tissue lipid metabolism during a 3 h post‐exercise period. 2 Six subjects were studied twice. In one experiment, they exercised for 90 min at 40 % of maximal O2 consumption (V̇O2, max) and in the other experiment they exercised at 60 %V̇O2, max for 60 min. For both experiments, catheters were inserted in an artery, a subcutaneous abdominal vein and a femoral vein. Adipose tissue metabolism and skeletal muscle (leg) metabolism were measured using Fick's principle. 3 The results show that the lipolytic rate in adipose tissue during exercise was the same in each experiment. Post‐exercise, there was a very fast decrease in lipolysis, but it began to increase about 1 h post‐exercise and remained elevated for the following 2 h. The increase in post‐exercise non‐esterified fatty acid (NEFA) mobilization was greater after 60 % exercise than after 40 % exercise. 4 It is concluded that the lipolytic rate in abdominal subcutaneous adipose tissue during exercise is the same whether the relative workload is 40 % or 60 % of maximum. Post‐exercise, there is a substantial lipid mobilization from adipose tissue and only a small fraction of this is taken up in the lower extremities. This leaves a substantial amount of NEFAs for either NEFA/TAG (triacylglycerol) recirculation post‐exercise or immediate oxidation.", "corpus_id": 24487533, "score": 0 }, { "doc_id": "24598126", "title": "Adipose tissue and skeletal muscle blood flow during mental stress.", "abstract": "Mental stress [a modified Stroop color word conflict test (CWT)] increased adipose tissue blood flow (ATBF; 133Xe clearance) by 70% and reduced adipose tissue vascular resistance (ATR) by 25% in healthy male volunteers. The vasculatures of adipose tissue (abdomen as well as thigh), skeletal muscle of the calf (133Xe clearance), and the entire calf (venous occlusion plethysmography) responded similarly. Arterial epinephrine (Epi) and glycerol levels were approximately doubled by stress. beta-Blockade by metoprolol (beta 1-selective) or propranolol (nonselective) attenuated CWT-induced tachycardia similarly. Metoprolol attenuated stress-induced vasodilation in the calf and tended to do so in adipose tissue. Propranolol abolished vasodilation in the calf and resulted in vasoconstriction during CWT in adipose tissue. Decreases in ATR, but not in skeletal muscle or calf vascular resistances, were correlated to increases in arterial plasma glycerol (r = -0.42, P less than 0.05), whereas decreases in skeletal muscle and calf vascular resistances, but not in ATR, were correlated to increases in arterial Epi levels (r = -0.69, P less than 0.01; and r = -0.43, P less than 0.05, respectively). The results suggest that mental stress increases nutritive blood flow in adipose tissue and skeletal muscle considerably, both through the elevation of perfusion pressure and via vasodilatation. Withdrawal of vasoconstrictor nerve activity, vascular beta 2-adrenoceptor stimulation by circulating Epi, and metabolic mechanisms (in adipose tissue) may contribute to the vasodilatation.", "corpus_id": 24598126, "score": 0 }, { "doc_id": "30071573", "title": "Postprandial substrate deposition in human forearm and adipose tissues in vivo.", "abstract": "1. Substrate movements in forearm muscle and subcutaneous adipose tissue were studied, by measurement of arteriovenous differences and blood flow, in seven normal subjects after an overnight fast and then for 6 h after ingestion of a mixed meal. Overall substrate balances were examined in terms of the flux of gram-atoms of carbon. 2. As found previously, the forearm was approximately in carbon balance (import equal to export) after the overnight fast, whereas adipose tissue was a net exporter of carbon, mainly in the form of non-esterified fatty acids. 3. After the meal, arterialized plasma concentrations of glucose and lactate rose sharply (peak at 60 min), whereas those of non-esterified fatty acids and glycerol fell (nadir at 60-120 min). Plasma triacylglycerol concentrations rose slowly to peak at 240 min;much of this rise was accounted for by a rise in the chylomicron fraction. 4. Both tissues took up glucose at an increased rate after the meal. Release of non-esterified fatty acids and glycerol from adipose tissue was suppressed. Clearance of triacylglycerol by both tissues increased after the meal, but was more marked in adipose tissue, where the fractional extraction of chylomicron-triacylglycerol reached 44% at 240 min. 5. The forearm rapidly became a considerable net importer of carbon, and remained so until 6 h after the meal when it was again in approximate carbon balance. Glucose uptake dominated the forearm carbon balance. Adipose tissue was a net importer of carbon from 30 min until 5 h after the meal and then reverted to net export. Clearance of triacylglycerol carbon made the largest contribution to this positive balance, but towards the end of the study this was increasingly counterbalanced by simultaneous non-esterified fatty acid release.", "corpus_id": 30071573, "score": 0 }, { "doc_id": "21137414", "title": "Blood flow in skin, subcutaneous adipose tissue and skeletal muscle in the forearm of normal man during an oral glucose load.", "abstract": "Blood flow to the forearm, and the subcutaneous tissue and skin in the forearm were measured by strain gauge plethysmography, 133Xe-elimination and Laser Doppler flowmetry during an oral glucose load (I g glucose kg-1 lean body mass) and during control conditions. The forearm blood flow remained constant during both experiments. Glucose induced a two-fold vasodilatation in subcutaneous tissue. In skin, glucose induced a relative vasodilatation and later a relative vasoconstriction compared with control experiments. When estimated from forearm blood flow and subcutaneous and skin blood flows, muscle blood flow decreased about 20-30% during both experiments. Proximal nervous blockade did not abolish the glucose-induced vasodilatation in subcutaneous tissue. In the glucose experiment, arterial glucose concentration increased to 7.8 +/- 1.17 mmol l-1 30 min after the load was given and then decreased to 4.5 +/- 0.34 mmol l-1 at the end of the experiment. In the control experiments glucose concentration was constant. Arterial noradrenaline concentration increased significantly from 1.0 +/- 0.13 to about 1.5 +/- 0.3 nmol l-1 120 min after glucose and remained at this level during the experiment. Similarly adrenaline increased from 0.16 +/- 0.11 to about 0.4 +/- 0.16 nmol l-1 180 min after glucose. It is hypothesized that the vasodilating effect of glucose in subcutaneous tissue is secondary to metabolic events connected to glucose uptake and energy deposition in adipose tissue.", "corpus_id": 21137414, "score": 0 }, { "doc_id": "43391702", "title": "Modification and validation of a commercially available portable detector for measurement of adipose tissue blood flow.", "abstract": "Adipose tissue blood flow is measured from the clearance of radioactive xenon from a depot. Traditionally, a NaI detector has been used to measure the residual depot of xenon. However, this is sensitive to movement artefacts. We tested a commercially available lightweight CsI detector which can be strapped to the anterior abdominal wall. In pilot studies the CsI detector produced higher values for adipose tissue blood flow than did a conventional NaI detector. It was modified by inclusion of spacers to distance it from the skin. Flow results generated by the modified detector were similar to those generated by the NaI detector, both after an overnight fast and during the increased blood flow after a meal. Individual decay patterns generated by the CsI detector were, however, significantly smoother than those from the NaI detector.", "corpus_id": 43391702, "score": 0 }, { "doc_id": "30843856", "title": "Cardiovascular and metabolic responses to low dose adrenaline infusion: an invasive study in humans.", "abstract": "Cardiovascular and metabolic responses to intravenous infusions of adrenaline (ADR), which raised arterial plasma ADR in a stepwise fashion from 0.3 to 1.3, 2.3 and 6.0 nmol/l, were studied in 11 healthy volunteers. ADR evoked marked and concentration-dependent increases in stroke volume and cardiac output (thermodilution), as well as decreases in the vascular resistances of the systemic circulation, calf and adipose tissue. These changes were significant from 1.3 nmol/l ADR. Less marked effects were found on blood pressure and heart rate. Significant arterial ADR concentration-effect relationships were found for cyclic AMP, glycerol, glucose, lactate and noradrenaline, but not for insulin. Cyclic AMP and glycerol were significantly elevated at 1.3, glucose at 2.3, but lactate not below 6.0 nmol/l ADR. Increases in adipose tissue blood flow and arterial glycerol levels were correlated (P less than 0.001), suggesting a metabolic component in the blood flow response of adipose tissue. Invasive haemodynamic measurements revealed that ADR at arterial concentrations within the lower physiological range had considerable effects on cardiac output and vascular resistances, despite moderate changes in the conventional non-invasive haemodynamic variables blood pressure and heart rate. ADR elicited clear-cut responses at arterial plasma concentrations attained during various kinds of mild to moderate stress.", "corpus_id": 30843856, "score": 0 }, { "doc_id": "24975143", "title": "Influence of circulating NE and Epi on adipose tissue vascular resistance and lipolysis in humans.", "abstract": "The effects of circulating norepinephrine (NE) and epinephrine (Epi) on vascular resistance in subcutaneous adipose tissue and the calf as well as on plasma glycerol, an indicator of lipolysis, were studied in healthy volunteers. Adipose tissue blood flow was determined by the local clearance of 99mTcO-4 or 133Xe. The two isotopes gave similar results. Calf blood flow was determined by venous occlusion plethysmography. Intravenous infusion of NE caused increases in systolic and diastolic blood pressures, adipose tissue and calf vascular resistances, and plasma glycerol and a decrease in plasma insulin and heart rate, all of which were significant when arterial plasma NE was elevated from 1.17 +/- 0.14 to 8.38 +/- 0.30 nM (n = 16). Epi reduced diastolic and mean arterial pressures and adipose tissue and calf vascular resistances and increased plasma glycerol without affecting systolic blood pressure or plasma insulin. An increase of arterial plasma Epi from 0.20 +/- 0.03 to 1.15 +/- 0.05 nM (n = 6) was sufficient to induce vasodilatation in adipose tissue and lipolysis. Human adipose tissue differs from canine adipose tissue inasmuch as Epi causes vasodilatation in humans (present results) but vasoconstriction in the dog (previous results), presumably due to a predominance of vascular beta 2-adrenoceptors in human and beta 1-adrenoceptors in canine adipose tissue. Furthermore, Epi is a considerably more potent lipolytic hormone than NE in humans but not in the dog. Our results indicate that both NE and Epi may influence human adipose tissue blood flow and lipolysis as circulating hormones.", "corpus_id": 24975143, "score": 0 }, { "doc_id": "12325578", "title": "Effects of epinephrine infusion on adipose tissue: interactions between blood flow and lipid metabolism.", "abstract": "Epinephrine has effects on both blood flow and metabolism in adipose tissue. To investigate how these effects might interact in vivo, epinephrine was infused into six healthy volunteers at a rate of 25 ng.kg-1.min-1. The rates of action of lipoprotein lipase and hormone-sensitive lipase in adipose tissue were calculated by measurement of arteriovenous differences across subcutaneous abdominal adipose tissue, and adipose tissue blood flow was measured. Epinephrine caused a significant rise in adipose tissue blood flow (P < 0.001), and the net efflux of nonesterified fatty acids (NEFA) from adipose tissue increased significantly (P < 0.05). Most of this efflux could be accounted for by hormone-sensitive lipase-derived NEFA efflux from cells (P < 0.05), but there was also a significant rise in the contribution of lipoprotein lipase-derived NEFA (P < 0.05). We conclude that adipose tissue blood flow plays an important role in the regulation of lipid metabolism, controlling substrate presentation for lipoprotein lipase and also preventing the local accumulation of fatty acids derived from both hormone-sensitive lipase and lipoprotein lipase.", "corpus_id": 12325578, "score": 0 }, { "doc_id": "45110450", "title": "Nitric oxide and beta-adrenergic stimulation are major regulators of preprandial and postprandial subcutaneous adipose tissue blood flow in humans.", "abstract": "BACKGROUND\nBlood flow mediates the metabolic and endocrine roles of adipose tissue. We have previously shown that the postprandial adipose tissue blood flow (ATBF) increase is dependent on insulin sensitivity. However, subcutaneous local insulin delivery had no demonstrable effect on either preprandial or postprandial ATBF. We hypothesized that insulin may act indirectly via sympathetic activation, mainly in the postprandial period, and that nitric oxide may be an overall major regulator of subcutaneous ATBF.\n\n\nMETHODS AND RESULTS\nWe investigated the endogenous preprandial and postprandial regulation of ATBF by applying local tissue blockade of beta-adrenergic (propranolol), alpha-adrenergic (phentolamine and yohimbine), and nitric oxide (NG-monomethyl-L-arginine, L-NMMA) regulation of blood flow. Healthy subjects (body mass index, 18 to 31 kg/m2) were challenged with 75 g glucose for endogenous stimulation of ATBF. We used the novel \"microinfusion\" technique, which allows for simultaneous local delivery of pharmacological agents (or contralateral saline) and measurement of ATBF with the 133Xe washout method. Compared with control, the preprandial ATBF was not affected by propranolol but was increased by 21% (P<0.013) and 15% (P=0.004) with phentolamine and yohimbine, respectively. A decrease of 42% (2.97+/-0.33 versus 4.75+/-0.47 mL x min(-1) x 100 g tissue(-1), P<0.01) was seen with L-NMMA. The postprandial response was blunted by 58% (0.81+/-0.42 versus 1.90+/-0.44 mL x min(-1) x 100 g tissue(-1), P<0.004) with propranolol, but neither phentolamine, yohimbine, or L-NMMA altered this response.\n\n\nCONCLUSIONS\nNitric oxide seems to determine the absolute level of ATBF, whereas a major proportion of the postprandial enhancement of ATBF is under beta-adrenergic regulation in vivo in humans.", "corpus_id": 45110450, "score": 0 } ]

{ "doc_id": "14828824", "title": "Structure-oriented substrate specificity engineering of aldehyde-deformylating oxygenase towards aldehydes carbon chain length", "abstract": "BackgroundAldehyde-deformylating oxygenase (ADO) is an important enzyme involved in the biosynthetic pathway of fatty alk(a/e)nes in cyanobacteria. However, ADO exhibits quite low chain-length specificity with respect to the substrates ranging from C4 to C18 aldehydes, which is not suitable for producing fuels with different properties or different chain lengths.ResultsBased on the crystal structures of cADOs (cyanobacterial ADO) with substrate analogs bound, some amino acids affecting the substrate specificity of cADO were identified, including the amino acids close to the aldehyde group and the hydrophobic tail of the substrate and those along the substrate channel. Using site-directed mutagenesis, selected amino acids were replaced with bulky ones introducing steric hindrance to the binding pocket via large functional groups. All mutants were overexpressed, purified and kinetically characterized. All mutants, except F87Y, displayed dramatically reduced activity towards C14,16,18 aldehydes. Notably, the substrate preferences of some mutants towards different chain-length substrates were enhanced: I24Y for n-heptanal, I27F for n-decanal and n-dodecanal, V28F for n-dodecanal, F87Y for n-decanal, C70F for n-hexanal, A118F for n-butanal, A121F for C4,6,7 aldehydes, V184F for n-dodecanal and n-decanal, M193Y for C6–10 aldehydes and L198F for C7–10 aldehydes. The impact of the engineered cADO mutants on the change of the hydrocarbon profile was demonstrated by co-expressing acyl-ACP thioesterase BTE, fadD and V184F in E. coli, showing that n-undecane was the main fatty alkane.ConclusionsSome amino acids, which can control the chain-length selectivity of substrates of cADO, were identified. The substrate specificities of cADO were successfully changed through structure-guided protein engineering, and some mutants displayed different chain-length preference. The in vivo experiments of V184F in genetically engineered E. coli proved the importance of engineered cADOs on the distribution of the fatty alkane profile. The results would be helpful for the production of fatty alk(a/e)nes in cyanobacteria with different properties.", "corpus_id": 14828824 }

[ { "doc_id": "30646431", "title": "Microbial Biosynthesis of Alkanes", "abstract": "Toward Alkane Synthesis Alkanes are major components of fossil fuels, and synthesis of alkanes remains a challenge in the conversion of renewable raw materials to fuels. Even though diverse organisms synthesize alkanes, synthesis pathways have remained elusive. Now Schirmer et al. (p. 559) describe an alkane biosynthesis pathway in cyanobacteria that converts intermediates of fatty acid metabolism to alkanes and alkenes. Heterologous expression of the biosynthetic genes resulted in production of alkanes in Escherichia coli. This pathway is likely to be a valuable tool in the production of biofuels. Alkane biosynthesis genes were identified in cyanobacteria and engineered into Escherichia coli for recombinant hydrocarbon production. Alkanes, the major constituents of gasoline, diesel, and jet fuel, are naturally produced by diverse species; however, the genetics and biochemistry behind this biology have remained elusive. Here we describe the discovery of an alkane biosynthesis pathway from cyanobacteria. The pathway consists of an acyl–acyl carrier protein reductase and an aldehyde decarbonylase, which together convert intermediates of fatty acid metabolism to alkanes and alkenes. The aldehyde decarbonylase is related to the broadly functional nonheme diiron enzymes. Heterologous expression of the alkane operon in Escherichia coli leads to the production and secretion of C13 to C17 mixtures of alkanes and alkenes. These genes and enzymes can now be leveraged for the simple and direct conversion of renewable raw materials to fungible hydrocarbon fuels.", "corpus_id": 30646431, "score": 1 }, { "doc_id": "23950309", "title": "A perspective: photosynthetic production of fatty acid-based biofuels in genetically engineered cyanobacteria.", "abstract": "Biofuels are expected to play a key role in the development of a sustainable, economical and environmentally safe source of energy. Microbes offer great potential for applications in technology based biofuel production. Three fundamental questions need to be addressed in order for the development of microbial synthesis of biofuels to be successful. Firstly, what energy resource platform could be used to make biofuels. Secondly, what type of biofuel is the ideal fuel molecule that should be targeted. Finally, what microbial system could be used to transform energy resources into the targeted biofuel molecules. In this perspective, the potential of using photosynthetic microbes (cyanobacteria in particular) in the solar energy driven conversion of carbon dioxide to fatty acid-based biofuels is explored.", "corpus_id": 23950309, "score": 0 }, { "doc_id": "46532799", "title": "Metabolic engineering of microbial pathways for advanced biofuels production.", "abstract": "Production of biofuels from renewable resources such as cellulosic biomass provides a source of liquid transportation fuel to replace petroleum-based fuels. This endeavor requires the conversion of cellulosic biomass into simple sugars, and the conversion of simple sugars into biofuels. Recently, microorganisms have been engineered to convert simple sugars into several types of biofuels, such as alcohols, fatty acid alkyl esters, alkanes, and terpenes, with high titers and yields. Here, we review recently engineered biosynthetic pathways from the well-characterized microorganisms Escherichia coli and Saccharomyces cerevisiae for the production of several advanced biofuels.", "corpus_id": 46532799, "score": 0 }, { "doc_id": "13349256", "title": "Next generation biofuel engineering in prokaryotes.", "abstract": "Next-generation biofuels must be compatible with current transportation infrastructure and be derived from environmentally sustainable resources that do not compete with food crops. Many bacterial species have unique properties advantageous to the production of such next-generation fuels. However, no single species possesses all characteristics necessary to make high quantities of fuels from plant waste or CO2. Species containing a subset of the desired characteristics are used as starting points for engineering organisms with all desired attributes. Metabolic engineering of model organisms has yielded high titer production of advanced fuels, including alcohols, isoprenoids, and fatty acid derivatives. Technical developments now allow engineering of native fuel producers, as well as lignocellulolytic and autotrophic bacteria, for the production of biofuels. Continued research on multiple fronts is required to engineer organisms for truly sustainable and economical biofuel production.", "corpus_id": 13349256, "score": 1 }, { "doc_id": "30617296", "title": "Production of advanced biofuels in engineered E. coli.", "abstract": "Commercial fermentation processes have long taken advantage of the synthetic power of living systems to rapidly and efficiently transform simple carbon sources into complex molecules. In this regard, the ability of yeasts to produce ethanol from glucose at exceptionally high yields has served as a key feature in its use as a fuel, but is also limited by the poor molecular properties of ethanol as a fuel such as high water miscibility and low energy density. Advances in metabolic engineering and synthetic biology allow us to begin constructing new high-flux pathways for production of next generation biofuels that are key to building a sustainable pipeline for liquid transportation fuels.", "corpus_id": 30617296, "score": 0 }, { "doc_id": "34696918", "title": "Carboxylic acid reductase is a versatile enzyme for the conversion of fatty acids into fuels and chemical commodities", "abstract": "Aliphatic hydrocarbons such as fatty alcohols and petroleum-derived alkanes have numerous applications in the chemical industry. In recent years, the renewable synthesis of aliphatic hydrocarbons has been made possible by engineering microbes to overaccumulate fatty acids. However, to generate end products with the desired physicochemical properties (e.g., fatty aldehydes, alkanes, and alcohols), further conversion of the fatty acid is necessary. A carboxylic acid reductase (CAR) from Mycobacterium marinum was found to convert a wide range of aliphatic fatty acids (C6–C18) into corresponding aldehydes. Together with the broad-substrate specificity of an aldehyde reductase or an aldehyde decarbonylase, the catalytic conversion of fatty acids to fatty alcohols (C8–C16) or fatty alkanes (C7–C15) was reconstituted in vitro. This concept was applied in vivo, in combination with a chain-length-specific thioesterase, to engineer Escherichia coli BL21(DE3) strains that were capable of synthesizing fatty alcohols and alkanes. A fatty alcohol titer exceeding 350 mg·L−1 was obtained in minimal media supplemented with glucose. Moreover, by combining the CAR-dependent pathway with an exogenous fatty acid-generating lipase, natural oils (coconut oil, palm oil, and algal oil bodies) were enzymatically converted into fatty alcohols across a broad chain-length range (C8–C18). Together with complementing enzymes, the broad substrate specificity and kinetic characteristics of CAR opens the road for direct and tailored enzyme-catalyzed conversion of lipids into user-ready chemical commodities.", "corpus_id": 34696918, "score": 1 }, { "doc_id": "38205202", "title": "Aldehyde Decarbonylases: Enigmatic Enzymes of Hydrocarbon Biosynthesis.", "abstract": "Long-chain alkane waxes are synthesized by a wide variety of organisms, including plants, animals and microorganisms.1-4 Although chemically alkanes are amongst the most boring of organic molecules, devoid of functionality and thus unreactive, they play essential roles in these organisms’ survival. Plants secrete what are termed “very long chain” alkane waxes (i.e. chain length ~ 30 carbons) onto their leaves and stems.3 These, together with wax esters formed from aliphatic alcohols and carboxylic acids of similar chain length, serve as a waterproof barrier to prevent desiccation. A wide variety of hydrocarbons, including branched and unsaturated molecules, are biosynthesized by insects.2 These are secreted onto the cuticle and play an important role as contact pheromones that mediate all manner of insect:insect recognition and social behaviors; they are also important in preventing desiccation, especially of larval forms.5 Waterfowl secrete alkane-rich oils from their uropygial (preening) glands; these are essential for waterproofing the birds’ feathers, which would otherwise become waterlogged and thus useless for insulation and flight.1 Many algae synthesize large amounts of long-chain alkanes that can comprise up to 30 % of the algae's dry weight.6 These accumulate in the area contained by the inner and outer cell walls known as the trilamellar structure and can be utilized to provide energy when photosynthesis is not possible.7 \n \nIn recent decades many human beings have become equally dependent on alkanes, in that this class of molecules is the major component of transportation fuels. These fuels are, of course, currently derived from fossil reserves and their combustion is a major source of greenhouse gases. The challenge of producing the next generation of biofuels – those that can effectively function as “drop-in” replacements for gasoline, diesel, and jet fuel – has led to renewed interest, especially in the area of mechanistic enzymology, in how alkanes are biosynthesized.8 \n \nThe synthesis of completely unfunctionalized molecules presents a challenge for a cell.9 Whereas as a chemist might accomplish this by reducing the corresponding alkene to an alkane using hydrogen and an activated transition metal catalyst, this approach is clearly not biochemically feasible. Historically, an important observation was that naturally-synthesized alkanes invariably comprise an odd number of carbons, suggesting that they are derived from fatty acid biosynthesis through loss of the carboxyl carbon.10 It was subsequently established that long-chain alkanes are synthesized from fatty acids through the intermediacy of the corresponding fatty aldehydes. These are the substrates for a group of enzymes, the aldehyde decarbonylases, which catalyze the removal of the aldehyde carbonyl group to form the alkane. It is the mechanisms of these enzymes that are the focus of this viewpoint. Whereas alkanes might be boring molecules, we hope to show that the mechanisms by which they are formed in Nature, and about which much still remains to be understood, are definitely not! \n \nAlthough all the various organisms so far investigated appear to synthesize alkanes using fatty aldehydes as the precursor, it has become clear that there are several mechanistically distinct classes of decarbonylases, as illustrated in Figure 1. In insects, the enzyme has been shown to be a cytochrome P450 protein,11,12 whereas in cyanobacteria it is a non-heme di-iron enzyme that is structurally related to enzymes such as ferritin and methane monooxygenase.3,13 In plants, the enzyme is an integral membrane protein that has some sequence similarity to the fatty acid hydroxylase superfamily and stearoyl-CoA desaturase.14 On this basis, it too is presumed to be a metalloenzyme, with iron the most likely metal. The different mechanisms of decarbonylation are reflected in the fate of the aldehyde carbon, which is converted to CO2 in insects,12 HCO2H in cyanobacteria,15,16 and CO in plants and algae.6,17 \n \n \n \nFigure 1 \n \nThe biosynthesis of alkanes proceeds in two steps from fatty acyl-CoA esters. The decarbonylation of the intermediate fatty aldehyde proceeds by one of three different mechanisms depending upon the organism. The insect AD is a membrane-bound P450 type ... \n \n \n \n \n2 Insect decarbonylases \nThe biosynthesis of hydrocarbons has been studied in a number of insect species including the domestic house fly, Musca domestica, the fruit fly Drosophila melanogaster, cockroaches Periplaneta americana and Blattella germanica, and the termite Zootermopsis angusticollis.18 Experiments on microsomal preparations of M. domestica demonstrated that molecular oxygen and NADPH were required for the conversion of (Z)-15-tetracosenal to (Z)-9-tricosene and, using 1-14C-material, that the aldehyde carbon was oxidized to CO2 in the process.12 Furthermore, antibodies to either house fly cytochrome P450 reductase or to a cytochrome P450 (CYP6A1) purified from the house fly inhibited (Z)-9-tricosene.19 These initial observations provided support for the involvement of a P450 enzyme in the reaction; this was more recently confirmed with the cloning and heterologous expression of the enzyme, CYP4G1, from Drosophila.11 \n \nFurther clues to the mechanism of hydrocarbon formation came from analyses of n-tricosane formed by M. domestica microsomal preparations incubated with [2,2-2H2,2-13C]-tetracosanoyl-CoA and [3,3-2H2,3-13C]-tetracosanoyl-CoA which demonstrated that the deuterium atoms on the 2- and 3-positions were retained in the hydrocarbon product.19 Analysis of [l-2H]-tetracosenal incubated with microsomal preparations demonstrated that the aldehyde proton on C-l was transferred to the (Z)-9-tricosene product. Alternative oxidizing agents such as hydrogen peroxide, cumene hydroperoxide, and iodosobenzene were shown to substitute for O2 and NADPH in the reaction. To accommodate these observations, a mechanism has been proposed, shown in Figure 2A, in which the high valent iron-oxo species, resulting from heterolytic cleavage of the O-O bond of the iron-peroxy intermediate, abstracts an electron from the carbonyl group of the aldehyde.19 The reduced iron-oxo species then attacks the carbonyl carbon of the aldehyde to form an iron-hemiacetal diradical. This intermediate is proposed to fragment to form an alkyl radical and an iron-bound formyl radical. In the final step, the alkyl radical then abstracts the formyl hydrogen to produce the hydrocarbon and CO2. \n \n \n \nFigure 2 \n \nComparison of the deformylation reactions catalyzed by insect AD (CYP4G1) and CYP2B4. A – Deformylation of fatty aldehydes by the insect AD is proposed to start with the high-valent iron-oxo species and results in the formation of CO2. The color-coding ... \n \n \n \nP450 enzymes catalyze a notably diverse range of oxidative transformations on a very wide range of substrates.20 Even so, the decarbonylase reaction stands out as being unusual. In most cases P450 enzymes oxidize aldehydes to carboxylic acids through a well understood mechanism involving hydrogen atom abstraction by the high valent iron-oxo intermediate followed by “rebound” of the iron-bound hydroxyl group to give the hydroxylated substrate.21 In some cases decarbonylation of the aldehyde does occur, notably in the aromatization reaction of androst-4-ene-3,17-dione to estrone catalyzed by human aromatase and the deformylation of cyclohexanal catalyzed by CYP2B4 (Figure 2B).20 However in these reactions, which are believed to involve the iron-peroxide form of P450, the aldehyde carbon is converted to formate, rather than CO2, and a double bond is introduced into the oxidized product.20 An intriguing question is how CYP4G1 controls the highly reactive iron-oxo intermediate to accomplish oxidative decarbonylation rather than simply oxidizing the aldehyde to a carboxylic acid, which, a priori, would appear to be a more likely fate for the substrate.", "corpus_id": 38205202, "score": 1 }, { "doc_id": "5749631", "title": "Detection of formate, rather than carbon monoxide, as the stoichiometric coproduct in conversion of fatty aldehydes to alkanes by a cyanobacterial aldehyde decarbonylase.", "abstract": "The second of two reactions in a recently discovered pathway through which saturated fatty acids are converted to alkanes (and unsaturated fatty acids to alkenes) in cyanobacteria entails scission of the C1-C2 bond of a fatty aldehyde intermediate by the enzyme aldehyde decarbonylase (AD), a ferritin-like protein with a dinuclear metal cofactor of unknown composition. We tested for and failed to detect carbon monoxide (CO), the proposed C1-derived coproduct of alkane synthesis, following the in vitro conversion of octadecanal (R-CHO, where R = n-C(17)H(35)) to heptadecane (R-H) by the Nostoc punctiforme AD isolated following its overproduction in Escherichia coli. Instead, we identified formate (HCO(2)(-)) as the stoichiometric coproduct of the reaction. Results of isotope-tracer experiments indicate that the aldehyde hydrogen is retained in the HCO(2)(-) and the hydrogen in the nascent methyl group of the alkane originates, at least in part, from solvent. With these characteristics, the reaction appears to be formally hydrolytic, but the improbability of a hydrolytic mechanism having the primary carbanion as the leaving group, the structural similarity of the ADs to other O(2)-activating nonheme di-iron proteins, and the dependence of in vitro AD activity on the presence of a reducing system implicate some type of redox mechanism. Two possible resolutions to this conundrum are suggested.", "corpus_id": 5749631, "score": 1 }, { "doc_id": "5575085", "title": "Conversion of fatty aldehydes to alka(e)nes and formate by a cyanobacterial aldehyde decarbonylase: cryptic redox by an unusual dimetal oxygenase.", "abstract": "Cyanobacterial aldehyde decarbonylase (AD) catalyzes conversion of fatty aldehydes (R-CHO) to alka(e)nes (R-H) and formate. Curiously, although this reaction appears to be redox-neutral and formally hydrolytic, AD has a ferritin-like protein architecture and a carboxylate-bridged dimetal cofactor that are both structurally similar to those found in di-iron oxidases and oxygenases. In addition, the in vitro activity of the AD from Nostoc punctiforme (Np) was shown to require a reducing system similar to the systems employed by these O(2)-utilizing di-iron enzymes. Here, we resolve this conundrum by showing that aldehyde cleavage by the Np AD also requires dioxygen and results in incorporation of (18)O from (18)O(2) into the formate product. AD thus oxygenates, without oxidizing, its substrate. We posit that (i) O(2) adds to the reduced cofactor to generate a metal-bound peroxide nucleophile that attacks the substrate carbonyl and initiates a radical scission of the C1-C2 bond, and (ii) the reducing system delivers two electrons during aldehyde cleavage, ensuring a redox-neutral outcome, and two additional electrons to return an oxidized form of the cofactor back to the reduced, O(2)-reactive form.", "corpus_id": 5575085, "score": 1 }, { "doc_id": "23228769", "title": "Evidence for only oxygenative cleavage of aldehydes to alk(a/e)nes and formate by cyanobacterial aldehyde decarbonylases.", "abstract": "Cyanobacterial aldehyde decarbonylases (ADs) catalyze the conversion of C(n) fatty aldehydes to formate (HCO(2)(-)) and the corresponding C(n-1) alk(a/e)nes. Previous studies of the Nostoc punctiforme (Np) AD produced in Escherichia coli (Ec) showed that this apparently hydrolytic reaction is actually a cryptically redox oxygenation process, in which one O-atom is incorporated from O(2) into formate and a protein-based reducing system (NADPH, ferredoxin, and ferredoxin reductase; N/F/FR) provides all four electrons needed for the complete reduction of O(2). Two subsequent publications by Marsh and co-workers [ Das, et al. ( 2011 ) Angew. Chem. Int. Ed. 50 , 7148 - 7152 ; Eser, et al. ( 2011 ) Biochemistry 50 , 10743 - 10750 ] reported that their Ec-expressed Np and Prochlorococcus marinus (Pm) AD preparations transform aldehydes to the same products more rapidly by an O(2)-independent, truly hydrolytic process, which they suggested proceeded by transient substrate reduction with obligatory participation by the reducing system (they used a chemical system, NADH and phenazine methosulfate; N/PMS). To resolve this discrepancy, we re-examined our preparations of both AD orthologues by a combination of (i) activity assays in the presence and absence of O(2) and (ii) (18)O(2) and H(2)(18)O isotope-tracer experiments with direct mass-spectrometric detection of the HCO(2)(-) product. For multiple combinations of the AD orthologue (Np and Pm), reducing system (protein-based and chemical), and substrate (n-heptanal and n-octadecanal), our preparations strictly require O(2) for activity and do not support detectable hydrolytic formate production, despite having catalytic activities similar to or greater than those reported by Marsh and co-workers. Our results, especially of the (18)O-tracer experiments, suggest that the activity observed by Marsh and co-workers could have arisen from contaminating O(2) in their assays. The definitive reaffirmation of the oxygenative nature of the reaction implies that the enzyme, initially designated as aldehyde decarbonylase when the C1-derived coproduct was thought to be carbon monoxide rather than formate, should be redesignated as aldehyde-deformylating oxygenase (ADO).", "corpus_id": 23228769, "score": 1 }, { "doc_id": "13057130", "title": "Oxygen-independent decarbonylation of aldehydes by cyanobacterial aldehyde decarbonylase: a new reaction of diiron enzymes.", "abstract": "The search for new biofuels has generated increased interest in biochemical pathways that produce hydrocarbons.[1] Although hydrocarbons are simple molecules, the biosynthesis of molecules that lack any chemical functional groups is surprisingly challenging.[2] Biochemical reactions that remove functionality, such as decarboxylations, dehydrations and reduction of double bonds, invariably rely on the presence of adjacent functional groups to stabilize unfavorable transition states. Enzymes involved in hydrocarbon biosynthesis are therefore of interest both for applications in biofuels production and because of the unusual and chemically difficult reactions they catalyze.[3] One enzyme that has attracted particular interest, is aldehyde decarbonylase (AD), which catalyzes the decarbonylation of long-chain fatty aldehydes, to the corresponding alkanes.[4]", "corpus_id": 13057130, "score": 1 }, { "doc_id": "21774073", "title": "Oxygen-independent alkane formation by non-heme iron-dependent cyanobacterial aldehyde decarbonylase: investigation of kinetics and requirement for an external electron donor.", "abstract": "Cyanobacterial aldehyde decarbonylase (cAD) is, structurally, a member of the di-iron carboxylate family of oxygenases. We previously reported that cAD from Prochlorococcus marinus catalyzes the unusual hydrolysis of aldehydes to produce alkanes and formate in a reaction that requires an external reducing system but does not require oxygen [Das et al. (2011) Angew. Chem. 50, 7148-7152]. Here we demonstrate that cADs from divergent cyanobacterial classes, including the enzyme from N. puntiformes that was reported to be oxygen dependent, catalyze aldehyde decarbonylation at a much faster rate under anaerobic conditions and that the oxygen in formate derives from water. The very low activity (<1 turnover/h) of cAD appears to result from inhibition by the ferredoxin reducing system used in the assay and the low solubility of the substrate. Replacing ferredoxin with the electron mediator phenazine methosulfate allowed the enzyme to function with various chemical reductants, with NADH giving the highest activity. NADH is not consumed during turnover, in accord with the proposed catalytic role for the reducing system in the reaction. With octadecanal, a burst phase of product formation, k(prod) = 3.4 ± 0.5 min(-1), is observed, indicating that chemistry is not rate-determining under the conditions of the assay. With the more soluble substrate, heptanal, k(cat) = 0.17 ± 0.01 min(-1) and no burst phase is observed, suggesting that a chemical step is limiting in the reaction of this substrate.", "corpus_id": 21774073, "score": 1 }, { "doc_id": "7725544", "title": "Conversion of fatty aldehydes into alk (a/e)nes by in vitro reconstituted cyanobacterial aldehyde-deformylating oxygenase with the cognate electron transfer system", "abstract": "BackgroundBiosynthesis of fatty alk(a/e)ne in cyanobacteria has been considered as a potential basis for the sunlight-driven and carbon-neutral bioprocess producing advanced solar biofuels. Aldehyde-deformylating oxygenase (ADO) is a key enzyme involved in that pathway. The heterologous or chemical reducing systems were generally used in in vitro ADO activity assay. The cognate electron transfer system from cyanobacteria to support ADO activity is still unknown.ResultsWe identified the potential endogenous reducing system including ferredoxin (Fd) and ferredoxin-NADP+ reductase (FNR) to support ADO activity in Synechococcus elongatus PCC7942. ADO (Synpcc7942_1593), FNR (SynPcc7942_0978), and Fd (SynPcc7942_1499) from PCC7942 were cloned, overexpressed, purified, and characterized. ADO activity was successfully supported with the endogenous electron transfer system, which worked more effectively than the heterologous and chemical ones. The results of the hybrid Fd/FNR reducing systems demonstrated that ADO was selective against Fd. And it was observed that the cognate reducing system produced less H2O2 than the heterologous one by 33% during ADO-catalyzed reactions. Importantly, kcat value of ADO 1593 using the homologous Fd/FNR electron transfer system is 3.7-fold higher than the chemical one.ConclusionsThe cognate electron transfer system from cyanobacteria to support ADO activity was identified and characterized. For the first time, ADO was functionally in vitro reconstituted with the endogenous reducing system from cyanobacteria, which supported greater activity than the surrogate and chemical ones, and produced less H2O2 than the heterologous one. The identified Fd/FNR electron transfer system will be potentially useful for improving ADO activity and further enhancing the biosynthetic efficiency of hydrocarbon biofuels in cyanobacteria.", "corpus_id": 7725544, "score": 1 }, { "doc_id": "17905439", "title": "Engineering self-sufficient aldehyde deformylating oxygenases fused to alternative electron transfer systems for efficient conversion of aldehydes into alkanes.", "abstract": "Self-sufficient aldehyde deformylating oxygenases (ADOs) from Synechococcus elongatus PCC7942 fused to alternative electron transfer systems were successfully designed, constructed, characterized and used for efficient conversion of aldehydes into alkanes for the first time.", "corpus_id": 17905439, "score": 1 }, { "doc_id": "9886134", "title": "Cyanobacterial aldehyde deformylase oxygenation of aldehydes yields n-1 aldehydes and alcohols in addition to alkanes.", "abstract": "Aldehyde-deformylating oxygenase (ADO) catalyzes O2-dependent release of the terminal carbon of a biological substrate, octadecanal, to yield formate and heptadecane in a reaction that requires external reducing equivalents. We show here that ADO also catalyzes incorporation of an oxygen atom from O2 into the alkane product to yield alcohol and aldehyde products. Oxygenation of the alkane product is much more pronounced with C9-10 aldehyde substrates, so that use of nonanal as the substrate yields similar amounts of octane, octanal, and octanol products. When using doubly-labeled [1,2-13C]-octanal as the substrate, the heptane, heptanal and heptanol products each contained a single 13C-label in the C-1 carbons atoms. The only one-carbon product identified was formate. [18O]-O2 incorporation studies demonstrated formation of [18O]-alcohol product, but rapid solvent exchange prevented similar determination for the aldehyde product. Addition of [1-13C]-nonanol with decanal as the substrate at the outset of the reaction resulted in formation of [1-13C]-nonanal. No 13C-product was formed in the absence of decanal. ADO contains an oxygen-bridged dinuclear iron cluster. The observation of alcohol and aldehyde products derived from the initially formed alkane product suggests a reactive species similar to that formed by methane monooxygenase (MMO) and other members of the bacterial multicomponent monooxygenase family. Accordingly, characterization by EPR and Mössbauer spectroscopies shows that the electronic structure of the ADO cluster is similar, but not identical, to that of MMO hydroxylase component. In particular, the two irons of ADO reside in nearly identical environments in both the oxidized and fully reduced states, whereas those of MMOH show distinct differences. These favorable characteristics of the iron sites allow a comprehensive determination of the spin Hamiltonian parameters describing the electronic state of the diferrous cluster for the first time for any biological system. The nature of the diiron cluster and the newly recognized products from ADO catalysis hold implications for the mechanism of C-C bond cleavage.", "corpus_id": 9886134, "score": 1 }, { "doc_id": "12493053", "title": "Structural insights into the catalytic mechanism of aldehyde-deformylating oxygenases", "abstract": "The fatty alk(a/e)ne biosynthesis pathway found in cyanobacteria gained tremendous attention in recent years as a promising alternative approach for biofuel production. Cyanobacterial aldehyde-deformylating oxygenase (cADO), which catalyzes the conversion of Cn fatty aldehyde to its corresponding Cn-1 alk(a/e)ne, is a key enzyme in that pathway. Due to its low activity, alk(a/e)ne production by cADO is an inefficient process. Previous biochemical and structural investigations of cADO have provided some information on its catalytic reaction. However, the details of its catalytic processes remain unclear. Here we report five crystal structures of cADO from the Synechococcus elongates strain PCC7942 in both its iron-free and iron-bound forms, representing different states during its catalytic process. Structural comparisons and functional enzyme assays indicate that Glu144, one of the iron-coordinating residues, plays a vital role in the catalytic reaction of cADO. Moreover, the helix where Glu144 resides exhibits two distinct conformations that correlates with the different binding states of the di-iron center in cADO structures. Therefore, our results provide a structural explanation for the highly labile feature of cADO di-iron center, which we proposed to be related to its low enzymatic activity. On the basis of our structural and biochemical data, a possible catalytic process of cADO was proposed, which could aid the design of cADO with improved activity.", "corpus_id": 12493053, "score": 1 }, { "doc_id": "5415037", "title": "Probing the mechanism of cyanobacterial aldehyde decarbonylase using a cyclopropyl aldehyde.", "abstract": "Cyanobacterial aldehyde decarbonylase (cAD) is a non-heme diiron oxygenase that catalyzes the conversion of fatty aldehydes to alkanes and formate. The mechanism of this chemically unusual reaction is poorly understood. We have investigated the mechanism of C1-C2 bond cleavage by cAD using a fatty aldehyde that incorporates a cyclopropyl group, which can act as a radical clock. When reacted with cAD, the cyclopropyl aldehyde produces 1-octadecene as the rearranged product, providing evidence for a radical mechanism for C-C bond scission. In an alternate pathway, the cyclopropyl aldehyde acts as a mechanism-based irreversible inhibitor of cAD through covalent binding of the alkyl chain to the enzyme.", "corpus_id": 5415037, "score": 1 }, { "doc_id": "11631033", "title": "Mechanistic insights from reaction of α-oxiranyl-aldehydes with cyanobacterial aldehyde deformylating oxygenase.", "abstract": "The biosynthesis of long-chain aliphatic hydrocarbons, which are derived from fatty acids, is widespread in Nature. The last step in this pathway involves the decarbonylation of fatty aldehydes to the corresponding alkanes or alkenes. In cyanobacteria, this is catalyzed by an aldehyde deformylating oxygenase. We have investigated the mechanism of this enzyme using substrates bearing an oxirane ring adjacent to the aldehyde carbon. The enzyme catalyzed the deformylation of these substrates to produce the corresponding oxiranes. Performing the reaction in D2O allowed the facial selectivity of proton addition to be examined by (1)H NMR spectroscopy. The proton is delivered with equal probability to either face of the oxirane ring, indicating the formation of an oxiranyl radical intermediate that is free to rotate during the reaction. Unexpectedly, the enzyme also catalyzes a side reaction in which oxiranyl-aldehydes undergo tandem deformylation to furnish alkanes two carbons shorter. We present evidence that this involves the rearrangement of the intermediate oxiranyl radical formed in the first step, resulting in aldehyde that is further deformylated in a second step. These observations provide support for a radical mechanism for deformylation and, furthermore, allow the lifetime of the radical intermediate to be estimated based on prior measurements of rate constants for the rearrangement of oxiranyl radicals.", "corpus_id": 11631033, "score": 0 }, { "doc_id": "27574600", "title": "Production of Propane and Other Short-Chain Alkanes by Structure-Based Engineering of Ligand Specificity in Aldehyde-Deformylating Oxygenase", "abstract": "Biocatalytic propane production: structure-based engineering of aldehyde-deformylating oxygenase improves specificity for short- and medium-chain-length aldehydes and enhances the propane generation in whole-cell biotransformations. This presents new opportunities for developing biocatalytic modules for the production of volatile \"drop-in\" biofuels.", "corpus_id": 27574600, "score": 1 }, { "doc_id": "9455072", "title": "Insights into Substrate and Metal Binding from the Crystal Structure of Cyanobacterial Aldehyde Deformylating Oxygenase with Substrate Bound", "abstract": "The nonheme diiron enzyme cyanobacterial aldehyde deformylating oxygenase, cADO, catalyzes the highly unusual deformylation of aliphatic aldehydes to alkanes and formate. We have determined crystal structures for the enzyme with a long-chain water-soluble aldehyde and medium-chain carboxylic acid bound to the active site. These structures delineate a hydrophobic channel that connects the solvent with the deeply buried active site and reveal a mode of substrate binding that is different from previously determined structures with long-chain fatty acids bound. The structures also identify a water channel leading to the active site that could facilitate the entry of protons required in the reaction. NMR studies examining 1-[13C]-octanal binding to cADO indicate that the enzyme binds the aldehyde form rather than the hydrated form. Lastly, the fortuitous cocrystallization of the metal-free form of the protein with aldehyde bound has revealed protein conformation changes that are involved in binding iron.", "corpus_id": 9455072, "score": 1 }, { "doc_id": "36636136", "title": "Desaturases: Emerging Models for Understanding Functional Diversification of Diiron-containing Enzymes*", "abstract": "Desaturases and related enzymes perform O2-dependent dehydrogenations initiated at unactivated C-H groups with the use of a diiron active site. Determination of the long-sought oxidized desaturase crystal structure facilitated structural comparison of the active sites of disparate diiron enzymes. Experiments on the castor desaturase are discussed that provide experimental support for a hypothesized ancestral oxidase enzyme in the context of the evolution of the diiron enzyme diverse functionality. We also summarize recent analysis of a castor mutant desaturase that provides valuable insights into the relationship of proposed substrate-binding modes with respect to a range of catalytic outcomes.", "corpus_id": 36636136, "score": 0 }, { "doc_id": "5223551", "title": "Metabolic engineering of microorganisms for biofuels production: from bugs to synthetic biology to fuels.", "abstract": "The ability to generate microorganisms that can produce biofuels similar to petroleum-based transportation fuels would allow the use of existing engines and infrastructure and would save an enormous amount of capital required for replacing the current infrastructure to accommodate biofuels that have properties significantly different from petroleum-based fuels. Several groups have demonstrated the feasibility of manipulating microbes to produce molecules similar to petroleum-derived products, albeit at relatively low productivity (e.g. maximum butanol production is around 20 g/L). For cost-effective production of biofuels, the fuel-producing hosts and pathways must be engineered and optimized. Advances in metabolic engineering and synthetic biology will provide new tools for metabolic engineers to better understand how to rewire the cell in order to create the desired phenotypes for the production of economically viable biofuels.", "corpus_id": 5223551, "score": 0 }, { "doc_id": "29232086", "title": "“Designer” Biodiesel: Optimizing Fatty Ester Composition to Improve Fuel Properties†", "abstract": "Biodiesel is a domestic and renewable alternative with the potential to replace some of the petrodiesel market. It is obtained from vegetable oils, animal fats, or other sources with a significant content of triacylglycerols by means of a transesterification reaction. The fatty acid profile of biodiesel thus corresponds to that of the parent oil or fat and is a major factor influencing fuel properties. Besides being renewable and of domestic origin, advantages of biodiesel compared to petrodiesel include biodegradability, higher flash point, reduction of most regulated exhaust emissions, miscibility in all ratios with petrodiesel, compatibility with the existing fuel distribution infrastructure, and inherent lubricity. Technical problems with biodiesel include oxidative stability, cold flow, and increased NOx exhaust emissions. Solutions to one of these problems often entail increasing the problematic behavior of another property and have included the use of additives or modifying the fatty acid compositi...", "corpus_id": 29232086, "score": 0 }, { "doc_id": "12362763", "title": "Overproduction of free fatty acids in E. coli: implications for biodiesel production.", "abstract": "Whereas microbial fermentation processes for producing ethanol and related alcohol biofuels are well established, biodiesel (methyl esters of fatty acids) is exclusively derived from plant oils. Slow cycle times for engineering oilseed metabolism and the excessive accumulation of glycerol as a byproduct are two major drawbacks of deriving biodiesel from plants. Although most bacteria produce fatty acids as cell envelope precursors, the biosynthesis of fatty acids is tightly regulated at multiple levels. By introducing four distinct genetic changes into the E. coli genome, we have engineered an efficient producer of fatty acids. Under fed-batch, defined media fermentation conditions, 2.5 g/L fatty acids were produced by this metabolically engineered E. coli strain, with a specific productivity of 0.024 g/h/g dry cell mass and a peak conversion efficiency of 4.8% of the carbon source into fatty acid products. At least 50% of the fatty acids produced were present in the free acid form.", "corpus_id": 12362763, "score": 0 }, { "doc_id": "21141714", "title": "Engineering acyl carrier protein to enhance production of shortened fatty acids", "abstract": "BackgroundThe acyl carrier protein (ACP) is an essential and ubiquitous component of microbial synthesis of fatty acids, the natural precursor to biofuels. Natural fatty acids usually contain long chains of 16 or more carbon atoms. Shorter carbon chains, with increased fuel volatility, are desired for internal combustion engines. Engineering the length specificity of key proteins in fatty acid metabolism, such as ACP, may enable microbial synthesis of these shorter chain fatty acids.ResultsWe constructed a homology model of the Synechococcus elongatus ACP, showing a hydrophobic pocket harboring the growing acyl chain. Amino acids within the pocket were mutated to increase steric hindrance to the acyl chain. Certain mutant ACPs, when over-expressed in Escherichia coli, increased the proportion of shorter chain lipids; I75 W and I75Y showed the strongest effects. Expression of I75 W and I75Y mutant ACPs also increased production of lauric acid in E. coli that expressed the C12-specific acyl-ACP thioesterase from Cuphea palustris.ConclusionsWe engineered the specificity of the ACP, an essential protein of fatty acid metabolism, to alter the E. coli lipid pool and enhance production of medium-chain fatty acids as biofuel precursors. These results indicate that modification of ACP itself could be combined with enzymes affecting length specificity in fatty acid synthesis to enhance production of commodity chemicals based on fatty acids.", "corpus_id": 21141714, "score": 0 }, { "doc_id": "30043486", "title": "A process for microbial hydrocarbon synthesis: Overproduction of fatty acids in Escherichia coli and catalytic conversion to alkanes", "abstract": "The development of renewable alternatives to diesel and jet fuels is highly desirable for the heavy transportation sector, and would offer benefits over the production and use of short‐chain alcohols for personal transportation. Here, we report the development of a metabolically engineered strain of Escherichia coli that overproduces medium‐chain length fatty acids via three basic modifications: elimination of β‐oxidation, overexpression of the four subunits of acetyl‐CoA carboxylase, and expression of a plant acyl–acyl carrier protein (ACP) thioesterase from Umbellularia californica (BTE). The expression level of BTE was optimized by comparing fatty acid production from strains harboring BTE on plasmids with four different copy numbers. Expression of BTE from low copy number plasmids resulted in the highest fatty acid production. Up to a seven‐fold increase in total fatty acid production was observed in engineered strains over a negative control strain (lacking β‐oxidation), with a composition dominated by C12 and C14 saturated and unsaturated fatty acids. Next, a strategy for producing undecane via a combination of biotechnology and heterogeneous catalysis is demonstrated. Fatty acids were extracted from a culture of an overproducing strain into an alkane phase and fed to a Pd/C plug flow reactor, where the extracted fatty acids were decarboxylated into saturated alkanes. The result is an enriched alkane stream that can be recycled for continuous extractions. Complete conversion of C12 fatty acids extracted from culture to alkanes has been demonstrated yielding a concentration of 0.44 g L−1 (culture volume) undecane. Biotechnol. Bioeng. 2010;106: 193–202. © 2010 Wiley Periodicals, Inc.", "corpus_id": 30043486, "score": 0 }, { "doc_id": "13464276", "title": "Optimization of fatty alcohol biosynthesis pathway for selectively enhanced production of C12/14 and C16/18 fatty alcohols in engineered Escherichia coli", "abstract": "BackgroundWith the increasing stress from oil price and environmental pollution, aroused attention has been paid to the microbial production of chemicals from renewable sources. The C12/14 and C16/18 alcohols are important feedstocks for the production of surfactants and detergents, which are widely used in the most respected consumer detergents, cleaning products and personal care products worldwide. Though bioproduction of fatty alcohols has been carried out in engineered E. coli, several key problems have not been solved in earlier studies, such as the quite low production of C16/18 alcohol, the lack of optimization of the fatty alcohol biosynthesis pathway, and the uncharacterized performance of the engineered strains in scaled-up system.ResultsWe improved the fatty alcohol production by systematically optimizing the fatty alcohol biosynthesis pathway, mainly targeting three key steps from fatty acyl-acyl carrier proteins (ACPs) to fatty alcohols, which are sequentially catalyzed by thioesterase, acyl-coenzyme A (CoA) synthase and fatty acyl-CoA reductase. By coexpression of thioesterase gene BTE, acyl-CoA synthase gene fadD and fatty acyl-CoA reductase gene acr1, 210.1 mg/L C12/14 alcohol was obtained. A further optimization of expression level of BTE, fadD and acr1 increased the C12/14 alcohol production to 449.2 mg/L, accounting for 75.0% of the total fatty alcohol production (598.6 mg/L). In addition, by coexpression of thioesterase gene ‘tesA, acyl-CoA synthase gene fadD and fatty acyl-CoA reductase gene FAR, 101.5 mg/L C16/18 alcohol was obtained, with C16/18 alcohol accounting for 89.2% of the total fatty alcohol production.ConclusionsTo our knowledge, this is the first report on selective production of C12/14 and C16/18 alcohols by microbial fermentation. This work achieved high-specificity production of both C12/14 and C16/18 alcohols. The encouraging 598.6 mg/L of fatty alcohols represents the highest titer reported so far. In addition, the 101.5 mg/L 89.2% C16/18 alcohol suggests an important breakthrough in C16/18 alcohol production. A more detailed optimization of the expression level of fatty alcohol biosynthesis pathway may contribute to a further improvement of fatty alcohol production.", "corpus_id": 13464276, "score": 0 }, { "doc_id": "14817456", "title": "De novo Biosynthesis of Biodiesel by Escherichia coli in Optimized Fed-Batch Cultivation", "abstract": "Biodiesel is a renewable alternative to petroleum diesel fuel that can contribute to carbon dioxide emission reduction and energy supply. Biodiesel is composed of fatty acid alkyl esters, including fatty acid methyl esters (FAMEs) and fatty acid ethyl esters (FAEEs), and is currently produced through the transesterification reaction of methanol (or ethanol) and triacylglycerols (TAGs). TAGs are mainly obtained from oilseed plants and microalgae. A sustainable supply of TAGs is a major bottleneck for current biodiesel production. Here we report the de novo biosynthesis of FAEEs from glucose, which can be derived from lignocellulosic biomass, in genetically engineered Escherichia coli by introduction of the ethanol-producing pathway from Zymomonas mobilis, genetic manipulation to increase the pool of fatty acyl-CoA, and heterologous expression of acyl-coenzyme A: diacylglycerol acyltransferase from Acinetobacter baylyi. An optimized fed-batch microbial fermentation of the modified E. coli strain yielded a titer of 922 mg L−1 FAEEs that consisted primarily of ethyl palmitate, -oleate, -myristate and -palmitoleate.", "corpus_id": 14817456, "score": 0 }, { "doc_id": "7694881", "title": "Fatty alcohol production in engineered E. coli expressing Marinobacter fatty acyl-CoA reductases", "abstract": "Although successful production of fatty alcohols in metabolically engineered Escherichia coli with heterologous expression of fatty acyl-CoA reductase has been reported, low biosynthetic efficiency is still a hurdle to be overcome. In this study, we examined the characteristics of two fatty acyl-CoA reductases encoded by Maqu_2220 and Maqu_2507 genes from Marinobacter aquaeolei VT8 on fatty alcohol production in E. coli. Fatty alcohols with diversified carbon chain length were obtained by co-expressing Maqu_2220 with different carbon chain length-specific acyl-ACP thioesterases. Both fatty acyl-CoA reductases displayed broad substrate specificities for C12–C18 fatty acyl chains in vivo. The optimized mutant strain of E. coli carrying the modified tesA gene and fadD gene from E. coli and Maqu_2220 gene from Marinobacter aquaeolei VT8 produced fatty alcohols at a remarkable level of 1.725 g/L under the fermentation condition.", "corpus_id": 7694881, "score": 0 }, { "doc_id": "85658872", "title": "Molecular Cloning: A Laboratory Manual", "abstract": "Molecular Cloning has served as the foundation of technical expertise in labs worldwide for 30 years. No other manual has been so popular, or so influential. Molecular Cloning, Fourth Edition, by the celebrated founding author Joe Sambrook and new co-author, the distinguished HHMI investigator Michael Green, preserves the highly praised detail and clarity of previous editions and includes specific chapters and protocols commissioned for the book from expert practitioners at Yale, U Mass, Rockefeller University, Texas Tech, Cold Spring Harbor Laboratory, Washington University, and other leading institutions. The theoretical and historical underpinnings of techniques are prominent features of the presentation throughout, information that does much to help trouble-shoot experimental problems. For the fourth edition of this classic work, the content has been entirely recast to include nucleic-acid based methods selected as the most widely used and valuable in molecular and cellular biology laboratories. Core chapters from the third edition have been revised to feature current strategies and approaches to the preparation and cloning of nucleic acids, gene transfer, and expression analysis. They are augmented by 12 new chapters which show how DNA, RNA, and proteins should be prepared, evaluated, and manipulated, and how data generation and analysis can be handled. The new content includes methods for studying interactions between cellular components, such as microarrays, next-generation sequencing technologies, RNA interference, and epigenetic analysis using DNA methylation techniques and chromatin immunoprecipitation. To make sense of the wealth of data produced by these techniques, a bioinformatics chapter describes the use of analytical tools for comparing sequences of genes and proteins and identifying common expression patterns among sets of genes. Building on thirty years of trust, reliability, and authority, the fourth edition of Mol", "corpus_id": 85658872, "score": 0 }, { "doc_id": "19894612", "title": "Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy", "abstract": "Significance Circular dichroism (CD) spectroscopy is widely used for protein secondary structure analysis. However, quantitative estimation for β-sheet–containing proteins is problematic due to the huge morphological and spectral diversity of β-structures. We show that parallel/antiparallel orientation and twisting of β-sheets account for the observed spectral diversity. Taking into account the twist of β-structures, our method accurately estimates the secondary structure for a broad range of protein folds, particularly for β-sheet–rich proteins and amyloid fibrils. Moreover, the method can predict the protein fold down to the topology level following the CATH classification. We provide a general tool for a quick and reliable structure analysis using conventional or synchrotron radiation CD spectroscopy, which is especially useful when X-ray or NMR techniques fail. Circular dichroism (CD) spectroscopy is a widely used technique for the study of protein structure. Numerous algorithms have been developed for the estimation of the secondary structure composition from the CD spectra. These methods often fail to provide acceptable results on α/β-mixed or β-structure–rich proteins. The problem arises from the spectral diversity of β-structures, which has hitherto been considered as an intrinsic limitation of the technique. The predictions are less reliable for proteins of unusual β-structures such as membrane proteins, protein aggregates, and amyloid fibrils. Here, we show that the parallel/antiparallel orientation and the twisting of the β-sheets account for the observed spectral diversity. We have developed a method called β-structure selection (BeStSel) for the secondary structure estimation that takes into account the twist of β-structures. This method can reliably distinguish parallel and antiparallel β-sheets and accurately estimates the secondary structure for a broad range of proteins. Moreover, the secondary structure components applied by the method are characteristic to the protein fold, and thus the fold can be predicted to the level of topology in the CATH classification from a single CD spectrum. By constructing a web server, we offer a general tool for a quick and reliable structure analysis using conventional CD or synchrotron radiation CD (SRCD) spectroscopy for the protein science research community. The method is especially useful when X-ray or NMR techniques fail. Using BeStSel on data collected by SRCD spectroscopy, we investigated the structure of amyloid fibrils of various disease-related proteins and peptides.", "corpus_id": 19894612, "score": 0 } ]

{ "doc_id": "13847493", "title": "An Unsupervised Approach for Extraction of Blood Vessels from Fundus Images", "abstract": "Pathological disorders may happen due to small changes in retinal blood vessels which may later turn into blindness. Hence, the accurate segmentation of blood vessels is becoming a challenging task for pathological analysis. This paper offers an unsupervised recursive method for extraction of blood vessels from ophthalmoscope images. First, a vessel-enhanced image is generated with the help of gamma correction and contrast-limited adaptive histogram equalization (CLAHE). Next, the vessels are extracted iteratively by applying an adaptive thresholding technique. At last, a final vessel segmented image is produced by applying a morphological cleaning operation. Evaluations are accompanied on the publicly available digital retinal images for vessel extraction (DRIVE) and Child Heart And Health Study in England (CHASE_DB1) databases using nine different measurements. The proposed method achieves average accuracies of 0.957 and 0.952 on DRIVE and CHASE_DB1 databases respectively.", "corpus_id": 13847493 }

[ { "doc_id": "3078440", "title": "Retinal Blood Vessel Segmentation Using Line Operators and Support Vector Classification", "abstract": "In the framework of computer-aided diagnosis of eye diseases, retinal vessel segmentation based on line operators is proposed. A line detector, previously used in mammography, is applied to the green channel of the retinal image. It is based on the evaluation of the average grey level along lines of fixed length passing through the target pixel at different orientations. Two segmentation methods are considered. The first uses the basic line detector whose response is thresholded to obtain unsupervised pixel classification. As a further development, we employ two orthogonal line detectors along with the grey level of the target pixel to construct a feature vector for supervised classification using a support vector machine. The effectiveness of both methods is demonstrated through receiver operating characteristic analysis on two publicly available databases of color fundus images.", "corpus_id": 3078440, "score": 0 }, { "doc_id": "6566349", "title": "Segmentation of retinal blood vessels using the radial projection and semi-supervised approach", "abstract": "Automatic segmentation of retinal blood vessels has become a necessary diagnostic procedure in ophthalmology. The blood vessels consist of two types of vessels, i.e., thin vessels and wide vessels. Therefore, a segmentation method may require two different processes to treat different vessels. However, traditional segmentation algorithms hardly draw a distinction between thin and wide vessels, but deal with them together. The major problems of these methods are as follows: (1) If more emphasis is placed on the extraction of thin vessels, the wide vessels tend to be over detected; and more artificial vessels are generated, too. (2) If more attention is paid on the wide vessels, the thin and low contrast vessels are likely to be missing. To overcome these problems, a novel scheme of extracting the retinal vessels based on the radial projection and semi-supervised method is presented in this paper. The radial projection method is used to locate the vessel centerlines which include the low-contrast and narrow vessels. Further, we modify the steerable complex wavelet to provide better capability of enhancing vessels under different scales, and construct the vector feature to represent the vessel pixel by line strength. Then, semi-supervised self-training is used for extraction of the major structures of vessels. The final segmentation is obtained by the union of the two types of vessels. Our approach is tested on two publicly available databases. Experiment results show that the method can achieve improved detection of thin vessels and decrease false detection of vessels in pathological regions compared to rival solutions.", "corpus_id": 6566349, "score": 0 }, { "doc_id": "944711", "title": "A New Supervised Method for Blood Vessel Segmentation in Retinal Images by Using Gray-Level and Moment Invariants-Based Features", "abstract": "This paper presents a new supervised method for blood vessel detection in digital retinal images. This method uses a neural network (NN) scheme for pixel classification and computes a 7-D vector composed of gray-level and moment invariants-based features for pixel representation. The method was evaluated on the publicly available DRIVE and STARE databases, widely used for this purpose, since they contain retinal images where the vascular structure has been precisely marked by experts. Method performance on both sets of test images is better than other existing solutions in literature. The method proves especially accurate for vessel detection in STARE images. Its application to this database (even when the NN was trained on the DRIVE database) outperforms all analyzed segmentation approaches. Its effectiveness and robustness with different image conditions, together with its simplicity and fast implementation, make this blood vessel segmentation proposal suitable for retinal image computer analyses such as automated screening for early diabetic retinopathy detection.", "corpus_id": 944711, "score": 0 }, { "doc_id": "7515294", "title": "An Ensemble Classification-Based Approach Applied to Retinal Blood Vessel Segmentation", "abstract": "This paper presents a new supervised method for segmentation of blood vessels in retinal photographs. This method uses an ensemble system of bagged and boosted decision trees and utilizes a feature vector based on the orientation analysis of gradient vector field, morphological transformation, line strength measures, and Gabor filter responses. The feature vector encodes information to handle the healthy as well as the pathological retinal image. The method is evaluated on the publicly available DRIVE and STARE databases, frequently used for this purpose and also on a new public retinal vessel reference dataset CHASE_DB1 which is a subset of retinal images of multiethnic children from the Child Heart and Health Study in England (CHASE) dataset. The performance of the ensemble system is evaluated in detail and the incurred accuracy, speed, robustness, and simplicity make the algorithm a suitable tool for automated retinal image analysis.", "corpus_id": 7515294, "score": 0 }, { "doc_id": "17256038", "title": "Retinal vessel extraction using Lattice Neural Networks with dendritic processing", "abstract": "Retinal images can be used to detect and follow up several important chronic diseases. The classification of retinal images requires an experienced ophthalmologist. This has been a bottleneck to implement routine screenings performed by general physicians. It has been proposed to create automated systems that can perform such task with little intervention from humans, with partial success. In this work, we report advances in such endeavor, by using a Lattice Neural Network with Dendritic Processing (LNNDP). We report results using several metrics, and compare against well known methods such as Support Vector Machines (SVM) and Multilayer Perceptrons (MLP). Our proposal shows better performance than other approaches reported in the literature. An additional advantage is that unlike those other tools, LNNDP requires no parameters, and it automatically constructs its structure to solve a particular problem. The proposed methodology requires four steps: (1) Pre-processing, (2) Feature computation, (3) Classification and (4) Post-processing. The Hotelling T(2) control chart was used to reduce the dimensionality of the feature vector, from 7 that were used before to 5 in this work. The experiments were run on images of DRIVE and STARE databases. The results show that on average, F1-Score is better in LNNDP, compared with SVM and MLP implementations. Same improvement is observed for MCC and the accuracy.", "corpus_id": 17256038, "score": 0 }, { "doc_id": "17250921", "title": "Blood Vessel Segmentation of Fundus Images by Major Vessel Extraction and Subimage Classification", "abstract": "This paper presents a novel three-stage blood vessel segmentation algorithm using fundus photographs. In the first stage, the green plane of a fundus image is preprocessed to extract a binary image after high-pass filtering, and another binary image from the morphologically reconstructed enhanced image for the vessel regions. Next, the regions common to both the binary images are extracted as the major vessels. In the second stage, all remaining pixels in the two binary images are classified using a Gaussian mixture model (GMM) classifier using a set of eight features that are extracted based on pixel neighborhood and first and second-order gradient images. In the third postprocessing stage, the major portions of the blood vessels are combined with the classified vessel pixels. The proposed algorithm is less dependent on training data, requires less segmentation time and achieves consistent vessel segmentation accuracy on normal images as well as images with pathology when compared to existing supervised segmentation methods. The proposed algorithm achieves a vessel segmentation accuracy of 95.2%, 95.15%, and 95.3% in an average of 3.1, 6.7, and 11.7 s on three public datasets DRIVE, STARE, and CHASE_DB1, respectively.", "corpus_id": 17250921, "score": 0 }, { "doc_id": "19776053", "title": "Delineation of blood vessels in pediatric retinal images using decision trees-based ensemble classification", "abstract": "PurposeAutomatic segmentation of the retinal vasculature is a first step in computer-assisted diagnosis and treatment planning. The extraction of retinal vessels in pediatric retinal images is challenging because of comparatively wide arterioles with a light streak running longitudinally along the vessel’s center, the central vessel reflex. A new method for automatic segmentation was developed and tested.Method   A supervised method for retinal vessel segmentation in the images of multi-ethnic school children was developed based on ensemble classifier of bootstrapped decision trees. A collection of dual Gaussian, second derivative of Gaussian and Gabor filters, along with the generalized multiscale line strength measure and morphological transformation is used to generate the feature vector. The feature vector encodes information to handle the normal vessels as well as the vessels with the central reflex. The methodology is evaluated on CHASE_DB1, a relatively new public retinal image database of multi-ethnic school children, which is a subset of retinal images from the Child Heart and Health Study in England (CHASE) dataset.Results   The segmented retinal images from the CHASE_DB1 database produced best case accuracy, sensitivity and specificity of 0.96, 0.74 and 0.98, respectively, and worst case measures of 0.94, 0.67 and 0.98, respectively.Conclusion   A new retinal blood vessel segmentation algorithm was developed and tested with a shared database. The observed accuracy, speed, robustness and simplicity suggest that the algorithm may be a suitable tool for automated retinal image analysis in large population-based studies.", "corpus_id": 19776053, "score": 0 }, { "doc_id": "33279586", "title": "Automated segmentation of exudates, haemorrhages, microaneurysms using single convolutional neural network", "abstract": "Abstract Screening for vision threatening diabetic retinopathy by grading digital retinal images reduces the risk of blindness in people with diabetes. Computer-aided diagnosis can aid human graders to cope with this mounting problem. We propose to use a 10-layer convolutional neural network to automatically, simultaneously segment and discriminate exudates, haemorrhages and micro-aneurysms. Input image is normalized before segmentation. The net is trained in two stages to improve performance. On average, our net on 30,275,903 effective points achieved a sensitivity of 0.8758 and 0.7158 for exudates and dark lesions on the CLEOPATRA database. It also achieved a sensitivity of 0.6257 and 0.4606 for haemorrhages and micro-aneurysms. This study shows that it is possible to get a single convolutional neural network to segment these pathological features on a wide range of fundus images with reasonable accuracy.", "corpus_id": 33279586, "score": 0 }, { "doc_id": "16461146", "title": "Segmentation of optic disc, fovea and retinal vasculature using a single convolutional neural network", "abstract": "We have developed and trained a convolutional neural network to automatically and simultaneously segment optic disc, fovea and blood vessels. Fundus images were normalized before segmentation was performed to enforce consistency in background lighting and contrast. For every effective point in the fundus image, our algorithm extracted three channels of input from the point’s neighbourhood and forwarded the response across the 7-layer network. The output layer consists of four neurons, representing background, optic disc, fovea and blood vessels. In average, our segmentation correctly classified 92.68% of the ground truths (on the testing set from Drive database). The highest accuracy achieved on a single image was 94.54%, the lowest 88.85%. A single convolutional neural network can be used not just to segment blood vessels, but also optic disc and fovea with good accuracy.", "corpus_id": 16461146, "score": 0 }, { "doc_id": "28013106", "title": "A new supervised retinal vessel segmentation method based on robust hybrid features", "abstract": "Abstract In this paper, we propose a new supervised retinal blood vessel segmentation method that combines a set of very robust features from different algorithms into a hybrid feature vector for pixel characterization. This 17-D feature vector consists of 13 Gabor filter responses computed at different configurations, contrast enhanced intensity, morphological top-hat transformed intensity, vesselness measure, and B-COSFIRE filter response. A random forest classifier, known for its speed, simplicity, and information fusion capability, is trained with the hybrid feature vector. The chosen combination of the different types of individually strong features results in increased local information with better discrimination for vessel and non-vessel pixels in both healthy and pathological retinal images. The proposed method is evaluated in detail on two publicly available databases DRIVE and STARE. Average classification accuracies of 0.9513 and 0.9605 on the DRIVE and STARE datasets, respectively, are achieved. When the majority of the common performance metrics are considered, our method is superior to the state-of-the-art methods. Performance results show that our method also outperforms the state-of-the-art methods in both cross training and pathological cases.", "corpus_id": 28013106, "score": 0 }, { "doc_id": "36433734", "title": "Retinal vessels segmentation based on level set and region growing", "abstract": "Abstract Retinal vessels play an important role in the diagnostic procedure of retinopathy. Accurate segmentation of retinal vessels is crucial for pathological analysis. In this paper, we propose a new retinal vessel segmentation method based on level set and region growing. Firstly, a retinal vessel image is preprocessed by the contrast-limited adaptive histogram equalization and a 2D Gabor wavelet to enhance the vessels. Then, an anisotropic diffusion filter is used to smooth the image and preserve vessel boundaries. Finally, the region growing method and a region-based active contour model with level set implementation are applied to extract retinal vessels, and their results are combined to achieve the final segmentation. Comparisons are conducted on the publicly available DRIVE and STARE databases using three different measurements. Experimental results show that the proposed method reaches an average accuracy of 94.77% on the DRIVE database and 95.09% on the STARE database.", "corpus_id": 36433734, "score": 0 }, { "doc_id": "17321107", "title": "An approach to localize the retinal blood vessels using bit planes and centerline detection", "abstract": "The change in morphology, diameter, branching pattern or tortuosity of retinal blood vessels is an important indicator of various clinical disorders of the eye and the body. This paper reports an automated method for segmentation of blood vessels in retinal images. A unique combination of techniques for vessel centerlines detection and morphological bit plane slicing is presented to extract the blood vessel tree from the retinal images. The centerlines are extracted by using the first order derivative of a Gaussian filter in four orientations and then evaluation of derivative signs and average derivative values is performed. Mathematical morphology has emerged as a proficient technique for quantifying the blood vessels in the retina. The shape and orientation map of blood vessels is obtained by applying a multidirectional morphological top-hat operator with a linear structuring element followed by bit plane slicing of the vessel enhanced grayscale image. The centerlines are combined with these maps to obtain the segmented vessel tree. The methodology is tested on three publicly available databases DRIVE, STARE and MESSIDOR. The results demonstrate that the performance of the proposed algorithm is comparable with state of the art techniques in terms of accuracy, sensitivity and specificity.", "corpus_id": 17321107, "score": 1 }, { "doc_id": "10597357", "title": "Retinal vessel extraction by matched filter with first-order derivative of Gaussian", "abstract": "Accurate extraction of retinal blood vessels is an important task in computer aided diagnosis of retinopathy. The matched filter (MF) is a simple yet effective method for vessel extraction. However, a MF will respond not only to vessels but also to non-vessel edges. This will lead to frequent false vessel detection. In this paper we propose a novel extension of the MF approach, namely the MF-FDOG, to detect retinal blood vessels. The proposed MF-FDOG is composed of the original MF, which is a zero-mean Gaussian function, and the first-order derivative of Gaussian (FDOG). The vessels are detected by thresholding the retinal image's response to the MF, while the threshold is adjusted by the image's response to the FDOG. The proposed MF-FDOG method is very simple; however, it reduces significantly the false detections produced by the original MF and detects many fine vessels that are missed by the MF. It achieves competitive vessel detection results as compared with those state-of-the-art schemes but with much lower complexity. In addition, it performs well at extracting vessels from pathological retinal images.", "corpus_id": 10597357, "score": 1 }, { "doc_id": "6881497", "title": "Detection of blood vessels in ophthalmoscope images using MF/ant (matched filter/ant colony) algorithm", "abstract": "Blood vessels in ophthalmoscope images play an important role in diagnosis of some serious pathologies on retinal images. Hence, accurate extraction of vessels is becoming a main topic of this research area. Matched filter (MF) implementation for blood vessel detection is one of the methods giving more accurate results. Using this filter alone might not recover all the vessels (especially the capillaries). In this paper, a novel approach (MF/ant algorithm) is proposed to overcome the deficiency of the MF. The proposed method is a hybrid model of matched filter and ant colony algorithm. In this work, the accuracy and parameters of the hybrid algorithm are also discussed. The proposed method shows its success using the well known reference ophthalmoscope images of DRIVE database.", "corpus_id": 6881497, "score": 1 }, { "doc_id": "8660192", "title": "Genetic algorithm matched filter optimization for automated detection of blood vessels from digital retinal images", "abstract": "Due to the importance of the matched filter in the automated detection of blood vessels in digital retinal images, improving its response is highly desirable. This filter may vary in many ways depending on the parameters that govern its response. In this paper, new parameters to optimize the sensitivity of the matched filter are found using genetic algorithms on the test set of the DRIVE databases. The area under the receiver operating curve (ROC) is used as a fitness function for the genetic algorithm. To evaluate the improved matched filter, the maximum average accuracy (MAA) is calculated to be 0.9422 and the average area under ROC is 0.9582.", "corpus_id": 8660192, "score": 1 }, { "doc_id": "10684069", "title": "Trainable COSFIRE filters for vessel delineation with application to retinal images", "abstract": "Retinal imaging provides a non-invasive opportunity for the diagnosis of several medical pathologies. The automatic segmentation of the vessel tree is an important pre-processing step which facilitates subsequent automatic processes that contribute to such diagnosis. We introduce a novel method for the automatic segmentation of vessel trees in retinal fundus images. We propose a filter that selectively responds to vessels and that we call B-COSFIRE with B standing for bar which is an abstraction for a vessel. It is based on the existing COSFIRE (Combination Of Shifted Filter Responses) approach. A B-COSFIRE filter achieves orientation selectivity by computing the weighted geometric mean of the output of a pool of Difference-of-Gaussians filters, whose supports are aligned in a collinear manner. It achieves rotation invariance efficiently by simple shifting operations. The proposed filter is versatile as its selectivity is determined from any given vessel-like prototype pattern in an automatic configuration process. We configure two B-COSFIRE filters, namely symmetric and asymmetric, that are selective for bars and bar-endings, respectively. We achieve vessel segmentation by summing up the responses of the two rotation-invariant B-COSFIRE filters followed by thresholding. The results that we achieve on three publicly available data sets (DRIVE: Se=0.7655, Sp=0.9704; STARE: Se=0.7716, Sp=0.9701; CHASE_DB1: Se=0.7585, Sp=0.9587) are higher than many of the state-of-the-art methods. The proposed segmentation approach is also very efficient with a time complexity that is significantly lower than existing methods.", "corpus_id": 10684069, "score": 1 }, { "doc_id": "18563753", "title": "Robust Vessel Segmentation in Fundus Images", "abstract": "One of the most common modalities to examine the human eye is the eye-fundus photograph. The evaluation of fundus photographs is carried out by medical experts during time-consuming visual inspection. Our aim is to accelerate this process using computer aided diagnosis. As a first step, it is necessary to segment structures in the images for tissue differentiation. As the eye is the only organ, where the vasculature can be imaged in an in vivo and noninterventional way without using expensive scanners, the vessel tree is one of the most interesting and important structures to analyze. The quality and resolution of fundus images are rapidly increasing. Thus, segmentation methods need to be adapted to the new challenges of high resolutions. In this paper, we present a method to reduce calculation time, achieve high accuracy, and increase sensitivity compared to the original Frangi method. This method contains approaches to avoid potential problems like specular reflexes of thick vessels. The proposed method is evaluated using the STARE and DRIVE databases and we propose a new high resolution fundus database to compare it to the state-of-the-art algorithms. The results show an average accuracy above 94% and low computational needs. This outperforms state-of-the-art methods.", "corpus_id": 18563753, "score": 0 }, { "doc_id": "33036339", "title": "Retinal vessel segmentation by improved matched filtering: evaluation on a new high-resolution fundus image database", "abstract": "Automatic assessment of retinal vessels plays an important role in the diagnosis of various eye, as well as systemic diseases. A public screening is highly desirable for prompt and effective treatment, since such diseases need to be diagnosed at an early stage. Automated and accurate segmentation of the retinal blood vessel tree is one of the challenging tasks in the computer-aided analysis of fundus images today. We improve the concept of matched filtering, and propose a novel and accurate method for segmenting retinal vessels. Our goal is to be able to segment blood vessels with varying vessel diameters in high-resolution colour fundus images. All recent authors compare their vessel segmentation results to each other using only low-resolution retinal image databases. Consequently, we provide a new publicly available high-resolution fundus image database of healthy and pathological retinas. Our performance evaluation shows that the proposed blood vessel segmentation approach is at least comparable with recent state-of-the-art methods. It outperforms most of them with an accuracy of 95% evaluated on the new database.", "corpus_id": 33036339, "score": 0 }, { "doc_id": "124335079", "title": "New Binary Hausdorff Symmetry measure based seeded region growing for retinal vessel segmentation", "abstract": "Abstract Automated retinal vessel segmentation plays an important role in computer-aided diagnosis of serious diseases such as glaucoma and diabetic retinopathy. This paper contributes, (1) new Binary Hausdorff Symmetry (BHS) measure based automatic seed selection, and (2) new edge distance seeded region growing (EDSRG) algorithm for retinal vessel segmentation. The proposed BHS measure directly provides a binary symmetry decision at each pixel without the computation of continuous symmetry map and image thresholding. In a multiscale mask, the BHS measure is computed using the distance sets of opposite direction angle bins with sub-pixel resolution. The computation of the BHS measure from the Hausdorff distance sets involves point set matching based geometrical interpretation of symmetry. Then, we design a new edge distance seeded region growing (EDSRG) algorithm with the acquired seeds. The performance evaluation in terms of sensitivity, specificity and accuracy is done on the publicly available DRIVE, STARE and HRF databases. The proposed method is found to achieve state-of-the-art vessel segmentation accuracy in three retinal databases; DRIVE-sensitivity (0.7337), specificity (0.9752), accuracy (0.9539); STARE-sensitivity (0.8403), specificity (0.9547), accuracy (0.9424); and HRF-sensitivity (0.8159), specificity (0.9525), accuracy (0.9420).", "corpus_id": 124335079, "score": 1 }, { "doc_id": "5298087", "title": "Iterative Vessel Segmentation of Fundus Images", "abstract": "This paper presents a novel unsupervised iterative blood vessel segmentation algorithm using fundus images. First, a vessel enhanced image is generated by tophat reconstruction of the negative green plane image. An initial estimate of the segmented vasculature is extracted by global thresholding the vessel enhanced image. Next, new vessel pixels are identified iteratively by adaptive thresholding of the residual image generated by masking out the existing segmented vessel estimate from the vessel enhanced image. The new vessel pixels are, then, region grown into the existing vessel, thereby resulting in an iterative enhancement of the segmented vessel structure. As the iterations progress, the number of false edge pixels identified as new vessel pixels increases compared to the number of actual vessel pixels. A key contribution of this paper is a novel stopping criterion that terminates the iterative process leading to higher vessel segmentation accuracy. This iterative algorithm is robust to the rate of new vessel pixel addition since it achieves 93.2-95.35% vessel segmentation accuracy with 0.9577-0.9638 area under ROC curve (AUC) on abnormal retinal images from the STARE dataset. The proposed algorithm is computationally efficient and consistent in vessel segmentation performance for retinal images with variations due to pathology, uneven illumination, pigmentation, and fields of view since it achieves a vessel segmentation accuracy of about 95% in an average time of 2.45, 3.95, and 8 s on images from three public datasets DRIVE, STARE, and CHASE_DB1, respectively. Additionally, the proposed algorithm has more than 90% segmentation accuracy for segmenting peripapillary blood vessels in the images from the DRIVE and CHASE_DB1 datasets.", "corpus_id": 5298087, "score": 1 }, { "doc_id": "8626432", "title": "An Active Contour Model for Segmenting and Measuring Retinal Vessels", "abstract": "This paper presents an algorithm for segmenting and measuring retinal vessels, by growing a ldquoRibbon of Twinsrdquo active contour model, which uses two pairs of contours to capture each vessel edge, while maintaining width consistency. The algorithm is initialized using a generalized morphological order filter to identify approximate vessels centerlines. Once the vessel segments are identified the network topology is determined using an implicit neural cost function to resolve junction configurations. The algorithm is robust, and can accurately locate vessel edges under difficult conditions, including noisy blurred edges, closely parallel vessels, light reflex phenomena, and very fine vessels. It yields precise vessel width measurements, with subpixel average width errors. We compare the algorithm with several benchmarks from the literature, demonstrating higher segmentation sensitivity and more accurate width measurement.", "corpus_id": 8626432, "score": 0 }, { "doc_id": "27699437", "title": "Automated extraction of retinal vasculature.", "abstract": "PURPOSE\nThe authors propose an algorithm that automatically extracts retinal vasculature and provides a simple measure to correct the extraction. The output of the method is a network of salient points, and blood vessels are drawn by connecting the salient points using a centripetal parameterized Catmull-Rom spline.\n\n\nMETHODS\nThe algorithm starts by background correction. The corrected image is filtered with a bank of Gabor kernels, and the responses are consolidated to form a maximal image. After that, the maximal image is thinned to get a network of 1-pixel lines, analyzed and pruned to locate forks and form branches. Finally, the Ramer-Douglas-Peucker algorithm is used to determine salient points. When extraction is not satisfactory, the user simply shifts the salient points to edit the segmentation.\n\n\nRESULTS\nOn average, the authors' extractions cover 93% of ground truths (on the Drive database).\n\n\nCONCLUSIONS\nBy expressing retinal vasculature as a series of connected points, the proposed algorithm not only provides a means to edit segmentation but also gives knowledge of the shape of the blood vessels and their connections.", "corpus_id": 27699437, "score": 0 }, { "doc_id": "62050043", "title": "Retinal blood vessel detection and tracking by matched Gaussian and Kalman filters", "abstract": "Detection and tracking algorithms of the blood vessel network in the retinal images are proposed. Two main groups of algorithms are employed for this task, i.e., scanning and tracking. According to the known blood vessel feature, a second-order derivative Gaussian matched filter is designed and used to locate the center point and width of a vessel in its cross sectional profile. Together with this the extended Kalman filter is employed for the optimal linear estimation of the next possible location of blood vessel segment by appropriate formulation of its pattern changing process and observation model. To check the bifurcation in the vessel network, a simple branching detection strategy is implemented during tracking. The proposed algorithms all work well in the whole tracking process and can detect more complete vessel network in the ocular fundus photographs.", "corpus_id": 62050043, "score": 0 }, { "doc_id": "2689378", "title": "Segmentation of blood vessels from red-free and fluorescein retinal images", "abstract": "The morphology of the retinal blood vessels can be an important indicator for diseases like diabetes, hypertension and retinopathy of prematurity (ROP). Thus, the measurement of changes in morphology of arterioles and venules can be of diagnostic value. Here we present a method to automatically segment retinal blood vessels based upon multiscale feature extraction. This method overcomes the problem of variations in contrast inherent in these images by using the first and second spatial derivatives of the intensity image that gives information about vessel topology. This approach also enables the detection of blood vessels of different widths, lengths and orientations. The local maxima over scales of the magnitude of the gradient and the maximum principal curvature of the Hessian tensor are used in a multiple pass region growing procedure. The growth progressively segments the blood vessels using feature information together with spatial information. The algorithm is tested on red-free and fluorescein retinal images, taken from two local and two public databases. Comparison with first public database yields values of 75.05% true positive rate (TPR) and 4.38% false positive rate (FPR). Second database values are of 72.46% TPR and 3.45% FPR. Our results on both public databases were comparable in performance with other authors. However, we conclude that these values are not sensitive enough so as to evaluate the performance of vessel geometry detection. Therefore we propose a new approach that uses measurements of vessel diameters and branching angles as a validation criterion to compare our segmented images with those hand segmented from public databases. Comparisons made between both hand segmented images from public databases showed a large inter-subject variability on geometric values. A last evaluation was made comparing vessel geometric values obtained from our segmented images between red-free and fluorescein paired images with the latter as the \"ground truth\". Our results demonstrated that borders found by our method are less biased and follow more consistently the border of the vessel and therefore they yield more confident geometric values.", "corpus_id": 2689378, "score": 0 }, { "doc_id": "11684340", "title": "Segmentation of retinal blood vessels by combining the detection of centerlines and morphological reconstruction", "abstract": "This paper presents an automated method for the segmentation of the vascular network in retinal images. The algorithm starts with the extraction of vessel centerlines, which are used as guidelines for the subsequent vessel filling phase. For this purpose, the outputs of four directional differential operators are processed in order to select connected sets of candidate points to be further classified as centerline pixels using vessel derived features. The final segmentation is obtained using an iterative region growing method that integrates the contents of several binary images resulting from vessel width dependent morphological filters. Our approach was tested on two publicly available databases and its results are compared with recently published methods. The results demonstrate that our algorithm outperforms other solutions and approximates the average accuracy of a human observer without a significant degradation of sensitivity and specificity", "corpus_id": 11684340, "score": 0 }, { "doc_id": "125992549", "title": "Automatic parameters selection of Gabor filters with the imperialism competitive algorithm with application to retinal vessel segmentation", "abstract": "Abstract Retinal images play an important role in the early diagnosis of diseases such as diabetes. In the present study, an automatic image processing technique is proposed to segment retinal blood vessels in fundus images. The technique includes the design of a bank of 180 Gabor filters with varying scale and elongation parameters. Furthermore, an optimization method, namely, the imperialism competitive algorithm (ICA), is adopted for automatic parameter selection of the Gabor filter. In addition, a systematic method is proposed to determine the threshold value for reliable performance. Finally, the performance of the proposed approach is analyzed and compared with that of other approaches on the basis of the publicly available DRIVE database. The proposed method achieves an area under the receiver operating characteristic curve of 0.953 and an average accuracy of up to 0.9392. Thus, the results show that the proposed method is well comparable with alternative methods in the literature.", "corpus_id": 125992549, "score": 0 }, { "doc_id": "13450824", "title": "Automatic Brain Tumor Segmentation byVariational Minimax Optimization Technique", "abstract": "The brain tumors are the mass of undifferentiated cells which undergoes uncontrolled proliferation of cells in the brain. Segmentation of these tumors is more difficult than natural. Because their functional sensitivity is higher than other images. Many different algorithms have been proposed for segmentation of these type of tumors in brain images. In this paper, we propose an approach in order to improve efficiency of the brain tumor segmentation through the minimax optimization that applies to the thresholding of the MRI brain image to segment tumor. The tumor segmentation is performed by the implementation of an optimistic technique called variational minimax optimization. The proposed system uses search of optimum threshold with an iterative line search technique with faster execution time of 15 seconds.", "corpus_id": 13450824, "score": 0 }, { "doc_id": "80608582", "title": "A thresholding based technique to extract retinal blood vessels from fundus images", "abstract": "Abstract Retinal imaging has become the significant tool among all the medical imaging technology, due to its capability to extract many data which is linked to various eye diseases. So, the accurate extraction of blood vessel is necessary that helps the eye care specialists and ophthalmologist to identify the diseases at the early stages. In this paper, we have proposed a computerized technique for extraction of blood vessels from fundus images. The process is conducted in three phases: (i) pre-processing where the image is enhanced using contrast limited adaptive histogram equalization and median filter, (ii) segmentation using mean-C thresholding to extract retinal blood vessels, (iii) post-processing where morphological cleaning operation is used to remove isolated pixels. The performance of the proposed method is tested on and experimental results show that our method achieve an accuracies of 0.955 and 0.954 on Digital retinal images for vessel extraction (DRIVE) and Child heart and health study in England (CHASE_DB1) databases respectively.", "corpus_id": 80608582, "score": 0 }, { "doc_id": "17702882", "title": "Automatic detection of microaneurysms in color fundus images", "abstract": "This paper addresses the automatic detection of microaneurysms in color fundus images, which plays a key role in computer assisted diagnosis of diabetic retinopathy, a serious and frequent eye disease. The algorithm can be divided into four steps. The first step consists in image enhancement, shade correction and image normalization of the green channel. The second step aims at detecting candidates, i.e. all patterns possibly corresponding to MA, which is achieved by diameter closing and an automatic threshold scheme. Then, features are extracted, which are used in the last step to automatically classify candidates into real MA and other objects; the classification relies on kernel density estimation with variable bandwidth. A database of 21 annotated images has been used to train the algorithm. The algorithm was compared to manually obtained gradings of 94 images; sensitivity was 88.5% at an average number of 2.13 false positives per image.", "corpus_id": 17702882, "score": 0 }, { "doc_id": "13496608", "title": "Edge Sensitive Variational Image Thresholding", "abstract": "In this paper we propose a locally adaptive image threshold technique via variational energy minimization. The novelty of the proposed method is that from an image it automatically computes the weights on the data fidelity and the regularization terms in the energy functional, unlike many other previously proposed variational formulations that require manual input of these weights by laborious trial and error. To achieve the automatic setting of the weighting parameters we propose a non-linear convex combination of the data fidelity and the regularization terms in the energy functional and seek the optimum threshold surface via minimax principle. Our choice of the novel energy functional allows fast computation of the unique minimax solution. As a specific segmentation application, the proposed technique shows promising results when applied to find lung boundary from MR imagery. Illustrative examples are also provided where the proposed method is observed to retain texture information better than other competing methods.", "corpus_id": 13496608, "score": 0 }, { "doc_id": "6614987", "title": "Quantitative design and evaluation of enhancement/thresholding edge detectors", "abstract": "Quantitative design and performance evaluation techniques are developed for the enhancement/thresholding class of image edge detectors. The design techniques are based on statistical detection theory and deterministic pattern-recognition classification procedures. The performance evaluation methods developed include: a)deterministic measurement of the edge gradient amplitude; b)comparison of the probabilities of correct and false edge detection; and c) figure of merit computation. The design techniques developed are used to optimally design a variety of small and large mask edge detectors. Theoretical and experimental comparisons of edge detectors are presented.", "corpus_id": 6614987, "score": 0 }, { "doc_id": "17692913", "title": "Image thresholding by variationalminimax optimization", "abstract": "Article history: Received 23 October 2007 Received in revised form 19 August 2008 Accepted 19 September 2008", "corpus_id": 17692913, "score": 0 }, { "doc_id": "29071354", "title": "An Adaptive Time-Stepping Scheme with Local Convergence Verification Using Support Vector Machines", "abstract": "An adaptive time-stepping scheme in accordance with the local convergence of computation often involves computationally expensive procedures. As a result, many computer simulators have avoided utilizing such an adaptive scheme, while its advantages are well recognized; the scheme not only efficiently allocates computational resources, but also makes the results of the computation more reliable. In this paper, we propose a fast adaptive time-stepping scheme, ATLAS (Adaptive Time-step Learning and Adjusting Scheme), which approximates such an expensive yet beneficial scheme by using support vector machines (SVMs). We demonstrate that ATLAS performs quite favorably when compared with computations without it. ATLAS can incorporate existing solvers and other fast but unreliable adaptive schemes to meet the different criteria required in various applications.", "corpus_id": 29071354, "score": 0 }, { "doc_id": "60452913", "title": "Morphological Image Analysis: Principles and Applications", "abstract": "From the Publisher: \nThe purpose of this book is to provide readers with an in-depth presentation of the principles and applications of morphological image analysis. This is achieved through a step by step process starting from the basic morphological operators and extending to the most recent advances which have proven their practical usefulness. This self-contained volume will be valuable to all engineers, scientists, and practitioners interested in the analysis and processing of digital images.", "corpus_id": 60452913, "score": 0 }, { "doc_id": "2545500", "title": "Measuring retinal vessel tortuosity in 10-year-old children: validation of the Computer-Assisted Image Analysis of the Retina (CAIAR) program.", "abstract": "PURPOSE\nTo examine the agreement of a novel computer program measuring retinal vessel tortuosity with subjective assessment of tortuosity in school-aged children.\n\n\nMETHODS\nCross-sectional study of 387 retinal vessels (193 arterioles, 194 veins) from 28 eyes of 14 children (aged 10 years). Retinal digital images were analyzed using the Computer Assisted Image Analysis of the Retina (CAIAR) program, including 14 measures of tortuosity. Vessels were graded (from 0 = none; to 5 = tortuous) independently by two observers. Interobserver agreement was assessed by using kappa statistics. Agreement with all 14 objective measures was assessed with correlation/regression analyses. Intersession repeatability (comparing morning and afternoon sessions) of tortuosity indices was calculated.\n\n\nRESULTS\nInterobserver agreement of vessel tortuosity within one grade was high (kappa = 0.97), with total agreement in 56% of grades and 42% differing by +/-1 grade. Tortuosity indices based on subdivided chord length methods showed strong log-linear associations with agreed subjective grades (typically r > 0.6; P < 0.001). An approach that averages the distance from the vessel to chord length along the length of the vessel showed best agreement (r = 0.8; P < 0.0001). Tortuosity measures based on curvature performed less well. Intersession repeatability of the vessel to chord technique was good, differing by values equivalent to <1 in subjective grade.\n\n\nCONCLUSIONS\nTortuosity indices based on changes in subdivided chord lengths showed optimal agreement with subjective assessment. The relation of these indices to ethnicity and cardiovascular risk factors in childhood should be examined further, as these indices may be a useful indicator of early vascular function.", "corpus_id": 2545500, "score": 0 }, { "doc_id": "3770261", "title": "Evaluation: from precision, recall and F-measure to ROC, informedness, markedness and correlation", "abstract": "Commonly used evaluation measures including Recall, Precision, F-Factor and Rand Accuracy are biased and should not be used without clear understanding of the biases, and corresponding identification of chance or base case levels of the statistic. Using these measures a system that performs worse in the objective sense of Informedness, can appear to perform better under any of these commonly used measures. We discuss several concepts and measures that reflect the probability that prediction is informed versus chance. Informedness and introduce Markedness as a dual measure for the probability that prediction is marked versus chance. Finally we demonstrate elegant connections between the concepts of Informedness, Markedness, Correlation and Significance as well as their intuitive relationships with Recall and Precision, and outline the extension from the dichotomous case to the general multi-class case. .", "corpus_id": 3770261, "score": 0 }, { "doc_id": "41726684", "title": "Detection of retinal blood vessels from ophthalmoscope images using morphological approach", "abstract": "Accurate segmentation of retinal blood vessels is an essential task for diagnosis of various pathological disorders. In this paper, a novel method has been introduced for segmenting retinal blood vessels which involves pre-processing, segmentation and post-processing. The pre-processing stage enhanced the image using contrast limited adaptive histogram equalization and 2D Gabor wavelet. The enhanced image is segmented using geodesic operators and a final segmentation output is obtained by applying a post-processing stage that involves hole filling and removal of isolated pixels. The performance of the proposed method is evaluated on the publicly available Digital retinal images for vessel extraction (DRIVE) and High-resolution fundus (HRF) databases using five different measurements and experimental analysis shows that the proposed method reach an average accuracy of 0.9541 on DRIVE database and 0.9568, 0.9478 and 0.9613 on HRF database with healthy, diabetic retinopathy (DR) and glaucomatous images respectively.", "corpus_id": 41726684, "score": 0 } ]

{ "doc_id": "54753461", "title": "Flow of a thixotropic or antithixotropic fluid in a slowly varying channel: the weakly advective regime", "abstract": "Abstract A general formulation of the governing equations for the slow, steady, two-dimensional flow of a thixotropic or antithixotropic fluid in a channel of slowly varying width is described. These equations are equivalent to the equations of classical lubrication theory for a Newtonian fluid, but incorporate the evolving microstructure of the fluid, described in terms of a scalar structure parameter. We demonstrate how the lubrication equations can be further simplified in the weakly advective regime in which the advective Deborah number is comparable to the aspect ratio of the flow, and present illustrative analytical and semi-analytical solutions for particular choices of the constitutive and kinetic laws, including a purely viscous Moore–Mewis–Wagner model and a regularised viscoplastic Houska model. The lubrication results also allow the calibration and validation of cross-sectionally averaged, or otherwise reduced, descriptions of thixotropic channel flow which provide a first step towards models of thixotropic flow in porous media, and we employ them to explain why such descriptions may be inadequate.", "corpus_id": 54753461 }

[ { "doc_id": "119789424", "title": "Thixotropy—a review", "abstract": "Abstract The ensuing mechanical response to stressing or straining a structured liquid results in various viscoelastic phenomena, either in the linear region where the microstructure responds linearly with respect to the stress and strain but does not itself change, or in the nonlinear region where the microstructure does change in response to the imposed stresses and strains, but does so reversibly. The complication of thixotropy arises because this reversible, microstructural change itself takes time to come about due to local spatial rearrangement of the components. This frequently found time-response of a microstructure that is itself changing with time makes thixotropic, viscoelastic behaviour one of the greatest challenges facing rheologists today, in terms of its accurate experimental characterisation and its adequate theoretical description. Here a history of thixotropy is given, together with a description of how it is understood today in various parts of the scientific community. Then a mechanistic description of thixotropy is presented, together with a series of applications where thixotropy is important. A list of different examples of thixotropic systems is then given. Finally the various kinds of theories that have been put forward to describe the phenomenon mathematically are listed.", "corpus_id": 119789424, "score": 1 }, { "doc_id": "122021633", "title": "Laminar, unidirectional flow of a thixotropic fluid in a circular pipe", "abstract": "Abstract In this paper we study the unidirectional, axisymmetric flow of a bentonite mud in a circular pipe. Bentonite mud is an inelastic, thixotropic, generalised-Newtonian fluid. We use a rheological model that characterises this behaviour in terms of a single parameter Λ which is a measure of the amount of structure in the fluid. The behaviour of Λ is determined by a single rate equation which models the tendency of fluid structure to increase whilst being limited by the imposed shear rate. We find that, for certain parameter ranges, the model is not structurally stable, but that this problem can be eliminated by including diffusion of fluid structure. A graph of the equilibrium shear stress for a given shear rate (the rheogram) is not monotonic, yet no mechanical instability occurs in pipe flow. We contrast this with recent work on the pipe flow of a Johnson-Segalman-Oldroyd fluid which displays spurting and oscillatory behaviour. The difference lies in the relative magnitude of normal stress effects in the two fluids. There appear to be no grounds for discarding the constitutive model studied here simply because of the non-monotonicity of the equilibrium rheogram.", "corpus_id": 122021633, "score": 1 }, { "doc_id": "121457657", "title": "Aging and free surface flow of a thixotropic fluid", "abstract": "Free surface flows of thixotropic fluids such as paints, self-compacting concrete, or natural mudflows are of noticeable practical interest. Here we study the basic characteristics of the uniform flow of a layer of thixotropic fluid under gravity. A theoretical approach relying on a simple thixotropy constitutive equation shows that after some time at rest over a small slope angle the fluid layer should start to flow rather abruptly beyond a new, larger, critical slope angle. The theory also predicts that the critical time at which the layer velocity should significantly increase is proportional to the duration of the preliminary rest and tends to infinity when the new slope approaches the critical slope. Experiments carried out with different suspensions show that the qualitative trends of the flows are in very good agreement with the theoretical predictions, except that the critical time for flow start appears to be proportional to a power 0.6 of the time of rest whereas the theory predicts a linear dep...", "corpus_id": 121457657, "score": 0 }, { "doc_id": "122346479", "title": "A study of start-up flow of thixotropic fluids including inertia effects on an inclined plane", "abstract": "Despite the practical importance of thixotropic fluids, there is no reliable way at present to predict the onset of thixotropic flow. The start-up flow of thixotropic fluids including inertia effects falling down along an inclined plate is studied in this paper. The effects of the unsteady term in the NS equations on the start-up process are clarified and a criterion parameter A is presented to measure this unsteady effect. The parameter A is defined as the ratio of the Reynolds number and generalized Weissenberg number W, where W is the ratio of the characteristic time of microstructure changes and the characteristic time of flow. According to flow characteristics, we classify the motion into three cases. In case 1, avalanche happens and the initial viscosity is big. The start-up process is divided into two stages: creep and flow. Velocity profiles of both stages are discussed. In this case, if A is small enough, the inertia effects could be neglected. Otherwise, the inertial unsteady term will protract ...", "corpus_id": 122346479, "score": 0 }, { "doc_id": "44551122", "title": "Avalanche behavior in yield stress fluids.", "abstract": "We show that, above a critical stress, typical yield stress fluids (gels and clay suspensions) and soft glassy materials (colloidal glasses) start flowing abruptly and subsequently accelerate, leading to avalanches that are remarkably similar to those of granular materials. Rheometrical tests reveal that this is associated with a bifurcation in rheological behavior: for small stresses, the viscosity increases in time; the material eventually stops flowing. For slightly larger stresses the viscosity decreases continuously in time; the flow accelerates. Thus the viscosity jumps discontinuously to infinity at the critical stress. We propose a simple physical model capable of reproducing these effects.", "corpus_id": 44551122, "score": 0 }, { "doc_id": "33752565", "title": "Dam Break Wave of Thixotropic Fluid", "abstract": "Thixotropy is the characteristic of a fluid to form a gelled structure over time when it is not subjected to shearing, and to liquefy when agitated. Thixotropic fluids are commonly used in the construction industry e.g., liquid concrete and drilling fluids, and related applications include some forms of mud flows and debris flows. This paper describes a basic study of dam break wave with thixotropic fluid. Theoretical considerations were developed based upon a kinematic wave approximation of the Saint-Venant equations down a prismatic sloping channel. A very simple thixotropic model, which predicts the basic rheological trends of such fluids, was used. It describes the instantaneous state of fluid structure by a single parameter. The analytical solution of the basic flow motion and rheology equations predicts three basic flow regimes depending upon the fluid properties and flow conditions, including the initial \"degree of jamming\" of the fluid related to its time of restructuration at rest. These findings were successfully compared with systematic bentonite suspension experiments. The present work is the first theoretical analysis combining the basic principles of unsteady flow motion with a thixotropic fluid model and systematic laboratory experiments.", "corpus_id": 33752565, "score": 1 }, { "doc_id": "121130948", "title": "Viscous fingering of a thixotropic fluid in a porous medium or a narrow fracture", "abstract": "Abstract We consider the flow of a fluid with a modified Bautista–Manero rheology injected radially into a porous medium or unidirectionally into a widening fracture. Linear stability analysis of the flows demonstrates that viscous fingering instabilities are possible, supported essentially by the thixotropic nature of the fluid: the growth rate of unstable perturbations scales approximately with the relaxation rate λ ˆ − 1 of the fluid, while their spatial scale is set in the radial case by ( Q ˆ λ ˆ ) 1 / 2 where Q ˆ is the areal injection rate, and in the fracture case by a ‘relaxation lengthscale’ which cannot be deduced by purely dimensional reasoning. It appears likely that the same instability mechanism can occur in other shear-thinning thixotropic fluids.", "corpus_id": 121130948, "score": 1 }, { "doc_id": "122188082", "title": "Understanding thixotropic and antithixotropic behavior of viscoelastic micellar solutions and liquid crystalline dispersions. I. The model", "abstract": "Abstract A simple model consisting of the Upper Convected Maxwell constitutive equation and a kinetic equation for destruction and construction of structure, first proposed by Fredrickson in 1970, is used here to reproduce the complex rheological behavior of viscoelastic systems that also exhibit thixotropy and rheopexy under shear flow. The model requires five parameters that have physical significance and that can be estimated from rheological measurements. Several steady and unsteady flow situations were analyzed with the model. The model predicts creep behavior, stress relaxation and the presence of thixotropic loops when the sample is subjected to transient stress cycles. Such behavior has been observed with surfactant-based solutions and dispersions. The role of the characteristic time for structure built up, λ, in the extent and shape of the thixotropic loops is demonstrated.", "corpus_id": 122188082, "score": 0 }, { "doc_id": "94356193", "title": "Leveling of thixotropic liquids", "abstract": "Abstract In this paper the effect of thixotropy in the hydrodynamic behavior of thin films is studied. The simple problem of leveling on a horizontal substrate is considered. The rheological properties of the material are assumed to evolve over time due purely to changes in its internal structure. These changes are modeled in terms of a single structural variable. Neither elastic nor yielding effects are taken into account. More specifically, two distinct rheological models are considered: the simple model proposed by Moore and the more complex model proposed by Baravanian et al. These models exhibit a large range of variation for the liquid viscosity across the film thickness. After deriving the hydrodynamic equations governing leveling flows with the standard assumptions required by the lubrication approximation and running time-dependent numerical simulations, the nonlinear leveling history of the liquid can be predicted as a function of the initial microstructural state, rheological parameters, and initial disturbance of the liquid free surface. The main effort of this work is devoted to devising approximation schemes which lead to significant simplifications of the governing equations and their numerical computations. By approximating the inverse of viscosity as a monotonic function between its substrate and free-surface values, excellent agreement is found for the film amplitude, irrespective of the values of the rheological parameters of both models. Finally, a linear analysis yields a generalization of the Orchard’s law of leveling for Newtonian liquids to take into account the effect of thixotropy.", "corpus_id": 94356193, "score": 1 }, { "doc_id": "110962703", "title": "Mathematical modeling of thixotropic drilling mud and crude oil flow in wells and pipelines—A review", "abstract": "Abstract Many drilling muds and crude oils are known to be thixotropic. Under a wide range of pressures, temperatures and flow regimes, they display unusual complex flow properties when flowing through wells (crude oils and drilling muds) and during storage and pipeline transportation (crude oils). Understanding and modeling the deviation from Newtonian behavior of drilling muds and crude oils are essential in accurately and optimally designing the flow systems associated with these fluids. Despite an impressive amount of experimental and rheological modeling studies concerning the non-Newtonian drilling mud and crude oil behavior, mathematical modeling studies taking into account their thixotropic properties are rare. In addition, there was no literature review of the knowledge gained to date. Thus, a review paper on studies addressing the mathematical modeling of thixotropic drilling mud and crude oil flow in wells and pipelines will pinpoint the challenges and limitations encountered in such studies. This will hopefully trigger further development and new research topics. This review paper focuses mainly on mathematical modeling studies concerning the well and pipeline flow of thixotropic drilling muds and crude oils. After describing how thixotropy is understood today inside and outside of the petroleum industry community, several mathematical models available in the literature are examined. Finally, challenges, limitations, and potential areas for the development of these models are presented.", "corpus_id": 110962703, "score": 0 }, { "doc_id": "115149076", "title": "Thixotropic gravity currents", "abstract": "Abstract We present a model for thixotropic gravity currents flowing down an inclined plane that combines lubrication theory for shallow flow with a rheological constitutive law describing the degree of microscopic structure. The model is solved numerically for a finite volume of fluid in both two and three dimensions. The results illustrate the importance of the degree of initial ageing and the spatio-temporal variations of the microstructure during flow. The fluid does not flow unless the plane is inclined beyond a critical angle that depends on the ageing time. Above that critical angle and for relatively long ageing times, the fluid dramatically avalanches downslope, with the current becoming characterized by a structured horseshoe-shaped remnant of fluid at the back and a raised nose at the advancing front. The flow is prone to a weak interfacial instability that occurs along the border between structured and de-structured fluid. Experiments with bentonite clay show broadly similar phenomenological behaviour to that predicted by the model. Differences between the experiments and the model are discussed.", "corpus_id": 115149076, "score": 0 }, { "doc_id": "93395336", "title": "Perspectives on shear banding in complex fluids", "abstract": "In this review, I present an idiosyncratic view of the current state of shear banding in complex fluids. Particular attention is paid to some of the outstanding issues and questions facing the field, including the applicability of models that have “traditionally” been used to model experiments; future directions and challenges for experimentalists; and some of the issues surrounding vorticity banding, which has been discussed theoretically and whose experiments are fewer in number yet, in many ways, more varied in character.", "corpus_id": 93395336, "score": 0 }, { "doc_id": "1274226", "title": "Phenomenology and physical origin of shear localization and shear banding in complex fluids", "abstract": "We review and compare the phenomenological aspects and physical origin of shear localization and shear banding in various material types, namely emulsions, suspensions, colloids, granular materials, and micellar systems. It appears that shear banding, which must be distinguished from the simple effect of coexisting static-flowing regions in yield stress fluids, occurs in the form of a progressive evolution of the local viscosity toward two significantly different values in two adjoining regions of the fluids in which the stress takes slightly different values. This suggests that from a global point of view, shear banding in these systems has a common physical origin: Two physical phenomena (for example, in colloids, destructuration due to flow and restructuration due to aging) are in competition, and depending on the flow conditions, one of them becomes dominant and makes the system evolve in a specific direction.", "corpus_id": 1274226, "score": 0 }, { "doc_id": "14829873", "title": "On the existence of a simple yield stress fluid behavior", "abstract": "Abstract Materials such as foams, concentrated emulsions, dense suspensions or colloidal gels, are yield stress fluids. Their steady flow behavior, characterized by standard rheometric techniques, is usually modeled by a Herschel–Bulkley law. The emergence of techniques that allow the measurement of their local flow properties (velocity and volume fraction fields) has led to observe new complex behaviors. It was shown that many of these materials exhibit shear banding in a homogeneous shear stress field, which cannot be accounted for by the standard steady-state constitutive laws of simple yield stress fluids. In some cases, it was also observed that the velocity fields under various conditions cannot be modeled with a single constitutive law and that nonlocal models are needed to describe the flows. Doubt may then be cast on any macroscopic characterization of such systems, and one may wonder if any material behaves in some conditions as a Herschel–Bulkley material. In this paper, we address the question of the existence of a simple yield stress fluid behavior. We first review experimental results from the literature and we point out the main factors (physical properties, experimental procedure) at the origin of flow inhomogeneities and nonlocal effects. It leads us to propose a well-defined procedure to ensure that steady-state bulk properties of the materials are studied. We use this procedure to investigate yield stress fluid flows with MRI techniques. We focus on nonthixotropic dense suspensions of soft particles (foams, concentrated emulsions, Carbopol gels). We show that, as long as they are studied in a wide (as compared to the size of the material mesoscopic elements) gap geometry, these materials behave as ‘simple yield stress fluids’: they are homogeneous, they do not exhibit steady-state shear banding, and their steady flow behavior in simple shear can be modeled by a local continuous monotonic constitutive equation which accounts for flows in various conditions and matches the macroscopic response.", "corpus_id": 14829873, "score": 0 }, { "doc_id": "122017144", "title": "Constitutive equations for thixotropic fluids", "abstract": "To distinguish it clearly from nonlinear viscoelasticity, we define “ideal thixotropy” as “a time-dependent viscous response to the history of the strain rate, with fading memory of that history,” endowing such fluids with memory but no elasticity. An “ideal thixotropic fluid” has instantaneous stress relaxation upon cessation of flow and no elastic recoil on removal of stress. We describe “nonideal thixotropic” fluids as those whose viscoelastic time scales governing stress relaxation are much shorter than those governing the thixotropic response. This ensures that a clear distinction can be maintained between “thixotropy” and “nonlinear viscoelasticity.” The stress tensor for an ideal thixotropic fluid can in general be expressed as a contraction product of a fourth rank viscosity tensor with the velocity gradient tensor, in which the viscosity tensor depends on the history of the flow. We show examples of constitutive equations that meet the definitions of ideal thixotropy or nonideal thixotropy. We al...", "corpus_id": 122017144, "score": 0 }, { "doc_id": "54753461", "title": "Flow of a thixotropic or antithixotropic fluid in a slowly varying channel: the weakly advective regime", "abstract": "Abstract A general formulation of the governing equations for the slow, steady, two-dimensional flow of a thixotropic or antithixotropic fluid in a channel of slowly varying width is described. These equations are equivalent to the equations of classical lubrication theory for a Newtonian fluid, but incorporate the evolving microstructure of the fluid, described in terms of a scalar structure parameter. We demonstrate how the lubrication equations can be further simplified in the weakly advective regime in which the advective Deborah number is comparable to the aspect ratio of the flow, and present illustrative analytical and semi-analytical solutions for particular choices of the constitutive and kinetic laws, including a purely viscous Moore–Mewis–Wagner model and a regularised viscoplastic Houska model. The lubrication results also allow the calibration and validation of cross-sectionally averaged, or otherwise reduced, descriptions of thixotropic channel flow which provide a first step towards models of thixotropic flow in porous media, and we employ them to explain why such descriptions may be inadequate.", "corpus_id": 54753461, "score": 1 }, { "doc_id": "122962089", "title": "On the lubrication paradox and the use of regularisation methods for lubrication flows", "abstract": "Abstract In this paper we complete the analysis of the flow of a Bingham fluid along a wavy-walled channel. We confirm numerically the results of [I. Frigaard, D. Ryan, Flow of a visco-plastic fluid in a channel of slowly varying width, J. Non-Newt. Fluid Mech. 123 (2004) 67–83], that there is a true rigid plug for a sufficiently small amplitude long wavelength perturbation of the uniform plane channel. For larger amplitude width perturbations the plug breaks and we provide a comparison between analytical estimates for the breaking amplitude and numerical computations using the augmented Lagrangian method. Plug breaking arises due to the creation of significant extensional stresses within the unyielded part of the fluid. When the plug breaks the extensional stresses govern the structure of the flow within the pseudo-plug. We provide a complete asymptotic solution for the flow in this situation, and compare against numerical computations. In the second part of the paper, we study the efficacity of viscosity regularisation methods for computing this type of flow. We show that accurate resolution of yield surface positions requires proper control of the numerical residuals and having a favourable ratio of regularisation error to critical strain rate. We show that failure to manage these errors means that regularisation methods can produce completely erroneous predictions of the yield surfaces, e.g. predicting broken plug regions when they are in fact intact. For general lubrication-type flows one does not have an estimate of these errors.", "corpus_id": 122962089, "score": 1 }, { "doc_id": "119749625", "title": "Models for flow of non-Newtonian and complex fluids through porous media", "abstract": "Abstract This article first provides a brief and simple account of continuum models for transport in porous media, and of the role of length scales in passing from pore-scale phenomena to “Darcy” continuum scale representations using averaged variables. It then examines the influence of non-Newtonian rheology on the single- and multi-phase transport parameters, i.e. Darcy viscosity, dispersion lengths and relative permeabilities. The aim is to deduce functional forms and values for these parameters given the rheological properties of the fluid or fluids in question, and the porosity, permeability, dispersion lengths and relative permeabilities (based on Newtonian fluids and equivalent capillary pressures) of the porous medium. It is concluded that micro-models, typically composed of capillary networks, applied at a sub-Darcy-scale, parameterised using data for flows of a well-characterised set of non-Newtonian fluids, are likely to provide the most reliable means.", "corpus_id": 119749625, "score": 0 }, { "doc_id": "122400979", "title": "A 1.5D numerical model for the start up of weakly compressible flow of a viscoplastic and thixotropic fluid in pipelines", "abstract": "Abstract We investigate the problem of the start up of a compressible flow in a pipeline filled with a viscoplastic and thixotropic material. The objective of this study is to examine the possibility that the flow can restart for a pressure drop below the value predicted by the conservative relation Δ p ˆ = 4 τ ˆ y L ˆ / D ˆ , where τ ˆ y denotes the yield stress, L ˆ the pipe length and D ˆ the pipe diameter, thanks to the combined effects of compressibility and thixotropy. Our numerical model is a compromise between a fully 2D model and a fully 1D model, i.e., a 1.5D model. Only the velocity component in the direction of the pipe axis is assumed non-zero but it is allowed to vary both in axial and radial directions. We show that this intermediate model yields accurate results which are consistent with the predictions of the fully 2D model. The gain in computing time while keeping an equivalent reliability in the numerical predictions enables us to investigate the effects of the compressibility and thixotropy dimensionless numbers at a reasonable cost.", "corpus_id": 122400979, "score": 1 }, { "doc_id": "120576811", "title": "Thixotropy : Build-up and breakdown curves during flow", "abstract": "Thixotropic systems are usually characterized by measuring the stress transients resulting from sudden changes in shear rate. By using a procedure that takes into account the transfer function of the transducer on a strain-controlled rheometer, the initial part of the transients could be accessed. In this manner complete transient stress curves and accurate constant-structure curves could be recorded on a model system consisting of fumed silica particles dispersed in a Newtonian medium. In agreement with previously obtained stress jump data [Dullaert and Mewis (2005b)], an initial viscoelastic response is detected that precedes the structural time effects in either build-up or breakdown experiments. The effect of flow history on the characteristic times and on the shape of the transient curves is investigated. It is shown that common assumptions in thixotropic models, such as a structure that can be characterized by a single parameter or the existence of exponential stress transients, do not generally hol...", "corpus_id": 120576811, "score": 0 }, { "doc_id": "119441196", "title": "Constitutive equations for extensional flow of wormlike micelles: stability analysis of the Bautista–Manero model", "abstract": "Abstract We carry out a stability analysis of the Bautista–Manero (B–M) constitutive equations for extensional flow of wormlike micelles. We show that all solutions for the steady-state extensional viscosity η E are unstable when the elongational rates ɛ ˙ exceed some critical value. In some cases the only real solution for the extensional viscosity is negative at intermediate values of the elongational rate. This critical elongational rate is not unfeasibly large, e.g., 250 s−1 for a typical EHAC solution. We note that the extension rates at which enhanced pressure drop is observed experimentally in porous media flow is generally well below the onset of the instability in the B–M model. However, the extension rates presented here are only average values for the porous media in question and at the pore scale a wide range of values will be encountered. For this reason, we require an improved rheological equation of state. We first separate the contributions to the viscosity of the solution and the wormlike micelles. Then, we remove the term containing the retardation time λ J . We now find that the extensional flow behaviour is well defined for both the transient and steady-state cases.", "corpus_id": 119441196, "score": 0 }, { "doc_id": "96769796", "title": "Thixotropic flow of toothpaste through extrusion dies", "abstract": "A commercial toothpaste is investigated in this work as a model paste system to study its processing characteristics in capillary flow using various dies. Its rheological behaviour has been determined as that of a yield-stress, thixotropic material with a time-dependent behaviour, and severe slip at the wall. The rheological data obtained from a parallel-plate rheometer were used to formulate a constitutive equation with a structural parameter which obeys a kinetic equation, typically used to model thixotropy. The predictive capabilities of this model are tested against capillary data for a variety of capillary dies having different length-to-diameter ratios (L/D), contraction angles (2a), and contraction ratios (Db/D) 2 , where Db is the diameter of the barrel of the capillary rheometer. The major trends are well captured by the thixotropic model and show that slip is the essential parameter in predicting the flow behaviour of toothpaste. 2011 Elsevier B.V. All rights reserved.", "corpus_id": 96769796, "score": 0 }, { "doc_id": "122603388", "title": "An exact solution for laminar, unidirectional flow of Houska thixotropic fluids in a circular pipe", "abstract": "Abstract Laminar flow of an incompressible thixotropic liquid which obeys the Houska model as its constitutive equation is investigated theoretically in a circular pipe under equilibrium (steady) conditions. Having derived the single differential equation governing fully-developed, unidirectional, pipe flow of this fluid model, it is shown that an analytical solution is possible for the linear case of the Houska model. The existence and uniqueness of the analytical solution so-obtained is examined theoretically. For the more general nonlinear case of the Houska model, the trust region algorithm is used to obtain numerical results for the flow characteristics. The effects of thixotropic parameters such as breakdown-to-rebuild ratio, viscosity ratio, and Bingham number are investigated on the structural parameter and velocity profiles. As a special case, pipe flow of a thixotropic fluid obeying the Moore model is addressed and a correct boundary condition is proposed at the pipe centerline for this particular fluid model.", "corpus_id": 122603388, "score": 0 }, { "doc_id": "49478481", "title": "The Stokes boundary layer for a thixotropic or antithixotropic fluid", "abstract": "We present a mathematical investigation of the oscillatory boundary layer (‘Stokes layer’) in a semi-infinite fluid bounded by an oscillating wall (the socalled ‘Stokes problem’), when the fluid has a thixotropic or antithixotropic rheology. We obtain asymptotic solutions in the limit of small-amplitude oscillations, and we use numerical integration to validate the asymptotic solutions and to explore the behaviour of the system for larger-amplitude oscillations. The solutions that we obtain differ significantly from the classical solution for a Newtonian fluid. In particular, for antithixotropic fluids the velocity reaches zero at a finite distance from the wall, in contrast to the exponential decay for a thixotropic or a Newtonian fluid. For small amplitudes of oscillation, three regimes of behaviour are possible: the structure parameter may take values defined instantaneously by the shear rate, or by a long-term average; or it may behave hysteretically. The regime boundaries depend on the precise specification of structure build-up and breakdown rates in the rheological model, illustrating the subtleties of complex fluid models in non-rheometric settings. For larger amplitudes of oscillation the dominant behaviour is hysteretic. We discuss in particular the relationship between the shear stress and the shear rate at the oscillating wall.", "corpus_id": 49478481, "score": 0 }, { "doc_id": "12227533", "title": "Plasticity and geophysical flows: A review", "abstract": "The objective of this review is to examine how the concept of plasticity is used in geophysical fluid dynamics. Rapid mass movements such as snow avalanches or debris flows involve slurries of solid particles (ice, boulder, clay, etc.) within an interstitial fluid (air, water). The bulk behavior of these materials has often been modeled as plastic materials, i.e., a plastic material yields and starts to flow once its stress state has significantly departed from equilibrium. Two plastic theories are of common use in fluid dynamics: Coulomb plasticity and viscoplasticity. These theories have little in common, since ideal Coulomb materials are two-phase materials for which pore pressure and friction play the key role in the bulk dynamics, whereas viscoplastic materials (e.g., Bingham fluids) typically behave as single-phase fluids on the macroscopic scale and exhibit a viscous behavior after yielding. Determining the rheological behavior of geophysical materials remains difficult because they encompass coarse, irregular particles over a very wide range of size. Consequently, the true nature of plastic behavior for geophysical flows is still vigorously debated. In this review, we first set out the continuum-mechanics principles used for describing plastic behavior. The notion of yield surface rather than yield stress is emphasized in order to better understand how tensorial constitutive equations can be derived from experimental data. The notion of single-phase or two-phase behaviors on the macroscopic scale is then examined using a microstructural analysis on idealized suspensions of spheres within a Newtonian fluid; for these suspensions, the single-phase approximation is valid only at very high or low Stokes numbers. Within this framework, the bulk stress tensor can also be constructed, which makes it possible to give a physical interpretation to yield stress. Most of the time, depending on the bulk properties (especially, particle size) and flow features, bulk behavior is either Coulomb-like or viscoplastic in simple-shear experiments. The consequences of the rheological properties on the flow features are also examined. Some remarkable properties of the governing equations describing thin layers flowing down inclined surfaces are discussed. Finally, the question of parameter fitting is tackled: since rheological properties cannot be measured directly in most cases, they must be evaluated from field data. As an example, we show that the Coulomb model successfully captures the main traits of avalanche motion, but statistical analysis demonstrates that the probability distribution of the friction coefficient is not universal.", "corpus_id": 12227533, "score": 0 }, { "doc_id": "122735397", "title": "The effect of a variable plastic viscosity on the restart problem of pipelines filled with gelled waxy crude oils", "abstract": "Abstract The effect of a variable plastic viscosity is numerically investigated on the success of the restart operation for a pipeline filled with fully-gelled waxy crude oil. To investigate the separate effects of structure- and shear-dependent viscosity, waxy crude oil is assumed to obey the Houska rheological model. In order to precisely capture the shape and position of the yielding surface, a variational approach is used to formulate the restart problem for this particular fluid model. The numerical results show that a variable plastic viscosity has a significant effect on the restart operation. For certain set of parameters the restart operation is shown to fail if the plastic viscosity is constant but is successful if the plastic viscosity is (moderately) structure-dependent. However, the time needed by the liquefied gel to discharge from the pipe outlet section is increased if the plastic viscosity is structure-dependent. Surprisingly, the shear-thinning behavior of waxy crude oil is predicted to lower the (steady) flow rate even when the restart is successful.", "corpus_id": 122735397, "score": 0 }, { "doc_id": "121018588", "title": "Flows of Materials with Yield", "abstract": "Steady, two‐dimensional flows of Bingham fluids are analyzed by means of a modified constitutive relation that applies everywhere in the flow field, in both yielded and practically unyielded regions. The conservation equations and the constitutive relation are solved simultaneously by Galerkin finite element and Newton iteration. This combination eliminates the necessity for tracking yield surfaces in the flow field. The analysis is applied to a one‐dimensional channel flow, a two‐dimensional boundary layer flow, and a two‐dimensional extrusion flow. The finite element predictions compare well with available analytic solutions for limiting cases.", "corpus_id": 121018588, "score": 0 }, { "doc_id": "122065201", "title": "Flow of a visco-plastic fluid in a channel of slowly varying width", "abstract": "Abstract We develop an asymptotic solution for the Poiseuille flow of a Bingham fluid along a two-dimensional channel of slowly varying width, for the case of small amplitude width variation, h . We show that an asymptotic solution with an intact unyielded plug region can be found for h less than a critical value h c ∼ O ( δ ) , where δ is the aspect ratio (channel half-width to wavelength of the variation). Our method involves no form of relaxation of the exact Bingham model. We provide upper and lower estimates for h c . The function h c / δ shows little variation with δ ≪ 1 , and exhibits a maximum in Bingham number, B , at around B ≈ 5 . There is a small variation in the true plug speed from that of the uniform channel flow. At small B the perturbed plug moves slightly slower than that in the uniform channel, whereas at large B the true plug moves faster than the uniform channel flow. Finally, we consider the structure of the flow for h ∼ O ( 1 ) , for which the plug has broken.", "corpus_id": 122065201, "score": 0 }, { "doc_id": "117738698", "title": "Advanced Transport Phenomena: Fluid Mechanics and Convective Transport Processes", "abstract": "1. A preview 2. Basic principles 3. Unidirectional and one-dimensional flow and heat transfer processes 4. An introduction to asymptotic approximations 5. The thin gap approximation - lubrication problems 6. The thin gap approximation - films with a free surface 7. Creeping flow - general properties and solutions for 2D and axisymmetric problems 8. Creeping flow - 3D problems 9. Convection effects and heat transfer for viscous flows 10. Boundary layer theory for laminar flows 11. Heat and mass transfer at large Reynolds number 12. Hydrodynamic stability Appendix A. Governing equations and vector operations in Cartesian, cylindrical and spherical coordinate systems Appendix B. Cartesian component notation.", "corpus_id": 117738698, "score": 0 }, { "doc_id": "59034342", "title": "Squeeze flow behavior of (soft glassy) thixotropic material", "abstract": "We study the flow behavior of a model soft glassy material − an aqueous suspension of Laponite − when it is squeezed between two circular parallel plates of different roughness. Aqueous suspension of Laponite shows a time dependent aging behavior as reflected in increased elastic modulus as well as yield stress, both of which however also decrease with an increase in the strength of deformation field thereby demonstrating typical thixotropic character. In a squeeze flow situation, under both force as well as velocity controlled modes; we find the behavior to be independent of the initial gap between the plates. In a constant force mode, the gap between the plates decreases until it reaches a finite limiting value, which is found to increase with an increase in age of the material as well as with a decrease in the applied force. In constant velocity experiments, at large gaps between the plates, normal force varies inversely with plate separation. The normal force is higher for a sample aged for a longer time as well as for a larger velocity of the top plate. We observe that the experimental behavior follows prediction of Herschel–Bulkley model solved for the squeeze flow (with different friction coefficients at the two plates) reasonably well under weak deformation fields. However, under strong deformation fields, experimental behavior deviates significantly from the prediction of Herschel–Bulkley model. This deviation arises due to melting or partial yielding of Laponite suspension under large deformation fields causing decrease in the viscosity, elastic modulus and the yield stress.", "corpus_id": 59034342, "score": 0 }, { "doc_id": "135541023", "title": "Squeeze Flow of Semi-Solid Slurries", "abstract": "A standard method used to determine material properties of semi-solid slurries is the squeeze flow experiment in which a fixed amount of material is squeezed under constant force or velocity. The relation between the force and the displacement provides information about the rheology of the slurry. The thixotropy and the time response of the sample however is rarely, if ever, taken into consideration. In this work we study how thixotropy affects the flow characteristics and consequently the predicted material properties. We show that depending on the method of compression and the thixotropic constants the flow can be significantly different. Therefore the predicted material constants can vary and hence cannot be unique.", "corpus_id": 135541023, "score": 0 }, { "doc_id": "55284857", "title": "Shallow flows of generalised Newtonian fluids on an inclined plane", "abstract": "We derive a general evolution equation for a shallow layer of a generalised Newtonian fluid undergoing two-dimensional gravity-driven flow on an inclined plane. The flux term appearing in this equation is expressed in terms of an integral involving the prescribed constitutive relation and, crucially, does not require explicit knowledge of the velocity profile of the flow; this allows the equation to be formulated for any generalised Newtonian fluid. In particular, we develop general solutions for travelling waves on a mild slope and for kinematic waves on a moderately steep slope; these results provide simple and accessible models of, for example, the propagation of non-Newtonian mud and debris flows.", "corpus_id": 55284857, "score": 0 } ]

{ "doc_id": "4506758", "title": "Anthropogenic forcing on tropospheric ozone and OH since preindustrial times", "abstract": "A global three-dimensional model of tropospheric chemistry is used to investigate the changes in tropospheric O3 and OH since preindustrial times as a result of fuel combustion and industry, biomass burning, and growth in atmospheric CH4. Model results indicate a 63% increase of the global tropospheric O3 burden from preindustrial times to present (80% and 50% in the northern and southern hemispheres, respectively). Anthropogenic emissions of NOx and of CO and hydrocarbons make comparable contributions to the global O3 increase (60% and 40% respectively), even though the local rate of tropospheric O3 production is generally NOχ limited. The rise in O3 production parallels closely the rise in the emissions of CO and hydrocarbon because the O3 yield per mole of CO or hydrocarbon oxidized has remained constant at 0.7–0.8 mol/mol since preindustrial times. In contrast, the O3 production efficiency per mole of NOχ emitted has decreased globally by a factor of 2. We find a 9% decrease in the global mean OH concentration (mass-weighted) since preindustrial times. A linear relationship is found in the model between the global mean OH concentration and the SN/SC3/2 ratio, where SN and SC are the sources of NOχ and of CO and hydrocarbons, respectively. The relative constancy of the global mean OH concentration since preindustrial times reflects the conservation of the SN/SC3/2 ratio despite large increases in both SN and SC. Comparisons of model results with reconstructed nineteenth century observations of O3 at continental sites indicate a systematic overestimate of about 5 ppbv. Correcting this overestimate would require either a large missing chemical sink for O3 or a downward revision of the natural NOχ source from lightning (3 Tg N yr−1 in our model). The nineteenth century observations of O3 over France show no vertical gradient between the boundary layer and the free troposphere, which is inconsistent with our current understanding of tropospheric O3. The model underestimates preindustrial CO concentrations derived from polar ice cores; these measurements are difficult to reconcile with any reasonable CO emission inventories.", "corpus_id": 4506758 }

[ { "doc_id": "4319679", "title": "Evaluation of the Montsouris series of ozone measurements made in the nineteenth century", "abstract": "There is growing evidence that ozone levels in the lower troposphere over the continents of the Northern Hemisphere have been increasing during the past decades1,2. Questions regarding pre-industrial or 'background' ozone concentrations have led to the search for data from the early days of ozone monitoring, during the second half of the last century. Unfortunately, most measurements were then made using Schönbein test paper, giving only semi-quantitative information due to poor standardization and the influence of humidity and wind speed on its sensitivity3–5. We have reinvesti-gated a set of ozone measurements gathered at the Observatoire de Montsouris, located on the outskirts of Paris, where a quantitative method was established in 18766 and used continuously for 34 years. The evaluation of the technique, together with the analysis of nearly 3,000 of the original daily measurements that previously remained unnoticed in a statistical bulletin of the City of Paris7, provides conclusive evidence that ozone levels in central Europe 100 years ago averaged 10 p.p.b. and exhibited a seasonal variation, with a maximum during the spring months. Comparisons with modern data show that ozone levels in rural areas have more than doubled over the past century and that the tropospheric ozone budget is now strongly influenced by photochemical production due to increased levels of NOx.", "corpus_id": 4319679, "score": 0 }, { "doc_id": "129369863", "title": "Tropospheric ozone in the nineteenth century: The Moncalieri series", "abstract": "A 26-year (1868–1893) data series of daily ozone readings performed at Moncalieri, northern Italy, by the Schonbein test paper technique has been analyzed. The availability of a series of simultaneous readings by the Schonbein and a quantitative technique (Levy, 1877) and the conversion chart for humidity by Linvill et al. (1980) allowed us to develop a procedure to convert the Moncalieri data into parts per billion by volume values. The results seem to indicate that in comparison to one century ago, the ozone level in Europe has increased by more than twice not only at the surface but also in the free troposphere.", "corpus_id": 129369863, "score": 1 }, { "doc_id": "140686628", "title": "Surface ozone levels at the end of the nineteenth century in South America", "abstract": "Records of surface ozone data collected twice a day by means of the Schonbein method at Villa Colon, Montevideo, Uruguay, during the years 1883–1885 and at Cordoba, Argentina, during the years 1886–1892 have been converted to present-day concentrations. Most of the uncertainties suffered from the original technique are removed by a two-step procedure, in particular a conversion algorithm for humidity and a linear regression constructed by simultaneous readings of Schonbein and a quantitative method. The relative error of this procedure, previously applied to the Moncalieri data series, is 33%. Within these limitations we can state that one century ago the surface ozone levels at that latitude of the southern hemisphere were comparable to those of Moncalieri and Montsouris. Furthermore, the recent levels observed in remote areas at that latitude are approximately twice as large as a century ago.", "corpus_id": 140686628, "score": 1 }, { "doc_id": "127671398", "title": "Evidence of a long‐term increase in tropospheric ozone from Pic du Midi data series: Consequences: Positive radiative forcing", "abstract": "The rate at which ozone is increasing in the troposphere is uncertain due to the lack of accurate long-term measurements. Old ozone measurements obtained at the Pic du Midi Observatory (3000 m high, southwestern France) were recently rediscovered. Four sets of data available at this station are presented herein: (1) 1874–1881 and (2) 1881–1909 by the Schonbein method and (3) 1982–1984 and (4) 1990–1993 by UV absorption analyzers. The results show an increase in ozone by a factor of 5 since the beginning of the twentieth century, corresponding to an exponential increase of 1.6% per year, although this trend is probably higher (2.4% per year) for the last few decades. A stable 10 ppb ozone mixing ratio is observed during the first 20 years of the series, which is representative of the preindustrial era ozone level. The increase is seen to start around 1895. Other data, obtained at various European high-altitude stations between 1920 and 1980, tie in closely with the Pic du Midi observations. A tentative evaluation of the impact of tropospheric ozone on radiative forcing confirms that ozone is currently the second most significant greenhouse gas, responsible for 22% and 13% of radiative forcing changes since 1800 in the northern and southern hemispheres, respectively. If these rates were to be maintained in the future, ozone would continue to evolve differently in the two hemispheres (maximum level in the northern hemisphere) and could make an even more significant contribution to the radiative forcing of the northern hemisphere.", "corpus_id": 127671398, "score": 1 }, { "doc_id": "27360206", "title": "The Oxidizing Capacity of the Earth's Atmosphere: Probable Past and Future Changes", "abstract": "The principal oxidants in the lower atmosphere are ozone (O3) and two by-products of O3 photodissociation, the hydroxyl radical (OH) and hydrogen peroxide (H2O2). A number of critical atmospheric chemical problems depend on the earth's \"oxidizing capacity,\" which is essentially the global burden of these oxidants. There is limited direct when, because of industrial and population growth, increasing amounts of O3 precursor trace gases (carbon monoxide, nitrogen oxides, and hydrocarbons) have been released into the atmosphere. The concentrations of O3 and possibly H2O2 have increased over large regions. Models predict that tropospheric O3 will increase ∼0.3 to 1% per year over the next 50 years with both positive and negative trends possible for OH and H2O2. Models and the observational network for oxidants are improving, but validation of global models is still at an early stage.", "corpus_id": 27360206, "score": 1 }, { "doc_id": "97875573", "title": "The changing photochemistry of the troposphere", "abstract": "The chemistry of the troposphere is substantially influenced by a wide range of chemical processes which are primarily driven by the action of solar ultraviolet radiation of wavelengths shorter than about 310 nm on ozone and water vapour. This leads to the formation of hydroxyl (OH) radicals which, despite very low tropospheric concentrations, remove most gases that are emitted into the atmosphere by natural and anthropogenic processes. Although tropospheric ozone only makes up about 10% of all atmospheric ozone, through the formation of OH, it determines the oxidation efficiency of the atmosphere and it is, therefore, of the utmost importance for maintaining the chemical composition of the atmosphere. Due to a variety of human activities, leading especially to increasing emissions of CH 4 , CO and NO x , it is conceivable that the concentrations of ozone are increasing in polluted and those of hydroxyl decreasing in clean tropospheric environments. The result is most likely an overall decrease in the oxidation efficiency of the atmosphere and consequently a buildup of several longlived trace gases that are primarily removed by reaction with OH. Here we discuss the most important processes that determine the oxidation efficiency of the atmosphere and give some examples of changes in O 3 , CO, and OH concentration distributions that may have occurred as a result of human activities. DOI: 10.1034/j.1600-0889.1991.t01-1-00012.x", "corpus_id": 97875573, "score": 0 }, { "doc_id": "129747977", "title": "The atmospheric CH 4 increase since the Last Glacial Maximum", "abstract": "An estimate of the distribution of wetland area and associated CH 4 emission is presented for the Last Glacial Maximum (LGM, 18 kyr BP, kiloyear Before Present) and the Pre-Industrial Holocene (PIH, 9000–200 years BP). The wetland source, combined with estimates of the other biogenic sources and sink, yields total source strengths of 120 and 180 Tg CH 4 /yr for LGM and PIH respectively. These source strengths are shown to be consistent with source estimates inferred from a photochemical model, and point to changes in wetland CH 4 source as a major factor driving the atmospheric CH 4 increase from LGM to PIH. DOI: 10.1034/j.1600-0889.1993.t01-2-00002.x", "corpus_id": 129747977, "score": 0 }, { "doc_id": "129083984", "title": "The chemical composition of ancient atmospheres: A model study constrained by ice core data", "abstract": "A coupled chemistry radiation transport two-dimensional model of the lower and middle atmosphere was adapted to study the chemical composition of the atmosphere at preindustrial time and last glacial maximum (LGM). The model was constrained by trace gas concentrations (CO2, CH4, and N2O) inferred from polar ice core records. The formulation of tropospheric dynamics and chemistry was improved in order to more accurately simulate the transport and the oxidation processes below the tropopause. Our objectives are to infer the changes in middle-atmosphere temperature, ozone layer, and oxidation capacity of the atmosphere (e.g., methane lifetime) over the last 18,000 years. A middle-atmosphere cooling was obtained between LGM and preindustrial Holocene (PIH) as well as between PIH and present time. This is mainly due to changes in the CO2 and chlorofluorocarbon (CFC) concentrations, respectively. CFCs are also the main contributors to the middle-atmosphere ozone decrease since PIH. Between LGM and PIH the compensating effects of CO2 and N2O lead to little variation in stratospheric ozone. A 17% decrease in tropospheric OH was obtained between LGM and PIH, whereas the model provides a 6% OH increase since PIH. The corresponding changes in the methane sink are too small to have played a dominant role in the past methane concentration changes. Our model derived methane emissions for LGM, PIH, and present time are in good agreement with methane sources evaluated during these three periods.", "corpus_id": 129083984, "score": 0 }, { "doc_id": "94320002", "title": "Ozone chemistry changes in the troposphere and consequent radiative forcing of climate.", "abstract": "A global three-dimensional transport/chemistry model of the troposphere has been applied to simulate changes in the chemical composition of the troposphere since pre-industrial times. Calculated increases of tropospheric O3 have been evaluated with a radiative transfer model. Our calculations confirm earlier studies that the combined effects of anthropogenic NOx, CO and CH4 emissions cause a strong enhancement of O3 levels throughout the global troposphere, while this blend of emissions does not seem to have affected global average OH concentrations significantly. In fact, anthropogenic NOx induced photochemistry may have compensated for the strong OH reduction which would have resulted from anthropogenic CO and CH4 emissions alone. Our model simulations suggest that during the past 1.5 Century net photochemical 03 formation in the global troposphere has changed sign, from -87 Tg/yr to 427 Tg/yr, caused mostly by anthropogenic emissions in the mid- latitude northern hemisphere and to a lesser extent by biomass burning emissions in the tropics. We calculate that the global O3 burden in the troposphere has increased by a factor of 1.7, the CO burden by a factor of 2.5 and that of H2O2 by a factor of 2. Preliminary calculations suggest that the global mean radiative forcing of climate by increasing tropospheric O3 is 0.55 W/m2 for the month July, maximizing in the mid-latitude northern hemisphere, and 0.44 W/m2 for January; the annual average, about 0.5 W/m2, is approximately one third of the radiative forcing by increasing CO2.", "corpus_id": 94320002, "score": 1 }, { "doc_id": "128764637", "title": "Three‐dimensional view of the large‐scale tropospheric ozone distribution over the North Atlantic Ocean during summer", "abstract": "A global chemical transport model is used to study the three-dimensional structure of the tropospheric ozone (O3) distribution over the North Atlantic Ocean during summer. A simplified representation of summertime O3 photochemistry appropriate for northern hemisphere midlatitudes is included in the model. The model is evaluated by comparing simulated O3 mixing ratios to summertime O3 measurements taken in and near the North Atlantic Ocean basin. The model successfully reproduces (1) the means and standard deviations of ozonesonde measurements over North America at 500 mbar; (2) the statistical characteristics of surface O3 data at Sable Island off the coast of North America and at Bermuda in the western North Atlantic; and (3) the mean midtropospheric O3 measured at Bermuda and also at the Azores in the eastern North Atlantic. The model underestimates surface O3 in the eastern North Atlantic, overestimates O3 in the lower free troposphere over the western North Atlantic, and also has difficulty simulating the upper tropospheric ozonesonde measurements over North America. An examination of the mean summertime O3 distribution simulated by the model shows a significant continental influence on boundary layer and free-tropospheric O3 over the western North Atlantic. The model has also been exercised using a preindustrial NOx emission scenario. By comparing the present-day and preindustrial simulations, we conclude that anthropogenic NOx emissions have significantly perturbed tropospheric O3 levels over most of the North Atlantic. We estimate that present-day O3 levels in the lower troposphere over the North Atlantic are at least twice as high as corresponding preindustrial O3 levels. We find that the anthropogenic impact is substantial even in the midtroposphere, where modeled present-day O3 mixing ratios are at least 1.5 times higher than preindustrial O3 levels.", "corpus_id": 128764637, "score": 0 }, { "doc_id": "128899405", "title": "The global impact of human activity on tropospheric ozone", "abstract": "Within a conceptual framework of stratospheric injection, CO-CH4 background tropospheric chemistry, parameterized pollution production in the continental boundary layer and surface deposition, we use an 11 level GCTM to simulate global distributions of present and pre-industrial tropospheric O3. The chemistry is driven by previously simulated present and pre-industrial NOx fields, while prescribed fields of CO, CH4 and H2O are held constant. An evaluation with measurements from 12 surface sites, 21 ozonesonde sites and 1 aircraft campaign finds agreement within ±25% for 73% of the observations while identifying systematic errors in the wintertime high-latitude Northern Hemisphere (NH), the Southern Hemisphere (SH) tropics during biomass burning, and the remote SH. We predict that human activity has increased the annual integral of tropospheric ozone by 39% with 3/4's of that increase in the free troposphere, though the boundary layer [BL] annual integral has increased by 66%. The 2 largest components of the global O3 budget are stratospheric injection at 696 TgO3/yr, and loss through dry deposition, which increases from 459 TgO3/yr to a present level of 825 TgO3/yr. While tropospheric chemistry's net contribution is relatively small, changing from a pre-industrial destruction of −236 TgO3/yr to a present production of +128 TgO3/yr, it is a balance between two much larger terms, −558 TgO3/yr of destruction in the background troposphere and +686 TgO3/yr of production in the polluted boundary layer. Human impact on O3 predominates in the summertime extratropical NH and in the tropics during their biomass burning seasons [increases of 50%–100% or more]. Conversely, there has been little increase in most of the upper troposphere [<20%], where ozone's influence on tropospheric climate is strongest.", "corpus_id": 128899405, "score": 1 }, { "doc_id": "129698847", "title": "Efficient Three-Dimensional Global Models for Climate Studies: Models I and II", "abstract": "Abstract A global atmospheric model is developed with a computational efficiency which allows long-range climate experiments. The model solves the simultaneous equations for conservation of mass, energy and momentum, and the equation of state on a grid. Differencing schemes for the dynamics are based on work of Arakawa; the schemes do not need any viscosity for numerical stability, and can thus yield good results with coarse resolution. Radiation is computed with a semi-implicit spectral integration, including all significant atmospheric gases, aerosols and cloud particles. Cloud cover and vertical distribution are computed. Convection mixes moisture, heat and momentum, with buoyant air allowed to penetrate to a height determined by its buoyancy. Ground temperature calculations include diurnal variation and seasonal heat storage. Ground hydrology incorporates a water-holding capacity appropriate for the root zone of local vegetation. Snow depth is computed. Snow albedo includes effects of snow age and mas...", "corpus_id": 129698847, "score": 0 }, { "doc_id": "129655694", "title": "GLOBAL EMISSIONS OF NITROGEN AND SULFUR OXIDES FROM 1860 TO 1980", "abstract": "Statistical models have been developed that relate the rate of emissions of a pollutant to the rate of fuel consumption. These relations may be used to estimate emissions in other regions, or at other times, if fuel consumption data are available. This approach has been used to estimate global emissions of nitrogen and sulfur oxides in fossil fuel combustion at ten year intervals from 1860 to 1980. Emissions from each of the populated continents, i.e., North America, South America, Asia, Europe, Africa and Oceania from 1930 to 1980 are also presented. When averaged globally over the 1860 to 1980 period, sulfur emissions increased at the rate of 2.9 percent per year and the nitrogen emissions at the rate of 3.4 percent per year. The ratio of global sulfur emissions to nitrogen emissions has declined steadily; it was nearly 5 in the 19th century and became 3 by 1980. After the second world war, the most rapid increases in emissions have been registered in Asia, South America, and Africa.", "corpus_id": 129655694, "score": 0 }, { "doc_id": "128477566", "title": "High‐resolution ammonium ice core record covering a complete glacial‐interglacial cycle", "abstract": "High-resolution ammonium measurements were performed along the Greenland Ice Core Program (GRIP) deep ice core, covering a complete climatic cycle. No overall anthropogenic increase is observed over the last 300 years; however, springtime concentrations have roughly doubled since 1950. Biomass burning is estimated to be a major source for ammonia emissions for preindustrial times. It contributes between 10% to 40% to the total ammonium deposited on the central Greenland ice sheet during the Holocene. No correlation is found between the ammonium summer concentrations recorded over the last 100 years and the area burned in northern North America, which is considered to be the main source area for ammonium deposited on the central Greenland ice sheet. This suggests that the meteorological factor is predominant for the pattern of ammonium spikes observed in the ice core. If unchanged meteorological conditions are assumed for the Holocene, as indicated by the δ18O ice record, a decreasing biomass burning activity toward present time can be derived from the ammonium ice record. Soil and vegetation emissions are responsible for the ammonium background concentrations in the ice. The record therefore may be used to trace back the biomass history of the North American continent. A pronounced decreasing trend in background ammonium is found during the Holocene, reflecting decreasing temperature and therefore lower NH3 emissions in the source region. Variations in the ammonium concentration during the glacial age are discussed in terms of changes in transport and deposition mechanisms and changes in source strength, which can be related to the extent of the Laurentide ice sheet. The data suggest that the Laurentide ice sheet was built up immediately after the last interglacial and went through several large fluctuations during the last ice age.", "corpus_id": 128477566, "score": 0 }, { "doc_id": "123541238", "title": "Ozone in Michigan's Environment 1876–1880", "abstract": "Abstract Atmospheric ozone was monitored in Michigan during the late 1880's using Schoenbein's test paper. A conversion chart was constructed to relate the Schoenbein ozone scale at various relative humidifies to ozone levels indicated by a Dasibi ozone monitor. Average monthly ozone values were highest during the spring months and lowest during the winter season. Highest recorded ozone levels accompanied southwest wind flow into Michigan. Ozone level increased with time as an air mass passed over Michigan and dropped immediately after frontal passage. These patterns are similar to patterns observed in today's data. These results strongly suggest that anthropogenic nitrogen emitted by actively growing green plants and soils is the major source of photochemical ozone precursors in earth's boundary layer.", "corpus_id": 123541238, "score": 0 }, { "doc_id": "121388357", "title": "Surface Ozone During the Second Half of the Nineteenth Century", "abstract": "Abstract During the last few years, increases in tropospheric ozone concentration have been detected and the need for more study has been recognized. There is very little knowledge about surface ozone background concentrations prior to the advent of widespread gasoline combustion. Therefore, the aim of this study was to uncover any useful information from the nineteenth century, and to explore the feasibility of converting it to obtain an approximate level of ozone concentration. After discovering ozone, Schonbein promulgated a simple method using iodized starch paper for qualitatively assessing its amount present in the air. This method was implemented at a few hundred sites, and although vulnerable to influence by humidity and oxidants in the air, continued to be used into the early years of this century. In the search for the best method of converting the Schonbein data, the most useful data sources turned out to be the 31-year series of regular quantitative ozone concentration measurements at Montsour...", "corpus_id": 121388357, "score": 0 }, { "doc_id": "129769497", "title": "Time variations of CO and O3 concentrations in a region subject to biomass burning", "abstract": "Carbon monoxide (CO) and ozone (O3) concentrations have been observed in the Brazilian Amazon region, at a site strongly affected by biomass burning (Cuiaba, 16°S, 58°W). Time variations are described for the first long-term program of studying the effect of biomass burning on O3 and CO over a complete seasonal cycle, including the seasonal maxima of 1987 and 1988. Concentrations of O3 are measured continuously, and CO samples are collected three times a week. In order to obtain elements for comparison, an identical observational program was maintained at a site totally outside of the direct influence of biomass burning (Natal, 6°S, 35°W). The biomass burning contribution to the Cuiaba concentrations of CO and O3 is very large. Diurnal maximum concentrations exceeded 90 ppbv (parts per billion by volume) O3 in 1987 and 120 ppbv O3 in 1988, in September. For the wet season, the monthly average ozone concentration in March–April is about 10 ppbv. During the month of maxima, September, the O3 concentration average was 41 ppbv for 1987 and 71 ppbv for 1988. The CO concentrations are about 90 ppbv in the wet season. In September, 460 ppbv and 660 ppbv of CO were observed for 1987 and 1988, respectively. At Natal the seasonal variation is of the order of a factor of 2. For the biomass burning site this factor is 4 for 1987 and almost 7 for 1988. In contrast, during the wet season, the concentrations of CO and O3 at both stations are about the same.", "corpus_id": 129769497, "score": 0 }, { "doc_id": "54707207", "title": "Simulation of summertime ozone over North America", "abstract": "The concentrations of O3 and its precursors over North America are simulated for three summer months with a three-dimensional, continental-scale photochemical model using meteorological input from the Goddard Institute for Space Studies (GISS) general circulation model (GCM). The model has 4°×5° grid resolution and represents non linear chemistry in urban and industrial plumes with a subgrid nested scheme. Simulated median afternoon O3 concentrations at rural U.S. sites are within 5 ppb of observations in most cases, except in the south central United States where concentrations are overpredicted by 15–20 ppb. The model captures successfully the development of regional high-O3 episodes over the northeastern United States on the back side of weak, warm, stagnant anticyclones. Simulated concentrations of CO and nonmethane hydrocarbons are generally in good agreement with observations, concentrations of NOx are underpredicted by 10–30%, and concentrations of peroxyacylnitrates (PANs) are overpredicted by a factor of 2 to 3. The overprediction of PANs is attributed to flaws in the photochemical mechanism, including excessive production from oxidation of isoprene, and may also reflect an underestimate of PANs deposition. Subgrid nonlinear chemistry as captured by the nested plumes scheme decreases the net O3 production computed in the United States boundary layer by 8% on average.", "corpus_id": 54707207, "score": 0 }, { "doc_id": "97532770", "title": "Ozone levels in Paris one century ago", "abstract": "Based on a procedure for re-evaluating historical ozone data previously developed by the authors, ozone observations by the Schoenbein method in the Paris air quality network during 1876 were discovered, re-analysed and a yearly ozone level map was derived.", "corpus_id": 97532770, "score": 0 }, { "doc_id": "55303824", "title": "Dry deposition parameterization in a chemistry general circulation model and its influence on the distribution of reactive trace gases.", "abstract": "A dry deposition scheme has been developed for the chemistry general circulation model to improve the description of the removal of chemically reactive trace gases at the earth's surface. The chemistry scheme simulates background CH 4 -CO-NO x -HO x photochemistry and calculates concentrations of, for example, HNO 3 , NO x , and O 3 . A resistance analog is used to parameterize the dry deposition velocity for these gases. The aerodynamic resistance is calculated from the model boundary layer stability, wind speed, and surface roughness, and a quasi-laminar boundary layer resistance is incorporated. The stomatal resistance is explicitly calculated and combined with representative cuticle and mesophyll resistances for each trace gas. The new scheme contributes to internal consistency in the model, in particular with respect to diurnal and seasonal cycles in both the chemistry and the planetary boundary layer processes and surface characteristics that control dry deposition. Evaluation of the model indicates satisfactory agreement between calculated and observed deposition velocities. Comparison of the results with model simulations in which the deposition velocity was kept constant indicates significant relative differences in deposition fluxes and surface layer trace gas concentrations up to about ±35%. Shortcomings are discussed, for example, violation of the constant flux approach for the surface layer, the lacking canopy description, and effects of surface water layers.", "corpus_id": 55303824, "score": 0 }, { "doc_id": "53509035", "title": "Regional budgets for nitrogen oxides from continental sources: Variations of rates for oxidation and deposition with season and distance from source regions", "abstract": "Measurements of nitrogen deposition and concentrations of NO, NO2, NOy (total oxidized N), and O3 have been made at Harvard Forest in central Massachusetts since 1990 to define the atmospheric budget for reactive N near a major source region. Total (wet plus dry) reactive N deposition for the period 1990–1996 averaged 47 mmol m−2 yr−1 (126 μmol m−2 d−1, 6.4 kg N ha−1 yr−1), with 34% contributed by dry deposition. Atmospheric input adds about 12% to the N made available annually by mineralization in the forest soil. The corresponding deposition rate at a distant site, Schefferville, Quebec, was 20 mmol m−2 d−1 during summer 1990. Both heterogeneous and homogeneous reactions efficiently convert NOx to HNO3 in the boundary layer. HNO3 is subsequently removed rapidly by either dry deposition or precipitation. The characteristic (e-folding) time for NOx oxidation ranges from 0.30 days in summer, when OH radical is abundant, to ∼1.5 days in the winter, when heterogeneous reactions are dominant and O3 concentrations are lowest. The characteristic time for removal of NOx oxidation products (defined as NOy minus NOx) from the boundary layer by wet and dry deposition is ∼1 day, except in winter when it decreases to 0.6 day. Biogenic hydrocarbons contribute to N deposition through formation of organic nitrates but are also precursors of reservoir species, such as peroxyacetylnitrate, that may be exported from the region. A simple model assuming pseudo first-order rates for oxidation of NOx, followed by deposition, predicts that 45% of NOx in the northeastern U.S. boundary layer is removed in 1 day during summer and 27% is removed in winter. It takes 3.5 and 5 days for 95% removal in summer and winter, respectively.", "corpus_id": 53509035, "score": 0 }, { "doc_id": "129182792", "title": "Summertime tropospheric ozone distributions over central and eastern Canada", "abstract": "Ozone measurements were obtained between the surface and the 6-km altitude on aircraft flights over central and eastern Canada during the summer 1990 NASA Global Tropospheric Experiment Arctic Boundary Layer Expedition (GTE/ABLE 3B). Tropospheric O3 budgets for these regions were observed to be highly variable and significantly impacted by long-range transport and regional scale air mass modification processes. For example, integrated O3 abundance below 5-km altitude averaged 40% and 30% greater in air masses influenced by anthropogenic sources and biomass burning, respectively, than in background (polar) air. Conversely, aged air transported from subtropical areas of the Pacific at times reduced O3 abundance in this height interval by up to 20%. Though intrusion of anthropogenic air was infrequent during the experiment period, the influence of biomass-burning emissions was particularly notable as two thirds of the flights sampled air influenced by plumes from fires burning in Alaska and western Canada. The impinging pollution, both natural and anthropogenic, not only elevated O3 levels directly but also was a source of reactive nitrogen (and nonmethane hydrocarbons) which generally increases the tropospheric lifetime of O3 via moderation of photochemical destruction rates.", "corpus_id": 129182792, "score": 0 }, { "doc_id": "53602164", "title": "Origin of tropospheric ozone at remote high northern latitudes in summer", "abstract": "Author(s): Mauzerall, DL; Jacob, DJ; Fan, SM; Bradshaw, JD; Gregory, GL; Sachse, GW; Blake, DR | Abstract: We quantify the tropospheric ozone budget over remote high northern latitudes in summer using chemical and meteorological measurements between 0 and 6-km made during the summer of 1990 Arctic Boundary Layer Expedition (ABLE 3B). We include all components of the ozone budget, both sinks (in situ photochemical loss and deposition); and sources (in situ photochemical production, advection of pollution ozone into the region, production in biomass wildfire plumes, and downwards transport from the upper troposphere/stratosphere). In situ production and loss of ozone are calculated with a photochemical model. The net influx of pollution ozone from North America and Eurasia is estimated from the average enhancement ratio of ΔO3/ΔC2Cl4 observed in pollution plumes and scaled by the net influx of C2Cl4. The contribution of ozone produced in biomass wildfire plumes is estimated from the average enhancement ratio of ΔO3/ΔCO in aged fire plumes. Regional photochemical production and loss in the 0-6 km column are found to be approximately equal; hence, net photochemical production is near zero. However, when ozone production and loss terms are separated, we find that dispersed in situ photochemical production driven by background NO levels (5-10 pptv) is the largest source term in the ozone budget (62%). Influx of stratospheric ozone is of secondary importance (27%), long-range transport of pollution ozone makes a small contribution (9%), and photochemical production of ozone within biomass wildfire plumes is a relatively negligible term (2%) in the budget. Biomass fires and transport of anthropogenic pollution into the region may however have a major effect on the ozone budget through enhancement of background NOx mixing ratios which increase dispersed photochemical production. Using a I-D time-dependent photochemical model between 0 and 6 km, we obtain good agreement between the observed and model-generated vertical ozone profiles. We find that in situ photochemistry within the 0-6 km column accounts for nearly 90% of the ozone mixing ratio within the boundary layer, while above 5 km it accounts for only about 40%. Although photochemical production of ozone within the 0-6 km column is larger than the other source terms combined, the 1-D model results indicate that influx from above is necessary to account for the observed increase in ozone mixing ratios with altitude. Copyright 1996 by the American Geophysical Union.", "corpus_id": 53602164, "score": 0 }, { "doc_id": "128586997", "title": "Ice core data of atmospheric carbon monoxide over Antarctica and Greenland during the last 200 years", "abstract": "The first polar ice core measurements of carbon monoxide compatible with atmospheric data were obtained using an improved experimental protocol. A new CO extraction method has been developed with special care to eliminate any CO contamination. The procedure has been applied to ice core samples originating from Antarctica and Greenland in order to reconstruct past CO variations over the last 200 years. Consistent results in terms of atmospheric concentrations are obtained. We find that CO concentration started to increase over Greenland around 1850 and that, by contrast, CO levels at high southern latitudes remained fairly constant between 1860 and 1916. Based on available data on past CO sources, a scenario is proposed for the CO increase observed in Greenland. In addition, our Greenland CO results suggest that simulations of preindustrial CO distribution could have underestimated CO concentrations mainly in the northern hemisphere leading to an overestimate of the change since preindustrial times, and to an underestimate of the past interhemispheric gradient of carbon monoxide.", "corpus_id": 128586997, "score": 1 }, { "doc_id": "129621114", "title": "Secular increase of the total vertical column abundance of carbon monoxide above central Europe since 1950", "abstract": "The secular increase of the total vertical column abundance of carbon monoxide has been derived from sets of infrared solar spectra recorded from an altitude of 3.58 km at the Jungfraujoch Station, Switzerland, in 1950–1951 and in 1985–1987. The results are based on equivalent width measurements of the R3 line of the 1-0 vibration-rotation band of 12C16O at 2159.30 cm−1. The set of 1985–1987 observations indicates a strong seasonal cycle in the total column abundance of CO, with a ±25% modulation between minimum values in late summer and the maximum values in late winter. Variability on shorter time scales is also present in both the old and recent data sets. The mean cumulative rate of increase of the total column abundance of CO above the Jungfraujoch is found to be (0.85 ± 0.20)%/yr between 1950–1951 and 1985–1987. The present findings are compared with trends reported in earlier studies.", "corpus_id": 129621114, "score": 0 }, { "doc_id": "129649951", "title": "Ozone production in the rural troposphere and the implications for regional and global ozone distributions", "abstract": "The relationship between O3 and NOx (NO + NO2) which was measured during summer and winter periods at Niwot Ridge, Colorado, has been analyzed and compared to model calculations. Both model calculations and observations show that the daily O3 production per unit of NOx is greater for lower NOx. Model calculations without nonmethane hydrocarbons (NMHC) tend to underestimate the O3 production rate at NOx higher than 1.5 parts per billion by volume and show the opposite dependence on NOx. The model calculations with NMHC are consistent with the observed data in this regime and demonstrate the importance of NMHC chemistry in the O3 production. In addition, at eight other rural stations with concurrent O3 and NOx measurements in the central and eastern United States the daily O3 increase in summer also agrees with the O3 and NOx relationship predicted by the model. The consistency of the observed and model-calculated daily summer O3 increase implies that the average O3 production in rural areas can be predicted if NOx is known. The dependence of O3 production rate on NOx deduced in this study provides the basis for a crude estimate of the total O3 production. For the United States an average summer column O3 production of about 1×1012Cm−2S−1 from anthropogenically emitted NOx and NMHC is estimated. This photochemical production is roughly 20 times the average cross-tropopause O3 flux. Production of O3 from NOx that is emitted from natural sources in the United States is estimated to range from 1.9×1011 to 12×1011 cm−2 s−1, which is somewhat smaller than ozone production from anthropogenic NOx sources. Extrapolation to the entire northern hemisphere shows that in the summer, 3 times as much O3 is generated from natural precursors as those of anthropogenic origin. The winter daily O3 production rate was found to be about 10% of the summer value at the same NOx level. However, because of longer NOx lifetime in the winter, the integrated O3 production over the lifetime of NOx may be comparable to the summer value. Moreover, because the natural NOx sources are substantially smaller in the winter, the wintertime O3 budget in the northern hemisphere should be dominated by ozone production from anthropogenic ozone precursors. The photochemical lifetime of O3 in the winter in the mid-latitude is approximately 200 days. We propose that this long lifetime allows anthropogenically produced O3 to accumulate and contribute substantially to the observed spring maximum that is usually attributed to stratospheric intrusion. Furthermore, the anthropogenic O3 may be transported not only zonally but also to lower latitudes. Thus the long-term interannual increase in O3, observed in the winter and spring seasons at Mauna Loa, may be due to the same anthropogenic influences as the similar winter trend observed at Hohenpeissenberg, Germany.", "corpus_id": 129649951, "score": 0 }, { "doc_id": "55943647", "title": "Dependence of ozone production on NO and hydrocarbons in the troposphere", "abstract": "An expression for the production rate of 03, P(O 3), is derived based on a radical budget equation applicable to low and high NOx conditions. Differentiation of this equation with respect to NO or hydrocarbons (HC) gives an approximate analytic formula in which the relative sensitivity of P(O3) to changes in NO or HC depends only on the fraction of radicals which are removed by reactions with NOx. This formula is tested by comparison with results from a photochemical calculation driven by trace gas observations from the 1995 Southern Oxidants Study (SOS) campaign in Nashville, Tennessee.", "corpus_id": 55943647, "score": 0 }, { "doc_id": "54753457", "title": "Tropospheric chemistry: A global perspective", "abstract": "A model for the photochemistry of the global troposphere constrained by observed concentrations of H2O, O3, CO, CH4, NO, NO2, and HNO3 is presented. Data for NO and NO2 are insufficient to define the global distribution of these gases but are nonetheless useful in limiting several of the more uncertain parameters of the model. Concentrations of OH, HO2, H2O2, NO, NO2, NO3, N2O5, HNO2, HO2NO2, CH3O2, CH3OOH, CH2O, and CH3CCl3 are calculated as functions of altitude, latitude, and season. Results imply that the source for nitrogen oxides in the remote troposphere is geographically dispersed and surprisingly small, less than 107 tons N yr−1. Global sources for CO and CH4 are 1.5 × 109 tons C yr−1 and 4.5 × 108 tons C yr−1, respectively. Carbon monoxide is derived from combustion of fossil fuel (15%) and oxidation of atmospheric CH4 (25%), with the balance from burning of vegetation and oxidation of biospheric hydrocarbons. Production of CO in the northern hemisphere exceeds that in the southern hemisphere by about a factor of 2. Industrial and agricultural activities provide approximately half the global source of CO. Oxidation of CO and CH4 provides sources of tropospheric O3 similar in magnitude to loss by in situ photochemistry. Observations of CH3CCl3 could offer an important check of the tropospheric model and results shown here suggest that computed concentrations of OH should be reliable within a factor of 2. A more definitive test requires better definition of release rates for CH3CCl3 and improved measurements for its distribution in the atmosphere.", "corpus_id": 54753457, "score": 0 } ]

{ "doc_id": "18933637", "title": "Deep divergence and rapid evolutionary rates in gut-associated Acetobacteraceae of ants", "abstract": "BackgroundSymbiotic associations between gut microbiota and their animal hosts shape the evolutionary trajectories of both partners. The genomic consequences of these relationships are significantly influenced by a variety of factors, including niche localization, interaction potential, and symbiont transmission mode. In eusocial insect hosts, socially transmitted gut microbiota may represent an intermediate point between free living or environmentally acquired bacteria and those with strict host association and maternal transmission.ResultsWe characterized the bacterial communities associated with an abundant ant species, Camponotus chromaiodes. While many bacteria had sporadic distributions, some taxa were abundant and persistent within and across ant colonies. Specially, two Acetobacteraceae operational taxonomic units (OTUs; referred to as AAB1 and AAB2) were abundant and widespread across host samples. Dissection experiments confirmed that AAB1 and AAB2 occur in C. chromaiodes gut tracts. We explored the distribution and evolution of these Acetobacteraceae OTUs in more depth. We found that Camponotus hosts representing different species and geographical regions possess close relatives of the Acetobacteraceae OTUs detected in C. chromaiodes. Phylogenetic analysis revealed that AAB1 and AAB2 join other ant associates in a monophyletic clade. This clade consists of Acetobacteraceae from three ant tribes, including a third, basal lineage associated with Attine ants. This ant-specific AAB clade exhibits a significant acceleration of substitution rates at the 16S rDNA gene and elevated AT content. Substitutions along 16S rRNA in AAB1 and AAB2 result in ~10 % reduction in the predicted rRNA stability.ConclusionsCombined, these patterns in Camponotus-associated Acetobacteraceae resemble those found in cospeciating gut associates that are both socially and maternally transmitted. These associates may represent an intermediate point along an evolutionary trajectory manifest most extremely in symbionts with strict maternal transmission. Collectively, these results suggest that Acetobacteraceae may be a frequent and persistent gut associate in Camponotus species and perhaps other ant groups, and that its evolution is strongly impacted by this host association.", "corpus_id": 18933637 }

[ { "doc_id": "3329126", "title": "Animals in a bacterial world, a new imperative for the life sciences", "abstract": "In the last two decades, the widespread application of genetic and genomic approaches has revealed a bacterial world astonishing in its ubiquity and diversity. This review examines how a growing knowledge of the vast range of animal–bacterial interactions, whether in shared ecosystems or intimate symbioses, is fundamentally altering our understanding of animal biology. Specifically, we highlight recent technological and intellectual advances that have changed our thinking about five questions: how have bacteria facilitated the origin and evolution of animals; how do animals and bacteria affect each other’s genomes; how does normal animal development depend on bacterial partners; how is homeostasis maintained between animals and their symbionts; and how can ecological approaches deepen our understanding of the multiple levels of animal–bacterial interaction. As answers to these fundamental questions emerge, all biologists will be challenged to broaden their appreciation of these interactions and to include investigations of the relationships between and among bacteria and their animal partners as we seek a better understanding of the natural world.", "corpus_id": 3329126, "score": 0 }, { "doc_id": "4420494", "title": "Metagenomic and functional analysis of hindgut microbiota of a wood-feeding higher termite", "abstract": "From the standpoints of both basic research and biotechnology, there is considerable interest in reaching a clearer understanding of the diversity of biological mechanisms employed during lignocellulose degradation. Globally, termites are an extremely successful group of wood-degrading organisms and are therefore important both for their roles in carbon turnover in the environment and as potential sources of biochemical catalysts for efforts aimed at converting wood into biofuels. Only recently have data supported any direct role for the symbiotic bacteria in the gut of the termite in cellulose and xylan hydrolysis. Here we use a metagenomic analysis of the bacterial community resident in the hindgut paunch of a wood-feeding ‘higher’ Nasutitermes species (which do not contain cellulose-fermenting protozoa) to show the presence of a large, diverse set of bacterial genes for cellulose and xylan hydrolysis. Many of these genes were expressed in vivo or had cellulase activity in vitro, and further analyses implicate spirochete and fibrobacter species in gut lignocellulose degradation. New insights into other important symbiotic functions including H2 metabolism, CO2-reductive acetogenesis and N2 fixation are also provided by this first system-wide gene analysis of a microbial community specialized towards plant lignocellulose degradation. Our results underscore how complex even a 1-μl environment can be.", "corpus_id": 4420494, "score": 0 }, { "doc_id": "30684741", "title": "Intestinal bacteria affect growth of Bacillus thuringiensis in larvae of the oriental tea tortrix, Homona magnanima diakonoff (Lepidoptera: tortricidae).", "abstract": "Spores and parasporal crystals of a Bacillus thuringiensis serovar aizawai were fed to fifth instar larvae of the oriental tea tortrix, Homona magnanima, that had been reared aseptically or that had been reared normally. Viable cell numbers of B. thuringiensis and other bacteria in H. magnanima larvae were estimated by homogenization of samples and dilution plating on peptone-polymyxin agar medium for B. thuringiensis cells and on nutrient agar medium for the other bacterial cells. B. thuringiensis did not grow in the larval cadavers of normally reared H. magnanima while bacteria other than B. thuringiensis grew rapidly. In contrast, B. thuringiensis within the larval cadavers of aseptically reared H. magnanima grew and increased 20 times. The bacteria other than B. thuringiensis from the sample homogenates of normally reared larvae that were fed on B. thuringiensis-treated diets had the same characteristics as the bacteria isolated from the guts of healthy H. magnanima larvae, which were putatively identified as Streptococcus spp. and Staphylococcus spp., typical intestinal bacteria of insects. The results strongly suggest that intestinal bacteria influence the growth of B. thuringiensis in the larvae.", "corpus_id": 30684741, "score": 0 }, { "doc_id": "12093403", "title": "Kin recognition in Drosophila: the importance of ecology and gut microbiota", "abstract": "The animal gut commonly contains a large reservoir of symbiotic microbes. Although these microbes have obvious functions in digestion and immune defence, gut microbes can also affect behaviour. Here, we explore whether gut microbiota has a role in kin recognition. We assessed whether relatedness, familiarity and food eaten during development altered copulation investment in three species of Drosophila with diverse ecologies. We found that a monandrous species exhibited true kin recognition, whereas familiarity determined kin recognition in a species living in dense aggregations. Finally, in a food generalist species, food eaten during development masked kin recognition. The effect of food type on copulation duration, in addition to the removal of this effect via antibiotic treatment, suggests the influence of bacteria associated with the gut. Our results provide the first evidence that varied ecologically determined mechanisms of kin recognition occur in Drosophila, and that gut bacteria are likely to have a key role in these mechanisms.", "corpus_id": 12093403, "score": 0 }, { "doc_id": "39667137", "title": "Costs and Benefits of High Mutation Rates: Adaptive Evolution of Bacteria in the Mouse Gut", "abstract": "We have shown that bacterial mutation rates change during the experimental colonization of the mouse gut. A high mutation rate was initially beneficial because it allowed faster adaptation, but this benefit disappeared once adaptation was achieved. Mutator bacteria accumulated mutations that, although neutral in the mouse gut, are often deleterious in secondary environments. Consistently, the competitiveness of mutator bacteria is reduced during transmission to and re-colonization of similar hosts. The short-term advantages and long-term disadvantages of mutator bacteria could account for their frequency in nature.", "corpus_id": 39667137, "score": 0 }, { "doc_id": "31881164", "title": "Acetic Acid Bacteria, Newly Emerging Symbionts of Insects", "abstract": "ABSTRACT Recent research in microbe-insect symbiosis has shown that acetic acid bacteria (AAB) establish symbiotic relationships with several insects of the orders Diptera, Hymenoptera, Hemiptera, and Homoptera, all relying on sugar-based diets, such as nectars, fruit sugars, or phloem sap. To date, the fruit flies Drosophila melanogaster and Bactrocera oleae, mosquitoes of the genera Anopheles and Aedes, the honey bee Apis mellifera, the leafhopper Scaphoideus titanus, and the mealybug Saccharicoccus sacchari have been found to be associated with the bacterial genera Acetobacter, Gluconacetobacter, Gluconobacter, Asaia, and Saccharibacter and the novel genus Commensalibacter. AAB establish symbiotic associations with the insect midgut, a niche characterized by the availability of diet-derived carbohydrates and oxygen and by an acidic pH, selective factors that support AAB growth. AAB have been shown to actively colonize different insect tissues and organs, such as the epithelia of male and female reproductive organs, the Malpighian tubules, and the salivary glands. This complex topology of the symbiosis indicates that AAB possess the keys for passing through body barriers, allowing them to migrate to different organs of the host. Recently, AAB involvement in the regulation of innate immune system homeostasis of Drosophila has been shown, indicating a functional role in host survival. All of these lines of evidence indicate that AAB can play different roles in insect biology, not being restricted to the feeding habit of the host. The close association of AAB and their insect hosts has been confirmed by the demonstration of multiple modes of transmission between individuals and to their progeny that include vertical and horizontal transmission routes, comprising a venereal one. Taken together, the data indicate that AAB represent novel secondary symbionts of insects.", "corpus_id": 31881164, "score": 1 }, { "doc_id": "12724658", "title": "Compartmentalized microbial composition, oxygen gradients and nitrogen fixation in the gut of Odontotaenius disjunctus", "abstract": "Coarse woody debris is an important biomass pool in forest ecosystems that numerous groups of insects have evolved to take advantage of. These insects are ecologically important and represent useful natural analogs for biomass to biofuel conversion. Using a range of molecular approaches combined with microelectrode measurements of oxygen, we have characterized the gut microbiome and physiology of Odontotaenius disjunctus, a wood-feeding beetle native to the eastern United States. We hypothesized that morphological and physiological differences among gut regions would correspond to distinct microbial populations and activities. In fact, significantly different communities were found in the foregut (FG), midgut (MG)/posterior hindgut (PHG) and anterior hindgut (AHG), with Actinobacteria and Rhizobiales being more abundant toward the FG and PHG. Conversely, fermentative bacteria such as Bacteroidetes and Clostridia were more abundant in the AHG, and also the sole region where methanogenic Archaea were detected. Although each gut region possessed an anaerobic core, micron-scale profiling identified radial gradients in oxygen concentration in all regions. Nitrogen fixation was confirmed by 15N2 incorporation, and nitrogenase gene (nifH) expression was greatest in the AHG. Phylogenetic analysis of nifH identified the most abundant transcript as related to Ni–Fe nitrogenase of a Bacteroidetes species, Paludibacter propionicigenes. Overall, we demonstrate not only a compartmentalized microbiome in this beetle digestive tract but also sharp oxygen gradients that may permit aerobic and anaerobic metabolism to occur within the same regions in close proximity. We provide evidence for the microbial fixation of N2 that is important for this beetle to subsist on woody biomass.", "corpus_id": 12724658, "score": 0 }, { "doc_id": "13395534", "title": "Acetic Acid Bacteria Genomes Reveal Functional Traits for Adaptation to Life in Insect Guts", "abstract": "Acetic acid bacteria (AAB) live in sugar rich environments, including food matrices, plant tissues, and the gut of sugar-feeding insects. By comparing the newly sequenced genomes of Asaia platycodi and Saccharibacter sp., symbionts of Anopheles stephensi and Apis mellifera, respectively, with those of 14 other AAB, we provide a genomic view of the evolutionary pattern of this bacterial group and clues on traits that explain the success of AAB as insect symbionts. A specific pre-adaptive trait, cytochrome bo3 ubiquinol oxidase, appears ancestral in AAB and shows a phylogeny that is congruent with that of the genomes. The functional properties of this terminal oxidase might have allowed AAB to adapt to the diverse oxygen levels of arthropod guts.", "corpus_id": 13395534, "score": 0 }, { "doc_id": "5663332", "title": "Geographical and ecological stability of the symbiotic mid‐gut microbiota in European firebugs, Pyrrhocoris apterus (Hemiptera, Pyrrhocoridae)", "abstract": "Symbiotic bacteria often play an essential nutritional role for insects, thereby allowing them to exploit novel food sources and expand into otherwise inaccessible ecological niches. Although many insects are inhabited by complex microbial communities, most studies on insect mutualists so far have focused on single endosymbionts and their interactions with the host. Here, we provide a comprehensive characterization of the gut microbiota of the red firebug (Pyrrhocoris apterus, Hemiptera, Pyrrhocoridae), a model organism for physiological and endocrinological research. A combination of several culture‐independent techniques (454 pyrosequencing, quantitative PCR and cloning/sequencing) revealed a diverse community of likely transient bacterial taxa in the mid‐gut regions M1, M2 and M4. However, the completely anoxic M3 region harboured a distinct microbiota consisting of facultative and obligate anaerobes including Actinobacteria (Coriobacterium glomerans and Gordonibacter sp.), Firmicutes (Clostri‐dium sp. and Lactococcus lactis) and Proteobacteria (Klebsiella sp. and a previously undescribed Rickettsiales bacterium). Characterization of the M3 microbiota in different life stages of P. apterus indicated that the symbiotic bacterial community is vertically transmitted and becomes well defined between the second and third nymphal instar, which coincides with the initiation of feeding. Comparing the mid‐gut M3 microbial communities of P. apterus individuals from five different populations and after feeding on three different diets revealed that the community composition is qualitatively and quantitatively very stable, with the six predominant taxa being consistently abundant. Our findings suggest that the firebug mid‐gut microbiota constitutes a functionally important and possibly coevolved symbiotic community.", "corpus_id": 5663332, "score": 0 }, { "doc_id": "12447966", "title": "Genomics and host specialization of honey bee and bumble bee gut symbionts", "abstract": "Significance Gut microbes are increasingly recognized as influential components of animal biology. Genomic, mechanistic, and evolutionary aspects of gut symbiont specialization remain understudied, however, largely due to the complexity of gut communities, especially in vertebrate systems. We show that the simple microbiota of eusocial bees exhibits host specificity and that coresident species in the bee gut possess complementary capabilities for energy metabolism, implying their occupancy in distinct ecological niches. In addition, coresidence in the gut of a host species results in horizontal exchange of genes between unrelated symbionts. Strains in different hosts have diverged, and honey bee symbionts are evolutionarily and functionally distinct from their bumble bee counterparts, indicating that gut symbionts may be critical elements in biological differences among bee species. Gilliamella apicola and Snodgrassella alvi are dominant members of the honey bee (Apis spp.) and bumble bee (Bombus spp.) gut microbiota. We generated complete genomes of the type strains G. apicola wkB1T and S. alvi wkB2T (isolated from Apis), as well as draft genomes for four other strains from Bombus. G. apicola and S. alvi were found to occupy very different metabolic niches: The former is a saccharolytic fermenter, whereas the latter is an oxidizer of carboxylic acids. Together, they may form a syntrophic network for partitioning of metabolic resources. Both species possessed numerous genes [type 6 secretion systems, repeats in toxin (RTX) toxins, RHS proteins, adhesins, and type IV pili] that likely mediate cell–cell interactions and gut colonization. Variation in these genes could account for the host fidelity of strains observed in previous phylogenetic studies. Here, we also show the first experimental evidence, to our knowledge, for this specificity in vivo: Strains of S. alvi were able to colonize their native bee host but not bees of another genus. Consistent with specific, long-term host association, comparative genomic analysis revealed a deep divergence and little or no gene flow between Apis and Bombus gut symbionts. However, within a host type (Apis or Bombus), we detected signs of horizontal gene transfer between G. apicola and S. alvi, demonstrating the importance of the broader gut community in shaping the evolution of any one member. Our results show that host specificity is likely driven by multiple factors, including direct host–microbe interactions, microbe–microbe interactions, and social transmission.", "corpus_id": 12447966, "score": 1 }, { "doc_id": "6821710", "title": "Strict Host-Symbiont Cospeciation and Reductive Genome Evolution in Insect Gut Bacteria", "abstract": "Host-symbiont cospeciation and reductive genome evolution have been identified in obligate endocellular insect symbionts, but no such example has been identified from extracellular ones. Here we first report such a case in stinkbugs of the family Plataspidae, wherein a specific gut bacterium is vertically transmitted via “symbiont capsule.” In all of the plataspid species, females produced symbiont capsules upon oviposition and their gut exhibited specialized traits for capsule production. Phylogenetic analysis showed that the plataspid symbionts constituted a distinct group in the γ-Proteobacteria, whose sister group was the aphid obligate endocellular symbionts Buchnera. Removal of the symbionts resulted in retarded growth, mortality, and sterility of the insects. The host phylogeny perfectly agreed with the symbiont phylogeny, indicating strict host-symbiont cospeciation despite the extracellular association. The symbionts exhibited AT-biased nucleotide composition, accelerated molecular evolution, and reduced genome size, as has been observed in obligate endocellular insect symbionts. These findings suggest that not the endocellular conditions themselves but the population genetic attributes of the vertically transmitted symbionts are probably responsible for the peculiar genetic traits of these insect symbionts. We proposed the designation “Candidatus Ishikawaella capsulata” for the plataspid symbionts. The plataspid stinkbugs, wherein the host-symbiont associations can be easily manipulated, provide a novel system that enables experimental approaches to previously untouched aspects of the insect-microbe mutualism. Furthermore, comparative analyses of the sister groups, the endocellular Buchnera and the extracellular Ishikawaella, would lead to insights into how the different symbiotic lifestyles have affected their genomic evolution.", "corpus_id": 6821710, "score": 1 }, { "doc_id": "7350788", "title": "Genomics and evolution of heritable bacterial symbionts.", "abstract": "Insect heritable symbionts have proven to be ubiquitous, based on molecular screening of various insect lineages. Recently, molecular and experimental approaches have yielded an immensely richer understanding of their diverse biological roles, resulting in a burgeoning research literature. Increasingly, commonalities and intermediates are being discovered between categories of symbionts once considered distinct: obligate mutualists that provision nutrients, facultative mutualists that provide protection against enemies or stress, and symbionts such as Wolbachia that manipulate reproductive systems. Among the most far-reaching impacts of widespread heritable symbiosis is that it may promote speciation by increasing reproductive and ecological isolation of host populations, and it effectively provides a means for transfer of genetic information among host lineages. In addition, insect symbionts provide some of the extremes of cellular genomes, including the smallest and the fastest evolving, raising new questions about the limits of evolution of life.", "corpus_id": 7350788, "score": 1 }, { "doc_id": "2696051", "title": "An out-of-body experience: the extracellular dimension for the transmission of mutualistic bacteria in insects", "abstract": "Across animals and plants, numerous metabolic and defensive adaptations are a direct consequence of symbiotic associations with beneficial microbes. Explaining how these partnerships are maintained through evolutionary time remains one of the central challenges within the field of symbiosis research. While genome erosion and co-cladogenesis with the host are well-established features of symbionts exhibiting intracellular localization and transmission, the ecological and evolutionary consequences of an extracellular lifestyle have received little attention, despite a demonstrated prevalence and functional importance across many host taxa. Using insect–bacteria symbioses as a model, we highlight the diverse routes of extracellular symbiont transfer. Extracellular transmission routes are unified by the common ability of the bacterial partners to survive outside their hosts, thereby imposing different genomic, metabolic and morphological constraints than would be expected from a strictly intracellular lifestyle. We emphasize that the evolutionary implications of symbiont transmission routes (intracellular versus extracellular) do not necessarily correspond to those of the transmission mode (vertical versus horizontal), a distinction of vital significance when addressing the genomic and physiological consequences for both host and symbiont.", "corpus_id": 2696051, "score": 1 }, { "doc_id": "8172213", "title": "Symbiont-Supplemented Maternal Investment Underpinning Host’s Ecological Adaptation", "abstract": "Maternal investment for offspring's growth and survival is widespread among diverse organisms. Vertical symbiont transmission via maternal passage is also pivotal for offspring's growth and survival in many organisms. Hence, it is expected that vertical symbiont transmission may coevolve with various organismal traits concerning maternal investment in offspring. Here we report a novel phenotypic syndrome entailing morphological, histological, behavioral, and ecological specializations for maternal investment and vertical symbiont transmission in stinkbugs of the family Urostylididae. Adult females develop huge ovaries exaggerated for polysaccharide excretion, possess novel ovipositor-associated organs for vertical transmission of a bacterial symbiont (\"Candidatus Tachikawaea gelatinosa\"), and lay eggs covered with voluminous symbiont-supplemented jelly. Newborns hatch in midwinter, feed solely on the jelly, acquire the symbiont, and grow during winter. In spring, the insects start feeding on plant sap, wherein the symbiont localizes to a specialized midgut region and supplies essential amino acids deficient in the host's diet. The reduced symbiont genome and host-symbiont cospeciation indicate their obligate association over evolutionary time. Experimental deprivation of the jelly results in nymphal mortality, whereas restoration of the jelly leads to recovered nymphal growth, confirming that the jelly supports nymphal growth in winter. Chemical analyses demonstrate that the galactan-based jelly contains a sufficient quantity of amino acids to sustain nymphal growth to the third instar. The versatile biological roles of the symbiont-containing egg-covering jelly highlight intricate evolutionary interactions between maternal resource investment and vertical symbiont transmission, which are commonly important for offspring's growth, survival, and ecological adaptation.", "corpus_id": 8172213, "score": 1 }, { "doc_id": "13296752", "title": "Functional diversity within the simple gut microbiota of the honey bee", "abstract": "Animals living in social communities typically harbor a characteristic gut microbiota important for nutrition and pathogen defense. Accordingly, in the gut of the honey bee, Apis mellifera, a distinctive microbial community, composed of a taxonomically restricted set of species specific to social bees, has been identified. Despite the ecological and economical importance of honey bees and the increasing concern about population declines, the role of their gut symbionts for colony health and nutrition is unknown. Here, we sequenced the metagenome of the gut microbiota of honey bees. Unexpectedly, we found a remarkable degree of genetic diversity within the few bacterial species colonizing the bee gut. Comparative analysis of gene contents suggests that different species harbor distinct functional capabilities linked to host interaction, biofilm formation, and carbohydrate breakdown. Whereas the former two functions could be critical for pathogen defense and immunity, the latter one might assist nutrient utilization. In a γ-proteobacterial species, we identified genes encoding pectin-degrading enzymes likely involved in the breakdown of pollen walls. Experimental investigation showed that this activity is restricted to a subset of strains of this species providing evidence for niche specialization. Long-standing association of these gut symbionts with their hosts, favored by the eusocial lifestyle of honey bees, might have promoted the genetic and functional diversification of these bee-specific bacteria. Besides revealing insights into mutualistic functions governed by the microbiota of this important pollinator, our findings indicate that the honey bee can serve as a model for understanding more complex gut-associated microbial communities.", "corpus_id": 13296752, "score": 0 }, { "doc_id": "84773313", "title": "Bacterial symbionts as mediators of ecologically important traits of insect hosts", "abstract": "1. Bacterial symbionts play a prominent role in insect nutritional ecology by aiding in digestion of food or providing nutrients that are limited or lacking in the diet. Thereby, endosymbionts open niches to their insect host that would otherwise be unavailable.", "corpus_id": 84773313, "score": 0 }, { "doc_id": "45094491", "title": "The bacterial communities in plant phloem‐sap‐feeding insects", "abstract": "The resident microbiota of animals represents an important contribution to the global microbial diversity, but it is poorly known in many animals. This study investigated the bacterial diversity in plant phloem‐sap‐feeding whiteflies, aphids and psyllids by pyrosequencing bacterial 16S rRNA gene amplicons. After correction for sequencing error, just 3–7 bacterial operational taxonomic units were recovered from each insect sample sequenced to sufficient depth for saturation of rarefaction curves. Most samples were dominated by primary and secondary symbionts, which are localized to insect cells or the body cavity, indicative of a dearth of bacterial colonists of the gut lumen. Diversity indices of the bacterial communities (Shannon's index: 0.40–1.46, Simpson's index: 0.15–0.74) did not differ significantly between laboratory and field samples of the phloem‐feeding insects, but were significantly lower than in drosophilid flies quantified by the same methods. Both the low bacterial content of the phloem sap diet and biological processes in the insect may contribute to the apparently low bacterial diversity in these phloem‐feeding insects.", "corpus_id": 45094491, "score": 0 }, { "doc_id": "9273396", "title": "Adaptive Immunity: Care for the community", "abstract": "A memory-based immune system may have evolved in vertebrates because of the need to recognize and manage complex communities of beneficial microbes.", "corpus_id": 9273396, "score": 0 }, { "doc_id": "21435555", "title": "The gut microbiota of insects - diversity in structure and function.", "abstract": "Insect guts present distinctive environments for microbial colonization, and bacteria in the gut potentially provide many beneficial services to their hosts. Insects display a wide range in degree of dependence on gut bacteria for basic functions. Most insect guts contain relatively few microbial species as compared to mammalian guts, but some insects harbor large gut communities of specialized bacteria. Others are colonized only opportunistically and sparsely by bacteria common in other environments. Insect digestive tracts vary extensively in morphology and physicochemical properties, factors that greatly influence microbial community structure. One obstacle to the evolution of intimate associations with gut microorganisms is the lack of dependable transmission routes between host individuals. Here, social insects, such as termites, ants, and bees, are exceptions: social interactions provide opportunities for transfer of gut bacteria, and some of the most distinctive and consistent gut communities, with specialized beneficial functions in nutrition and protection, have been found in social insect species. Still, gut bacteria of other insects have also been shown to contribute to nutrition, protection from parasites and pathogens, modulation of immune responses, and communication. The extent of these roles is still unclear and awaits further studies.", "corpus_id": 21435555, "score": 0 }, { "doc_id": "43304236", "title": "Diversity and evolutionary patterns of bacterial gut associates of corbiculate bees", "abstract": "The animal gut is a habitat for diverse communities of microorganisms (microbiota). Honeybees and bumblebees have recently been shown to harbour a distinct and species poor microbiota, which may confer protection against parasites. Here, we investigate diversity, host specificity and transmission mode of two of the most common, yet poorly known, gut bacteria of honeybees and bumblebees: Snodgrassella alvi (Betaproteobacteria) and Gilliamella apicola (Gammaproteobacteria). We analysed 16S rRNA gene sequences of these bacteria from diverse bee host species across most of the honeybee and bumblebee phylogenetic diversity from North America, Europe and Asia. These focal bacteria were present in 92% of bumblebee species and all honeybee species but were found to be absent in the two related corbiculate bee tribes, the stingless bees (Meliponini) and orchid bees (Euglossini). Both Snodgrassella alvi and Gilliamella apicola phylogenies show significant topological congruence with the phylogeny of their bee hosts, albeit with a considerable degree of putative host switches. Furthermore, we found that phylogenetic distances between Gilliamella apicola samples correlated with the geographical distance between sampling locations. This tentatively suggests that the environmental transmission rate, as set by geographical distance, affects the distribution of G. apicola infections. We show experimentally that both bacterial taxa can be vertically transmitted from the mother colony to daughter queens, and social contact with nest mates after emergence from the pupa greatly facilitates this transmission. Therefore, sociality may play an important role in vertical transmission and opens up the potential for co‐evolution or at least a close association of gut bacteria with their hosts.", "corpus_id": 43304236, "score": 0 }, { "doc_id": "8854653", "title": "Stability and phylogenetic correlation in gut microbiota: lessons from ants and apes", "abstract": "Correlation between gut microbiota and host phylogeny could reflect codiversification over shared evolutionary history or a selective environment that is more similar in related hosts. These alternatives imply substantial differences in the relationship between host and symbiont, but can they be distinguished based on patterns in the community data themselves? We explored patterns of phylogenetic correlation in the distribution of gut bacteria among species of turtle ants (genus Cephalotes), which host a dense gut microbial community. We used 16S rRNA pyrosequencing from 25 Cephalotes species to show that their gut community is remarkably stable, from the colony to the genus level. Despite this overall similarity, the existing differences among species' microbiota significantly correlated with host phylogeny. We introduced a novel analytical technique to test whether these phylogenetic correlations are derived from recent bacterial evolution, as would be expected in the case of codiversification, or from broader shifts more likely to reflect environmental filters imposed by factors such as diet or habitat. We also tested this technique on a published data set of ape microbiota, confirming earlier results while revealing previously undescribed patterns of phylogenetic correlation. Our results indicated a high degree of partner fidelity in the Cephalotes microbiota, suggesting that vertical transmission of the entire community could play an important role in the evolution and maintenance of the association. As additional comparative microbiota data become available, the techniques presented here can be used to explore trends in the evolution of host‐associated microbial communities.", "corpus_id": 8854653, "score": 1 }, { "doc_id": "24777606", "title": "Gut Symbiotic Bacteria of the Genus Burkholderia in the Broad-Headed Bugs Riptortus clavatus and Leptocorisa chinensis (Heteroptera: Alydidae)", "abstract": "ABSTRACT The Japanese common broad-headed bugs Riptortus clavatus and Leptocorisa chinensis possess a number of crypts in the posterior region of the midgut, whose lumen contains a copious amount of bacterial cells. We characterized the gut symbiotic bacteria by using molecular phylogenetic analysis, light and electron microscopy, in situ hybridization, and PCR-based detection techniques. Restriction fragment length polymorphism analysis of 16S rRNA gene clones suggested that a single bacterium dominated the microbiota in the crypts of the both bug species. The predominant 16S rRNA gene sequences obtained from different individuals and species of the bugs were not identical but were very similar to each other. Homology searches in the DNA databases revealed that the sequences showed the highest levels of similarity (96% to 99%) to the sequences of Burkholderia spp. belonging to the β subdivision of the class Proteobacteria. In situ hybridization with specific oligonucleotide probes confirmed the localization of the Burkholderia symbiont in the lumen of the midgut crypts. Electron microscopy showed that the lumen of the crypts was filled with rod-shaped bacteria of a single morphotype. Molecular phylogenetic analysis demonstrated that the Burkholderia symbionts of the bugs formed a well-defined monophyletic group, although the group also contained several environmental Burkholderia strains. The phylogenetic relationship of the Burkholderia symbionts did not reflect the relationship of the host bug species at all. The sequences from R. clavatus and the sequences from L. chinensis did not form clades but were intermingled in the phylogeny, suggesting that horizontal transmission of the symbiont might have occasionally occurred between populations and species of the bugs.", "corpus_id": 24777606, "score": 0 }, { "doc_id": "23977970", "title": "Establishment of Characteristic Gut Bacteria during Development of the Honeybee Worker", "abstract": "ABSTRACT Previous surveys have shown that adult honeybee (Apis mellifera) workers harbor a characteristic gut microbiota that may play a significant role in bee health. For three major phylotypes within this microbiota, we have characterized distributions and abundances across the life cycle and among gut organs. These distinctive phylotypes, called Beta, Firm-5, and Gamma-1 (BFG), were assayed using quantitative PCR, fluorescent in situ hybridization (FISH) microscopy, and the experimental manipulation of inoculation routes within developing bees. Adult workers (9 to 30 days posteclosion) contained a large BFG microbiota with a characteristic distribution among gut organs. The crop and midgut were nearly devoid of these phylotypes, while the ileum and rectum together contained more than 95% of the total BFG microbiota. The ileum contained a stratified community in which the Beta and Gamma-1 phylotypes dominated, filling the longitudinal folds of this organ. Deep sequencing of 16S rRNA genes showed clear differences among communities in midgut, ileum, and rectum. In contrast with older workers, larvae and newly emerged workers contain few or no bacteria, and their major food source, bee bread, lacks most characteristic phylotypes. In experiments aimed at determining the route of inoculation, newly emerged workers (NEWs) sometimes acquired the typical phylotypes through contact with older workers, contact with the hive, and emergence from the brood cell; however, transmission was patchy in these assays. Our results outline a colonization pattern for the characteristic phylotypes through A. mellifera ontogeny. We propose the names “Candidatus Snodgrassella alvi” and “Candidatus Gilliamella apicola” for the Beta and Gamma-1 phylotypes, respectively.", "corpus_id": 23977970, "score": 0 }, { "doc_id": "2569896", "title": "Accelerated evolution and Muller's rachet in endosymbiotic bacteria.", "abstract": "Many bacteria live only within animal cells and infect hosts through cytoplasmic inheritance. These endosymbiotic lineages show distinctive population structure, with small population size and effectively no recombination. As a result, endosymbionts are expected to accumulate mildly deleterious mutations. If these constitute a substantial proportion of new mutations, endosymbionts will show (i) faster sequence evolution and (ii) a possible shift in base composition reflecting mutational bias. Analyses of 16S rDNA of five independently derived endosymbiont clades show, in every case, faster evolution in endosymbionts than in free-living relatives. For aphid endosymbionts (genus Buchnera), coding genes exhibit accelerated evolution and unusually low ratios of synonymous to nonsynonymous substitutions compared to ratios for the same genes for enterics. This concentration of the rate increase in nonsynonymous substitutions is expected under the hypothesis of increased fixation of deleterious mutations. Polypeptides for all Buchnera genes analyzed have accumulated amino acids with codon families rich in A+T, supporting the hypothesis that substitutions are deleterious in terms of polypeptide function. These observations are best explained as the result of Muller's ratchet within small asexual populations, combined with mutational bias. In light of this explanation, two observations reported earlier for Buchnera, the apparent loss of a repair gene and the overproduction of a chaperonin, may reflect compensatory evolution. An alternative hypothesis, involving selection on genomic base composition, is contradicted by the observation that the speedup is concentrated at nonsynonymous sites.", "corpus_id": 2569896, "score": 0 }, { "doc_id": "45577989", "title": "Acetic Acid Bacterial Biota of the Pink Sugar Cane Mealybug, Saccharococcus sacchari, and Its Environs", "abstract": "Saccharococcus sacchari is the primary colonizer of the developing “sterile” tissue between the leaf sheath and stem of sugar cane. The honeydew secreted by the mealybugs is acidic (about pH 3) and supports an atypical epiphytic microbiota dominated by acetobacter-like bacteria and acidophilic yeast species. However, Erwinia and Leuconostoc species predominate within the leaf sheath pocket region when the mealybugs die out. The unidentified acetobacters were readily isolated from S. sacchari throughout its life cycle and from other genera of mealybugs on sugar cane and various other plants, both above and below ground. No other insect present on sugar cane was a significant vector of acetic acid bacteria. The major factors restricting microbial diversity within the environs of mealybugs were considered to be yeast activity along with bacterial production of acetic acid, ketogluconic acids, and gamma-pyrones, in association with their lowering of pH. The microbial products may aid in suppressing the attack by the parasitic mold Aspergillus parasiticus on mealybugs but could act as attractants for the predatory fruit fly Cacoxenus perspicax.", "corpus_id": 45577989, "score": 0 }, { "doc_id": "19868936", "title": "Phylogenetic Characterization of Two Novel Commensal Bacteria Involved with Innate Immune Homeostasis in Drosophila melanogaster", "abstract": "ABSTRACT During a previous study on the molecular interaction between commensal bacteria and host gut immunity, two novel bacterial strains, A911T and G707T, were isolated from the gut of Drosophila melanogaster. In this study, these strains were characterized in a polyphasic taxonomic study using phenotypic, genetic, and chemotaxonomic analyses. We show that the strains represent novel species in the family Acetobacteraceae. Strain G707T, a highly pathogenic organism, represents a new species in the genus Gluconobacter, “Gluconobacter morbifer” sp. nov. (type strain G707 = KCTC 22116T = JCM 15512T). Strain A911T, dominantly present in the normal Drosphila gut community, represents a novel genus and species, designated “Commensalibacter intestini” gen. nov., sp. nov. (type strain A911 = KCTC 22117T = JCM 15511T).", "corpus_id": 19868936, "score": 0 }, { "doc_id": "1341266", "title": "Evolution of host specialization in gut microbes: the bee gut as a model", "abstract": "Bacterial symbionts of eukaryotes often give up generalist lifestyles to specialize to particular hosts. The eusocial honey bees and bumble bees harbor two such specialized gut symbionts, Snodgrassella alvi and Gilliamella apicola. Not only are these microorganisms specific to bees, but different strains of these bacteria tend to assort according to host species. By using in-vivo microbial transplant experiments, we show that the observed specificity is, at least in part, due to evolved physiological barriers that limit compatibility between a host and a potential gut colonizer. How and why such specialization occurs is largely unstudied for gut microbes, despite strong evidence that it is a general feature in many gut communities. Here, we discuss the potential factors that favor the evolution of host specialization, and the parallels that can be drawn with parasites and other symbiont systems. We also address the potential of the bee gut as a model for exploring gut community evolution.", "corpus_id": 1341266, "score": 0 }, { "doc_id": "32534515", "title": "Highly similar microbial communities are shared among related and trophically similar ant species", "abstract": "Ants dominate many terrestrial ecosystems, yet we know little about their nutritional physiology and ecology. While traditionally viewed as predators and scavengers, recent isotopic studies revealed that many dominant ant species are functional herbivores. As with other insects with nitrogen‐poor diets, it is hypothesized that these ants rely on symbiotic bacteria for nutritional supplementation. In this study, we used cloning and 16S sequencing to further characterize the bacterial flora of several herbivorous ants, while also examining the beta diversity of bacterial communities within and between ant species from different trophic levels. Through estimating phylogenetic overlap between these communities, we tested the hypothesis that ecologically or phylogenetically similar groups of ants harbor similar microbial flora. Our findings reveal: (i) clear differences in bacterial communities harbored by predatory and herbivorous ants; (ii) notable similarities among communities from distantly related herbivorous ants and (iii) similar communities shared by different predatory army ant species. Focusing on one herbivorous ant tribe, the Cephalotini, we detected five major bacterial taxa that likely represent the core microbiota. Metabolic functions of bacterial relatives suggest that these microbes may play roles in fixing, recycling, or upgrading nitrogen. Overall, our findings reveal that similar microbial communities are harbored by ants from similar trophic niches and, to a greater extent, by related ants from the same colonies, species, genera, and tribes. These trends hint at coevolved histories between ants and microbes, suggesting new possibilities for roles of bacteria in the evolution of both herbivores and carnivores from the ant family Formicidae.", "corpus_id": 32534515, "score": 0 }, { "doc_id": "206732892", "title": "Surveying the Microbiome of Ants: Comparing 454 Pyrosequencing with Traditional Methods To Uncover Bacterial Diversity", "abstract": "ABSTRACT We are only beginning to understand the depth and breadth of microbial associations across the eukaryotic tree of life. Reliably assessing bacterial diversity is a key challenge, and next-generation sequencing approaches are facilitating this endeavor. In this study, we used 16S rRNA amplicon pyrosequencing to survey microbial diversity in ants. We compared 454 libraries with Sanger-sequenced clone libraries as well as cultivation of live bacteria. Pyrosequencing yielded 95,656 bacterial 16S rRNA reads from 19 samples derived from four colonies of one ant species. The most dominant bacterial orders in the microbiome of the turtle ant Cephalotes varians were Rhizobiales, Burkholderiales, Opitutales, Xanthomonadales, and Campylobacterales, as revealed through both 454 sequencing and cloning. Even after stringent quality filtering, pyrosequencing recovered 445 microbe operational taxonomic units (OTUs) not detected with traditional techniques. In comparing bacterial communities associated with specific tissues, we found that gut tissues had significantly higher diversity than nongut tissues, and many of the OTUs identified from these groups clustered within ant-specific lineages, indicating a deep coevolutionary history of Cephalotes ants and their associated microbes. These lineages likely function as nutritional symbionts. One of four ant colonies investigated was infected with a Spiroplasma sp. (order Entomoplasmatales), a potential ant pathogen. Our work shows that the microbiome associated with Cephalotes varians is dominated by a few dozen bacterial lineages and that 454 sequencing is a cost-efficient tool to screen ant symbiont diversity.", "corpus_id": 206732892, "score": 0 }, { "doc_id": "10310898", "title": "Long PCR improves Wolbachia DNA amplification: wsp sequences found in 76% of sixty‐three arthropod species", "abstract": "Bacteria belonging to the genus Wolbachia are associated with a variety of reproductive anomalies in arthropods. Allele‐specific polymerase chain reaction (= Standard PCR) routinely has been used to amplify Wolbachia DNA from arthropods. While testing the two‐spotted spider mite Tetranychus urticae and other arthropods known to be infected with Wolbachia, Standard PCR frequently produced false negatives, perhaps because the DNA from the arthropod host interfered with amplification by Taq DNA polymerase. Long PCR, which uses two enzymes (Taq and Pwo), consistently amplified Wolbachia DNA and a sensitivity analysis indicated that Long PCR was approximately six orders of magnitude more sensitive than Standard PCR in amplifying plasmid DNA spiked into insect genomic DNA. A survey indicated that 76% of sixty‐two arthropod species and two subspecies in thirteen orders tested positive for the Wolbachia wsp sequence by Long PCR, which is considerably higher than the rate of 16.9% obtained previously for the ftsZ sequence using Standard PCR ( Werren, J.H., Windsor, D. and Gao, L. (1995a)Proc R Soc Lond B 262: 197–204). A subsample of Long PCR products from fourteen arthropod species and two subspecies were sequenced, both directly and after cloning. Two A‐ and eleven B‐Wolbachia strains were detected and their wsp sequences displayed a maximum of 23.7% sequence divergence at this locus. Two new groups (named Fus and Ten) were identified in addition to nineteen reported earlier ( Zhou, W., Rousset, F. and O’Neill, S.L. (1998)Proc R Soc Lond B 265: 1–7; van Meer, M.M.M., Witteveldt, J. and Stouthamer, R. (1999)Insect Mol Biol 8: 399–408), because they displayed more than 2.5% sequence divergence from other Wolbachia wsp sequences. PCR products from seventeen of twenty‐nine (59%) arthropod species analysed could not be sequenced directly due to apparent infection by multiple Wolbachia strains. The wsp sequences cloned from two such species (Plutella xylostella and Trichoplusia ni) indicated both A‐ and B‐Wolbachia were present in a single individual. Hence, superinfection also may be more widespread than the 1.2% incidence previously estimated.", "corpus_id": 10310898, "score": 0 }, { "doc_id": "4412331", "title": "Somatic stem cell niche tropism in Wolbachia", "abstract": "Wolbachia are intracellular bacteria found in the reproductive tissue of all major groups of arthropods. They are transmitted vertically from the female hosts to their offspring, in a pattern analogous to mitochondria inheritance. But Wolbachia phylogeny does not parallel that of the host, indicating that horizontal infectious transmission must also occur. Insect parasitoids are considered the most likely vectors, but the mechanism for horizontal transfer is largely unknown. Here we show that newly introduced Wolbachia cross several tissues and infect the germline of the adult Drosophila melanogaster female. Through investigation of bacterial migration patterns during the course of infection, we found that Wolbachia reach the germline through the somatic stem cell niche in the D. melanogaster germarium. In addition, our data suggest that Wolbachia are highly abundant in the somatic stem cell niche of long-term infected hosts, implying that this location may also contribute to efficient vertical transmission. This is, to our knowledge, the first report of an intracellular parasite displaying tropism for a stem cell niche.", "corpus_id": 4412331, "score": 0 }, { "doc_id": "12960744", "title": "The inconstant gut microbiota of Drosophila species revealed by 16S rRNA gene analysis", "abstract": "The gut microorganisms in some animals are reported to include a core microbiota of consistently associated bacteria that is ecologically distinctive and may have coevolved with the host. The core microbiota is promoted by positive interactions among bacteria, favoring shared persistence; its retention over evolutionary timescales is evident as congruence between host phylogeny and bacterial community composition. This study applied multiple analyses to investigate variation in the composition of gut microbiota in drosophilid flies. First, the prevalence of five previously described gut bacteria (Acetobacter and Lactobacillus species) in individual flies of 21 strains (10 Drosophila species) were determined. Most bacteria were not present in all individuals of most strains, and bacterial species pairs co-occurred in individual flies less frequently than predicted by chance, contrary to expectations of a core microbiota. A complementary pyrosequencing analysis of 16S rRNA gene amplicons from the gut microbiota of 11 Drosophila species identified 209 bacterial operational taxonomic units (OTUs), with near-saturating sampling of sequences, but none of the OTUs was common to all host species. Furthermore, in both of two independent sets of Drosophila species, the gut bacterial community composition was not congruent with host phylogeny. The final analysis identified no common OTUs across three wild and four laboratory samples of D. melanogaster. Our results yielded no consistent evidence for a core microbiota in Drosophila. We conclude that the taxonomic composition of gut microbiota varies widely within and among Drosophila populations and species. This is reminiscent of the patterns of bacterial composition in guts of some other animals, including humans.", "corpus_id": 12960744, "score": 0 }, { "doc_id": "24733011", "title": "Intracellular endosymbiotic bacteria of Camponotus species (carpenter ants): systematics, evolution and ultrastructural characterization", "abstract": "Intracellular endosymbiotic bacteria inherent to ants of the genus Camponotus were characterized. The bacteria were localized in bacteriocytes, which are specialized cells of both workers and queen ants; these cells are intercalated between epithelial cells of the midgut. The bacteriocytes show a different morphology from the normal epithelial cells and carry a large number of the rod‐shaped Gram‐negative bacteria free in the cytoplasm. The bacteria were never observed in the neighbouring epithelial cells, but they were found intracellularly in oocytes, strongly indicating a maternal transmission of the bacteria. The 16S DNA encoding rrs loci of the endosymbionts of four species of the genus Camponotus derived either from Germany (C. herculeanus and C. ligniperdus), North America (C. floridanus) or South America (C. rufipes) were cloned after polymerase chain reaction (PCR) amplification using oligonucleotides complementary to all so far known eubacterial rrs sequences. The DNA sequences of the rrs loci of the four endosymbionts were determined, and, using various genus‐ and species‐specific oligonucleotides derived from variable regions in the rrs sequences, the identity of the bacteria present in the bacteriocytes and the ovarian cells was confirmed by PCR and in situ hybridization techniques. Comparison of the 16S DNA sequences with the available database showed the endosymbiotic bacteria to be members of the γ‐subclass of Proteobacteria. They formed a distinct taxonomic group, a sister taxon of the taxons defined by the tsetse fly and aphid endosymbionts. Within the γ‐subclass, the cluster of the ant, tsetse fly and aphid endosymbionts are placed adjacent to the family of Enterobacteriaceae. The evolutionary tree of the ant endosymbionts reflects the systematic classification and geographical distribution of their host insects, indicating an early co‐evolution of the symbiotic partners and a vertical transmission of the bacteria.", "corpus_id": 24733011, "score": 0 }, { "doc_id": "37697771", "title": "Investigating Deep Phylogenetic Relationships among Cyanobacteria and Plastids by Small Subunit rRNA Sequence Analysis 1", "abstract": "Small subunit rRNA sequence data were generated for 27 strains of cyanobacteria and incorporated into a phylogenetic analysis of 1,377 aligned sequence positions from a diverse sampling of 53 cyanobacteria and 10 photosynthetic plastids. Tree inference was carried out using a maximum likelihood method with correction for site‐to‐site variation in evolutionary rate. Confidence in the inferred phylogenetic relationships was determined by construction of a majority‐rule consensus tree based on alternative topologies not considered to be statistically significantly different from the optimal tree. The results are in agreement with earlier studies in the assignment of individual taxa to specific sequence groups. Several relationships not previously noted among sequence groups are indicated, whereas other relationships previously supported are contradicted. All plastids cluster as a strongly supported monophyletic group arising near the root of the cyanobacterial line of descent.", "corpus_id": 37697771, "score": 0 }, { "doc_id": "10358275", "title": "Reagent and laboratory contamination can critically impact sequence-based microbiome analyses", "abstract": "BackgroundThe study of microbial communities has been revolutionised in recent years by the widespread adoption of culture independent analytical techniques such as 16S rRNA gene sequencing and metagenomics. One potential confounder of these sequence-based approaches is the presence of contamination in DNA extraction kits and other laboratory reagents.ResultsIn this study we demonstrate that contaminating DNA is ubiquitous in commonly used DNA extraction kits and other laboratory reagents, varies greatly in composition between different kits and kit batches, and that this contamination critically impacts results obtained from samples containing a low microbial biomass. Contamination impacts both PCR-based 16S rRNA gene surveys and shotgun metagenomics. We provide an extensive list of potential contaminating genera, and guidelines on how to mitigate the effects of contamination.ConclusionsThese results suggest that caution should be advised when applying sequence-based techniques to the study of microbiota present in low biomass environments. Concurrent sequencing of negative control samples is strongly advised.", "corpus_id": 10358275, "score": 0 }, { "doc_id": "14701241", "title": "Ribosomal Database Project: data and tools for high throughput rRNA analysis", "abstract": "Ribosomal Database Project (RDP; http://rdp.cme.msu.edu/) provides the research community with aligned and annotated rRNA gene sequence data, along with tools to allow researchers to analyze their own rRNA gene sequences in the RDP framework. RDP data and tools are utilized in fields as diverse as human health, microbial ecology, environmental microbiology, nucleic acid chemistry, taxonomy and phylogenetics. In addition to aligned and annotated collections of bacterial and archaeal small subunit rRNA genes, RDP now includes a collection of fungal large subunit rRNA genes. RDP tools, including Classifier and Aligner, have been updated to work with this new fungal collection. The use of high-throughput sequencing to characterize environmental microbial populations has exploded in the past several years, and as sequence technologies have improved, the sizes of environmental datasets have increased. With release 11, RDP is providing an expanded set of tools to facilitate analysis of high-throughput data, including both single-stranded and paired-end reads. In addition, most tools are now available as open source packages for download and local use by researchers with high-volume needs or who would like to develop custom analysis pipelines.", "corpus_id": 14701241, "score": 1 }, { "doc_id": "22851266", "title": "Origin and Effect of Alpha 2.2 Acetobacteraceae in Honey Bee Larvae and Description of Parasaccharibacter apium gen. nov., sp. nov", "abstract": "ABSTRACT The honey bee hive environment contains a rich microbial community that differs according to niche. Acetobacteraceae Alpha 2.2 (Alpha 2.2) bacteria are present in the food stores, the forager crop, and larvae but at negligible levels in the nurse and forager midgut and hindgut. We first sought to determine the source of Alpha 2.2 in young larvae by assaying the diversity of microbes in nurse crops, hypopharyngeal glands (HGs), and royal jelly (RJ). Amplicon-based pyrosequencing showed that Alpha 2.2 bacteria occupy each of these environments along with a variety of other bacteria, including Lactobacillus kunkeei. RJ and the crop contained fewer bacteria than the HGs, suggesting that these tissues are rather selective environments. Phylogenetic analyses showed that honey bee-derived Alpha 2.2 bacteria are specific to bees that “nurse” the hive's developing brood with HG secretions and are distinct from the Saccharibacter-type bacteria found in bees that provision their young differently, such as with a pollen ball coated in crop-derived contents. Acetobacteraceae can form symbiotic relationships with insects, so we next tested whether Alpha 2.2 increased larval fitness. We cultured 44 Alpha 2.2 strains from young larvae that grouped into nine distinct clades. Three isolates from these nine clades flourished in royal jelly, and one isolate increased larval survival in vitro. We conclude that Alpha 2.2 bacteria are not gut bacteria but are prolific in the crop-HG-RJ-larva niche, passed to the developing brood through nurse worker feeding behavior. We propose the name Parasaccharibacter apium for this bacterial symbiont of bees in the genus Apis.", "corpus_id": 22851266, "score": 0 }, { "doc_id": "41186667", "title": "THE LOCAL‐CLOCK PERMUTATION TEST: A SIMPLE TEST TO COMPARE RATES OF MOLECULAR EVOLUTION ON PHYLOGENETIC TREES", "abstract": "Rates of molecular evolution vary substantially between lineages, and a growing effort is directed at uncovering the causes and consequences of this variation. Comparing local‐clocks (rates of molecular evolution estimated from different sets of branches of a phylogenetic tree) is a common tool in this research effort. Here, I show that a commonly used test (the Likelihood Ratio Test, LRT) will not be statistically valid for comparing local‐clocks in most cases. Instead, I propose the local‐clock permutation test (LCPT), a simple test that can be used to test the significance of differences between local‐clocks. The LCPT could also be used to test for differences between any parameter that can be assigned to individual branches on a phylogenetic tree. Using simulated data, I show that the LCPT has good power to detect differences between local‐clocks.", "corpus_id": 41186667, "score": 0 }, { "doc_id": "17155122", "title": "The Gut Bacteria Associated with Camponotus japonicus Mayr with Culture-Dependent and DGGE Methods", "abstract": "The bacterial composition and distribution in the different gut regions of Camponotus japonicus were investigated using both culture-dependent method and culture-independent method of polymerase chain reaction and denaturing gradient gel electrophoresis (PCR–DGGE). Five different bacterial strains were isolated using culture-dependent method, and they all belong to the phylum Firmicutes, including three genera of bacteria Bacillus,Paenibacillus, and Enterococcus. Bacillus cereus and Enterococcus mundtii were found in the midgut; Paenibacillus sp. was isolated from the hindgut; and the other two Bacillus spp. were isolated from the crop. Twelve distinct DGGE bands were found using PCR–DGGE method, and their sequences blasting analysis shows that they are members of the Proteobacteria and the Firmicutes, respectively, including three genera (Pseudomonas, Candidatus Blochmannia, Fructobacillus) and one uncultured bacterium, in which Pseudomonas was the most dominant bacteria group in all the three gut regions. According to the DGGE profile, the three gut regions had very similar gut communities, and all the DGGE bands were presented in the midgut and hindgut, while just two bands representing Blochmannia were not present in the crop. The results of our study indicate that the gut of C. japonicus harbors several other bacteria besides the obligate endosymbionts Blochmannia, and more work should be carried on to verify if they are common in the guts of other Camponotus ants.", "corpus_id": 17155122, "score": 0 }, { "doc_id": "18775372", "title": "A Metatranscriptomic Approach to the Identification of Microbiota Associated with the Ant Formica exsecta", "abstract": "Social insects live in cooperative colonies, often in high densities and with closely related individuals, and interact using social contact behaviours. Compared to solitary insects, social insects have evolved multi-level immunity that includes immune responses common to holometabolous insects, and social immunity, which is exclusive to social taxa. This suggests that social insects may be subject to high pathogen pressure, yet relatively little is known about the range of symbiotic and pathogenic microbial communities that associate with social insects. In this study we examined transcriptome data generated from the ant Formica exsecta for sequences identifying as microbes (or other organisms potentially of non-ant origin). Sequences showing homology to two viruses and several other potentially or obligate intracellular organisms, such as Wolbachia, Arsenophonus, Entomoplasmatales and Microsporidia, were present in the transcriptome data. These homologous sequence matches correspond to genera/species that have previously been associated with a variety of insects, including social insects. There were also sequences with identity to several other microbes such as common moulds and soil bacteria. We conclude that this sequence data provides a starting point for a deeper understanding of the biological interactions between a species of ant and the micro- and macrobiotic communities that it potentially encounters.", "corpus_id": 18775372, "score": 0 }, { "doc_id": "16285607", "title": "The Gut Bacterial Communities Associated with Lab-Raised and Field-Collected Ants of Camponotusfragilis (Formicidae: Formicinae)", "abstract": "Camponotus is the second largest ant genus and known to harbor the primary endosymbiotic bacteria of the genus Blochmannia. However, little is known about the effect of diet and environment changes on the gut bacterial communities of these ants. We investigated the intestinal bacterial communities in the lab-raised and field-collected ants of Camponotus fragilis which is found in the southwestern United States and northern reaches of Mexico. We determined the difference of gut bacterial composition and distribution among the crop, midgut, and hindgut of the two types of colonies. Number of bacterial species varied with the methods of detection and the source of the ants. Lab-raised ants yielded 12 and 11 species using classical microbial culture methods and small-subunit rRNA genes (16S rRNAs) polymerase chain reaction-restriction fragment-length polymorphism analysis, respectively. Field-collected ants yielded just 4 and 1–3 species using the same methods. Most gut bacterial species from the lab-raised ants were unevenly distributed among the crop, midgut, and hindgut, and each section had its own dominant bacterial species. Acetobacter was the prominent bacteria group in crop, accounting for about 55 % of the crop clone library. Blochmannia was the dominant species in midgut, nearly reaching 90 % of the midgut clone library. Pseudomonas aeruginosa dominated the hindgut, accounting for over 98 % of the hindgut clone library. P. aeruginosa was the only species common to all three sections. A comparison between lab-raised and field-collected ants, and comparison with other species, shows that gut bacterial communities vary with local environment and diet. The bacterial species identified here were most likely commensals with little effect on their hosts or mild pathogens deleterious to colony health.", "corpus_id": 16285607, "score": 0 }, { "doc_id": "83448", "title": "Distinctive Gut Microbiota of Honey Bees Assessed Using Deep Sampling from Individual Worker Bees", "abstract": "Surveys of 16S rDNA sequences from the honey bee, Apis mellifera, have revealed the presence of eight distinctive bacterial phylotypes in intestinal tracts of adult worker bees. Because previous studies have been limited to relatively few sequences from samples pooled from multiple hosts, the extent of variation in this microbiota among individuals within and between colonies and locations has been unclear. We surveyed the gut microbiota of 40 individual workers from two sites, Arizona and Maryland USA, sampling four colonies per site. Universal primers were used to amplify regions of 16S ribosomal RNA genes, and amplicons were sequenced using 454 pyrotag methods, enabling analysis of about 330,000 bacterial reads. Over 99% of these sequences belonged to clusters for which the first blastn hits in GenBank were members of the known bee phylotypes. Four phylotypes, one within Gammaproteobacteria (corresponding to “Candidatus Gilliamella apicola”) one within Betaproteobacteria (“Candidatus Snodgrassella alvi”), and two within Lactobacillus, were present in every bee, though their frequencies varied. The same typical bacterial phylotypes were present in all colonies and at both sites. Community profiles differed significantly among colonies and between sites, mostly due to the presence in some Arizona colonies of two species of Enterobacteriaceae not retrieved previously from bees. Analysis of Sanger sequences of rRNA of the Snodgrassella and Gilliamella phylotypes revealed that single bees contain numerous distinct strains of each phylotype. Strains showed some differentiation between localities, especially for the Snodgrassella phylotype.", "corpus_id": 83448, "score": 0 }, { "doc_id": "7239539", "title": "Metagenomic and metaproteomic insights into bacterial communities in leaf-cutter ant fungus gardens", "abstract": "Herbivores gain access to nutrients stored in plant biomass largely by harnessing the metabolic activities of microbes. Leaf-cutter ants of the genus Atta are a hallmark example; these dominant neotropical herbivores cultivate symbiotic fungus gardens on large quantities of fresh plant forage. As the external digestive system of the ants, fungus gardens facilitate the production and sustenance of millions of workers. Using metagenomic and metaproteomic techniques, we characterize the bacterial diversity and physiological potential of fungus gardens from two species of Atta. Our analysis of over 1.2 Gbp of community metagenomic sequence and three 16S pyrotag libraries reveals that in addition to harboring the dominant fungal crop, these ecosystems contain abundant populations of Enterobacteriaceae, including the genera Enterobacter, Pantoea, Klebsiella, Citrobacter and Escherichia. We show that these bacterial communities possess genes associated with lignocellulose degradation and diverse biosynthetic pathways, suggesting that they play a role in nutrient cycling by converting the nitrogen-poor forage of the ants into B-vitamins, amino acids and other cellular components. Our metaproteomic analysis confirms that bacterial glycosyl hydrolases and proteins with putative biosynthetic functions are produced in both field-collected and laboratory-reared colonies. These results are consistent with the hypothesis that fungus gardens are specialized fungus–bacteria communities that convert plant material into energy for their ant hosts. Together with recent investigations into the microbial symbionts of vertebrates, our work underscores the importance of microbial communities in the ecology and evolution of herbivorous metazoans.", "corpus_id": 7239539, "score": 0 }, { "doc_id": "3266211", "title": "Bacterial symbiont sharing in Megalomyrmex social parasites and their fungus‐growing ant hosts", "abstract": "Bacterial symbionts are important fitness determinants of insects. Some hosts have independently acquired taxonomically related microbes to meet similar challenges, but whether distantly related hosts that live in tight symbiosis can maintain similar microbial communities has not been investigated. Varying degrees of nest sharing between Megalomyrmex social parasites (Solenopsidini) and their fungus‐growing ant hosts (Attini) from the genera Cyphomyrmex, Trachymyrmex and Sericomyrmex allowed us to address this question, as both ant lineages rely on the same fungal diet, interact in varying intensities and are distantly related. We used tag‐encoded FLX 454 pyrosequencing and diagnostic PCR to map bacterial symbiont diversity across the Megalomyrmex phylogenetic tree, which also contains free‐living generalist predators. We show that social parasites and hosts share a subset of bacterial symbionts, primarily consisting of Entomoplasmatales, Bartonellaceae, Acinetobacter, Wolbachia and Pseudonocardia and that Entomoplasmatales and Bartonellaceae can co‐infect specifically associated combinations of hosts and social parasites with identical 16S rRNA genotypes. We reconstructed in more detail the population‐level infection dynamics for Entomoplasmatales and Bartonellaceae in Megalomyrmex symmetochus guest ants and their Sericomyrmex amabilis hosts. We further assessed the stability of the bacterial communities through a diet manipulation experiment and evaluated possible transmission modes in shared nests such as consumption of the same fungus garden food, eating of host brood by social parasites, trophallaxis and grooming interactions between the ants, or parallel acquisition from the same nest environment. Our results imply that cohabiting ant social parasites and hosts may obtain functional benefits from bacterial symbiont transfer even when they are not closely related.", "corpus_id": 3266211, "score": 0 }, { "doc_id": "17403205", "title": "Waste management in the leaf-cutting ant Atta colombica", "abstract": "Unlike most leaf-cutting ants, which have underground waste dumps, the leaf-cutting ant Atta colombica dumps waste in a heap outside the nest. Waste is hazardous, as it is contaminated with pathogens. We investigated the organization of the workforce involved in outside-nest tasks (foraging, waste disposal) and quantified task switching and heap location to test hypotheses that these tasks are organized to minimize contact between the heap and foraging entrances and trails. Waste management is an important task: 11% of externally working ants were either transporting waste or manipulating waste on the heap, and the other 89% were foragers. There is strict division of labor between foragers and waste workers, with no task switching. Waste management also has division of labor and is undertaken by transporters that carry waste to the heap margins and heap workers that manage the heap. Waste heaps are always located downhill from nest entrances. The distance to the waste heap is positively related to colony size and negatively related to slope. Foraging trails avoid the heap, with 92% of trails going away from the heap. This avoidance behavior is costly, increasing foraging trail length by at least 6%. Waste management in A. colombica is a sophisticated system that encompasses both work and spatial organization. This organization is probably adaptive in reducing disease transmission. Division of labor separates waste management from foraging, reducing the likelihood of foragers becoming contaminated with waste. The downhill location of heaps reduces waste entering entrances during rain. The orientation of foraging trails reduces the possibility of foragers becoming accidentally contaminated with waste. Copyright 2002.", "corpus_id": 17403205, "score": 0 }, { "doc_id": "10644572", "title": "Microbiomes of ant castes implicate new microbial roles in the fungus-growing ant Trachymyrmex septentrionalis", "abstract": "Fungus-growing ants employ several defenses against diseases, including disease-suppressing microbial biofilms on their integument and in fungal gardens. Here, we compare the phenology of microbiomes in natural nests of the temperate fungus-growing ant Trachymyrmex septentrionalis using culture-dependent isolations and culture-independent 16S-amplicon 454-sequencing. 454-sequencing revealed diverse actinobacteria associated with ants, including most prominently Solirubrobacter (12.2–30.9% of sequence reads), Pseudonocardia (3.5–42.0%), and Microlunatus (0.4–10.8%). Bacterial abundances remained relatively constant in monthly surveys throughout the annual active period (late winter to late summer), except Pseudonocardia abundance declined in females during the reproductive phase. Pseudonocardia species found on ants are phylogenetically different from those in gardens and soil, indicating ecological separation of these Pseudonocardia types. Because the pathogen Escovopsis is not known to infect gardens of T. septentrionalis, the ant-associated microbes do not seem to function in Escovopsis suppression, but could protect against ant diseases, help in nest sanitation, or serve unknown functions.", "corpus_id": 10644572, "score": 0 }, { "doc_id": "1892954", "title": "Bacterial gut symbionts are tightly linked with the evolution of herbivory in ants", "abstract": "Ants are a dominant feature of terrestrial ecosystems, yet we know little about the forces that drive their evolution. Recent findings illustrate that their diets range from herbivorous to predaceous, with “herbivores” feeding primarily on exudates from plants and sap-feeding insects. Persistence on these nitrogen-poor food sources raises the question of how ants obtain sufficient nutrition. To investigate the potential role of symbiotic microbes, we have surveyed 283 species from 18 of the 21 ant subfamilies using molecular techniques. Our findings uncovered a wealth of bacteria from across the ants. Notable among the surveyed hosts were herbivorous “turtle ants” from the related genera Cephalotes and Procryptocerus (tribe Cephalotini). These commonly harbored bacteria from ant-specific clades within the Burkholderiales, Pseudomonadales, Rhizobiales, Verrucomicrobiales, and Xanthomonadales, and studies of lab-reared Cephalotes varians characterized these microbes as symbiotic residents of ant guts. Although most of these symbionts were confined to turtle ants, bacteria from an ant-specific clade of Rhizobiales were more broadly distributed. Statistical analyses revealed a strong relationship between herbivory and the prevalence of Rhizobiales gut symbionts within ant genera. Furthermore, a consideration of the ant phylogeny identified at least five independent origins of symbioses between herbivorous ants and related Rhizobiales. Combined with previous findings and the potential for symbiotic nitrogen fixation, our results strongly support the hypothesis that bacteria have facilitated convergent evolution of herbivory across the ants, further implicating symbiosis as a major force in ant evolution.", "corpus_id": 1892954, "score": 0 }, { "doc_id": "206536986", "title": "Drosophila Microbiome Modulates Host Developmental and Metabolic Homeostasis via Insulin Signaling", "abstract": "Successful development of fruit flies depends on a gut bacterium that interacts with its host’s insulin-signaling pathway. The symbiotic microbiota profoundly affect many aspects of host physiology; however, the molecular mechanisms underlying host-microbe cross-talk are largely unknown. Here, we show that the pyrroloquinoline quinone–dependent alcohol dehydrogenase (PQQ-ADH) activity of a commensal bacterium, Acetobacter pomorum, modulates insulin/insulin-like growth factor signaling (IIS) in Drosophila to regulate host homeostatic programs controlling developmental rate, body size, energy metabolism, and intestinal stem cell activity. Germ-free animals monoassociated with PQQ-ADH mutant bacteria displayed severe deregulation of developmental and metabolic homeostasis. Importantly, these defects were reversed by enhancing host IIS or by supplementing the diet with acetic acid, the metabolic product of PQQ-ADH.", "corpus_id": 206536986, "score": 0 }, { "doc_id": "22867620", "title": "Sequence evolution in bacterial endosymbionts having extreme base compositions.", "abstract": "A major limitation on ability to reconstruct bacterial evolution is the lack of dated ancestors that might be used to evaluate and calibrate molecular clocks. Vertically transmitted symbionts that have cospeciated with animal hosts offer a firm basis for calibrating sequence evolution in bacteria, since fossils of the hosts can be used to date divergence events. Sequences for a functionally diverse set of genes have been obtained for bacterial endosymbionts (Buchnera) from two pairs of aphid host species, each pair diverging 50-70 MYA. Using these dates and estimated numbers of Buchnera generations per year, we calculated rates of base substitution for neutral and selected sites of protein-coding genes and overall rates for rRNA genes. Buchnera shows homogeneity among loci with regard to synonymous rate. The Buchnera synonymous rate is about twice that for low-codon-bias genes of Escherichia coli-Salmonella typhimurium on an absolute timescale, and fourfold higher on a generational timescale. Nonsynonymous substitutions show a greater rate disparity in favor of Buchnera, a result consistent with a genomewide decrease in selection efficiency in Buchnera. Ratios of synonymous to nonsynonymous substitutions differ for the two pairs of Buchnera, indicating that selection efficiency varies among lineages. Like numerous other intracellular bacteria, such as Rickettsia and Wolbachia, Buchnera has accumulated amino acids with codons rich in A or T. Phylogenetic reconstruction of amino acid replacements indicates that replacements yielding increased A + T predominated early in the evolution of Buchnera, with the trend slowing or stopping during the last 50 Myr. This suggests that base composition in Buchnera has approached a limit enforced by selective constraint acting on protein function.", "corpus_id": 22867620, "score": 0 }, { "doc_id": "20685627", "title": "Deleterious mutations destabilize ribosomal RNA in endosymbiotic bacteria.", "abstract": "In populations that are small and asexual, mutations with slight negative effects on fitness will drift to fixation more often than in large or sexual populations in which they will be eliminated by selection. If such mutations occur in substantial numbers, the combined effects of long-term asexuality and small population size may result in substantial accumulation of mildly deleterious substitutions. Prokaryotic endosymbionts of animals that are transmitted maternally for very long periods are effectively asexual and experience smaller effective population size than their free-living relatives. The contrast between such endosymbionts and related free-living bacteria allows us to test whether a population structure imposing frequent bottlenecks and asexuality does lead to an accumulation of slightly deleterious substitutions. Here we show that several independently derived insect endosymbionts, each with a long history of maternal transmission, have accumulated destabilizing base substitutions in the highly conserved 16S rRNA. Stabilities of Domain I of this subunit are 15-25% lower in endosymbionts than in closely related free-living bacteria. By mapping destabilizing substitutions onto a reconstructed phylogeny, we show that decreased ribosomal stability has evolved separately in each endosymbiont lineage. Our phylogenetic approach allows us to demonstrate statistical significance for this pattern: becoming endosymbiotic predictably results in decreased stability of rRNA secondary structure.", "corpus_id": 20685627, "score": 0 }, { "doc_id": "8563161", "title": "Hidden Diversity in Honey Bee Gut Symbionts Detected by Single-Cell Genomics", "abstract": "Microbial communities in animal guts are composed of diverse, specialized bacterial species, but little is known about how gut bacteria diversify to produce genetically and ecologically distinct entities. The gut microbiota of the honey bee, Apis mellifera, presents a useful model, because it consists of a small number of characteristic bacterial species, each showing signs of diversification. Here, we used single-cell genomics to study the variation within two species of the bee gut microbiota: Gilliamella apicola and Snodgrassella alvi. For both species, our analyses revealed extensive variation in intraspecific divergence of protein-coding genes but uniformly high levels of 16S rRNA similarity. In both species, the divergence of 16S rRNA loci appears to have been curtailed by frequent recombination within populations, while other genomic regions have continuously diverged. Furthermore, gene repertoires differ markedly among strains in both species, implying distinct metabolic capabilities. Our results show that, despite minimal divergence at 16S rRNA genes, in situ diversification occurs within gut communities and generates bacterial lineages with distinct ecological niches. Therefore, important dimensions of microbial diversity are not evident from analyses of 16S rRNA, and single cell genomics has potential to elucidate processes of bacterial diversification.", "corpus_id": 8563161, "score": 0 }, { "doc_id": "2916377", "title": "Regulation of midgut growth, development, and metamorphosis.", "abstract": "The insect midgut is an important site of entry for pathogens and insect control agents. This review focuses on recent information related to midgut epithelial growth, metamorphosis, and repair as a defense against pathogens. The roles of stem cell mitogens and differentiation factors are described. Included is a discussion of apoptosis and autophagy in the yellow body. Sloughing, also described, protects the midgut from virus infections and bacterial toxins through death and replacement of affected cells. The mechanisms by which the repair process reduces the effectiveness of pest control strategies are discussed. Primary tissue culture methods also are described, and their value in understanding the mechanisms by which biologically based insecticides work is discussed.", "corpus_id": 2916377, "score": 0 }, { "doc_id": "206720060", "title": "High-Resolution Analysis of Gut Environment and Bacterial Microbiota Reveals Functional Compartmentation of the Gut in Wood-Feeding Higher Termites (Nasutitermes spp.)", "abstract": "ABSTRACT Higher termites are characterized by a purely prokaryotic gut microbiota and an increased compartmentation of their intestinal tract. In soil-feeding species, each gut compartment has different physicochemical conditions and is colonized by a specific microbial community. Although considerable information has accumulated also for wood-feeding species of the genus Nasutitermes, including cellulase activities and metagenomic data, a comprehensive study linking physicochemical gut conditions with the structure of the microbial communities in the different gut compartments is lacking. In this study, we measured high-resolution profiles of H2, O2, pH, and redox potential in the gut of Nasutitermes corniger termites, determined the fermentation products accumulating in the individual gut compartments, and analyzed the bacterial communities in detail by pyrotag sequencing of the V3-V4 region of the 16S rRNA genes. The dilated hindgut paunch (P3 compartment) was the only anoxic gut region, showed the highest density of bacteria, and accumulated H2 to high partial pressures (up to 12 kPa). Molecular hydrogen is apparently produced by a dense community of Spirochaetes and Fibrobacteres, which also dominate the gut of other Nasutitermes species. All other compartments, such as the alkaline P1 compartment (average pH, 10.0), showed high redox potentials and comprised small but distinct populations characteristic for each gut region. In the crop and the posterior hindgut compartments, the community was even more diverse than in the paunch. Similarities in the communities of the posterior hindgut and crop suggested that proctodeal trophallaxis or coprophagy also occurs in higher termites. The large sampling depths of pyrotag sequencing in combination with the determination of important physicochemical parameters allow cautious conclusions concerning the functions of particular bacterial lineages in the respective gut sections to be drawn.", "corpus_id": 206720060, "score": 0 }, { "doc_id": "2628114", "title": "Bacteria Associated with Gut Lumen of Camponotus japonicus Mayr", "abstract": "ABSTRACT \n Camponotus ants harbor the obligate intracellular endosymbiont Blochmannia in their midgut bacteriocytes, but little is known about intestinal bacteria living in the gut lumen. In this paper we reported the results of a survey of the intestinal microflora of Camponotus japonicus Mayr based on small-subunit rRNA genes (16S rRNAs) polymerase chain reaction (PCR)-restriction fragment-length polymorphism analysis of worker guts. From 107 clones, 11 different restriction fragment-length polymorphism profiles were identified, and sequences blasting analysis found these represent four types of bacteria. Most (91.6%) of the clones were “Candidatus Blochmannia”, the obligate endosymbionts of Camponotus ants, and 6.5% of the clones were “Candidatus Serratia symbiotica”, a secondary endosymbiont of aphids; the remaining 2% clones were Fructobacillus fructosus and uncultured Burkholderiales bacterium, respectively. These results show that the diversity of gut bacteria in C. japonicus was low. “Candidatus Serratia symbiotica” was identified from Camponotus ants for the first time, an interesting result because Blochmannia's closest bacterial relative is also in the genus Serratia. This discovery supports the scenario that consumption of aphid honeydew or tissue provides an initial step in the evolution of an advanced symbiosis, and suggests that Camponotus ant could acquire other secondary endosymbionts from Hemiptera host through their diet. In addition, Burkholderiales bacterium also was identified from the gut of C. japonicus for the first time, and whether it is a nitrogen-recycling endosymbiont in Camponotus ants needs to be investigated further.", "corpus_id": 2628114, "score": 0 }, { "doc_id": "14261473", "title": "A Veritable Menagerie of Heritable Bacteria from Ants, Butterflies, and Beyond: Broad Molecular Surveys and a Systematic Review", "abstract": "Maternally transmitted bacteria have been important players in the evolution of insects and other arthropods, affecting their nutrition, defense, development, and reproduction. Wolbachia are the best studied among these and typically the most prevalent. While several other bacteria have independently evolved a heritable lifestyle, less is known about their host ranges. Moreover, most groups of insects have not had their heritable microflora systematically surveyed across a broad range of their taxonomic diversity. To help remedy these shortcomings we used diagnostic PCR to screen for five groups of heritable symbionts—Arsenophonus spp., Cardinium hertigii, Hamiltonella defensa, Spiroplasma spp., and Wolbachia spp.—across the ants and lepidopterans (focusing, in the latter case, on two butterfly families—the Lycaenidae and Nymphalidae). We did not detect Cardinium or Hamiltonella in any host. Wolbachia were the most widespread, while Spiroplasma (ants and lepidopterans) and Arsenophonus (ants only) were present at low levels. Co-infections with different Wolbachia strains appeared especially common in ants and less so in lepidopterans. While no additional facultative heritable symbionts were found among ants using universal bacterial primers, microbes related to heritable enteric bacteria were detected in several hosts. In summary, our findings show that Wolbachia are the dominant heritable symbionts of ants and at least some lepidopterans. However, a systematic review of symbiont frequencies across host taxa revealed that this is not always the case across other arthropods. Furthermore, comparisons of symbiont frequencies revealed that the prevalence of Wolbachia and other heritable symbionts varies substantially across lower-level arthropod taxa. We discuss the correlates, potential causes, and implications of these patterns, providing hypotheses on host attributes that may shape the distributions of these influential bacteria.", "corpus_id": 14261473, "score": 0 }, { "doc_id": "1751531", "title": "Practical innovations for high-throughput amplicon sequencing", "abstract": "We describe improvements for sequencing 16S ribosomal RNA (rRNA) amplicons, a cornerstone technique in metagenomics. Through unique tagging of template molecules before PCR, amplicon sequences can be mapped to their original templates to correct amplification bias and sequencing error with software we provide. PCR clamps block amplification of contaminating sequences from a eukaryotic host, thereby substantially enriching microbial sequences without introducing bias.", "corpus_id": 1751531, "score": 0 }, { "doc_id": "14824124", "title": "Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample", "abstract": "The ongoing revolution in high-throughput sequencing continues to democratize the ability of small groups of investigators to map the microbial component of the biosphere. In particular, the coevolution of new sequencing platforms and new software tools allows data acquisition and analysis on an unprecedented scale. Here we report the next stage in this coevolutionary arms race, using the Illumina GAIIx platform to sequence a diverse array of 25 environmental samples and three known “mock communities” at a depth averaging 3.1 million reads per sample. We demonstrate excellent consistency in taxonomic recovery and recapture diversity patterns that were previously reported on the basis of metaanalysis of many studies from the literature (notably, the saline/nonsaline split in environmental samples and the split between host-associated and free-living communities). We also demonstrate that 2,000 Illumina single-end reads are sufficient to recapture the same relationships among samples that we observe with the full dataset. The results thus open up the possibility of conducting large-scale studies analyzing thousands of samples simultaneously to survey microbial communities at an unprecedented spatial and temporal resolution.", "corpus_id": 14824124, "score": 0 }, { "doc_id": "25422900", "title": "Barcoded Primers Used in Multiplex Amplicon Pyrosequencing Bias Amplification", "abstract": "ABSTRACT “Barcode-tagged” PCR primers used for multiplex amplicon sequencing generate a thus-far-overlooked amplification bias that produces variable terminal restriction fragment length polymorphism (T-RFLP) and pyrosequencing data from the same environmental DNA template. We propose a simple two-step PCR approach that increases reproducibility and consistently recovers higher genetic diversity in pyrosequencing libraries.", "corpus_id": 25422900, "score": 0 }, { "doc_id": "32942576", "title": "QIIME allows analysis of high-throughput community sequencing data", "abstract": "Supplementary Figure 1 Overview of the analysis pipeline. Supplementary Table 1 Details of conventionally raised and conventionalized mouse samples. Supplementary Discussion Expanded discussion of QIIME analyses presented in the main text; Sequencing of 16S rRNA gene amplicons; QIIME analysis notes; Expanded Figure 1 legend; Links to raw data and processed output from the runs with and without denoising.", "corpus_id": 32942576, "score": 0 }, { "doc_id": "7181682", "title": "UPARSE: highly accurate OTU sequences from microbial amplicon reads", "abstract": "Amplified marker-gene sequences can be used to understand microbial community structure, but they suffer from a high level of sequencing and amplification artifacts. The UPARSE pipeline reports operational taxonomic unit (OTU) sequences with ≤1% incorrect bases in artificial microbial community tests, compared with >3% incorrect bases commonly reported by other methods. The improved accuracy results in far fewer OTUs, consistently closer to the expected number of species in a community.", "corpus_id": 7181682, "score": 0 }, { "doc_id": "24262446", "title": "Assembling Genomic DNA Sequences with PHRAP", "abstract": "The PHRAP assembly program provides rapid comparison, alignment, and assembly of large sets of DNA sequences. PHRAP compares sequences by searching for pairs of perfectly matching “words” or sequence regions that meet certain criteria. If a match is found, PHRAP then tries to extend the alignment into overlapping sections called contigs. PHRAP uses quality values produced by the PHRED basecaller to strike a balance between tolerance of discrepancies and prevention of stacking repeat sequences. The PHRAP assembly algorithm is generally used as part of the PHRED/PHRAP/Consed software suite for sequence analysis. This unit presents instructions for basic usage of the PHRAP assembler, including preparation of the input files (Support Protocols 1 and 2) and explanation of output files (Basic Protocols 1 and 2). Several command line options for changing the PHRAP assembly parameters are also discussed (Basic Protocol 3).", "corpus_id": 24262446, "score": 0 }, { "doc_id": "19801242", "title": "Infernal 1.0: inference of RNA alignments", "abstract": "SUMMARY\nINFERNAL builds consensus RNA secondary structure profiles called covariance models (CMs), and uses them to search nucleic acid sequence databases for homologous RNAs, or to create new sequence- and structure-based multiple sequence alignments.\n\n\nAVAILABILITY\nSource code, documentation and benchmark downloadable from http://infernal.janelia.org. INFERNAL is freely licensed under the GNU GPLv3 and should be portable to any POSIX-compliant operating system, including Linux and Mac OS/X.", "corpus_id": 19801242, "score": 0 }, { "doc_id": "5776452", "title": "Query-Dependent Banding (QDB) for Faster RNA Similarity Searches", "abstract": "When searching sequence databases for RNAs, it is desirable to score both primary sequence and RNA secondary structure similarity. Covariance models (CMs) are probabilistic models well-suited for RNA similarity search applications. However, the computational complexity of CM dynamic programming alignment algorithms has limited their practical application. Here we describe an acceleration method called query-dependent banding (QDB), which uses the probabilistic query CM to precalculate regions of the dynamic programming lattice that have negligible probability, independently of the target database. We have implemented QDB in the freely available Infernal software package. QDB reduces the average case time complexity of CM alignment from LN 2.4 to LN 1.3 for a query RNA of N residues and a target database of L residues, resulting in a 4-fold speedup for typical RNA queries. Combined with other improvements to Infernal, including informative mixture Dirichlet priors on model parameters, benchmarks also show increased sensitivity and specificity resulting from improved parameterization.", "corpus_id": 5776452, "score": 0 }, { "doc_id": "11215325", "title": "RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies", "abstract": "Motivation: Phylogenies are increasingly used in all fields of medical and biological research. Moreover, because of the next-generation sequencing revolution, datasets used for conducting phylogenetic analyses grow at an unprecedented pace. RAxML (Randomized Axelerated Maximum Likelihood) is a popular program for phylogenetic analyses of large datasets under maximum likelihood. Since the last RAxML paper in 2006, it has been continuously maintained and extended to accommodate the increasingly growing input datasets and to serve the needs of the user community. Results: I present some of the most notable new features and extensions of RAxML, such as a substantial extension of substitution models and supported data types, the introduction of SSE3, AVX and AVX2 vector intrinsics, techniques for reducing the memory requirements of the code and a plethora of operations for conducting post-analyses on sets of trees. In addition, an up-to-date 50-page user manual covering all new RAxML options is available. Availability and implementation: The code is available under GNU GPL at https://github.com/stamatak/standard-RAxML. Contact: alexandros.stamatakis@h-its.org Supplementary information: Supplementary data are available at Bioinformatics online.", "corpus_id": 11215325, "score": 0 }, { "doc_id": "17114182", "title": "Among-site rate variation and its impact on phylogenetic analyses.", "abstract": "Although several decades of study have revealed the ubiquity of variation of evolutionary rates among sites, reliable methods for studying rate variation were not developed until very recently. Early methods fit theoretical distributions to the numbers of changes at sites inferred by parsimony and substantially underestimate the rate variation. Recent analyses show that failure to account for rate variation can have drastic effects, leading to biased dating of speciation events, biased estimation of the transition:transversion rate ratio, and incorrect reconstruction of phylogenies.", "corpus_id": 17114182, "score": 0 }, { "doc_id": "26387069", "title": "jModelTest 2: more models, new heuristics and parallel computing", "abstract": "jModelTest 2: more models, new heuristics and parallel computing Diego Darriba, Guillermo L. Taboada, Ramón Doallo and David Posada Supplementary Table 1. New features in jModelTest 2 Supplementary Table 2. Model selection accuracy Supplementary Table 3. Mean square errors for model averaged estimates Supplementary Note 1. Hill-climbing hierarchical clustering algorithm Supplementary Note 2. Heuristic filtering Supplementary Note 3. Simulations from prior distributions Supplementary Note 4. Speed-up benchmark on real and simulated datasets", "corpus_id": 26387069, "score": 0 }, { "doc_id": "9428738", "title": "Selecting the best-fit model of nucleotide substitution.", "abstract": "Despite the relevant role of models of nucleotide substitution in phylogenetics, choosing among different models remains a problem. Several statistical methods for selecting the model that best fits the data at hand have been proposed, but their absolute and relative performance has not yet been characterized. In this study, we compare under various conditions the performance of different hierarchical and dynamic likelihood ratio tests, and of Akaike and Bayesian information methods, for selecting best-fit models of nucleotide substitution. We specifically examine the role of the topology used to estimate the likelihood of the different models and the importance of the order in which hypotheses are tested. We do this by simulating DNA sequences under a known model of nucleotide substitution and recording how often this true model is recovered by the different methods. Our results suggest that model selection is reasonably accurate and indicate that some likelihood ratio test methods perform overall better than the Akaike or Bayesian information criteria. The tree used to estimate the likelihood scores does not influence model selection unless it is a randomly chosen tree. The order in which hypotheses are tested, and the complexity of the initial model in the sequence of tests, influence model selection in some cases. Model fitting in phylogenetics has been suggested for many years, yet many authors still arbitrarily choose their models, often using the default models implemented in standard computer programs for phylogenetic estimation. We show here that a best-fit model can be readily identified. Consequently, given the relevance of models, model fitting should be routine in any phylogenetic analysis that uses models of evolution.", "corpus_id": 9428738, "score": 0 }, { "doc_id": "16088459", "title": "MrBayes 3.2: Efficient Bayesian Phylogenetic Inference and Model Choice Across a Large Model Space", "abstract": "Abstract Since its introduction in 2001, MrBayes has grown in popularity as a software package for Bayesian phylogenetic inference using Markov chain Monte Carlo (MCMC) methods. With this note, we announce the release of version 3.2, a major upgrade to the latest official release presented in 2003. The new version provides convergence diagnostics and allows multiple analyses to be run in parallel with convergence progress monitored on the fly. The introduction of new proposals and automatic optimization of tuning parameters has improved convergence for many problems. The new version also sports significantly faster likelihood calculations through streaming single-instruction-multiple-data extensions (SSE) and support of the BEAGLE library, allowing likelihood calculations to be delegated to graphics processing units (GPUs) on compatible hardware. Speedup factors range from around 2 with SSE code to more than 50 with BEAGLE for codon problems. Checkpointing across all models allows long runs to be completed even when an analysis is prematurely terminated. New models include relaxed clocks, dating, model averaging across time-reversible substitution models, and support for hard, negative, and partial (backbone) tree constraints. Inference of species trees from gene trees is supported by full incorporation of the Bayesian estimation of species trees (BEST) algorithms. Marginal model likelihoods for Bayes factor tests can be estimated accurately across the entire model space using the stepping stone method. The new version provides more output options than previously, including samples of ancestral states, site rates, site dN/dS rations, branch rates, and node dates. A wide range of statistics on tree parameters can also be output for visualization in FigTree and compatible software.", "corpus_id": 16088459, "score": 0 }, { "doc_id": "29050879", "title": "Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure.", "abstract": "A dynamic programming algorithm for prediction of RNA secondary structure has been revised to accommodate folding constraints determined by chemical modification and to include free energy increments for coaxial stacking of helices when they are either adjacent or separated by a single mismatch. Furthermore, free energy parameters are revised to account for recent experimental results for terminal mismatches and hairpin, bulge, internal, and multibranch loops. To demonstrate the applicability of this method, in vivo modification was performed on 5S rRNA in both Escherichia coli and Candida albicans with 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate, dimethyl sulfate, and kethoxal. The percentage of known base pairs in the predicted structure increased from 26.3% to 86.8% for the E. coli sequence by using modification constraints. For C. albicans, the accuracy remained 87.5% both with and without modification data. On average, for these sequences and a set of 14 sequences with known secondary structure and chemical modification data taken from the literature, accuracy improves from 67% to 76%. This enhancement primarily reflects improvement for three sequences that are predicted with <40% accuracy on the basis of energetics alone. For these sequences, inclusion of chemical modification constraints improves the average accuracy from 28% to 78%. For the 11 sequences with <6% pseudoknotted base pairs, structures predicted with constraints from chemical modification contain on average 84% of known canonical base pairs.", "corpus_id": 29050879, "score": 0 } ]

{ "doc_id": "15684756", "title": "Proteolytic Pathways Induced by Herbicides That Inhibit Amino Acid Biosynthesis", "abstract": "Background The herbicides glyphosate (Gly) and imazamox (Imx) inhibit the biosynthesis of aromatic and branched-chain amino acids, respectively. Although these herbicides inhibit different pathways, they have been reported to show several common physiological effects in their modes of action, such as increasing free amino acid contents and decreasing soluble protein contents. To investigate proteolytic activities upon treatment with Gly and Imx, pea plants grown in hydroponic culture were treated with Imx or Gly, and the proteolytic profile of the roots was evaluated through fluorogenic kinetic assays and activity-based protein profiling. Results Several common changes in proteolytic activity were detected following Gly and Imx treatment. Both herbicides induced the ubiquitin-26 S proteasome system and papain-like cysteine proteases. In contrast, the activities of vacuolar processing enzymes, cysteine proteases and metacaspase 9 were reduced following treatment with both herbicides. Moreover, the activities of several putative serine protease were similarly increased or decreased following treatment with both herbicides. In contrast, an increase in YVADase activity was observed under Imx treatment versus a decrease under Gly treatment. Conclusion These results suggest that several proteolytic pathways are responsible for protein degradation upon herbicide treatment, although the specific role of each proteolytic activity remains to be determined.", "corpus_id": 15684756 }

[ { "doc_id": "84996492", "title": "Action mechanisms of acetolactate synthase-inhibiting herbicides ☆", "abstract": "Herbicides that target the acetolactate synthase (ALS) are among the most widely used weed control chemicals since their introduction into the marketplace in the early 1980s, including five classes (sulfonylureas, imidazolinones, triazolopyrimidines, pyrimidinylthio (or oxy)-benzoates and sulfonylamino-carbonyltriazolinones). The mechanism researches have progressed unprecedentedly in the last two decades. Primary mode of action of the ALS-inhibiting herbicides that interfere with the activity of ALS enzyme seems no longer in doubt. Three lines of investigation from physiology, genetics, molecular and chemical structure aspects came together to prove that ALS is the site of action. Researches on the effects of branched chain amino acids (BCAAs) synthesis or protein metabolism caused by ALS-inhibiting herbicide elicit lots of disputations. Besides these two main works, other secondary effects of ALS inhibition, such as buildup of 2-ketobutyrate (α-ketobutyrate or 2-KB) or 2-aminobutyrate (2-AB, the transamination product of 2-KB), depletion of intermediates of the pathway for some critical processes, disruption of photosynthesis transport and respiration system etc., have also been implicated in the mechanism of plant death. However, there are still some disputations and doubts on the precise mechanisms that need further probing into. Further more, as many ALS-inhibiting herbicides and their derivatives are chiral with one or even more enantiomers, which may behave quite differently in biochemical processes, the effects and the environmental fate of chiral herbicides need to be investigated stereospecifically. By this, we can have a better understanding about the herbicides and avoid unnecessary pollution load.", "corpus_id": 84996492, "score": 0 }, { "doc_id": "28208927", "title": "The herbicide glyphosate is a potent inhibitor of 5-enolpyruvyl-shikimic acid-3-phosphate synthase.", "abstract": "Abstract The broadspectrum herbicide glyphosate (N-[phosphonomethyl]-glycine), which causes the accumulation of shikimic acid in plant tissues, inhibits the enzymatic conversion of shikimic acid to anthranilic acid in a cell-free extract of Aerobacter , aerogenes 50% at 5 to 7 μM concentrations. Of the four enzymes involved in the transformation, only 5-enolpyruvylshikimic acid-3-phosphate synthase is inhibited by the herbicide.", "corpus_id": 28208927, "score": 0 }, { "doc_id": "22530267", "title": "Evolved glyphosate-resistant weeds around the world: lessons to be learnt.", "abstract": "Glyphosate is the world's most important herbicide, with many uses that deliver effective and sustained control of a wide spectrum of unwanted (weedy) plant species. Until recently there were relatively few reports of weedy plant species evolving resistance to glyphosate. Since 1996, the advent and subsequent high adoption of transgenic glyphosate-resistant crops in the Americas has meant unprecedented and often exclusive use of glyphosate for weed control over very large areas. Consequently, in regions of the USA where transgenic glyphosate-resistant crops dominate, there are now evolved glyphosate-resistant populations of the economically damaging weed species Ambrosia artemissifolia L., Ambrosia trifida L., Amaranthus palmeri S Watson, Amaranthus rudis JD Sauer, Amaranthus tuberculatus (Moq) JD Sauer and various Conyza and Lolium spp. Likewise, in areas of transgenic glyphosate-resistant crops in Argentina and Brazil, there are now evolved glyphosate-resistant populations of Sorghum halepense (L.) Pers and Euphorbia heterophylla L. respectively. As transgenic glyphosate-resistant crops will remain very popular with producers, it is anticipated that glyphosate-resistant biotypes of other prominent weed species will evolve over the next few years. Therefore, evolved glyphosate-resistant weeds are a major risk for the continued success of glyphosate and transgenic glyphosate-resistant crops. However, glyphosate-resistant weeds are not yet a problem in many parts of the world, and lessons can be learnt and actions taken to achieve glyphosate sustainability. A major lesson is that maintenance of diversity in weed management systems is crucial for glyphosate to be sustainable. Glyphosate is essential for present and future world food production, and action to secure its sustainability for future generations is a global imperative.", "corpus_id": 22530267, "score": 0 }, { "doc_id": "30515287", "title": "Fermentative metabolism is induced by inhibiting different enzymes of the branched-chain amino acid biosynthesis pathway in pea plants.", "abstract": "The inhibition of branched-chain amino acid (BCAA) biosynthesis was evaluated in pea plants in relation to the ability for induction of fermentative metabolism under aerobic conditions. Chlorsulfuron and imazethapyr (inhibitors of acetolactate synthase, ALS, EC 4.1.3.18) produced a strong induction of pyruvate decarboxylase (PDC, EC 4.1.1.1) and alcohol dehydrogenase (ADH, EC 1.1.1.1) activities and a lesser induction of lactate dehydrogenase (LDH, EC 1.1.1.27) and alanine aminotransferase (AlaAT, EC 2.6.1.2) activities in roots. Inhibition of the second enzyme of the BCAA biosynthesis (ketol-acid reductoisomerase, KARI, EC 1.1.1.86) by Hoe 704 (2-dimethylphosphinoyl-2-hydroxyacetic acid) and CPCA (1,1-cyclopropanedicarboxylic acid) enhanced fermentative enzyme activities including PDC, ADH, and AlaAT. Fermentative metabolism induction occurring with ALS- and KARI-inhibitors was related to a higher expression of PDC. In the case of KARI inhibition, it is proposed that fermentation induction is due to an inhibition of ALS activity resulted from an increase in acetolactate concentration. Fermentative metabolism induction in roots, or at least ethanolic fermentation, appeared to be a general physiological response to the BCAA biosynthesis inhibition.", "corpus_id": 30515287, "score": 0 }, { "doc_id": "24979982", "title": "Impairment of carbon metabolism induced by the herbicide glyphosate.", "abstract": "The herbicide glyphosate reduces plant growth and causes plant death by inhibiting the biosynthesis of aromatic amino acids. The objective of this work was to determine whether glyphosate-treated plants show a carbon metabolism pattern comparable to that of plants treated with herbicides that inhibit branched-chain amino acid biosynthesis. Glyphosate-treated plants showed impaired carbon metabolism with an accumulation of carbohydrates in the leaves and roots. The growth inhibition detected after glyphosate treatment suggested impaired metabolism that impedes the utilization of available carbohydrates or energy at the expected rate. These effects were common to both types of amino acid biosynthesis inhibitors. Under aerobic conditions, ethanolic fermentative metabolism was enhanced in the roots of glyphosate-treated plants. This fermentative response was not related to changes in the respiratory rate or to a limitation of the energy charge. This response, which was similar for both types of herbicides, might be considered a general response to stress conditions.", "corpus_id": 24979982, "score": 1 }, { "doc_id": "7005593", "title": "Carbohydrate accumulation in leaves of plants treated with the herbicide chlorsulfuron or imazethapyr is due to a decrease in sink strength.", "abstract": "Herbicides that inhibit branched chain amino acid biosynthesis produce a rapid carbohydrate increase in leaves of treated plants. The relationship between these processes is not known nor is the importance of carbohydrate accumulation in the growth inhibition caused by these herbicides. This work analyzes carbohydrate concentration in sources and sinks after herbicide treatments in pea (Pisum sativum L.), as well as photosynthetic carbon assimilation, using two classes of chemicals, chlorsulfuron and imazethapyr, applied to roots or leaves. The most remarkable result was that, in addition to carbohydrate accumulation in leaves, accumulation of sucrose and/or starch in roots was detected. This pattern of carbohydrate accumulation was similar for both herbicides and independent of whether the herbicides were applied to leaves or roots. This indicates that root growth inhibition was not caused by sugar starvation in sinks. Nevertheless, the results are consistent with a decrease in sink strength, leading to the inhibition of photoassimilate translocation.", "corpus_id": 7005593, "score": 0 }, { "doc_id": "43434948", "title": "The possible role of quinate in the mode of action of glyphosate and acetolactate synthase inhibitors.", "abstract": "BACKGROUND\nThe herbicide glyphosate inhibits the biosynthesis of aromatic amino acids by blocking the shikimate pathway. Imazethapyr and chlorsulfuron are two herbicides that act by inhibiting branched-chain amino acid biosynthesis. These herbicides stimulate secondary metabolism derived from the aromatic amino acids. The aim of this study was to test if they cause any cross-effect in the amino acid content and if they have similar effects on the shikimate pathway.\n\n\nRESULTS\nThe herbicides inhibiting two different amino acid biosynthesis pathways showed a common pattern in general content of free amino acids. There was a general increase in total free amino acid content, with a transient decrease in the proportion of amino acids whose pathways were specifically inhibited. Afterwards, an increase in these inhibited amino acids was detected; this was probably related to proteolysis. All herbicides caused quinate accumulation. Exogenous application of quinate arrested growth, decreased net photosynthesis and stomatal conductance and was ultimately lethal, similarly to glyphosate and imazethapyr.\n\n\nCONCLUSIONS\nQuinate accumulation was a common effect of the two different classes of herbicide. Moreover, exogenous quinate application had phytotoxic effects, showing that this plant metabolite can trigger the toxic effects of the herbicides. This ability to mimic the herbicide effects suggests a possible link between the mode of action of these herbicides and the potential role of quinate as a natural herbicide.", "corpus_id": 43434948, "score": 1 }, { "doc_id": "25079067", "title": "Nitrogen assimilation studies using 15N in soybean plants treated with imazethapyr, an inhibitor of branched-chain amino acid biosynthesis.", "abstract": "The pattern of nitrogen assimilation in soybean plants treated with a herbicide that inhibits branched-chain amino acid biosynthesis was evaluated by (15)N isotopic analysis. The herbicide imazethapyr caused a strong decrease in nitrate uptake by roots, partly due to a reduced stomatal conductance. The inhibition of (15)N uptake was accompanied by a decrease in the (15)N content in the plant and, concomitantly, an inhibition of translocation to the shoot. Imazethapyr inhibited nitrate reductase activity in leaves and roots. Among all parameters studied, \"de novo\" synthesis of proteins was the first parameter of the N assimilation metabolism affected by the herbicide. These results show that this class of herbicides totally damages N metabolism and indicates a regulatory effect on N uptake and translocation that would be mediated by the increase in free amino acid pool provoked by the inhibition of branched-chain amino acid biosynthesis.", "corpus_id": 25079067, "score": 0 }, { "doc_id": "37436809", "title": "Unraveling the role of fermentation in the mode of action of acetolactate synthase inhibitors by metabolic profiling.", "abstract": "Herbicides that inhibit branched chain amino acid biosynthesis induce aerobic fermentation. The role of fermentation in the mode of action of these herbicides is not known, nor is the importance of this physiological response in the growth inhibition and the lethality caused by them. Metabolic profiling was used to compare the effects of the herbicide imazethapyr (IM) on pea plants with two other treatments that also induce fermentation: hypoxia and the exogenous supply pyruvate for seven days. While hypoxic roots did not show internal anoxia, feeding pyruvate or applying IM to the roots led to internal anoxia, probably related to the respiratory burst detected. The three treatments induced ethanol fermentation, but fermentation induced following herbicide treatment was earlier than that following pyruvate supply and was not associated with a decrease in the energy status. No striking changes were detected in the metabolic profiling of hypoxic roots, indicating that metabolism was only slightly impaired. Feeding pyruvate resulted in marked succinate accumulation and a general amino acid accumulation. IM-treated roots showed a general accumulation of glycolytic metabolites upstream of pyruvate, a decrease in some TCA intermediates and an increase in the free amino acid pool sizes. All treatments caused GABA and putrescine accumulation. Our results indicate that IM supply impairs carbon/nitrogen metabolism and this impaired metabolism is likely to be related to the growth arrest detected. As growth is arrested, carbohydrates and glycolytic intermediates accumulate and energy becomes more available.", "corpus_id": 37436809, "score": 0 }, { "doc_id": "4639276", "title": "Branched-chain amino acid biosynthesis inhibitors: herbicide efficacy is associated with an induced carbon-nitrogen imbalance.", "abstract": "Acetolactate synthase (ALS; EC 4.1.3.18) and ketol-acid reductoisomerase (KARI; EC 1.1.1.86) are two consecutive enzymes in the biosynthesis of branched-chain amino acids. Several commercial herbicides inhibit ALS as their primary site of action. KARI has also attracted attention as a potential target for herbicides. Although potent and selective inhibitors of KARI have been discovered, these inhibitors display less herbicidal activity than ALS-inhibiting herbicides. To obtain a better understanding of these findings, we have compared the physiological effects induced in pea plants after KARI or ALS inhibition. Although, both types of inhibitors induce growth arrest and photosynthesis inhibition, plant death occurs more rapidly under ALS inhibition than KARI inhibition. Carbohydrates accumulated in the leaves and roots following treatments with both inhibitors. The carbohydrate accumulation in the leaves occurred as a consequence of a decrease in sink strength. In contrast, the free amino acid content was only affected through ALS inhibition. These results indicate that although KARI and ALS inhibition block the same biosynthetic pathway and exert common effects on carbon metabolism, nitrogen metabolism is more affected via ALS than KARI inhibition. Thus, metabolic alterations in nitrogen metabolism induced through ALS inhibitors might contribute to the increased efficacy of these chemicals as herbicides.", "corpus_id": 4639276, "score": 0 }, { "doc_id": "24839876", "title": "Imazethapyr, an inhibitor of the branched-chain amino acid biosynthesis, induces aerobic fermentation in pea plants.", "abstract": "Acetolactate synthase (ALS; EC 4.1.3.18) inhibition is the primary mechanism of action of imazethapyr (IM). However, the precise mechanisms that links ALS inhibition with plant death have not been elucidated. Supply of IM to pea (Pisum sativum L) plants produced an immediate cessation of growth, caused a 50% inhibition of the in vivo ALS activity within 1 day of treatment, and a remarkable accumulation (2.7-times) of free amino acids after 3 days. Carbohydrates (soluble and starch) were accumulated in both leaves and roots. Accumulation of soluble sugars in roots preceded that of starch in leaves, suggesting that the accumulation of carbohydrates in leaves is not the reason for the arrested root growth. A transient pyruvate accumulation was observed in roots, 1 day after the onset of IM supply. This was coincident with an increase in pyruvate decarboxylase (EC 4.1.1.1), and later increases in alcohol dehydrogenase (EC 1.1.1.1), lactate dehydrogenase (EC 1.1.1.27), and alanine amino transferase (EC 2.6.1.2) activities. This enhancement of fermentative activities was coincident with a slight decrease in aerobic respiration. The overall data suggest that the impairment of ALS activity may lead to a fermentative metabolism that may be involved in growth inhibition and plant death.", "corpus_id": 24839876, "score": 0 }, { "doc_id": "25008804", "title": "Amino Acid Metabolism of Lemna minor L. : II. Responses to Chlorsulfuron.", "abstract": "Chlorsulfuron, an inhibitor of acetolactate synthase (EC 4.1.3.18) (TB Ray 1984 Plant Physiol 75: 827-831), markedly inhibited the growth of Lemna minor at concentrations of 10(-8) molar and above, but had no inhibitory effects on growth at 10(-9) molar. At growth inhibitory concentrations, chlorsulfuron caused a pronounced increase in total free amino acid levels within 24 hours. Valine, leucine, and isoleucine, however, became smaller percentages of the total free amino acid pool as the concentration of chlorsulfuron was increased. At concentrations of chlorsulfuron of 10(-8) molar and above, a new amino acid was accumulated in the free pool. This amino acid was identified as alpha-amino-n-butyrate by chemical ionization and electron impact gas chromatography-mass spectrometry. The amount of alpha-amino-n-butyrate increased from undetectable levels in untreated plants, to as high as 840 nanomoles per gram fresh weight (2.44% of the total free pool) in plants treated with 10(-4) molar chlorsulfuron for 24 hours. The accumulation of this amino acid was completely inhibited by methionine sulfoximine. Chlorsulfuron did not inhibit the methionine sulfoximine induced accumulations of valine, leucine, and isoleucine, supporting the idea that the accumulation of the branched-chain amino acids in methionine sulfoximine treated plants is the result of protein turnover rather than enhanced synthesis. Protein turnover may be primarily responsible for the failure to achieve complete depletion of valine, leucine, and isoleucine even at concentrations of chlorsulfuron some 10(4) times greater than that required to inhibit growth. Tracer studies with (15)N demonstrate that chlorsulfuron inhibits the incorporation of (15)N into valine, leucine, and isoleucine. The alpha-amino-n-butyrate accumulated in the presence of chlorsulfuron and [(15)N]H(4) (+) was heavily labeled with (15)N at early time points and appeared to be derived by transamination from a rapidly labeled amino acid such as glutamate or alanine. We propose that chlorsulfuron inhibition of acetolactate synthase may lead to accumulation of 2-oxobutyrate in the isoleucine branch of the pathway, and transamination of 2-oxobutyrate to alpha-amino-n-butyrate by a constitutive transaminase utilizing either glutamate or alanine as alpha-amino-N donors.", "corpus_id": 25008804, "score": 0 }, { "doc_id": "6309234", "title": "Structure, function and regulation of plant proteasomes.", "abstract": "Proteasomes are large multisubunit, multicatalytic proteases responsible for most of the cytosolic and nuclear protein degradation, and their structure and functions are conserved in eukaryotes. Proteasomes were originally identified as the proteolytic module of the ubiquitin-dependent proteolysis pathway. Today we know that proteasomes also mediate ubiquitin-independent proteolysis, that they have RNAse activity, and play a non-proteolytic role in transcriptional regulation. Here we present an overview of the current knowledge of proteasome function and regulation in plants and highlight the role of proteasome-dependent protein degradation in the control of plant development and responses to the environment.", "corpus_id": 6309234, "score": 0 }, { "doc_id": "30739151", "title": "Contribution of Proteasomal β-Subunits to the Cleavage of Peptide Substrates Analyzed with Yeast Mutants*", "abstract": "Proteasomes generate peptides that can be presented by major histocompatibility complex (MHC) class I molecules in vertebrate cells. Using yeast 20 S proteasomes carrying different inactivated β-subunits, we investigated the specificities and contributions of the different β-subunits to the degradation of polypeptide substrates containing MHC class I ligands and addressed the question of additional proteolytically active sites apart from the active β-subunits. We found a clear correlation between the contribution of the different subunits to the cleavage of fluorogenic and long peptide substrates, with β5/Pre2 cleaving after hydrophobic, β2/Pup1 after basic, and β1/Pre3 after acidic residues, but with the exception that β2/Pup1 and β1/Pre3 can also cleave after some hydrophobic residues. All proteolytic activities including the “branched chain amino acid-preferring” component are associated with β5/Pre2, β1/Pre3, or β2/Pup1, arguing against additional proteolytic sites. Because of the high homology between yeast and mammalian 20 S proteasomes in sequence and subunit topology and the conservation of cleavage specificity between mammalian and yeast proteasomes, our results can be expected to also describe most of the proteolytic activity of mammalian 20 S proteasomes leading to the generation of MHC class I ligands.", "corpus_id": 30739151, "score": 0 }, { "doc_id": "6333363", "title": "Storage Protein Accumulation in the Absence of the Vacuolar Processing Enzyme Family of Cysteine Proteases Online version contains Web-only data. Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.016378.", "abstract": "The role(s) of specific proteases in seed protein processing is only vaguely understood; indeed, the overall role of processing in stable protein deposition has been the subject of more speculation than direct investigation. Seed-type members of the vacuolar processing enzyme (VPE) family were hypothesized to perform a unique function in seed protein processing, but we demonstrated previously that Asn-specific protein processing in developing Arabidopsis seeds occurs independently of this VPE activity. Here, we describe the unexpected expression of vegetative-type VPEs in developing seeds and test the role(s) of all VPEs in seed storage protein accumulation by systematically stacking knockout mutant alleles of all four members (αVPE, βVPE, γVPE, and δVPE) of the VPE gene family in Arabidopsis. The complete removal of VPE function in the αvpe βvpe γvpe δvpe quadruple mutant resulted in a total shift of storage protein accumulation from wild-type processed polypeptides to a finite number of prominent alternatively processed polypeptides cleaved at sites other than the conserved Asn residues targeted by VPE. Although alternatively proteolyzed legumin-type globulin polypeptides largely accumulated as intrasubunit disulfide-linked polypeptides with apparent molecular masses similar to those of VPE-processed legumin polypeptides, they showed markedly altered solubility and protein assembly characteristics. Instead of forming 11S hexamers, alternatively processed legumin polypeptides were deposited primarily as 9S complexes. However, despite the impact on seed protein processing, plants devoid of all known functional VPE genes appeared unchanged with regard to protein content in mature seeds, relative mobilization rates of protein reserves during germination, and vegetative growth. These findings indicate that VPE-mediated Asn-specific proteolytic processing, and the physiochemical property changes attributed to this specific processing step, are not required for the successful deposition and mobilization of seed storage protein in the protein storage vacuoles of Arabidopsis seeds.", "corpus_id": 6333363, "score": 0 }, { "doc_id": "34255106", "title": "A Plant Vacuolar Protease, VPE, Mediates Virus-Induced Hypersensitive Cell Death", "abstract": "Programmed cell death (PCD) in animals depends on caspase protease activity. Plants also exhibit PCD, for example as a response to pathogens, although a plant caspase remains elusive. Here we show that vacuolar processing enzyme (VPE) is a protease essential for a virus-induced hypersensitive response that involves PCD. VPE deficiency prevented virus-induced hypersensitive cell death in tobacco plants. VPE is structurally unrelated to caspases, although VPE has a caspase-1 activity. Thus, plants have evolved a regulated cellular suicide strategy that, unlike PCD of animals, is mediated by VPE and the cellular vacuole.", "corpus_id": 34255106, "score": 1 }, { "doc_id": "38399498", "title": "Selective inhibition of plant serine hydrolases by agrochemicals revealed by competitive ABPP.", "abstract": "Organophosphate and -phosphonates and their thio derivatives are often used in agroindustry as herbicides and insecticides, but their potential off-targets in the plant are poorly investigated. Here, we use competitive activity-based protein profiling (ABPP) of serine hydrolases (SHs) to detect targets of these agrochemicals and other compounds in Arabidopsis thaliana. Using broad-range and specific probes, and by overexpression of various SHs in planta, we are able to confirm eight SH-compound interactions, including selective inhibition of carboxylesterase CXE12, prolyloligopeptidase, methylesterase MES2 and tripeptidyl peptidase TPP2. These observations can be used for the design of novel probes and selective inhibitors and may help to assess physiological effects of agrochemicals on crop plants.", "corpus_id": 38399498, "score": 0 }, { "doc_id": "40791575", "title": "Changes in the Expression and the Enzymic Properties of the 20S Proteasome in Sugar-Starved Maize Roots. Evidence for an in Vivo Oxidation of the Proteasome1", "abstract": "The 20S proteasome (multicatalytic proteinase) was purified from maize (Zea mays L. cv DEA 1992) roots through a five-step procedure. After biochemical characterization, it was shown to be similar to most eukaryotic proteasomes. We investigated the involvement of the 20S proteasome in the response to carbon starvation in excised maize root tips. Using polyclonal antibodies, we showed that the amount of proteasome increased in 24-h-carbon-starved root tips compared with freshly excised tips, whereas the mRNA levels of α3 and β6 subunits of 20S proteasome decreased. Moreover, in carbon-starved tissues, chymotrypsin-like and caseinolytic activities of the 20S proteasome were found to increase, whereas trypsin-like activities decreased. The measurement of specific activities and kinetic parameters of 20S proteasome purified from 24-h-starved root tips suggested that it was subjected to posttranslational modifications. Using dinitrophenylhydrazine, a carbonyl-specific reagent, we observed an increase in carbonyl residues in 20S proteasome purified from starved root tips. This means that 20S proteasome was oxidized during starvation treatment. Moreover, an in vitro mild oxidative treatment of 20S proteasome from non-starved material resulted in the activation of chymotrypsin-like, peptidyl-glutamyl-peptide hydrolase and caseinolytic-specific activities and in the inhibition of trypsin-like specific activities, similar to that observed for proteasome from starved root tips. Our results provide the first evidence, to our knowledge, for an in vivo carbonylation of the 20S proteasome. They suggest that sugar deprivation induces an oxidative stress, and that oxidized 20S proteasome could be associated to the degradation of oxidatively damaged proteins in carbon starvation situations.", "corpus_id": 40791575, "score": 0 }, { "doc_id": "857435", "title": "Caspase-like activity in the seedlings of Pisum sativum eliminates weaker shoots during early vegetative development by induction of cell death.", "abstract": "Activation of aspartate-specific cysteine proteases (caspases) plays a crucial role in programmed cell death (PCD) in animals. Although to date caspases have not been identified in plants, caspase-like activity was described in tobacco during a hypersensitive response to pathogens and in Arabidopsis and tomato cell cultures during chemical-induced PCD. Caspase-like activity was also detected in the course of plant development during petal senescence and endosperm PCD. It is shown here that caspase-like proteases play a crucial role in the developmental cell death of secondary shoots of pea seedlings that emerge after removal of the epicotyl. Caspase-like activity was induced in senescing secondary shoots, but not in dominant growing shoots, in contrast to the papain-like cysteine protease activity that was stronger in the dominant shoot. Revitalization of the senescing shoot by cutting of the dominant shoot reduced the caspase-like activity. Injection of caspase or cysteine protease inhibitors into the remaining epicotyl tissue suppressed the death of the secondary shoots, producing seedlings with two equal shoots. These results suggest that shoot selection in pea seedlings is controlled by PCD, through the activation of caspase-like proteases.", "corpus_id": 857435, "score": 0 }, { "doc_id": "24978657", "title": "20S proteasome and accumulation of oxidized and ubiquitinated proteins in maize leaves subjected to cadmium stress.", "abstract": "In order to examine the possible involvement of the 20S proteasome in degradation of oxidized proteins, the effects of different cadmium concentrations on its activities, protein abundance and oxidation level were studied using maize (Zea mays L.) leaf segments. The accumulation of carbonylated and ubiquitinated proteins was also investigated. Treatment with 50 microM CdCl(2) increased both trypsin- and PGPH-like activities of the 20S proteasome. The incremental changes in 20S proteasome activities were probably caused by an increased level of 20S proteasome oxidation, with this being responsible for degradation of the oxidized proteins. When leaf segments were treated with 100 microM CdCl(2), the chymotrysin- and trypsin-like activities of the 20S proteasome also decreased, with a concomitant increase in accumulation of carbonylated and ubiquitinated proteins. With both Cd(2+) concentrations, the abundance of the 20S proteasome protein remained similar to the control experiments. These results provide evidence for the involvement of this proteolytic system in cadmium-stressed plants.", "corpus_id": 24978657, "score": 1 }, { "doc_id": "39276601", "title": "Serpin1 of Arabidopsis thaliana is a suicide inhibitor for metacaspase 9.", "abstract": "Metacaspases are distant relatives of animal caspases found in plants, fungi and protozoa. We demonstrated previously that two type II metacaspases of Arabidopsis thaliana, AtMC4 and AtMC9 are Arg/Lys-specific cysteine-dependent proteases. We screened a combinatorial tetrapeptide library of 130,321 substrates with AtMC9. Here, we show that AtMC9 is a strict Arg/Lys-specific protease. Based on the position-specific scoring matrix derived from the substrate library results, the tetrapeptide Val-Arg-Pro-Arg was identified as an optimized substrate. AtMC9 had a kcat/KM of 4.6x10(5) M-1 s-1 for Ac-Val-Arg-Pro-Arg-amido-4-methyl-coumarin, representing a more than 10-fold improvement over existing fluorogenic substrates. A yeast two-hybrid screen with catalytically inactive AtMC9 as bait identified a serine protease inhibitor, designated AtSerpin1, which was found to be a potent inhibitor of AtMC9 activity in vitro through cleavage of its reactive center loop and covalent binding to AtMC9. On the basis of the substrate profiling of AtMC9 and confirmation through site-directed mutagenesis, the inhibitory P4-P1 cleavage site of AtSerpin1 was determined to be Ile-Lys-Leu-Arg351. Further mutagenesis of the AtSerpin1 inhibitory cleavage site modulated AtMC9 inhibition positively or negatively. Both AtMC9 and AtSerpin1 were localized in the extracellular space, suggesting an in vivo interaction as well. To our knowledge, this is the first report of plant protease inhibition by a plant serpin.", "corpus_id": 39276601, "score": 0 }, { "doc_id": "35892002", "title": "Proteasome activity profiling: a simple, robust and versatile method revealing subunit-selective inhibitors and cytoplasmic, defense-induced proteasome activities.", "abstract": "The proteasome plays essential roles in nearly all biological processes in plant defense and development, yet simple methods for displaying proteasome activities in extracts and living tissues are not available to plant science. Here, we introduce an easy and robust method to simultaneously display the activities of all three catalytic proteasome subunits in plant extracts or living plant tissues. The method is based on a membrane-permeable, small-molecule fluorescent probe that irreversibly reacts with the catalytic site of the proteasome catalytic subunits in an activity-dependent manner. Activities can be quantified from fluorescent protein gels and used to study proteasome activities in vitro and in vivo. We demonstrate that proteasome catalytic subunits can be selectively inhibited by aldehyde-based inhibitors, including the notorious caspase-3 inhibitor DEVD. Furthermore, we show that the proteasome activity, but not its abundance, is significantly increased in Arabidopsis upon treatment with benzothiadiazole (BTH). This upregulation of proteasome activity depends on NPR1, and occurs mostly in the cytoplasm. The simplicity, robustness and versatility of this method will make this method widely applicable in plant science.", "corpus_id": 35892002, "score": 1 }, { "doc_id": "12267709", "title": "Activity profiling of vacuolar processing enzymes reveals a role for VPE during oomycete infection.", "abstract": "Vacuolar processing enzymes (VPEs) are important cysteine proteases that are implicated in the maturation of seed storage proteins, and programmed cell death during plant-microbe interactions and development. Here, we introduce a specific, cell-permeable, activity-based probe for VPEs. This probe is highly specific for all four Arabidopsis VPEs, and labeling is activity-dependent, as illustrated by sensitivity for inhibitors, pH and reducing agents. We show that the probe can be used for in vivo imaging and displays multiple active isoforms of VPEs in various tissues and in both monocot and dicot plant species. Thus, VPE activity profiling is a robust, simple and powerful tool for plant research for a wide range of applications. Using VPE activity profiling, we discovered that VPE activity is increased during infection with the oomycete pathogen Hyaloperonospora arabidopsidis (Hpa). The enhanced VPE activity is host-derived and EDS1-independent. Sporulation of Hpa is reduced on vpe mutant plants, demonstrating a role for VPE during compatible interactions that is presumably independent of programmed cell death. Our data indicate that, as an obligate biotroph, Hpa takes advantage of increased VPE activity in the host, e.g. to mediate protein turnover and nutrient release.", "corpus_id": 12267709, "score": 1 }, { "doc_id": "25821996", "title": "Heterologous Expression and Molecular and Cellular Characterization of CaPUB1 Encoding a Hot Pepper U-Box E3 Ubiquitin Ligase Homolog1[C]", "abstract": "The U-box motif is a conserved domain found in the diverse isoforms of E3 ubiquitin ligase in eukaryotes. From water-stressed hot pepper (Capsicum annuum L. cv Pukang) plants, we isolated C. annuum putative U-box protein 1 (CaPUB1), which encodes a protein containing a single U-box motif in its N-terminal region. In vitro ubiquitination and site-directed mutagenesis assays revealed that CaPUB1 possessed E3 ubiquitin ligase activity and that the U-box motif was indeed essential for its enzyme activity. RNA gel-blot analysis showed that CaPUB1 mRNA was induced rapidly by a broad spectrum of abiotic stresses, including drought, high salinity, cold temperature, and mechanical wounding, but not in response to ethylene, abscisic acid, or a bacterial pathogen, suggesting its role in the early events in the abiotic-related defense response. Because transgenic work was extremely difficult in hot pepper, in this study we overexpressed CaPUB1 in Arabidopsis (Arabidopsis thaliana) to provide cellular information on the function of this gene in the development and plant responses to abiotic stresses. Transgenic Arabidopsis plants that constitutively expressed the CaPUB1 gene under the control of the cauliflower mosaic virus 35S promoter had markedly longer hypocotyls and roots and grew more rapidly than the wild type, leading to an early bolting phenotype. Microscopic analysis showed that 35S∷CaPUB1 roots had increased numbers of small-sized cells, resulting in disordered, highly populated cell layers in the cortex, endodermis, and stele. In addition, CaPUB1-overexpressing plants displayed increased sensitivity to water stress and mild salinity. These results indicate that CaPUB1 is functional in Arabidopsis cells, thereby effectively altering cell and tissue growth and also the response to abiotic stresses. Comparative proteomic analysis showed that the level of RPN6 protein, a non-ATPase subunit of the 26S proteasome complex, was significantly reduced in 35S∷CaPUB1 seedlings as compared to the wild type. Pull-down and ubiquitination assays demonstrated that RPN6 interacted physically with CaPUB1 and was ubiquitinated in a CaPUB1-dependent manner in vitro. Although the physiological function of CaPUB1 is not yet clear, there are several possibilities for its involvement in a subset of physiological responses to counteract dehydration and high-salinity stresses in transgenic Arabidopsis seedlings.", "corpus_id": 25821996, "score": 0 }, { "doc_id": "1451914", "title": "The ubiquitin/26S proteasome pathway, the complex last chapter in the life of many plant proteins.", "abstract": "Plants use a repertoire of methods to control the level and activity of their constituent proteins. One method, whose prominence is only now being appreciated, is selective protein breakdown by the ubiquitin/26S proteasome pathway. Remarkably, recent analyses of the near-complete Arabidopsis thaliana genome identified >1300 genes, or approximately 5% of the proteome, involved in the ubiquitin/26S proteasome pathway, making it one of the most elaborate regulatory mechanisms in plants. Molecular genetic analyses have also connected individual components to almost all aspects of plant biology, including the cell-cycle, embryogenesis, photomorphogenesis, circadian rhythms, hormone signaling, homeosis, disease resistance and senescence. Consequently, it appears that the ubiquitin/26S proteasome pathway rivals transcription complexes and protein kinase cascades as the main player in plant cell regulation.", "corpus_id": 1451914, "score": 0 }, { "doc_id": "46686274", "title": "Protein degradation in signaling.", "abstract": "Recent studies have linked proteolysis by the ubiquitin/proteasome pathway to a variety of signaling pathways in higher plants. These links were uncovered by characterization of mutants altered in signaling or by targeted disruption of components of the proteolytic pathway. Significant advances have recently revealed connections between proteolysis and hormone responses, light perception, environmental adaptation, and floral development.", "corpus_id": 46686274, "score": 0 }, { "doc_id": "20602188", "title": "Dynamics of ubiquitin conjugation during heat-shock response revealed by using a monoclonal antibody specific to multi-ubiquitin chains.", "abstract": "Levels of intracellular multi-ubiquitinated proteins in heat-shocked HeLa cells were investigated using a monoclonal antibody specific to multi-ubiquitin chains. After heat-shock treatment at 42-44 degrees C for 30 min, the level of multi-ubiquitinated proteins increased within the first 2 h at 37 degrees C and returned to the initial level within the following 2 h. The accumulation of multi-ubiquitin conjugates was elevated by increasing the temperature, while the opposite was the case for the level of ubiquitinated histone H2A. Immunocytochemical analysis revealed that the amount of ubiquitin conjugates rapidly increased in the cytosol and concomitantly decreased in the nucleus under heat-shock conditions. The heat-shock treatment elicited little apparent change in the activity of the 26S proteasome, but it did induce a gradual increase in activity of the ubiquitinating enzyme system. These results strongly suggest that the level of cytoplasmic multi-ubiquitinated proteins and that of nuclear ubiquitinated histone H2A increases and decreases, respectively, in response to heat shock and that the heat-shock-induced accumulation of multi-ubiquitinated proteins is caused by activation of the ubiquitinating enzyme system rather than inactivation of the 26S proteasome.", "corpus_id": 20602188, "score": 0 }, { "doc_id": "40406825", "title": "Ubiquitin- and proteasome-dependent proteolysis in plants.", "abstract": "In recent years it has become obvious that protein degradation is an important catabolic process during development in plants and animals. One very conserved degradative system is the ubiquitin- and proteasome-dependent proteolytic pathway, which is found in all eukaryotes from yeast to mammals and plants. The pathway consists of two parts, one in which chains of ubiquitin are conjugated to substrate proteins, and one in which these substrate proteins are either degraded by the 26S proteasome or are de-ubiquitinated. The ubiquitin- and proteasome-dependent pathway degrades a wide range of proteins in the nucleus and cytoplasm. It is highly specific, but controls a large number of cellular events due to the diversity in the conjugating enzymes. This pathway is important for removal of abnormal/damaged proteins that have had their recognition sites exposed as well as for control of specific transcription factors and cell cycle regulators. In plants, ubiquitin- and proteasome-dependent proteolysis is known to be involved in regulation of the cell cycle and transcription factors as well as endoplasmic reticulum-associated protein degradation, stress response and developmental processes, such as xylogenesis and senescence.", "corpus_id": 40406825, "score": 0 }, { "doc_id": "6785586", "title": "Proteolytic system in sunflower (Helianthus annuus L.) leaves under cadmium stress.", "abstract": "The effect of oxidative stress induced by cadmium on growth parameters and on the balance between protein synthesis and degradation was studied in sunflower (Helianthus annuus L.) leaves. Plants were germinated for 10 days and then transferred to hydroponic medium devoid (control) or containing 100, 200 and 300μM CdCl2. Analyses were performed between days 0 and 4 of Cd-treatment. All Cd(2+) concentrations significantly reduced leaf area and, fresh and dry weight, but leaf relative water content only decreased with 200 and 300μM Cd(2+). Control and treated plants had similar soluble protein content and showed the same rate of soluble protein labeling under the assay conditions. Although protease activity increased with cadmium treatment, proteasome activity was significantly inhibited. Expression of 20S proteasome remained similar to controls in cadmium treated plants. Cadmium caused an increase in ubiquitin-conjugated proteins and carbonyl groups content of treated plants, compared to control values. Cadmium induced an increase in protease specific activity; nevertheless, this increase was not relevant enough to avoid accumulation of oxidized proteins. Oxidation of proteins is one of the most important effects of cadmium treatment. The results presented here provide evidence for the role of the proteolytic system in sunflower plants subjected to cadmium stress.", "corpus_id": 6785586, "score": 0 }, { "doc_id": "3048535", "title": "Heavy metals effects on proteolytic system in sunflower leaves.", "abstract": "Plant proteolytic system includes proteases, mainly localized inside the organelles, and the ubiquitin-proteasome pathway in both, the cytoplasm and the nucleus. It was recently demonstrated that under severe Cd stress sunflower (Helianthus annuus L.) proteasome activity is reduced and this results in accumulation of oxidized proteins. In order to test if under other heavy metal stresses sunflower proteolytic system undergoes similar changes, an hydroponic experiment was carried out. Ten days old sunflower plants were transferred to hydroponic culture solutions devoid (control) or containing 100 microM of AlCl(3), CoCl(2), CuCl(2), CrCl(3), HgCl(2), NiCl(2), PbCl(2) or ZnCl(2) and analyzed for protein oxidative damage and proteolytic activities. After 4 days of metal treatment, only Co(2+), Cu(2+), Hg(2+), and Ni(2+) were found to increase carbonyl groups content. Except for Al(3+) and Zn(2+), all metals tested significantly reduced all proteasome activities (chymotrypsin-like, trypsin-like and PGPH) and acid and neutral proteases activities. The effect on basic proteases was more variable. Abundance of 20S protein after metal treatments was similar to that obtained for control samples. Co(2+), Cu(2+), Hg(2+), Ni(2+), Cr(3+), and Pb(2+) induced accumulation of ubiquitin conjugated proteins. It is concluded that heavy metal effects on proteolytic system cannot be generalized; however, impairment of proteasome functionality and decreased proteases activities seem to be a common feature involved in metal toxicity to plants.", "corpus_id": 3048535, "score": 0 }, { "doc_id": "17074168", "title": "Minitags for small molecules: detecting targets of reactive small molecules in living plant tissues using 'click chemistry'.", "abstract": "Small molecules offer unprecedented opportunities for plant research since plants respond to, metabolize, and react with a diverse range of endogenous and exogenous small molecules. Many of these small molecules become covalently attached to proteins. To display these small molecule targets in plants, we introduce a two-step labelling method for minitagged small molecules. Minitags are small chemical moieties (azide or alkyne) that are inert under biological conditions and have little influence on the membrane permeability and specificity of the small molecule. After labelling, proteomes are extracted under denaturing conditions and minitagged proteins are coupled to reporter tags through a 'click chemistry' reaction. We introduce this two-step labelling procedure in plants by studying the well-characterized targets of E-64, a small molecule cysteine protease inhibitor. In contrast to biotinylated E-64, minitagged E-64 efficiently labels vacuolar proteases in vivo. We displayed, purified and identified targets of a minitagged inhibitor that targets the proteasome and cysteine proteases in living plant cells. Chemical interference assays with inhibitors showed that MG132, a frequently used proteasome inhibitor, preferentially inhibits cysteine proteases in vivo. The two-step labelling procedure can be applied on detached leaves, cell cultures, seedlings and other living plant tissues and, when combined with photoreactive groups, can be used to identify targets of herbicides, phytohormones and reactive small molecules selected from chemical genetic screens.", "corpus_id": 17074168, "score": 0 }, { "doc_id": "32913592", "title": "Mining the active proteome in plant science and biotechnology.", "abstract": "Protein activity is essential functional information, yet difficult to predict from transcript or protein data. Activity-based protein profiling (ABPP) displays active proteins in proteomes using small molecule probes that irreversibly label proteins in their active state. Here, we review proof-of-concept ABPP studies in plant science. These studies displayed activities of dozens of plant cysteine proteases, lipases, methylesterases and the proteasome. ABPP in plants revealed differential protein activities in development and immunity and uncovered striking selectivity of pathogen-derived inhibitors and unexpected targets of commercial inhibitors. The unique, high-content information of ABPP and the robustness and simplicity of the assays will make ABPP a powerful tool in future plant science and biotechnology.", "corpus_id": 32913592, "score": 0 }, { "doc_id": "24391435", "title": "L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L.", "abstract": "1. L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) at a concentration of 0.5 mM had no effect on the serine proteinases plasma kallikrein and leucocyte elastase or the metalloproteinases thermolysin and clostridial collagenase. In contrast, 10 muM-E-64 rapidly inactivated the cysteine proteinases cathepsins B, H and L and papain (t0.5 = 0.1-17.3s). The streptococcal cysteine proteinase reacted much more slowly, and there was no irreversible inactivation of clostripain. The cysteine-dependent exopeptidase dipeptidyl peptidase I was very slowly inactivated by E-64. 2. the active-site-directed nature of the interaction of cathepsin B and papain with E-64 was established by protection of the enzyme in the presence of the reversible competitive inhibitor leupeptin and by the stereospecificity for inhibition by the L as opposed to the D compound. 3. It was shown that the rapid stoichiometric reaction of the cysteine proteinases related to papain can be used to determine the operational molarity of solutions of the enzymes and thus to calibrate rate assays. 4. The apparent second-order rate constants for the inactivation of human cathepsins B and H and rat cathepsin L by a series of structural analogues of E-64 are reported, and compared with those for some other active-site-directed inhibitors of cysteine proteinases. 5. L-trans-Epoxysuccinyl-leucylamido(3-methyl)butane (Ep-475) was found to inhibit cathepsins B and L more rapidly than E-64. 6. Fumaryl-leucylamido(3-methyl)butane (Dc-11) was 100-fold less reactive than the corresponding epoxide, but was nevertheless about as effective as iodoacetate.", "corpus_id": 24391435, "score": 0 }, { "doc_id": "23964868", "title": "Arabidopsis sensitivity to protein synthesis inhibitors depends on 26S proteasome activity", "abstract": "The 26S proteasome (26SP), the central protease of the ubiquitin-dependent proteolysis pathway, controls the regulated proteolysis of functional proteins and the removal of misfolded and damaged proteins. In Arabidopsis, cellular and stress response phenotypes of a number of mutants with partially impaired 26SP function have been reported. Here, we describe the responses of proteasome mutants to protein synthesis inhibitors. We show that the rpt2a-3, rpn10-1 and rpn12a-1 mutants are hypersensitive to the antibiotic hygromycin B, and tolerant to the translation inhibitor cycloheximide (CHX) and herbicide l-phosphinothricin (PPT). In addition to the novel mechanism for herbicide tolerance, our data suggests that the combination of hygromycin B, CHX and PPT growth-response assays could be used as a facile diagnostic tool to detect altered 26SP function in plant mutants and transgenic lines.", "corpus_id": 23964868, "score": 0 }, { "doc_id": "3231431", "title": "VPEγ Exhibits a Caspase-like Activity that Contributes to Defense against Pathogens", "abstract": "BACKGROUND\nCaspases are a family of aspartate-specific cysteine proteases that play an essential role in initiating and executing programmed cell death (PCD) in metazoans. Caspase-like activities have been shown to be required for the initiation of PCD in plants, but the genes encoding those activities have not been identified. VPEgamma, a cysteine protease, is induced during senescence, a form of PCD in plants, and is localized in precursor protease vesicles and vacuoles, compartments associated with PCD processes in plants.\n\n\nRESULTS\nWe show that VPEgamma binds in vivo to a general caspase inhibitor and to caspase-1-specific inhibitors, which block the activity of VPEgamma. A cysteine protease inhibitor, cystatin, accumulates to 20-fold higher levels in vpegamma mutants. Homologs of cystatin are known to suppress hypersensitive cell death in plant and animal systems. We also report that infection with an avirulent strain of Pseudomonas syringae results in an increase of caspase-1 activity, and this increase is partially suppressed in vpegamma mutants. Plants overexpressing VPEgamma exhibit a greater amount of ion leakage during infection with P. syringae, suggesting that VPEgamma may regulate cell death progression during plant-pathogen interaction. VPEgamma expression is induced after infection with P. syringae, Botrytis cinerea, and turnip mosaic virus, and knockout of VPEgamma results in increased susceptibility to these pathogens.\n\n\nCONCLUSIONS\nWe conclude that VPEgamma is a caspase-like enzyme that has been recruited in plants to regulate vacuole-mediated cell dismantling during cell death, a process that has significant influence in the outcome of a diverse set of plant-pathogen interactions.", "corpus_id": 3231431, "score": 0 }, { "doc_id": "35397718", "title": "Vacuolar processing enzyme is self‐catalytically activated by sequential removal of the C‐terminal and N‐terminal propeptides", "abstract": "A vacuolar processing enzyme (VPE) responsible for maturation of various vacuolar proteins is synthesized as an inactive precursor. To clarify how to convert the VPE precursor into the active enzyme, we expressed point mutated VPE precursors of castor bean in the pep4 strain of Saccharomyces cerevisiae. A VPE with a substitution of the active site Cys with Gly showed no ability to convert itself into the mature form, although a wild VPE had the ability. The mutated VPE was converted by the action of the VPE that had been purified from castor bean. Substitution of the conserved Asp‐Asp at the putative cleavage site of the C‐terminal propeptide with Gly‐Gly abolished both the conversion into the mature form and the activation of the mutated VPE. In vitro assay with synthetic peptides demonstrated that a VPE exhibited activity towards Asp residues and that a VPE cleaved an Asp‐Gln bond to remove the N‐terminal propeptide. Taken together, the results indicate that the VPE is self‐catalytically maturated to be converted into the active enzyme by removal of the C‐terminal propeptide and subsequent removal of the N‐terminal one.", "corpus_id": 35397718, "score": 0 }, { "doc_id": "2373305", "title": "Identification of early intermediates of caspase activation using selective inhibitors and activity-based probes.", "abstract": "Caspases are cysteine proteases that are key effectors in apoptotic cell death. Currently, there is a lack of tools that can be used to monitor the regulation of specific caspases in the context of distinct apoptotic programs. We describe the development of highly selective inhibitors and active site probes and their applications to directly monitor executioner (caspase-3 and -7) and initiator (caspase-8 and -9) caspase activity. Specifically, these reagents were used to dissect the kinetics of caspase activation upon stimulation of apoptosis in cell-free extracts and intact cells. These studies identified a full-length caspase-7 intermediate that becomes catalytically activated early in the pathway and whose further processing is mediated by mature executioner caspases rather than initiator caspases. This form also shows distinct inhibitor sensitivity compared to processed caspase-7. Our data suggest that caspase-7 activation proceeds through a previously uncharacterized intermediate that is formed without cleavage of the intact zymogen.", "corpus_id": 2373305, "score": 0 }, { "doc_id": "1965489", "title": "The Involvement of Cysteine Proteases and Protease Inhibitor Genes in the Regulation of Programmed Cell Death in Plants", "abstract": "Programmed cell death (PCD) is a process by which cells in many organisms die. The basic morphological and biochemical features of PCD are conserved between the animal and plant kingdoms. Cysteine proteases have emerged as key enzymes in the regulation of animal PCD. Here, we show that in soybean cells, PCD-activating oxidative stress induced a set of cysteine proteases. The activation of one or more of the cysteine proteases was instrumental in the PCD of soybean cells. Inhibition of the cysteine proteases by ectopic expression of cystatin, an endogenous cysteine protease inhibitor gene, inhibited induced cysteine protease activity and blocked PCD triggered either by an avirulent strain of Pseudomonas syringae pv glycinea or directly by oxidative stress. Similar expression of serine protease inhibitors was ineffective. A glutathione S-transferase–cystatin fusion protein was used to purify and characterize the induced proteases. Taken together, our results suggest that plant PCD can be regulated by activity poised between the cysteine proteases and the cysteine protease inhibitors. We also propose a new role for proteinase inhibitor genes as modulators of PCD in plants.", "corpus_id": 1965489, "score": 0 }, { "doc_id": "206528776", "title": "Arabidopsis Type I Metacaspases Control Cell Death", "abstract": "The Yin and Yang of Plant Caspases The function of plant metacaspases, identified by limited sequence homology to the animal caspases that control cell death, has remained elusive. Coll et al. (p. 1393) have now elucidated the actions of two metacaspases in the small plant Arabidopsis. One metacaspase, AtMC1, promoted cell death, and the other, AtMC2, acted antagonistically to stall cell death. The results help to elucidate the mechanisms by which plants control cell survival during development and defend against pathogen attack. An ancient link between cell death control and innate immune receptor function has been discovered in plants. Metacaspases are distant relatives of animal caspases found in protozoa, fungi, and plants. Limited experimental data exist defining their function(s), despite their discovery by homology modeling a decade ago. We demonstrated that two type I metacaspases, AtMC1 and AtMC2, antagonistically control programmed cell death in Arabidopsis. AtMC1 is a positive regulator of cell death and requires conserved caspase-like putative catalytic residues for its function. AtMC2 negatively regulates cell death. This function is independent of the putative catalytic residues. Manipulation of the Arabidopsis type I metacaspase regulatory module can nearly eliminate the hypersensitive cell death response (HR) activated by plant intracellular immune receptors. This does not lead to enhanced pathogen proliferation, decoupling HR from restriction of pathogen growth.", "corpus_id": 206528776, "score": 0 }, { "doc_id": "15539325", "title": "Diversity of Serine Hydrolase Activities of Unchallenged and Botrytis-infected Arabidopsis thaliana*S", "abstract": "Activity-based protein profiling is a powerful method to display enzyme activities in proteomes and provides crucial information on enzyme activity rather than protein or transcript abundance. We applied activity-based protein profiling using fluorophosphonate-based probes to display the activities of Ser hydrolases in the model plant Arabidopsis thaliana. Multidimensional protein identification technology and in-gel analysis of fluorophosphonate-labeled leaf extracts revealed over 50 Ser hydrolases, including dozens of proteases, esterases, and lipases, representing over 10 different enzyme families. Except for some well characterized Ser hydrolases like subtilases TPP2 and ARA12, prolyl oligopeptidase acylamino acid-releasing enzyme, serine carboxypeptidase-like SNG1 and BRS1, carboxylesterase-like CXE12, methylesterases MES2 and MES3, and S-formylglutathione hydrolase, the majority of these serine hydrolases have not been described before. We studied transiently expressed SNG1 and investigated plants infected with the fungal pathogen Botrytis cinerea. Besides the down-regulation of several Arabidopsis Ser hydrolase activities during Botrytis infection, we detected the activities of Botrytis-derived cutinases and lipases, which are thought to contribute to pathogenicity.", "corpus_id": 15539325, "score": 0 }, { "doc_id": "7028167", "title": "Natural products in crop protection.", "abstract": "The tremendous increase in crop yields associated with the 'green' revolution has been possible in part by the discovery and utilization of chemicals for pest control. However, concerns over the potential impact of pesticides on human health and the environment has led to the introduction of new pesticide registration procedures, such as the Food Quality Protection Act in the United States. These new regulations have reduced the number of synthetic pesticides available in agriculture. Therefore, the current paradigm of relying almost exclusively on chemicals for pest control may need to be reconsidered. New pesticides, including natural product-based pesticides are being discovered and developed to replace the compounds lost due to the new registration requirements. This review covers the historical use of natural products in agricultural practices, the impact of natural products on the development of new pesticides, and the future prospects for natural products-based pest management.", "corpus_id": 7028167, "score": 0 }, { "doc_id": "19953887", "title": "Why have no new herbicide modes of action appeared in recent years?", "abstract": "Herbicides with new modes of action are badly needed to manage the evolution of resistance of weeds to existing herbicides. Yet no major new mode of action has been introduced to the market place for about 20 years. There are probably several reasons for this. New potential products may have remained dormant owing to concerns that glyphosate-resistant (GR) crops have reduced the market for a new herbicide. The capture of a large fraction of the herbicide market by glyphosate with GR crops led to significantly diminished herbicide discovery efforts. Some of the reduced herbicide discovery research was also due to company consolidations and the availability of more generic herbicides. Another problem might be that the best herbicide molecular target sites may have already been discovered. However, target sites that are not utilized, for which there are inhibitors that are highly effective at killing plants, suggests that this is not true. Results of modern methods of target site discovery (e.g. gene knockout methods) are mostly not public, but there is no evidence of good herbicides with new target sites coming from these approaches. In summary, there are several reasons for a long dry period for new herbicide target sites; however, the relative magnitude of each is unclear. The economic stimulus to the herbicide industry caused by the evolution of herbicide-resistant weeds, especially GR weeds, may result in one or more new modes of action becoming available in the not too distant future.", "corpus_id": 19953887, "score": 0 } ]

{ "doc_id": "53281248", "title": "3D organization of chicken genome demonstrates evolutionary conservation of topologically associated domains and highlights unique architecture of erythrocytes’ chromatin", "abstract": "Abstract How chromosomes are folded, spatially organized and regulated in three dimensions inside the cell nucleus are among the longest standing questions in cell biology. Genome-wide chromosome conformation capture (Hi-C) technique allowed identifying and characterizing spatial chromatin compartments in several mammalian species. Here, we present the first genome-wide analysis of chromatin interactions in chicken embryonic fibroblasts (CEF) and adult erythrocytes. We showed that genome of CEF is partitioned into topologically associated domains (TADs), distributed in accordance with gene density, transcriptional activity and CTCF-binding sites. In contrast to mammals, where all examined somatic cell types display relatively similar spatial organization of genome, chicken erythrocytes strongly differ from fibroblasts, showing pronounced A- and B- compartments, absence of typical TADs and formation of long-range chromatin interactions previously observed on mitotic chromosomes. Comparing mammalian and chicken genome architectures, we provide evidence highlighting evolutionary role of chicken TADs and their significance in genome activity and regulation.", "corpus_id": 53281248 }

[ { "doc_id": "54528074", "title": "A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping", "abstract": "We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs \"facing\" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats.", "corpus_id": 54528074, "score": 1 }, { "doc_id": "4301920", "title": "Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions", "abstract": "The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories, and numerous models have been proposed for how chromosomes fold within chromosome territories. These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid advances in the study of three-dimensional genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide. Here we investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term ‘topological domains’, as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes. Finally, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome.", "corpus_id": 4301920, "score": 1 }, { "doc_id": "85587387", "title": "Comparison of the 3D organization of sperm and fibroblast genomes using the Hi-C approach", "abstract": "The 3D organization of the genome is tightly connected to its biological function. The Hi-C approach was recently introduced as a method that can be used to identify higher-order chromatin interactions genome-wide. The aim of this study was to determine genome-wide chromatin interaction frequencies using the Hi-C approach in mouse sperm cells and embryonic fibroblasts. The obtained results demonstrated that the 3D genome organizations of sperm and fibroblast cells show a high degree of similarity both with each other and with the previously described mouse embryonic stem (ES) cells. Both A- and B-compartments and topologically associated domains (TADs) are present in spermatozoa and fibroblasts. Nevertheless, sperm cells and fibroblasts exhibited statistically significant differences between each other in the contact probabilities of defined loci. Tight packaging of the sperm genome resulted in an enrichment of long-range contacts compared with the fibroblasts. However, only 30% of the differences in the number of contacts are based on differences in the densities of their genome packages; the main source of the differences is the gain or loss of contacts that are specific for defined genome regions. An analysis of interchromosomal contacts in both cell types demonstrated that the large chromosomes showed a tendency to interact with each other more than with the small chromosomes and vice versa. We found that the dependence of the contact probability P(s) on genomic distance for sperm is in a good agreement with the fractal globular folding of chromatin. The similarity of the spatial DNA organization in sperm and somatic cell genomes suggests the stability of the 3D structure of genomes through generations.", "corpus_id": 85587387, "score": 1 }, { "doc_id": "5712528", "title": "Erez Lieberman-Aiden Principles of the Human Genome Comprehensive Mapping of Long-Range Interactions Reveals Folding", "abstract": "clicking here. colleagues, clients, or customers by , you can order high-quality copies for your If you wish to distribute this article to others here. following the guidelines can be obtained by Permission to republish or repurpose articles or portions of articles ): April 4, 2012 www.sciencemag.org (this information is current as of The following resources related to this article are available online at http://www.sciencemag.org/content/326/5950/289.full.html version of this article at: including high-resolution figures, can be found in the online Updated information and services,", "corpus_id": 5712528, "score": 0 }, { "doc_id": "207691808", "title": "Structural and functional diversity of Topologically Associating Domains", "abstract": "Recent studies have shown that chromosomes in a range of organisms are compartmentalized in different types of chromatin domains. In mammals, chromosomes form compartments that are composed of smaller Topologically Associating Domains (TADs). TADs are thought to represent functional domains of gene regulation but much is still unknown about the mechanisms of their formation and how they exert their regulatory effect on embedded genes. Further, similar domains have been detected in other organisms, including flies, worms, fungi and bacteria. Although in all these cases these domains appear similar as detected by 3C‐based methods, their biology appears to be quite distinct with differences in the protein complexes involved in their formation and differences in their internal organization. Here we outline our current understanding of such domains in different organisms and their roles in gene regulation.", "corpus_id": 207691808, "score": 0 }, { "doc_id": "4428682", "title": "Spatial partitioning of the regulatory landscape of the X-inactivation centre", "abstract": "In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C) and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.", "corpus_id": 4428682, "score": 0 }, { "doc_id": "15754842", "title": "Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions", "abstract": "Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.", "corpus_id": 15754842, "score": 0 }, { "doc_id": "7814568", "title": "Stable Chromosome Condensation Revealed by Chromosome Conformation Capture", "abstract": "Chemical cross-linking and DNA sequencing have revealed regions of intra-chromosomal interaction, referred to as topologically associating domains (TADs), interspersed with regions of little or no interaction, in interphase nuclei. We find that TADs and the regions between them correspond with the bands and interbands of polytene chromosomes of Drosophila. We further establish the conservation of TADs between polytene and diploid cells of Drosophila. From direct measurements on light micrographs of polytene chromosomes, we then deduce the states of chromatin folding in the diploid cell nucleus. Two states of folding, fully extended fibers containing regulatory regions and promoters, and fibers condensed up to 10-fold containing coding regions of active genes, constitute the euchromatin of the nuclear interior. Chromatin fibers condensed up to 30-fold, containing coding regions of inactive genes, represent the heterochromatin of the nuclear periphery. A convergence of molecular analysis with direct observation thus reveals the architecture of interphase chromosomes.", "corpus_id": 7814568, "score": 0 }, { "doc_id": "4463482", "title": "Formation of new chromatin domains determines pathogenicity of genomic duplications", "abstract": "Chromosome conformation capture methods have identified subchromosomal structures of higher-order chromatin interactions called topologically associated domains (TADs) that are separated from each other by boundary regions. By subdividing the genome into discrete regulatory units, TADs restrict the contacts that enhancers establish with their target genes. However, the mechanisms that underlie partitioning of the genome into TADs remain poorly understood. Here we show by chromosome conformation capture (capture Hi-C and 4C-seq methods) that genomic duplications in patient cells and genetically modified mice can result in the formation of new chromatin domains (neo-TADs) and that this process determines their molecular pathology. Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans, showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure. In contrast, overlapping duplications that extended over the next boundary into the neighbouring TAD (inter-TAD), resulted in the formation of a new chromatin domain (neo-TAD) that was isolated from the rest of the genome. As a consequence of this insulation, inter-TAD duplications had no phenotypic effect. However, incorporation of the next flanking gene, Kcnj2, in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype. Our findings provide evidence that TADs are genomic regulatory units with a high degree of internal stability that can be sculptured by structural genomic variations. This process is important for the interpretation of copy number variations, as these variations are routinely detected in diagnostic tests for genetic disease and cancer. This finding also has relevance in an evolutionary setting because copy-number differences are thought to have a crucial role in the evolution of genome complexity.", "corpus_id": 4463482, "score": 0 }, { "doc_id": "4886462", "title": "Polymer physics predicts the effects of structural variants on chromatin architecture", "abstract": "Structural variants (SVs) can result in changes in gene expression due to abnormal chromatin folding and cause disease. However, the prediction of such effects remains a challenge. Here we present a polymer-physics-based approach (PRISMR) to model 3D chromatin folding and to predict enhancer–promoter contacts. PRISMR predicts higher-order chromatin structure from genome-wide chromosome conformation capture (Hi-C) data. Using the EPHA4 locus as a model, the effects of pathogenic SVs are predicted in silico and compared to Hi-C data generated from mouse limb buds and patient-derived fibroblasts. PRISMR deconvolves the folding complexity of the EPHA4 locus and identifies SV-induced ectopic contacts and alterations of 3D genome organization in homozygous or heterozygous states. We show that SVs can reconfigure topologically associating domains, thereby producing extensive rewiring of regulatory interactions and causing disease by gene misexpression. PRISMR can be used to predict interactions in silico, thereby providing a tool for analyzing the disease-causing potential of SVs.The authors present a polymer-physics-based approach (PRISMR) to model 3D chromatin folding and to predict enhancer–promoter contacts. PRISMR correctly predicts ectopic contacts induced by pathogenic SVs at the mouse Epha4 locus.", "corpus_id": 4886462, "score": 0 }, { "doc_id": "29437101", "title": "CTCF: an architectural protein bridging genome topology and function", "abstract": "The eukaryotic genome is organized in the three-dimensional nuclear space in a specific manner that is both a cause and a consequence of its function. This organization is partly established by a special class of architectural proteins, of which CCCTC-binding factor (CTCF) is the best characterized. Although CTCF has been assigned various roles that are often contradictory, new results now help to draw a unifying model to explain the many functions of this protein. CTCF creates boundaries between topologically associating domains in chromosomes and, within these domains, facilitates interactions between transcription regulatory sequences. Thus, CTCF links the architecture of the genome to its function.", "corpus_id": 29437101, "score": 0 }, { "doc_id": "17731758", "title": "Comparative Hi-C Reveals that CTCF Underlies Evolution of Chromosomal Domain Architecture", "abstract": "Summary Topological domains are key architectural building blocks of chromosomes, but their functional importance and evolutionary dynamics are not well defined. We performed comparative high-throughput chromosome conformation capture (Hi-C) in four mammals and characterized the conservation and divergence of chromosomal contact insulation and the resulting domain architectures within distantly related genomes. We show that the modular organization of chromosomes is robustly conserved in syntenic regions and that this is compatible with conservation of the binding landscape of the insulator protein CTCF. Specifically, conserved CTCF sites are co-localized with cohesin, are enriched at strong topological domain borders, and bind to DNA motifs with orientations that define the directionality of CTCF’s long-range interactions. Conversely, divergent CTCF binding between species is correlated with divergence of internal domain structure, likely driven by local CTCF binding sequence changes, demonstrating how genome evolution can be linked to a continuous flux of local conformation changes. We also show that large-scale domains are reorganized during genome evolution as intact modules.", "corpus_id": 17731758, "score": 0 }, { "doc_id": "2936092", "title": "The 3D organization of chromatin explains evolutionary fragile genomic regions.", "abstract": "Genomic rearrangements are a major source of evolutionary divergence in eukaryotic genomes, a cause of genetic diseases and a hallmark of tumor cell progression, yet the mechanisms underlying their occurrence and evolutionary fixation are poorly understood. Statistical associations between breakpoints and specific genomic features suggest that genomes may contain elusive “fragile regions” with a higher propensity for breakage. Here, we use ancestral genome reconstructions to demonstrate a near-perfect correlation between gene density and evolutionary rearrangement breakpoints. Simulations based on functional features in the human genome show that this pattern is best explained as the outcome of DNA breaks that occur in open chromatin regions coming into 3D contact in the nucleus. Our model explains how rearrangements reorganize the order of genes in an evolutionary neutral fashion and provides a basis for understanding the susceptibility of “fragile regions” to breakage.", "corpus_id": 2936092, "score": 0 }, { "doc_id": "205242677", "title": "Chromatin architecture reorganization during stem cell differentiation", "abstract": "Higher-order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin dynamics during mammalian development and lineage specification remains to be determined. By mapping genome-wide chromatin interactions in human embryonic stem (ES) cells and four human ES-cell-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome. By integrating chromatin interaction maps with haplotype-resolved epigenome and transcriptome data sets, we find widespread allelic bias in gene expression correlated with allele-biased chromatin states of linked promoters and distal enhancers. Our results therefore provide a global view of chromatin dynamics and a resource for studying long-range control of gene expression in distinct human cell lineages.", "corpus_id": 205242677, "score": 1 }, { "doc_id": "206985941", "title": "Gene density, transcription, and insulators contribute to the partition of the Drosophila genome into physical domains.", "abstract": "The mechanisms responsible for the establishment of physical domains in metazoan chromosomes are poorly understood. Here we find that physical domains in Drosophila chromosomes are demarcated at regions of active transcription and high gene density that are enriched for transcription factors and specific combinations of insulator proteins. Physical domains contain different types of chromatin defined by the presence of specific proteins and epigenetic marks, with active chromatin preferentially located at the borders and silenced chromatin in the interior. Domain boundaries participate in long-range interactions that may contribute to the clustering of regions of active or silenced chromatin in the nucleus. Analysis of transgenes suggests that chromatin is more accessible and permissive to transcription at the borders than inside domains, independent of the presence of active or silencing histone modifications. These results suggest that the higher-order physical organization of chromatin may impose an additional level of regulation over classical epigenetic marks.", "corpus_id": 206985941, "score": 1 }, { "doc_id": "26369791", "title": "Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains.", "abstract": "Recent advances enabled by the Hi-C technique have unraveled many principles of chromosomal folding that were subsequently linked to disease and gene regulation. In particular, Hi-C revealed that chromosomes of animals are organized into topologically associating domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression. Mechanisms that underlie partitioning of the genome into TADs remain poorly understood. To explore principles of TAD folding in Drosophila melanogaster, we performed Hi-C and poly(A)(+) RNA-seq in four cell lines of various origins (S2, Kc167, DmBG3-c2, and OSC). Contrary to previous studies, we find that regions between TADs (i.e., the inter-TADs and TAD boundaries) in Drosophila are only weakly enriched with the insulator protein dCTCF, while another insulator protein Su(Hw) is preferentially present within TADs. However, Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. Accordingly, we find that binding of insulator proteins dCTCF and Su(Hw) predicts TAD boundaries much worse than active chromatin marks do. Interestingly, inter-TADs correspond to decompacted inter-bands of polytene chromosomes, whereas TADs mostly correspond to densely packed bands. Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin. We propose the mechanism of TAD self-assembly based on the ability of nucleosomes from inactive chromatin to aggregate, and lack of this ability in acetylated nucleosomal arrays. Finally, we test this hypothesis by polymer simulations and find that TAD partitioning may be explained by different modes of inter-nucleosomal interactions for active and inactive chromatin.", "corpus_id": 26369791, "score": 1 }, { "doc_id": "7814568", "title": "Stable Chromosome Condensation Revealed by Chromosome Conformation Capture", "abstract": "Chemical cross-linking and DNA sequencing have revealed regions of intra-chromosomal interaction, referred to as topologically associating domains (TADs), interspersed with regions of little or no interaction, in interphase nuclei. We find that TADs and the regions between them correspond with the bands and interbands of polytene chromosomes of Drosophila. We further establish the conservation of TADs between polytene and diploid cells of Drosophila. From direct measurements on light micrographs of polytene chromosomes, we then deduce the states of chromatin folding in the diploid cell nucleus. Two states of folding, fully extended fibers containing regulatory regions and promoters, and fibers condensed up to 10-fold containing coding regions of active genes, constitute the euchromatin of the nuclear interior. Chromatin fibers condensed up to 30-fold, containing coding regions of inactive genes, represent the heterochromatin of the nuclear periphery. A convergence of molecular analysis with direct observation thus reveals the architecture of interphase chromosomes.", "corpus_id": 7814568, "score": 0 }, { "doc_id": "9610072", "title": "Investigation of the spatial genome organization of mouse sperm and fibroblasts by the Hi-C method", "abstract": "The spatial organization of eukaryotic genome plays an important role in the control of gene expression. The new Hi-C method allows investigation of chromosome contact in the three-dimensional architecture of the whole genome; however, it has not yet been applied to study the spatial configuration of the germ cells genome. Here we describe a protocol for production and quality control of Hi-C DNA libraries from mouse sperm cells and fibroblasts. Our results demonstrate that the Hi-C method can be used for studying the spatial organization of the densely packed sperm genome.", "corpus_id": 9610072, "score": 0 }, { "doc_id": "4608120", "title": "The chicken as a model for large-scale analysis of vertebrate gene function", "abstract": "The chicken has been an important experimental system for developmental biology, immunology and microbiology, having led to many fundamental discoveries. The increase in genomic resources, easy access to the embryo and the application of RNA interference mean that it will be easy and quick to use chick embryos to screen the function of many genes during embryonic development. So, it seems likely that the chicken will increasingly be the system of choice for many vertebrate biologists who are interested in gene function.", "corpus_id": 4608120, "score": 0 }, { "doc_id": "3604062", "title": "Emergence of the chicken as a model organism: implications for agriculture and biology.", "abstract": "Many of the features of the chicken make it an ideal model organism for phylogenetics and embryology, along with applications in agriculture and medicine. The availability of new tools such as whole genome gene expression arrays and single nucleotide polymorphism panels, coupled with the genome sequence, will enhance this position. These advances are reviewed and their implications are discussed.", "corpus_id": 3604062, "score": 0 }, { "doc_id": "4328989", "title": "Continental breakup and the ordinal diversification of birds and mammals", "abstract": "THE classical hypothesis for the diversification of birds and mammals proposes that most of the orders diverged rapidly in adaptive radiations after the Cretaceous/Tertiary (K/T) extinction event 65 million years ago1–3. Evidence is provided by the near-absence of fossils representing modern orders before the K/T boundary4,5. However, fossil-based estimates of divergence time are known to be conservative because of sampling biases6, and some molecular/time estimates point to earlier divergences among orders7–10. In an attempt to resolve this controversy, we have estimated times of divergence among avian and mammalian orders with a comprehensive set of genes that exhibit a constant rate of substitution. Here we report molecular estimates of divergence times that average about 50–90% earlier than those predicted by the classical hypothesis, and show that the timing of these divergences coincides with the Mesozoic fragmentation of emergent land areas. This suggests that continental breakup may have been an important mechanism in the ordinal diversification of birds and mammals.", "corpus_id": 4328989, "score": 0 }, { "doc_id": "19133627", "title": "The dynamics of chromosome evolution in birds and mammals", "abstract": "Comparative mapping, which compares the location of homologous genes in different species, is a powerful tool for studying genome evolution. Comparative maps suggest that rates of chromosomal change in mammals can vary from one to ten rearrangements per million years. On the basis of these rates we would expect 84 to 600 conserved segments in a chicken comparison with human or mouse. Here we build comparative maps between these species and estimate that numbers of conserved segments are in the lower part of this range. We conclude that the organization of the human genome is closer to that of the chicken than the mouse and by adding comparative mapping results from a range of vertebrates, we identify three possible phases of chromosome evolution. The relative stability of genomes such as those of the chicken and human will enable the reconstruction of maps of ancestral vertebrates.", "corpus_id": 19133627, "score": 0 }, { "doc_id": "13790868", "title": "Third Report on Chicken Genes and Chromosomes 2015", "abstract": "Opening insights into new technologies in avian genomics \n \nThe chicken has long been a model organism for genetic and developmental studies. It is now beginning to take its place as a model genome, opening up the fields of phylogenetics and comparative genomics like never before. This report comes at a time of huge technological advances (particularly in sequencing methodologies) and summarizes the current efforts to complete the gaps in the genome. It describes the progress that has been made in genomic annotation, particularly with respect to noncoding RNAs and genetic variants. Reviews of comparative genomics, avian evolution and sex determination are included as well as transcriptomic case studies and developments in epigenetic studies. The Third Report on Chicken Genes and Chromosomes also features the National Avian Research Facility and how it has developed into a resource for the study of avian biology, genetics, infection and disease. In this volume researchers interested in genetics, genomics and evolution will find detailed information that has not been available until now.", "corpus_id": 13790868, "score": 0 }, { "doc_id": "14410644", "title": "Comparative genomics reveals insights into avian genome evolution and adaptation", "abstract": "Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.", "corpus_id": 14410644, "score": 0 }, { "doc_id": "40123069", "title": "Evolutionary stasis: the stable chromosomes of birds.", "abstract": "Evolution at the molecular level is manifested in a variety of types of change in DNA sequences, including changes in the structure and organisation of chromosomes. However, in birds chromosomal evolution occurs at an unusually slow rate and recent whole-genome comparisons have shown that many chromosomes have remained more or less intact during avian evolution. Here I discuss progress in the development of genetic maps of natural bird populations, which has revealed that the evolutionary stasis of chromosomes often extends to conservation of gene order. The evolutionary stability of bird chromosomes, which might relate to a low frequency of transposable elements, will facilitate the transfer of genomic information from model to non-model organisms and might have a connection to the rarity of postzygotic incompatibilities observed in birds.", "corpus_id": 40123069, "score": 0 }, { "doc_id": "617330", "title": "Second report on chicken genes and chromosomes 2005", "abstract": "Citation for published version: Schmid, M, Nanda, I, Hoehn, H, Schartl, M, Haaf, T, Buerstedde, J-M, Arakawa, H, Caldwell, RB, Weigend, S, Burt, DW, Smith, J, Griffin, DK, Masabanda, JS, Groenen, MAM, Crooijmans, RPMA, Vignal, A, Fillon, V, Morisson, M, Pitel, F, Vignoles, M, Garrigues, A, Gellin, J, Rodionov, AV, Galkina, SA, Lukina, NA, Ben-Ari, G, Blum, S, Hillel, J, Twito, T, Lavi, U, David, L, Feldman, MW, Delany, ME, Conley, CA, Fowler, VM, Hedges, SB, Godbout, R, Katyal, S, Smith, C, Hudson, Q, Sinclair, A & Mizuno, S 2005, 'Second report on chicken genes and chromosomes 2005', Cytogenetic and Genome Research, vol. 109, no. 4, pp. 415-79. https://doi.org/10.1159/000084205", "corpus_id": 617330, "score": 0 }, { "doc_id": "10719821", "title": "Arrangements of macro- and microchromosomes in chicken cells", "abstract": "Arrangements of chromosome territories in nuclei of chicken fibroblasts and neurons were analysed employing multicolour chromosome painting, laser confocal scanning microscopy and three-dimensional (3D) reconstruction. The chicken karyotype consists of 9 pairs of macrochromosomes and 30 pairs of microchromosomes. Although the latter represent only 23% of the chicken genome they contain almost 50% of its genes. We show that territories of microchromosomes in fibroblasts and neurons were clustered within the centre of the nucleus, while territories of the macrochromosomes were preferentially located towards the nuclear periphery. In contrast to these highly consistent radial arrangements, the relative arrangements of macrochromosome territories with respect to each other (side-by-side arrangements) were variable. A stringent radial arrangement of macro- and microchromosomes was found in mitotic cells. Replication labelling studies revealed a pattern of DNA replication similar to mammalian cell nuclei: gene dense, early replicating chromatin mostly represented by microchromosomes, was located within the nuclear interior, surrounded by a rim of late replicating chromatin. These results support the evolutionary conservation of several features of higher-order chromatin organization between mammals and birds despite the differences in their karyotypes.", "corpus_id": 10719821, "score": 0 }, { "doc_id": "5984913", "title": "Nuclei of chicken neurons in tissues and three-dimensional cell cultures are organized into distinct radial zones", "abstract": "We used chicken retinospheroids (RS) to study the nuclear architecture of vertebrate cells in a three-dimensional (3D) cell culture system. The results showed that the different neuronal cell types of RS displayed an extreme form of radial nuclear organization. Chromatin was arranged into distinct radial zones which became already visible after DAPI staining. The distinct zones were enriched in different chromatin modifications and in different types of chromosomes. Active isoforms of RNA polymerase II were depleted in the outermost zone. Also chromocenters and nucleoli were radially aligned in the nuclear interior. The splicing factor SC35 was enriched at the central zone and did not show the typical speckled pattern of distribution. Evaluation of neuronal and non-neuronal chicken tissues showed that the highly ordered form of radial nuclear organization was also present in neuronal chicken tissues. Furthermore, the data revealed that the neuron-specific nuclear organization was remodeled when cells spread on a flat substrate. Monolayer cultures of a chicken cell line did not show this extreme form of radial organization. Rather, such monolayer cultures displayed features of nuclear organization which have been described before for many different types of monolayer cells. The finding that an extreme form radial nuclear organization, which has not been described before, is present in RS and tissues, but not in cells spread on a flat substrate, suggests that it would be important to complement studies on nuclear architecture performed with monolayer cells by studies on 3D cell culture systems and tissues.", "corpus_id": 5984913, "score": 0 }, { "doc_id": "41194025", "title": "An Appraisal of Nuclear Organisation in Interphase Embryonic Fibroblasts of Chicken, Turkey and Duck", "abstract": "Determining the nuclear ‘addresses’ of chromosome territories is a well-documented means of assaying for nuclear organisation in many cell types and species. Data in avian species are however limited at best, despite the pivotal role played by birds (particularly chickens) in agriculture, and as model organisms in developmental biology. That is, studies have hitherto focussed mostly on mammals (especially humans) and have demonstrated the importance of chromosome territory positioning in embryology, disease and evolution. Thus a detailed study of nuclear organisation in many species, many cell types and many developmental stages in birds is warranted, however, before this is achieved, ‘baseline’ needs to be established to determine precisely the relative locations of chromosome territories in at least 1 cell type of at least 1 bird. With this in mind we hybridised FISH probes from chicken chromosomes 1–28 to embryonic fibroblast nuclei, determining nuclear addresses using a newly developed plug-in to the image analysis package ImageJ. In our experience, evenly spaced representative BAC clones yielded more consistent results than hybridisation of chromosome paints. Results suggested that chromosome territory distribution best fitted a chromosome size-based (rather than gene density-based) pattern. Identical BAC clones were then hybridised to turkey and duck in a comparative genomic strategy. Observations were consistent with those seen in chicken (although, less well-defined in duck), providing preliminary evidence of conservation throughout evolution.", "corpus_id": 41194025, "score": 0 }, { "doc_id": "336073", "title": "Three-dimensional architecture of tandem repeats in chicken interphase nucleus", "abstract": "Tandem repeats belong to a class of genomic repetitive elements that form arrays of head-to-tail monomers. Due to technical difficulties in sequencing and assembly of large tandem repeat arrays, it remains largely unknown by which mechanisms tandem-repeat-containing regions aid in maintenance of ordered radial genome organization during interphase. Here we analyzed spatial distribution of several types of tandem repeats in interphase nuclei of chicken MDCC-MSB1 cells and somatic tissues relative to heterochromatin compartments and nuclear center. We showed that telomere and subtelomere repeats generally localize at the nuclear or chromocenters periphery. A tandem repeat known as CNM, typical for centromere regions of gene-dense microchromosomes, forms interchromosome clusters and occupies DAPI-positive chromocenters that appear predominantly within the nuclear interior. In contrast, centromere-specific tandem repeats of the majority of gene-poor macrochromosomes are embedded into the peripheral layer of heterochromatin. Chicken chromocenters rarely comprise centromere sequences of both macro- and microchromosomes, whose territories localize in different radial nuclear zones. Possible mechanisms of observed tandem repeats positioning and its implication in highly ordered arrangement of chromosome territories in chicken interphase nucleus are discussed.", "corpus_id": 336073, "score": 0 }, { "doc_id": "6674536", "title": "RNA synthesis in chicken erythrocytes.", "abstract": "CHICKEN erythrocyte nuclei were reported not to synthesize RNA1, and consequently have been used to study reactivation of nuclear synthesis2–4. In some ducks, however, mature erythrocyte nuclei continue to synthesize some RNA5–7, and we have found that the erythrocytes of adult chickens synthesize substantial amounts of RNA. We have found none in which the erythrocytes have no synthetic activity.", "corpus_id": 6674536, "score": 0 }, { "doc_id": "9102802", "title": "A chicken red cell inhibitor of transcription associated with the terminally differentiated state", "abstract": "When a red cell nuclear extract (RCE) from adult chickens was injected into Xenopus oocytes along with the chicken beta globin gene, transcript levels were dramatically reduced compared to injection of DNA alone. The inhibitory action of the RCE was not specific to the beta globin gene since the Herpes thymidine kinase and Xenopus 5S RNA gene transcript levels were similarly reduced. Transcriptional repression was observed even after passage of the RCE through oocyte cytoplasm to the nucleus. The inhibitory activity binds to DNA cellulose, which suggests that the inhibitor either binds to DNA or associates with DNA-binding proteins. Nuclease digestion of the chromatin assembled on injected beta globin DNA revealed that inhibition was not associated with local changes in chromatin structure. Extracts from 9-d chicken embryonic erythroid cells, in which the endogenous beta globin gene is actively expressed, did not inhibit transcription. The inhibitory activity is, therefore, restricted to transcriptionally quiescent, adult erythrocytes. Since the inhibitory effects were seen with both polymerase II and III directed genes, we speculate that the activity may be part of the extreme transcriptional repression which occurs in the terminally differentiated erythrocyte.", "corpus_id": 9102802, "score": 0 }, { "doc_id": "22005627", "title": "Electron-microscope observations on the organization of the nucleus in chicken erythrocytes and a superunit thread hypothesis for chromosome structure.", "abstract": "Previously it was shown that when condensed chromatin from several different types of cell is stained with uranyl-lead and examined in thin sections in the electron microscope, the stain is distributed into a dot-dash pattern arising from threads, with lesser-staining intermediate areas. We now show that when a section through chicken erythrocyte chromatin is stained with ethanolic phosphotungstic acid (PTA) the stain distribution is homogeneous. This shows that the lesser-staining regions after uranyl-lead, cannot be an overlap artifact. We conclude that the stains and hence the molecules in chromatin are distributed between 2 phases, an o - and an e -phase, so called because the structural units in chromatin are arranged in an orderly way at the surface of the nucleus and give rise to oddly ( o ) and evenly ( e ) numbered bands. Measurements of electron density per unit thickness, proportional to the number of stain molecules per unit volume, are made in thin sections through erythrocytes and reticulocytes from adult hen, 4-day-old chicks and 17-day embryos. The results indicate differences in the packing of the molecules in chromatin and further show that the e -phase is quite likely to have a higher DNA to protein ratio than the o -phase. After uranyl-lead stain the visibility of the dot-dash pattern in cells from adult hen is relatively low due, we propose, to closer packing. In micrographs through condensed chromatin treated with uranyl-lead the eye selects out only the densely stained dots and dashes, width 17 nm. When erythrocyte chromatin is partially or completely disrupted in various ways, threads 25-30 nm then become visible. We propose that condensed chromatin in intact cells contains structural units which consist of a central element, width 17 nm previously referred to as the unit thread, forming the e -phase, surrounded by a cylindrical shell forming the o -phase. This socalled superunit thread is similar in width, about 25-30 nm, to that reported by other workers in preparations of chromosomes spread on water surfaces. The hypothesis therefore helps explain what appeared to be discrepancies in thread dimensions. Certain other ultrastructural features of erythrocyte nuclei are also reported which are either pertinent to the general aim of this study, namely the way in which nucleoproteins fold up in chromosomes, or to biochemical studies, to be reported shortly, in which attempts are made to locate the proteins removed from isolated erythrocyte nuclei during subsequent washing in salt solutions.", "corpus_id": 22005627, "score": 0 }, { "doc_id": "16368817", "title": "STRUCTURE IN NUCLEATED ERYTHROCYTES", "abstract": "The structure of the nucleated erythrocyte of frog and chicken has been investigated by electron microscopy and correlated with the distribution of haemoglobin and DNA-containing material determined by haem absorption and Feulgen staining in the light microscope. The nuclei of both species are found to contain haemoglobin which is continuous with the haemoglobin in the cytoplasm through holes or pores in the nuclear envelope. In addition the nucleus of the frog erythrocyte sometimes contains a single invagination which is lined by the nuclear envelope. The structure of the nuclear envelope and the pores and the organisation of the nucleus are similar to those already described for other somatic cells. Erythrocytes differ from the cells previously studied in that a continuity, via the nuclear pores, of chemical substance in the interior of the nucleus and in the cytoplasm can be directly demonstrated. This is due to the fact that the cytoplasm of erythrocytes is simple, consisting predominantly of haemoglobin, and that haemoglobin is easily recognised by its specific absorption. The static pictures obtained by electron microscopy have been supplemented by observations in phase-contrast of the changes in refraction of the cell contents due to the diffusion of the haemoglobin from the nucleus into the cytoplasm during haemolysis.", "corpus_id": 16368817, "score": 0 }, { "doc_id": "24085208", "title": "Evidence for short-range helical order in the 30-nm chromatin fibers of erythrocyte nuclei", "abstract": "Chromatin folding in eukaryotes fits the genome into the limited volume of the cell nucleus. Formation of higher-order chromatin structures attenuates DNA accessibility, thus contributing to the control of essential genome functions such as transcription, DNA replication, and repair. The 30-nm fiber is thought to be the first hierarchical level of chromatin folding, but the nucleosome arrangement in the compact 30-nm fiber was previously unknown. We used cryoelectron tomography of vitreous sections to determine the structure of the compact, native 30-nm fiber of avian erythrocyte nuclei. The predominant geometry of the 30-nm fiber revealed by subtomogram averaging is a left-handed two-start helix with approximately 6.5 nucleosomes per 11 nm, in which the nucleosomes are juxtaposed face-to-face but are shifted off their superhelical axes with an axial translation of approximately 3.4 nm and an azimuthal rotation of approximately 54°. The nucleosomes produce a checkerboard pattern when observed in the direction perpendicular to the fiber axis but are not interdigitated. The nucleosome packing within the fibers shows larger center-to-center internucleosomal distances than previously anticipated, thus excluding the possibility of core-to-core interactions, explaining how transcription and regulation factors can access nucleosomes.", "corpus_id": 24085208, "score": 0 }, { "doc_id": "22550844", "title": "Visualization of chromatin folding patterns in chicken erythrocytes by atomic force microscopy (AFM)", "abstract": "The organization of the higher order structure of chromatin in chicken erythrocytes has been examined with tapping-mode scanning force microscopy under conditions close to their native environment. Reproducible high-resolution AFM images of chromatin compaction at several levels can be demonstrated. An extended beads-on-a-string (width of ∼ 15-20nm, height of ∼ 2-3nm for each individual nucleosome) can be consistently observed. Furthermore, superbeads (width of ∼ 40nm, height of ∼ 7nm) are demonstrated. Visualization of the solenoid conformation at the level of 30nm chromatin fiber is attained either by using AFM or by using electron microscopy. In addition, tightly coiled chromatin fibers (∼ 50-60nm and ∼ 90-110nm) can be revealed. Our data suggest that the chromatin in the interphase nucleus of chicken erythrocyte represents a high-order conformation and AFM provides useful high-resolution structural information concerning the folding pattern of interphase chromatin fibers.", "corpus_id": 22550844, "score": 0 }, { "doc_id": "12692652", "title": "Structure of the chromosomal material in inactive nuclei of chicken red blood cells", "abstract": "Electron microscope sections have been cut of chicken red blood cell nuclei by a novel procedure that produces zones of material below 100 Å in thickness. After fixing and staining, electron dense structures are observed that have dimensions closely correlating with those determined for nucleosomes. These structures appear as wedge-shaped or as circular objects with a diameter of approximately 90–100 Å. Five to eight of these objects are arranged in a spiral around a central core giving rise to a 250–300 Å structure which may represent a superbead or a cross section of a solenoidal fibre.", "corpus_id": 12692652, "score": 0 }, { "doc_id": "10704569", "title": "Ultrastructural and biochemical observations on interphase nuclei isolated from chicken erythrocytes.", "abstract": "Adult hen erythrocyte nuclei are isolated from cells or haemolysed in situ by acting on the plasma membrane with rotating knives or with non-ionic detergents. When the isolation medium contains magnesium ions (1 mM), sucrose (0-4 M) and Tris buffer (0.01 M, pH 7-5) called SMTOG (see text), the ultrastructure in thin sections through the condensed chromatin bodies, after staining with either uranyl-lead or phosphotungstic acid (PTA), is similar to that found in the intact cell. Hence it can be concluded that the 2 phases which comprise chromatin, the o- and e-phase, survive nuclear isolation. These are so called because the structural units in chromatin are arranged at the surface of the nucleus into one or more layers and give rise to oddly (o) and evenly (e) numbered bands. The 0-phase is also largely retained after extensive washing in 0-07 M NaC1 as shown by electron microscopy and biochemical measurements; only 6% of the total nuclear protein is removed, a value small compared with the fractional amount of the chromatin protein calculated to lie in the o-phase, about 70%. After extensive washing in saline-EDTA there are structural changes in chromatin, but biochemical data show that the molecules in the o-phase are also largely retained; loss of protein amounts to between 5 and 11%. These data suggest that the o-phase is a structural component of the chromatin bodies. They support the hypothesis that condensed chromatin is formed by folding superunit threads. These units consist of a central thread-like element about 17 nm diameter which stains preferentially with uranyl-lead and forms the e-phase, with an outer cylindrical shell forming the o-phase of total diameter about 28nm. The 5-10% proteins removed by salt washes are located exclusively in a particulate component, quite likely the chromatin. They have been examined by sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis. There are about 10 or more protein species, ranging in molecular weight from 21000 upwards. The groups of large granules previously found in the nuclear sap of intact erythrocytes are shown to be associated with an amorphous or finely fibrillar body.", "corpus_id": 10704569, "score": 0 }, { "doc_id": "38737614", "title": "MENT, a Heterochromatin Protein That Mediates Higher Order Chromatin Folding, Is a New Serpin Family Member*", "abstract": "Terminal cell differentiation is correlated with the extensive sequestering of previously active genes into compact transcriptionally inert heterochromatin. In vertebrate blood cells, these changes can be traced to the accumulation of a developmentally regulated heterochromatin protein, MENT. Cryoelectron microscopy of chicken granulocyte chromatin, which is highly enriched with MENT, reveals exceptionally compact polynucleosomes, which maintain a level of higher order folding above that imposed by linker histones. The amino acid sequence of MENT reveals a close structural relationship with serpins, a large family of proteins known for their ability to undergo dramatic conformational transitions. Conservation of the “hinge region” consensus in MENT indicates that this ability is retained by the protein. MENT is distinguished from the other serpins by being a basic protein, containing several positively charged surface clusters, which are likely to be involved in ionic interactions with DNA. One of the positively charged domains bears a significant similarity to the chromatin binding region of nuclear lamina proteins and with the A·T-rich DNA-binding motif, which may account for the targeting of MENT to peripheral heterochromatin. MENT ectopically expressed in a mammalian cell line is transported into nuclei and is associated with intranuclear foci of condensed chromatin.", "corpus_id": 38737614, "score": 0 }, { "doc_id": "9768636", "title": "Stage-specific expression and localization of MENT, a nuclear protein associated with chromatin condensation in terminally differentiating avian erythroid cells.", "abstract": "Polyclonal antibodies have been raised against a non-histone protein (MENT) which has been previously shown to be associated with the repressed chromatin of mature chicken erythrocytes and to promote the in vitro condensation of chromatin of immature erythrocyte nuclei. Here we report that the expression pattern of MENT closely follows chromatin condensation in maturing avian erythrocytes of definitive and primary lineages. Accumulation of MENT correlates more strongly with chromatin condensation than does accumulation of histone H5. In addition to being present in erythrocytes, the protein was also found in neutrophil nuclei and an immunofluorescence reaction was observed with embryonic (nucleated) thrombocytes. MENT was not detected in other chicken tissues (brain, liver, testis). In intact erythrocytes, MENT immunofluorescence was found in foci close to the nuclear periphery, while in isolated, decondensed nuclei, the fluorescence signal was uniformly distributed. In neutrophil nuclei, containing approximately 10 times more MENT than adult erythrocytes, intense staining associated with the peripheral heterochromatin was observed. These findings are discussed in regard to a possible mechanism for chromatin condensation by MENT.", "corpus_id": 9768636, "score": 0 }, { "doc_id": "907584", "title": "Chromatin compaction in terminally differentiated avian blood cells: the role of linker histone H5 and non-histone protein MENT", "abstract": "Chromatin has a tendency to shift from a relatively decondensed (active) to condensed (inactive) state during cell differentiation due to interactions of specific architectural and/or regulatory proteins with DNA. A promotion of chromatin folding in terminally differentiated avian blood cells requires the presence of either histone H5 in erythrocytes or non-histone protein, myeloid and erythroid nuclear termination stage-specific protein (MENT), in white blood cells (lymphocytes and granulocytes). These highly abundant proteins assist in folding of nucleosome arrays and self-association of chromatin fibers into compacted chromatin structures. Here, we briefly review structural aspects and molecular mode of action by which these unrelated proteins can spread condensed chromatin to form inactivated regions in the genome.", "corpus_id": 907584, "score": 0 }, { "doc_id": "40555987", "title": "Changes in histone acetyl content and in nuclear non-histone protein composition of avian erythroid cells at different stages of maturation.", "abstract": "Abstract Duck erythroid cells were fractionated by centrifugation in bovine serum albumin density gradients. Differences in cell density were correlated with the stage of maturation as determined by biochemical and morphological parameters. Avian erythroid cells increase in density as they mature. Cell populations corresponding to known stages in differentiation were compared with regard to histone composition and degree of acetylation, nature and amount of the non-histone nuclear proteins, and DNA and RNA synthetic capacities. Although the total histone to DNA ratio of the chromatin does not vary appreciably during maturation, the relative proportion of the erythroid cell-specific histone F2c increases at least 2-fold with the increasing age of the cell, whereas the other histones, except F2a2, decrease. The degree of acetylation of histones F2a1 and F3 decreases with the increasing age of the cell. The non-histone protein complement of the erythroid cell nucleus decreases 6-fold during maturation. Analysis of the non-histone proteins in polyacrylamide gels containing sodium dodecyl sulfate shows a limited heterogeneity and a remarkable similarity in their electrophoretic patterns at different stages in maturation. Quantitative rather than qualitative changes predominate as maturation proceeds. The decline in non-histone protein content with age is striking particularly in the lower molecular weight components. However, a protein band of molecular weight 55,000 is conserved selectively during maturation and it represents the predominant component of the non-histone nuclear proteins of the mature erythrocyte. The nucleoprotein changes occurring during erythrocyte maturation parallel a decrease in the amount of chromatin-associated RNA and the rate of RNA synthesis. The average RNA synthetic capacity of the isolated erythroblasts and early polychromatic erythrocytes is about 8 times higher than that of the mature erythrocyte fraction.", "corpus_id": 40555987, "score": 0 }, { "doc_id": "2099779", "title": "Chromosome-Specific Intron Size Differences in the Avian CHD Gene Provide an Efficient Method for Sex Identification in Birds", "abstract": "to this problem for some species (e.g. Griffiths and Holland 1990, Quinn et al. 1990, Rabenold et al. 1991, Dvorak et al. 1992, Longmire et al. 1993, Ogawa et al. 1997), but their use requires considerable xpertise, and often their taxonomic range is limited. More recently, PCR-based approaches that are technically simpler and that have broad taxonomic utility have been developed (Ogawa et al. 1997). The discovery of a highly conserved gene (CHD) that is linked to the W and a non-W chromosome in", "corpus_id": 2099779, "score": 0 }, { "doc_id": "16338704", "title": "The chicken erythrocyte epigenome", "abstract": "BackgroundTranscriptional regulation is impacted by multiple layers of genome organization. A general feature of transcriptionally active chromatin is sensitivity to DNase I and association with acetylated histones. However, very few of these active DNase I-sensitive domains, such as the chicken erythrocyte β-globin domain, have been identified and characterized. In chicken polychromatic erythrocytes, dynamically acetylated histones associated with DNase I-sensitive, transcriptionally active chromatin prevent histone H1/H5-induced insolubility at physiological ionic strength.ResultsHere, we identified and mapped out all the transcriptionally active chromosomal domains in the chicken polychromatic erythrocyte genome by combining a powerful chromatin fractionation method with next-generation DNA and RNA sequencing. Two classes of transcribed chromatin organizations were identified on the basis of the extent of solubility at physiological ionic strength. Highly transcribed genes were present in multigenic salt-soluble chromatin domains ranging in length from 30 to over 150 kb. We identified over 100 highly expressed genes that were organized in broad dynamically highly acetylated, salt-soluble chromatin domains. Highly expressed genes were associated with H3K4me3 and H3K27ac and produced discernible antisense transcripts. The moderately- and low-expressing genes had highly acetylated, salt-soluble chromatin regions confined to the 5′ end of the gene.ConclusionsOur data provide a genome-wide profile of chromatin signatures in relation to expression levels in chicken polychromatic erythrocytes.", "corpus_id": 16338704, "score": 0 }, { "doc_id": "29179977", "title": "NEMO: a tool for analyzing gene and chromosome territory distributions from 3D-FISH experiments", "abstract": "UNLABELLED\nThree-dimensional fluorescence in situ hybridization (3D-FISH) is used to study the organization and the positioning of chromosomes or specific sequences such as genes or RNA in cell nuclei. Many different programs (commercial or free) allow image analysis for 3D-FISH experiments. One of the more efficient open-source programs for automatically processing 3D-FISH microscopy images is Smart 3D-FISH, an ImageJ plug-in designed to automatically analyze distances between genes. One of the drawbacks of Smart 3D-FISH is that it has a rather basic user interface and produces its results in various text and image files thus making the data post-processing step time consuming. We developed a new Smart 3D-FISH graphical user interface, NEMO, which provides all information in the same place so that results can be checked and validated efficiently. NEMO gives users the ability to drive their experiments analysis in either automatic, semi-automatic or manual detection mode. We also tuned Smart 3D-FISH to better analyze chromosome territories.\n\n\nAVAILABILITY\nNEMO is a stand-alone Java application available for Windows and Linux platforms. The program is distributed under the creative commons licence and can be freely downloaded from https://www-lgc.toulouse.inra.fr/nemo", "corpus_id": 29179977, "score": 0 }, { "doc_id": "43216", "title": "A simple and effective method for ultrastructural analysis of mitosis in Drosophila S2 cells", "abstract": "Graphical abstract", "corpus_id": 43216, "score": 0 }, { "doc_id": "13131970", "title": "NIH Image to ImageJ: 25 years of image analysis", "abstract": "For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.", "corpus_id": 13131970, "score": 0 }, { "doc_id": "206596581", "title": "Juicebox Provides a Visualization System for Hi-C Contact Maps with Unlimited Zoom.", "abstract": "Hi-C experiments study how genomes fold in 3D, generating contact maps containing features as small as 20 bp and as large as 200 Mb. Here we introduce Juicebox, a tool for exploring Hi-C and other contact map data. Juicebox allows users to zoom in and out of Hi-C maps interactively, just as a user of Google Earth might zoom in and out of a geographic map. Maps can be compared to one another, or to 1D tracks or 2D feature sets.", "corpus_id": 206596581, "score": 0 }, { "doc_id": "205254836", "title": "Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition", "abstract": "Chromatin is reprogrammed after fertilization to produce a totipotent zygote with the potential to generate a new organism. The maternal genome inherited from the oocyte and the paternal genome provided by sperm coexist as separate haploid nuclei in the zygote. How these two epigenetically distinct genomes are spatially organized is poorly understood. Existing chromosome conformation capture-based methods are not applicable to oocytes and zygotes owing to a paucity of material. To study three-dimensional chromatin organization in rare cell types, we developed a single-nucleus Hi-C (high-resolution chromosome conformation capture) protocol that provides greater than tenfold more contacts per cell than the previous method. Here we show that chromatin architecture is uniquely reorganized during the oocyte-to-zygote transition in mice and is distinct in paternal and maternal nuclei within single-cell zygotes. Features of genomic organization including compartments, topologically associating domains (TADs) and loops are present in individual oocytes when averaged over the genome, but the presence of each feature at a locus varies between cells. At the sub-megabase level, we observed stochastic clusters of contacts that can occur across TAD boundaries but average into TADs. Notably, we found that TADs and loops, but not compartments, are present in zygotic maternal chromatin, suggesting that these are generated by different mechanisms. Our results demonstrate that the global chromatin organization of zygote nuclei is fundamentally different from that of other interphase cells. An understanding of this zygotic chromatin ‘ground state’ could potentially provide insights into reprogramming cells to a state of totipotency.", "corpus_id": 205254836, "score": 0 }, { "doc_id": "9216383", "title": "Identification of alternative topological domains in chromatin", "abstract": "Chromosome conformation capture experiments have led to the discovery of dense, contiguous, megabase-sized topological domains that are similar across cell types and conserved across species. These domains are strongly correlated with a number of chromatin markers and have since been included in a number of analyses. However, functionally-relevant domains may exist at multiple length scales. We introduce a new and efficient algorithm that is able to capture persistent domains across various resolutions by adjusting a single scale parameter. The ensemble of domains we identify allows us to quantify the degree to which the domain structure is hierarchical as opposed to overlapping, and our analysis reveals a pronounced hierarchical structure in which larger stable domains tend to completely contain smaller domains. The identified novel domains are substantially different from domains reported previously and are highly enriched for insulating factor CTCF binding and histone marks at the boundaries.", "corpus_id": 9216383, "score": 0 }, { "doc_id": "18511888", "title": "Comparing clusterings---an information based distance", "abstract": "This paper proposes an information theoretic criterion for comparing two partitions, or clusterings, of the same data set. The criterion, called variation of information (VI), measures the amount of information lost and gained in changing from clustering C to clustering C^'. The basic properties of VI are presented and discussed. We focus on two kinds of properties: (1) those that help one build intuition about the new criterion (in particular, it is shown the VI is a true metric on the space of clusterings), and (2) those that pertain to the comparability of VI values over different experimental conditions. As the latter properties have rarely been discussed explicitly before, other existing comparison criteria are also examined in their light. Finally we present the VI from an axiomatic point of view, showing that it is the only ''sensible'' criterion for comparing partitions that is both aligned to the lattice and convexely additive. As a consequence, we prove an impossibility result for comparing partitions: there is no criterion for comparing partitions that simultaneously satisfies the above two desirable properties and is bounded.", "corpus_id": 18511888, "score": 0 }, { "doc_id": "16535258", "title": "Chicken interferome: avian interferon-stimulated genes identified by microarray and RNA-seq of primary chick embryo fibroblasts treated with a chicken type I interferon (IFN-α)", "abstract": "Viruses that infect birds pose major threats—to the global supply of chicken, the major, universally-acceptable meat, and as zoonotic agents (e.g. avian influenza viruses H5N1 and H7N9). Controlling these viruses in birds as well as understanding their emergence into, and transmission amongst, humans will require considerable ingenuity and understanding of how different species defend themselves. The type I interferon-coordinated response constitutes the major antiviral innate defence. Although interferon was discovered in chicken cells, details of the response, particularly the identity of hundreds of stimulated genes, are far better described in mammals. Viruses induce interferon-stimulated genes but they also regulate the expression of many hundreds of cellular metabolic and structural genes to facilitate their replication. This study focusses on the potentially anti-viral genes by identifying those induced just by interferon in primary chick embryo fibroblasts. Three transcriptomic technologies were exploited: RNA-seq, a classical 3′-biased chicken microarray and a high density, “sense target”, whole transcriptome chicken microarray, with each recognising 120–150 regulated genes (curated for duplication and incorrect assignment of some microarray probesets). Overall, the results are considered robust because 128 of the compiled, curated list of 193 regulated genes were detected by two, or more, of the technologies.", "corpus_id": 16535258, "score": 0 }, { "doc_id": "13792002", "title": "Genome-wide CTCF distribution in vertebrates defines equivalent sites that aid the identification of disease-associated genes", "abstract": "Many genomic alterations associated with human diseases localize in noncoding regulatory elements located far from the promoters they regulate, making it challenging to link noncoding mutations or risk-associated variants with target genes. The range of action of a given set of enhancers is thought to be defined by insulator elements bound by the 11 zinc-finger nuclear factor CCCTC-binding protein (CTCF). Here we analyzed the genomic distribution of CTCF in various human, mouse and chicken cell types, demonstrating the existence of evolutionarily conserved CTCF-bound sites beyond mammals. These sites preferentially flank transcription factor–encoding genes, often associated with human diseases, and function as enhancer blockers in vivo, suggesting that they act as evolutionarily invariant gene boundaries. We then applied this concept to predict and functionally demonstrate that the polymorphic variants associated with multiple sclerosis located within the EVI5 gene impinge on the adjacent gene GFI1.", "corpus_id": 13792002, "score": 0 }, { "doc_id": "16826326", "title": "MEME-ChIP: motif analysis of large DNA datasets", "abstract": "Motivation: Advances in high-throughput sequencing have resulted in rapid growth in large, high-quality datasets including those arising from transcription factor (TF) ChIP-seq experiments. While there are many existing tools for discovering TF binding site motifs in such datasets, most web-based tools cannot directly process such large datasets. Results: The MEME-ChIP web service is designed to analyze ChIP-seq ‘peak regions’—short genomic regions surrounding declared ChIP-seq ‘peaks’. Given a set of genomic regions, it performs (i) ab initio motif discovery, (ii) motif enrichment analysis, (iii) motif visualization, (iv) binding affinity analysis and (v) motif identification. It runs two complementary motif discovery algorithms on the input data—MEME and DREME—and uses the motifs they discover in subsequent visualization, binding affinity and identification steps. MEME-ChIP also performs motif enrichment analysis using the AME algorithm, which can detect very low levels of enrichment of binding sites for TFs with known DNA-binding motifs. Importantly, unlike with the MEME web service, there is no restriction on the size or number of uploaded sequences, allowing very large ChIP-seq datasets to be analyzed. The analyses performed by MEME-ChIP provide the user with a varied view of the binding and regulatory activity of the ChIP-ed TF, as well as the possible involvement of other DNA-binding TFs. Availability: MEME-ChIP is available as part of the MEME Suite at http://meme.nbcr.net. Contact: t.bailey@uq.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.", "corpus_id": 16826326, "score": 0 }, { "doc_id": "22621225", "title": "Novel Insights into Chromosome Evolution in Birds, Archosaurs, and Reptiles", "abstract": "Homologous synteny blocks (HSBs) and evolutionary breakpoint regions (EBRs) in mammalian chromosomes are enriched for distinct DNA features, contributing to distinct phenotypes. To reveal HSB and EBR roles in avian evolution, we performed a sequence-based comparison of 21 avian and 5 outgroup species using recently sequenced genomes across the avian family tree and a newly-developed algorithm. We identified EBRs and HSBs in ancestral bird, archosaurian (bird, crocodile, and dinosaur), and reptile chromosomes. Genes involved in the regulation of gene expression and biosynthetic processes were preferably located in HSBs, including for example, avian-specific HSBs enriched for genes involved in limb development. Within birds, some lineage-specific EBRs rearranged genes were related to distinct phenotypes, such as forebrain development in parrots. Our findings provide novel evolutionary insights into genome evolution in birds, particularly on how chromosome rearrangements likely contributed to the formation of novel phenotypes.", "corpus_id": 22621225, "score": 0 }, { "doc_id": "9476999", "title": "CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription", "abstract": "Spatial genome organization and its effect on transcription remains a fundamental question. We applied an advanced chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) strategy to comprehensively map higher-order chromosome folding and specific chromatin interactions mediated by CCCTC-binding factor (CTCF) and RNA polymerase II (RNAPII) with haplotype specificity and nucleotide resolution in different human cell lineages. We find that CTCF/cohesin-mediated interaction anchors serve as structural foci for spatial organization of constitutive genes concordant with CTCF-motif orientation, whereas RNAPII interacts within these structures by selectively drawing cell-type-specific genes toward CTCF foci for coordinated transcription. Furthermore, we show that haplotype variants and allelic interactions have differential effects on chromosome configuration, influencing gene expression, and may provide mechanistic insights into functions associated with disease susceptibility. 3D genome simulation suggests a model of chromatin folding around chromosomal axes, where CTCF is involved in defining the interface between condensed and open compartments for structural regulation. Our 3D genome strategy thus provides unique insights in the topological mechanism of human variations and diseases.", "corpus_id": 9476999, "score": 0 }, { "doc_id": "23083829", "title": "Formation of Chromosomal Domains by Loop Extrusion.", "abstract": "Topologically associating domains (TADs) are fundamental structural and functional building blocks of human interphase chromosomes, yet the mechanisms of TAD formation remain unclear. Here, we propose that loop extrusion underlies TAD formation. In this process, cis-acting loop-extruding factors, likely cohesins, form progressively larger loops but stall at TAD boundaries due to interactions with boundary proteins, including CTCF. Using polymer simulations, we show that this model produces TADs and finer-scale features of Hi-C data. Each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops. Loop extrusion both explains diverse experimental observations-including the preferential orientation of CTCF motifs, enrichments of architectural proteins at TAD boundaries, and boundary deletion experiments-and makes specific predictions for the depletion of CTCF versus cohesin. Finally, loop extrusion has potentially far-ranging consequences for processes such as enhancer-promoter interactions, orientation-specific chromosomal looping, and compaction of mitotic chromosomes.", "corpus_id": 23083829, "score": 0 }, { "doc_id": "25054466", "title": "Unusual compartmentalization of CTCF and other transcription factors in the course of terminal erythroid differentiation.", "abstract": "It is demonstrated that in chicken embryonic and mature erythrocyte nuclei the distribution of a versatile transcription factor CTCF differs drastically from its distribution in nuclei of proliferating erythroid and non-erythroid cells. In the latter case CTCF was distributed throughout the whole nucleus volume, being concentrated in many small compartments (punctuate nuclear staining). In contrast, in embryonic and mature erythrocytes CTCF was concentrated in a limited number of large compartments. These large CTCF-containing compartments were not observed in other cells. Occasionally, but not in all cells, some of these compartments were localized close to nucleoli but did not colocalize with them. In mature erythrocytes a clear exclusion of CTCF-containing compartments from the chromatin domain was observed. This exclusion correlated with a tight association of CTCF with the nuclear matrix. Concentration in relatively large compartments and exclusion from the chromatin domain in nuclei of mature erythrocytes were also observed for RNA polymerase II and several transcription factors. The data are discussed in the context of a hypothesis postulating that relocalization of different components of the transcriptional machinery from the chromatin domain into the interchromatin compartment is an important step of the terminal inactivation of chicken erythrocyte nuclei.", "corpus_id": 25054466, "score": 0 }, { "doc_id": "207102336", "title": "The fractal globule as a model of chromatin architecture in the cell", "abstract": "The fractal globule is a compact polymer state that emerges during polymer condensation as a result of topological constraints which prevent one region of the chain from passing across another one. This long-lived intermediate state was introduced in 1988 (Grosberg et al. 1988) and has not been observed in experiments or simulations until recently (Lieberman-Aiden et al. 2009). Recent characterization of human chromatin using a novel chromosome conformational capture technique brought the fractal globule into the spotlight as a structural model of human chromosome on the scale of up to 10 Mb (Lieberman-Aiden et al. 2009). Here, we present the concept of the fractal globule, comparing it to other states of a polymer and focusing on its properties relevant for the biophysics of chromatin. We then discuss properties of the fractal globule that make it an attractive model for chromatin organization inside a cell. Next, we connect the fractal globule to recent studies that emphasize topological constraints as a primary factor driving formation of chromosomal territories. We discuss how theoretical predictions, made on the basis of the fractal globule model, can be tested experimentally. Finally, we discuss whether fractal globule architecture can be relevant for chromatin packing in other organisms such as yeast and bacteria.", "corpus_id": 207102336, "score": 0 }, { "doc_id": "206663897", "title": "A pathway for mitotic chromosome formation", "abstract": "Tracking mitotic chromosome formation How cells pack DNA into fully compact, rod-shaped chromosomes during mitosis has fascinated cell biologists for more than a century. Gibcus et al. delineated the conformational transition trajectory from interphase chromatin to mitotic chromosomes minute by minute during the cell cycle. The mitotic chromosome is organized in a spiral staircase architecture in which chromatin loops emanate radially from a centrally located helical scaffold. The molecular machines condensin I and II play distinct roles in these processes: Condensin II is essential for helical winding, whereas condensin I modulates the organization within each helical turn. Science, this issue p. eaao6135 Mitotic chromosome folding involves formation of increasingly compacted helically arranged nested loop arrays. INTRODUCTION During mitosis, cells compact their chromosomes into dense rod-shaped structures to ensure their reliable transmission to daughter cells. Our work explores how cells achieve this compaction. We integrate genetic, genomic, and computational approaches to characterize the key steps in mitotic chromosome formation from the G2 nucleus to metaphase, and we identify roles of specific molecular machines, condensin I and II, in these major conformational transitions. RATIONALE We used chicken DT-40 cells expressing an analog-sensitive CDK1 to produce cell cultures that synchronously enter mitosis. We collected cells at key time points during mitotic entry; analyzed chromosome organization by microscopy, chromosome conformation capture, and polymer simulations; and delineated a pathway of mitotic chromosome formation. We used engineered cell lines to study the function of condensin complexes, which are critical for mitotic chromosome formation. We fused condensin I and II subunits to plant auxin-inducible degron domains, thus enabling their rapid depletion in late G2 just before mitotic entry. These cell lines allowed us to determine the roles of condensin I and II in specific steps of the mitotic chromosome morphogenesis pathway. RESULTS Our analysis of G2 chromosomes reveals hallmarks of interphase chromosomes, including topologically associating domains and compartments. Upon entry into prophase, this organization is lost within minutes, and by late prophase, chromosomes are folded as arrays of consecutive loops condensed around a central axis. These loops project with random but mutually correlated angles from the axis. During prometaphase, the loop array undergoes two major reorganizations. First, it acquires a helical arrangement of loops. Polymer simulations of Hi-C data show that the centrally located axis acquires a helical twist so that consecutive loops emanate as the steps of a spiral staircase. Second, the chromatin loops become nested with ~400-kb outer loops split up by ~80-kb inner loops. As prometaphase proceeds, chromosomes shorten through progressive helical winding, with the numbers of loops per turn increasing. As a result, the size of a helical turn grows from ~3 Mb (~40 loops) to ~12 Mb (~150 loops). Depletion of condensin I or II before mitotic entry revealed their differing roles in mitotic chromosome formation. Either condensin can mediate loop array formation. However, condensin II is required for the helical twisting of the scaffold from which loops emanate, whereas condensin I modulates the size and arrangement of nested inner loops. CONCLUSION We describe a pathway of mitotic chromosome folding that unifies many previous observations. In prophase, condensins mediate the loss of interphase organization and the formation of arrays of consecutive loops. In prometaphase, chromosomes adopt a spiral staircase–like structure with a helically arranged axial scaffold of condensin II at the bases of chromatin loops. The condensin II loops are further compacted by condensin I into clusters of smaller nested loops that are additionally collapsed by chromatin-to-chromatin attractions. The combination of nested loops distributed around a helically twisted axis plus dense chromatin packing achieves the 10,000-fold compaction of chromatin into linearly organized chromosomes that is required for accurate chromosome segregation when cells divide. A pathway for mitotic chromosome formation. In prophase, condensins mediate the loss of interphase chromosome conformation, and loop arrays are formed. In prometaphase, the combined action of condensin I (blue spheres in the bottom diagram) and II (red spheres) results in helically arranged nested loop arrays. Mitotic chromosomes fold as compact arrays of chromatin loops. To identify the pathway of mitotic chromosome formation, we combined imaging and Hi-C analysis of synchronous DT40 cell cultures with polymer simulations. Here we show that in prophase, the interphase organization is rapidly lost in a condensin-dependent manner, and arrays of consecutive 60-kilobase (kb) loops are formed. During prometaphase, ~80-kb inner loops are nested within ~400-kb outer loops. The loop array acquires a helical arrangement with consecutive loops emanating from a central “spiral staircase” condensin scaffold. The size of helical turns progressively increases to ~12 megabases during prometaphase. Acute depletion of condensin I or II shows that nested loops form by differential action of the two condensins, whereas condensin II is required for helical winding.", "corpus_id": 206663897, "score": 0 }, { "doc_id": "1452561", "title": "Upgrading short-read animal genome assemblies to chromosome level using comparative genomics and a universal probe set.", "abstract": "Most recent initiatives to sequence and assemble new species' genomes de novo fail to achieve the ultimate endpoint to produce contigs, each representing one whole chromosome. Even the best-assembled genomes (using contemporary technologies) consist of subchromosomal-sized scaffolds. To circumvent this problem, we developed a novel approach that combines computational algorithms to merge scaffolds into chromosomal fragments, PCR-based scaffold verification, and physical mapping to chromosomes. Multigenome-alignment-guided probe selection led to the development of a set of universal avian BAC clones that permit rapid anchoring of multiple scaffolds to chromosomes on all avian genomes. As proof of principle, we assembled genomes of the pigeon (Columbia livia) and peregrine falcon (Falco peregrinus) to chromosome levels comparable, in continuity, to avian reference genomes. Both species are of interest for breeding, cultural, food, and/or environmental reasons. Pigeon has a typical avian karyotype (2n = 80), while falcon (2n = 50) is highly rearranged compared to the avian ancestor. By using chromosome breakpoint data, we established that avian interchromosomal breakpoints appear in the regions of low density of conserved noncoding elements (CNEs) and that the chromosomal fission sites are further limited to long CNE \"deserts.\" This corresponds with fission being the rarest type of rearrangement in avian genome evolution. High-throughput multiple hybridization and rapid capture strategies using the current BAC set provide the basis for assembling numerous avian (and possibly other reptilian) species, while the overall strategy for scaffold assembly and mapping provides the basis for an approach that (provided metaphases can be generated) could be applied to any animal genome.", "corpus_id": 1452561, "score": 0 }, { "doc_id": "24983622", "title": "Topologically associating domains and their long-range contacts are established during early G1 coincident with the establishment of the replication-timing program.", "abstract": "Mammalian genomes are partitioned into domains that replicate in a defined temporal order. These domains can replicate at similar times in all cell types (constitutive) or at cell type-specific times (developmental). Genome-wide chromatin conformation capture (Hi-C) has revealed sub-megabase topologically associating domains (TADs), which are the structural counterparts of replication domains. Hi-C also segregates inter-TAD contacts into defined 3D spatial compartments that align precisely to genome-wide replication timing profiles. Determinants of the replication-timing program are re-established during early G1 phase of each cell cycle and lost in G2 phase, but it is not known when TAD structure and inter-TAD contacts are re-established after their elimination during mitosis. Here, we use multiplexed 4C-seq to study dynamic changes in chromatin organization during early G1. We find that both establishment of TADs and their compartmentalization occur during early G1, within the same time frame as establishment of the replication-timing program. Once established, this 3D organization is preserved either after withdrawal into quiescence or for the remainder of interphase including G2 phase, implying 3D structure is not sufficient to maintain replication timing. Finally, we find that developmental domains are less well compartmentalized than constitutive domains and display chromatin properties that distinguish them from early and late constitutive domains. Overall, this study uncovers a strong connection between chromatin re-organization during G1, establishment of replication timing, and its developmental control.", "corpus_id": 24983622, "score": 0 }, { "doc_id": "207701149", "title": "CTCF and Cohesin in Genome Folding and Transcriptional Gene Regulation.", "abstract": "Genome function, replication, integrity, and propagation rely on the dynamic structural organization of chromosomes during the cell cycle. Genome folding in interphase provides regulatory segmentation for appropriate transcriptional control, facilitates ordered genome replication, and contributes to genome integrity by limiting illegitimate recombination. Here, we review recent high-resolution chromosome conformation capture and functional studies that have informed models of the spatial and regulatory compartmentalization of mammalian genomes, and discuss mechanistic models for how CTCF and cohesin control the functional architecture of mammalian chromosomes.", "corpus_id": 207701149, "score": 0 }, { "doc_id": "196649122", "title": "Emerging Evidence of Chromosome Folding by Loop Extrusion", "abstract": "Chromosome organization poses a remarkable physical problem with many biological consequences: how can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of loop extrusion with barrier elements, and review recent experimental studies that provide strong support for loop extrusion, focusing on perturbations to CTCF and cohesin assayed via Hi-C in interphase. Finally, we discuss a likely molecular mechanism of loop extrusion by SMC complexes.", "corpus_id": 196649122, "score": 0 }, { "doc_id": "196638091", "title": "Chromatin organization by an interplay of loop extrusion and compartmental segregation", "abstract": "Mammalian chromatin is organized on length scales ranging from individual nucleosomes to chromosomal territories. At intermediate scales two dominant features emerge in interphase: (i) alternating regions (<5Mb) of active and inactive chromatin that spatially segregate into different compartments, and (ii) domains (<1Mb), i.e. regions that preferentially interact internally, which are also termed topologically associating domains (TADs) and are central to gene regulation. There is growing evidence that TADs are formed by active extrusion of chromatin loops by cohesin, whereas compartments are established by a phase separation process according to local chromatin states. Here we use polymer simulations to examine how the two processes, loop extrusion and compartmental segregation, work collectively and potentially interfere in shaping global chromosome organization. Our integrated model faithfully reproduces Hi-C data from previously puzzling experimental observations, where targeting of the TAD-forming machinery led to changes in compartmentalization. Specifically, depletion of chromatin-associated cohesin reduced TADs and revealed hidden, finer compartments, while increased processivity of cohesin led to stronger TADs and reduced compartmentalization, and depletion of the TAD boundary protein, CTCF, weakened TADs while leaving compartments unaffected. We reveal that these experimental perturbations are special cases of a general polymer phenomenon of active mixing by loop extrusion. This also predicts that interference with chromatin epigenetic states or nuclear volume would affect compartments but not TADs. Our results suggest that chromatin organization on the megabase scale emerges from competition of non-equilibrium active loop extrusion and epigenetically defined compartment structure.", "corpus_id": 196638091, "score": 0 }, { "doc_id": "3792791", "title": "Activation of the alpha-globin gene expression correlates with dramatic upregulation of nearby non-globin genes and changes in local and large-scale chromatin spatial structure", "abstract": "BackgroundIn homeotherms, the alpha-globin gene clusters are located within permanently open genome regions enriched in housekeeping genes. Terminal erythroid differentiation results in dramatic upregulation of alpha-globin genes making their expression comparable to the rRNA transcriptional output. Little is known about the influence of the erythroid-specific alpha-globin gene transcription outburst on adjacent, widely expressed genes and large-scale chromatin organization. Here, we have analyzed the total transcription output, the overall chromatin contact profile, and CTCF binding within the 2.7 Mb segment of chicken chromosome 14 harboring the alpha-globin gene cluster in cultured lymphoid cells and cultured erythroid cells before and after induction of terminal erythroid differentiation.ResultsWe found that, similarly to mammalian genome, the chicken genomes is organized in TADs and compartments. Full activation of the alpha-globin gene transcription in differentiated erythroid cells is correlated with upregulation of several adjacent housekeeping genes and the emergence of abundant intergenic transcription. An extended chromosome region encompassing the alpha-globin cluster becomes significantly decompacted in differentiated erythroid cells, and depleted in CTCF binding and CTCF-anchored chromatin loops, while the sub-TAD harboring alpha-globin gene cluster and the upstream major regulatory element (MRE) becomes highly enriched with chromatin interactions as compared to lymphoid and proliferating erythroid cells. The alpha-globin gene domain and the neighboring loci reside within the A-like chromatin compartment in both lymphoid and erythroid cells and become further segregated from the upstream gene desert upon terminal erythroid differentiation.ConclusionsOur findings demonstrate that the effects of tissue-specific transcription activation are not restricted to the host genomic locus but affect the overall chromatin structure and transcriptional output of the encompassing topologically associating domain.", "corpus_id": 3792791, "score": 0 }, { "doc_id": "26012476", "title": "Erythroblast cell lines transformed by a temperature‐sensitive mutant of avian erythroblastosis virus: A model system to study erythroid differentiation in vitro", "abstract": "A continuous chicken erythroblast cell line transformed by the temperature‐sensitive mutant ts34 of avian erythroblastosis virus was developed. This cell line, designated HD3, could be induced to terminally differentiate by shift to the nonpermissive temperature. The differentiated cells resembled erythrocytes as judged by morphology, expression of hemoglobin as determined by benzidine staining and radioimmunoassay, and by the expression of differentiation‐specific cell surface antigens. Terminal differentiation was dependent on an erythropoietin‐like activity present in anemic chicken serum. In contrast, induction of differentiation in the same cells by butyric acid was erythropoietin independent and did not lead to the formation of erythrocytes. In addition, we found that the responsiveness to temperature inducibility and to butyric acid could be dissociated in variant sublines of HD3 and that both types of differentiation inducers appear to act via different pathways.", "corpus_id": 26012476, "score": 0 }, { "doc_id": "11141995", "title": "Organization of the Mitotic Chromosome", "abstract": "Chromosome Conundrum The three-dimensional organization of chromosomal DNA within the cell nucleus plays an important role in gene regulation. Naumova et al. (p. 948, published online 7 November; see the Perspective by Kleckner et al.) used chromosome conformation capture-based methods in human tissue culture cells to analyze the higher order folding of human chromosomes across the cell cycle. During interphase the chromosomes showed locus-specific compart-mentalization. In mitotic cells, on the other hand, the chromosome organization was more linear, consistent with arrays of consecutive chromatin loops. Chromosome conformation changes dramatically during the cell cycle and is unlikely to carry epigenetic information. [Also see Perspective by Kleckner et al.] Mitotic chromosomes are among the most recognizable structures in the cell, yet for over a century their internal organization remains largely unsolved. We applied chromosome conformation capture methods, 5C and Hi-C, across the cell cycle and revealed two distinct three-dimensional folding states of the human genome. We show that the highly compartmentalized and cell type–specific organization described previously for nonsynchronous cells is restricted to interphase. In metaphase, we identified a homogenous folding state that is locus-independent, common to all chromosomes, and consistent among cell types, suggesting a general principle of metaphase chromosome organization. Using polymer simulations, we found that metaphase Hi-C data are inconsistent with classic hierarchical models and are instead best described by a linearly organized longitudinally compressed array of consecutive chromatin loops.", "corpus_id": 11141995, "score": 0 }, { "doc_id": "21885013", "title": "Linkage of the major histocompatibility (B) complex and the nucleolar organizer in the chicken. Assignment to a microchromosome.", "abstract": "The linkage relationship and chromosomal locations of the major histocompatibility (B) complex and nucleolar organizers (18S + 28S ribosomal RNA genes) were studied in normal and aneuploid chickens. The Balloantigens were defined by hemagglutination, using monospecific alloantisera. A chicken having three B haplotypes was detected and used in test matings to normal disomic chickens. Additional cases of birds having three different haplotypes were generated in the progeny of such matings. Analysis of the segregation patterns of B haplotypes suggested that the chickens with an additional haplotype were trisomics. Chickens having three B haplotypes also displayed a maximum of three nucleoli in somatic cells instead of the normal two nucleoli of diploids. This indicated the presence of an additional nucleolus organizing region (NOR). Cytogenetic and cytochemical studies were performed on cells of normal and putative trisomic chickens. All chickens displayed a normal array of chromosomes for pairs 1 through 9. Silver staining differentiated Ag-NORs on the long arms of two and three microchromosomes in disomic and trisomic types, respectively. Viable tetrasomic chickens, produced from inter se matings of trisomics, displayed four nucleoli and four Ag-NORs in somatic cell preparations. These results indicate that the DNA sequences encoding the B histocompatibility antigens and the 18S + 28S ribosomal RNAs are linked on an acrocentric microchromosome in the domestic chicken.", "corpus_id": 21885013, "score": 0 }, { "doc_id": "11488636", "title": "Architecture and organization of chicken microchromosome 16: order of the NOR, MHC-Y, and MHC-B subregions.", "abstract": "Here we present a high-resolution cytogenomic analysis of chicken microchromosome 16. We established the location of the major histocompatibility complex (MHC)-B and -Y subregions relative to each other and to the nucleolus organizer region (NOR) encoding the 18S-5.8S-28S ribosomal DNA. To do so, we employed multicolor fluorescence in situ hybridization using large-insert bacterial artificial chromosome clones with fully sequenced inserts or repetitive sequence probes specific for the subregion of interest. We show that the MHC-Y and -B regions are located on the same side of the NOR, rather than opposite ends, as previously proposed. On the q arm, the MHC-Y is closely adjacent to the NOR, whereas the MHC-B is distal near the q-terminus. A relatively large GC-rich region separates the 2 MHC subregions and includes a specialized structure, a secondary constriction. We propose that the GC-rich large physical distance is the basis for the lack of genetic linkage between the NOR and MHC-B and between the MHC-Y and -B. An integrated model for GGA 16 is presented that incorporates gene complex order in the context of key architectural features including p and q arms, primary (centromere) and secondary constrictions, telomeres, as well as AT- and GC-rich regions.", "corpus_id": 11488636, "score": 0 }, { "doc_id": "29903214", "title": "Nucleolar changes in maturing avian erythroblasts and erythrocytes", "abstract": "SummaryMaturing erythroblasts and erythrocytes were studied in chickens and adult hens to provide more information on the presence and frequency of various nucleolar types in these cells. Nucleoli were present at all stages of erythroblastic and erythrocytic development except in the case of a few reticulocytes and the mature erythrocytes. The number of nucleoli per cell (expressed as the nucleolar coefficient) reached a maximum at the stage of the polychromatic erythroblast. Early erythroblasts were characterized by the presence of compact nucleoli or nucleoli with nucleolonemata. Ring shaped nucleoli and micronucleoli increased in number with further maturation. Cells of the final erythroblast stage (orthochromatic erythroblasts) contained mostly micronucleoli, and micronucleoli alone were present in reticulocytes and mature erythrocytes.", "corpus_id": 29903214, "score": 0 }, { "doc_id": "31826876", "title": "DNA synthesis in purified populations of avian erythroid cells.", "abstract": "SUMMARY By the use of equilibrium density-gradient centrifugation erythroblasts and early polychromatic erythrocyte8 have been isolated from avian anaemic bone marrow. Cells from both the unfractionated and purified preparations have been characterized in terms of their histological type, size, haemoglobin content and ability to synthesize DNA. Erythroblasts were the only cells to synthesize DNA and it appeared that their progeny, the polychromatic erythrocyte, failed to enter a new S phase. The experimental system described allows biochemical characterization of earlier stages of avian erythropoiesis than has previously been possible.", "corpus_id": 31826876, "score": 0 } ]

{ "doc_id": "8547327", "title": "Universally-Convergent Squared-Operator Iteration Methods for Solitary Waves in General Nonlinear Wave Equations", "abstract": "Three new iteration methods, namely the squared-operator method, the modified squared-operator method, and the power-conserving squared-operator method, for solitary waves in general scalar and vector nonlinear wave equations are proposed. These methods are based on iterating new differential equations whose linearization operators are squares of those for the original equations, together with acceleration techniques. The first two methods keep the propagation constants fixed, while the third method keeps the powers (or other arbitrary functionals) of the solution fixed. It is proved that all these methods are guaranteed to converge to any solitary wave (either ground state or not) as long as the initial condition is sufficiently close to the corresponding exact solution, and the time step in the iteration schemes is below a certain threshold value. Furthermore, these schemes are fast-converging, highly accurate, and easy to implement. If the solitary wave exists only at isolated propagation constant values, the corresponding squared-operator methods are developed as well. These methods are applied to various solitary wave problems of physical interest, such as higher-gap vortex solitons in the two-dimensional nonlinear Schrodinger equations with periodic potentials, and isolated solitons in GinzburgLandau equations, and some new types of solitary wave solutions are obtained. It is also demonstrated that the modified squared-operator method delivers the best performance among the methods proposed in this article.", "corpus_id": 8547327 }

[ { "doc_id": "18517436", "title": "Why Newton's method is hard for travelling waves: Small denominators, KAM theory, Arnold's linear Fourier problem, non-uniqueness, constraints and erratic failure", "abstract": "Nonlinear travelling waves and standing waves can computed by discretizing the appropriate partial differential equations and then solving the resulting system of nonlinear algebraic equations. Here, we show that the ''small denominator'' problem of Kolmogorov-Arnold-Moser (KAM) theory is equally awkward for numerical algorithms. Furthermore, Newton's iteration combined with continuation in a parameter often exhibits ''erratic failure'' even in the absence of bifurcation. Wave resonances can interlock a countable infinity of branches in an extremely complex topology, as will be illustrated through the fifth-degree Korteweg-deVries equation. Continuation can easily jump, unsuspected, from one branch to another. Constraints, sometimes finite and sometimes infinite in number, are usually needed to specify a unique solution. This confluence of numerical difficulties can be overcome only by combining the latest numerical algorithms with a strong understanding of travelling wave physics.", "corpus_id": 18517436, "score": 0 }, { "doc_id": "18096951", "title": "Internal oscillations and instability characteristics of (2+1)-dimensional solitons in a saturable nonlinear medium.", "abstract": "Two related problems on scalar (2+1)-dimensional solitons in a saturable nonlinear medium are investigated. The first one is the internal oscillations of fundamental (single-hump) solitons. Internal modes which cause these oscillations, both with and without angular dependence, are discovered. The visual effect of angle-dependent internal modes on the soliton can be a rotation or spatially uneven breathing of the perturbed soliton. These internal oscillations are very robust and persist for a very long distance. The second problem is the instability of double-hump and radially symmetric solitons. Unstable eigenmodes of these solitons are presented. Contrary to intuition, the instability growth rates decrease to zero when the soliton power becomes high. Thus the instability is strongly suppressed at high powers. This phenomenon is corroborated by our direct numerical simulations.", "corpus_id": 18096951, "score": 0 }, { "doc_id": "123170", "title": "Localized excitations and their thresholds", "abstract": "We propose a numerical method for identifying localized excitations in discrete nonlinear Schrodinger type models. This methodology, based on the application of a nonlinear iterative version of the Rayleigh-Ritz variational principle yields breather excitations in a very fast and efficient way in one or higher spatial dimensions. The typical convergence properties of the method are found to be super-linear. The usefulness of this technique is illustrated by studying the properties of the recently developed theoretical criteria for the excitation power thresholds for nonlinear modes.", "corpus_id": 123170, "score": 1 }, { "doc_id": "41891464", "title": "Convergence of Petviashvili's Iteration Method for Numerical Approximation of Stationary Solutions of Nonlinear Wave Equations", "abstract": "We analyze a heuristic numerical method suggested by V. I. Petviashvili in 1976 for approximation of stationary solutions of nonlinear wave equations. The method is used to construct numerically the solitary wave solutions, such as solitons, lumps, and vortices, in a space of one and higher dimensions. Assuming that the stationary solution exists, we find conditions when the iteration method converges to the stationary solution and when the rate of convergence is the fastest. The theory is illustrated with examples of physical interest such as generalized Korteweg--de Vries, Benjamin--Ono, Zakharov--Kuznetsov, Kadomtsev--Petviashvili, and Klein--Gordon equations.", "corpus_id": 41891464, "score": 1 }, { "doc_id": "20459026", "title": "Spectral renormalization method for computing self-localized solutions to nonlinear systems.", "abstract": "A new numerical scheme for computing self-localized states--or solitons--of nonlinear waveguides is proposed. The idea behind the method is to transform the underlying equation governing the soliton, such as a nonlinear Schrödinger-type equation, into Fourier space and determine a nonlinear nonlocal integral equation coupled to an algebraic equation. The coupling prevents the numerical scheme from diverging. The nonlinear guided mode is then determined from a convergent fixed point iteration scheme. This spectral renormalization method can find wide applications in nonlinear optics and related fields such as Bose-Einstein condensation and fluid mechanics.", "corpus_id": 20459026, "score": 0 }, { "doc_id": "17743324", "title": "Optimizing Schrödinger Functionals Using Sobolev Gradients: Applications to Quantum Mechanics and Nonlinear Optics", "abstract": "In this paper we study the application of the Sobolev gradients technique to the problem of minimizing several Schrodinger functionals related to timely and difficult nonlinear problems in quantum mechanics and nonlinear optics. We show that these gradients act as preconditioners over traditional choices of descent directions in minimization methods and show a computationally inexpensive way to obtain them using a discrete Fourier basis and a fast Fourier transform. We show that the Sobolev preconditioning provides a great convergence improvement over traditional techniques for finding solutions with minimal energy as well as stationary states and suggest a generalization of the method using arbitrary linear operators.", "corpus_id": 17743324, "score": 1 }, { "doc_id": "14293581", "title": "Computing the Ground State Solution of Bose-Einstein Condensates by a Normalized Gradient Flow", "abstract": "In this paper, we present a continuous normalized gradient flow (CNGF) and prove its energy diminishing property, which provides a mathematical justification of the imaginary time method used in the physics literature to compute the ground state solution of Bose--Einstein condensates (BEC). We also investigate the energy diminishing property for the discretization of the CNGF. Two numerical methods are proposed for such discretizations: one is the backward Euler centered finite difference (BEFD) method, the other is an explicit time-splitting sine-spectral (TSSP) method. Energy diminishing for BEFD and TSSP for the linear case and monotonicity for BEFD for both linear and nonlinear cases are proven. Comparison between the two methods and existing methods, e.g., Crank--Nicolson finite difference (CNFD) or forward Euler finite difference (FEFD), shows that BEFD and TSSP are much better in terms of preserving the energy diminishing property of the CNGF. Numerical results in one, two, and three dimensions with magnetic trap confinement potential, as well as a potential of a stirrer corresponding to a far-blue detuned Gaussian laser beam, are reported to demonstrate the effectiveness of BEFD and TSSP methods. Furthermore we observe that the CNGF and its BEFD discretization can also be applied directly to compute the first excited state solution in BEC when the initial data is chosen as an odd function.", "corpus_id": 14293581, "score": 1 }, { "doc_id": "207052769", "title": "Ground States and Dynamics of Multicomponent Bose-Einstein Condensates", "abstract": "We study numerically the time-independent vector Gross--Pitaevskii equations (VGPEs) for ground states and time-dependent VGPEs with (or without) an external driven field for dynamics describing a multicomponent Bose--Einstein condensate (BEC) at zero or a very low temperature. In preparation for the numerics, we scale the three-dimensional (3d) VGPEs, approximately reduce it to lower dimensions, present a continuous normalized gradient flow (CNGF) to compute ground states of multicomponent BEC, prove energy diminishing of the CNGF, which provides a mathematical justification, and discretize it by the backward Euler finite difference (BEFD), which is monotone in linear and nonlinear cases and preserves energy diminishing property in the linear case. Then we use a time-splitting sine-spectral (TSSP) method to discretize the time-dependent VGPEs with an external driven field for computing dynamics of multicomponent BEC. The merits of the TSSP method for VGPEs are that it is explicit, unconditionally stable,...", "corpus_id": 207052769, "score": 0 }, { "doc_id": "119402331", "title": "Rayleigh functional for nonlinear systems", "abstract": "We introduce Rayleigh functional for nonlinear systems. It is defined using the energy functional and the normalization properties of the variables of variation. The key property of the Rayleigh quotient for linear systems is preserved in our definition: the extremals of the Rayleigh functional coincide with the stationary solutions of the Euler-Lagrange equation. Moreover, the second variation of the Rayleigh functional defines stability of the solution. This gives rise to a powerful numerical optimization method in the search for the energy minimizers. It is shown that the well-known imaginary time relaxation is a special case of our method. To illustrate the method we find the stationary states of Bose-Einstein condensates in various geometries. Finally, we show that the Rayleigh functional also provides a simple way to derive analytical identities satisfied by the stationary solutions of the critical nonlinear equations. We also show that the functional used in Phys. Rev. A 66, 036612 (2002) is erroneous.", "corpus_id": 119402331, "score": 1 }, { "doc_id": "2050784", "title": "A generalized Petviashvili iteration method for scalar and vector Hamiltonian equations with arbitrary form of nonlinearity", "abstract": "The Petviashvili's iteration method has been known as a rapidly converging numerical algorithm for obtaining fundamental solitary wave solutions of stationary scalar nonlinear wave equations with power-law nonlinearity: -Mu+up=0, where M is a positive definite self-adjoint operator and p=const. In this paper, we propose a systematic generalization of this method to both scalar and vector Hamiltonian equations with arbitrary form of nonlinearity and potential functions. For scalar equations, our generalized method requires only slightly more computational effort than the original Petviashvili method.", "corpus_id": 2050784, "score": 1 }, { "doc_id": "43188859", "title": "Matrix analysis", "abstract": "Linear algebra and matrix theory are fundamental tools in mathematical and physical science, as well as fertile fields for research. This new edition of the acclaimed text presents results of both classic and recent matrix analyses using canonical forms as a unifying theme, and demonstrates their importance in a variety of applications. The authors have thoroughly revised, updated, and expanded on the first edition. The book opens with an extended summary of useful concepts and facts and includes numerous new topics and features, such as: - New sections on the singular value and CS decompositions - New applications of the Jordan canonical form - A new section on the Weyr canonical form - Expanded treatments of inverse problems and of block matrices - A central role for the Von Neumann trace theorem - A new appendix with a modern list of canonical forms for a pair of Hermitian matrices and for a symmetric-skew symmetric pair - Expanded index with more than 3,500 entries for easy reference - More than 1,100 problems and exercises, many with hints, to reinforce understanding and develop auxiliary themes such as finite-dimensional quantum systems, the compound and adjugate matrices, and the Loewner ellipsoid - A new appendix provides a collection of problem-solving hints.", "corpus_id": 43188859, "score": 0 }, { "doc_id": "120384250", "title": "Quantum mechanics: Non-relativistic theory,", "abstract": "The basic concepts of quantum mechanics Energy and momentum Schrodinger's equation Angular momentum Perturbation theory Spin The identity of particles The atom The theory of symmetry Polyatomic molecules Motion in a magnetic field Nuclear structure Elastic collisions Mathematical appendices.", "corpus_id": 120384250, "score": 0 }, { "doc_id": "53493166", "title": "Some properties of nonlinear wave systems", "abstract": "Nonlinear wave phenomena remain poorly understood, and significant results are limited to either very special examples or situations for which perturbation methods are adequate. The former case is typified by exactly solvable equations and the important role played by solitons. For the latter class of problems, the evolution of weak interactions, resonances, and slowly varying wave trains are well-known examples. Despite the limitations of each approach, these studies have stimulated a large volume of mathematical research and considerable interest in the applied disciplines. One objective of the present paper is to report on some results for nonlinear wave systems that do not fall into either of the above categories. The appro'ach taken is to study a particular case in some detail and, on the basis of the results obtained, to speculate on some anticipated general characteristics of nonlinear", "corpus_id": 53493166, "score": 1 }, { "doc_id": "122651582", "title": "Defect solitons in photonic lattices", "abstract": "Nonlinear defect-modes (defect-solitons) in optically-induced one-dimensional photonic lattices with a single-site repulsive defect are predicted and observed. These defect solitons bifurcate from linear defect modes and are fully stable.", "corpus_id": 122651582, "score": 0 }, { "doc_id": "120155656", "title": "Buckling and vibration of a rotating spoke", "abstract": "SummaryThe buckling and vibration of the spoke of a rotating wheel is examined.Since the axial load is a function of position closed form solutions for the eigenmodes are proscribed and recourse is made to regular and singular perturbation expansions in terms of several dimensionless parameters appearing in the governing equations. Some numerical results are also included in the interest of completeness.", "corpus_id": 120155656, "score": 0 }, { "doc_id": "38255655", "title": "Observation of second-band vortex solitons in 2D photonic lattices.", "abstract": "We demonstrate second-band bright vortex-array solitons in photonic lattices. This constitutes the first experimental observation of higher-band solitons in any 2D periodic system. These solitons possess complex intensity and phase structures, yet they can be excited by a simple highly localized vortex-ring beam. Finally, we show that the linear diffraction of such beams exhibits preferential transport along the lattice axes.", "corpus_id": 38255655, "score": 1 }, { "doc_id": "19275786", "title": "Observation of vortex-ring \"discrete\" solitons in 2D photonic lattices", "abstract": "We present the experimental observation of both on-site and off-site vortex ring solitons of unity topological charge in a nonlinear photonic lattice, along with a theoretical study of their propagation dynamics and stability", "corpus_id": 19275786, "score": 0 }, { "doc_id": "13999756", "title": "Observation of discrete vortex solitons in optically induced photonic lattices.", "abstract": "We report on the first experimental observation of discrete vortex solitons in two-dimensional optically induced photonic lattices. We demonstrate strong stabilization of an optical vortex by the lattice in a self-focusing nonlinear medium and study the generation of the discrete vortices from a broad class of singular beams.", "corpus_id": 13999756, "score": 0 }, { "doc_id": "14622682", "title": "Dipole and Quadrupole Solitons in Optically Induced Two-Dimensional Photonic Lattices: Theory and Experiment", "abstract": "Dipole and quadrupole solitons in a two-dimensional photorefractive optical lattice are investigated both theoretically and experimentally. It is shown theoretically that out-of-phase dipole solitons and quadrupole solitons exist and are linearly stable in the intermediate-intensity regime. In-phase dipole and quadrupole solitons, however, are always linearly unstable, but their instabilities are rather weak in the low-intensity regime. Experimentally, both types of dipole solitons are observed, and the experimental results agree qualitatively with the theoretical predictions. In addition, we have observed the anisotropic effect of the photorefractive crystal in the dipole-soliton formation.", "corpus_id": 14622682, "score": 0 }, { "doc_id": "122617329", "title": "Optical solitons due to quadratic nonlinearities: from basic physics to futuristic applications", "abstract": "We present an overview of nonlinear phenomena related to optical quadratic solitons—intrinsically multicomponent localized states of light, which can exist in media without inversion symmetry at the molecular level. Starting with presentation of a few derivation schemes of basic equations describing three-wave parametric wave mixing in di7ractive and=or dispersive quadratic media, we discuss their continuous wave solutions and modulational instability phenomena, and then move to the classi8cation and stability analysis of the parametric solitary waves. Not limiting ourselves to the simplest spatial and temporal quadratic solitons we also overview results related to the spatio-temporal solitons (light bullets), higher order quadratic solitons, solitons due to competing nonlinearities, dark solitons, gap solitons, cavity solitons and vortices. Special attention is paid to a comprehensive discussion of the recent experimental demonstrations of the parametric solitons including their interactions and switching. We also discuss connections of quadratic solitons with other types of solitons in optics and their interdisciplinary signi8cance. c", "corpus_id": 122617329, "score": 0 }, { "doc_id": "11927752", "title": "Two-dimensional optical lattice solitons.", "abstract": "We study various families of two-dimensional discrete or lattice solitons, and show that they are possible only when their power level exceeds a critical threshold. In addition, we show that gap-lattice solitons exist only when the lattice possesses a complete 2D band gap. Our results suggest that these conditions are universally valid, irrespective of the nature of the nonlinearity or the specific structure of the index lattice. The analysis explains fundamental aspects of behavior of two-dimensional discrete solitons that have been very recently observed in photosensitive optical crystals.", "corpus_id": 11927752, "score": 0 }, { "doc_id": "166916", "title": "Fundamental and vortex solitons in a two-dimensional optical lattice.", "abstract": "Fundamental and vortex solitons in a two-dimensional optically induced waveguide array are reported. In the strong localization regime the fundamental soliton is largely confined to one lattice site, whereas the vortex state comprises four fundamental modes superimposed in a square configuration with a phase structure that is topologically equivalent to the conventional vortex. However, in the weak localization regime, both the fundamental and the vortex solitons spread over many lattice sites. We further show that fundamental and the vortex solitons are stable against small perturbations in the strong localization regime.", "corpus_id": 166916, "score": 0 }, { "doc_id": "10424505", "title": "Photonic crystals for matter waves: Bose-Einstein condensates in optical lattices.", "abstract": "We overview our recent theoretical studies on nonlinear atom optics of the Bose-Einstein condensates (BECs) loaded into optical lattices. In particular, we describe the band-gap spectrum and nonlinear localization of BECs in one- and two-dimensional optical lattices. We discuss the structure and stability properties of spatially localized states (matter-wave solitons) in 1D lattices, as well as trivial and vortex-like bound states of 2D gap solitons. To highlight similarities between the behavior of coherent light and matter waves in periodic potentials, we draw useful parallels with the physics of coherent light waves in nonlinear photonic crystals and optically-induced photonic lattices.", "corpus_id": 10424505, "score": 0 }, { "doc_id": "21248490", "title": "Efficient Numerical Continuation and Stability Analysis of Spatiotemporal Quadratic Optical Solitons", "abstract": "A numerical method is set out which efficiently computes stationary (z-independent) two- and three-dimensional spatiotemporal solitons in second-harmonic-generating media. The method relies on a Chebyshev decomposition with an infinite mapping, bunching the collocation points near the soliton core. Known results for the type-I interaction are extended and a stability boundary is found by two-parameter continuation as defined by the Vakhitov--Kolokolov criteria. The validity of this criterion is demonstrated in (2+1) dimensions by simulation and direct calculation of the linear spectrum. The method has wider applicability for general soliton-bearing equations in (2+1) and (3+1) dimensions.", "corpus_id": 21248490, "score": 0 }, { "doc_id": "10990559", "title": "Stable vortex and dipole vector solitons in a saturable nonlinear medium.", "abstract": "We study both analytically and numerically the existence, uniqueness, and stability of vortex and dipole vector solitons in a saturable nonlinear medium in (2+1) dimensions. We construct perturbation series expansions for the vortex and dipole vector solitons near the bifurcation point, where the vortex and dipole components are small. We show that both solutions uniquely bifurcate from the same bifurcation point. We also prove that both vortex and dipole vector solitons are linearly stable in the neighborhood of the bifurcation point. Far from the bifurcation point, the family of vortex solitons becomes linearly unstable via oscillatory instabilities, while the family of dipole solitons remains stable in the entire domain of existence. In addition, we show that an unstable vortex soliton breaks up either into a rotating dipole soliton or into two rotating fundamental solitons.", "corpus_id": 10990559, "score": 0 } ]

{ "doc_id": "1317137", "title": "Pain in veterans of the Gulf War of 1991: a systematic review", "abstract": "BackgroundVeterans of the Persian Gulf War of 1991 have reported a range of adverse health symptoms. This systematic review aims to identify all studies that have compared the prevalence of symptoms of pain in veterans of the Gulf War to that in a non-Gulf military comparison group, and to determine whether Gulf War veterans are at increased risk of reporting pain.MethodsStudies published between January 1990 and May 2004 were identified by searching a large number of electronic databases. Reference lists and websites were also searched and key researchers were contacted. Studies were included if they reported the prevalence of any symptom or condition that included the word \"pain\" in Gulf War veterans and in a comparison group of non-Gulf veterans. 2401 abstracts were independently reviewed by two authors.ResultsTwenty studies fulfilled the inclusion criteria. Five main sites of pain were identified (muscle, joint, chest/heart, back and abdominal pain) and separate meta-analyses were performed to summarise the results related to each site. A greater proportion of Gulf veterans reported symptoms at each site of pain when compared to a non-Gulf military group. Gulf deployment was most strongly associated with abdominal pain, with Gulf veterans being more than three times more likely to report such pain than a comparison group (OR 3.23; 95%CI 2.31–4.51). Statistical heterogeneity between study estimates was significant, probably due to variation in measured periods of prevalence and symptom measurement methods.ConclusionA higher proportion of veterans of the Persian Gulf War of 1991 reported symptoms of pain than military comparison groups. This is consistent with previously demonstrated increased reporting of more general symptoms (fatigue, multiple chemical sensitivity, post traumatic stress disorder) in these veterans compared with non-Gulf military groups. However, the primary studies were heterogeneous and varied greatly in quality.", "corpus_id": 1317137 }

[ { "doc_id": "41053440", "title": "Musculoskeletal manifestations, pain, and quality of life in Persian Gulf War veterans referred for rheumatologic evaluation.", "abstract": "OBJECTIVE\nPain in the joints and other areas has been a frequent complaint among veterans of Operation Desert Storm who are experiencing unexplained illness. We characterized the rheumatic manifestations of a group of veterans of the Persian Gulf War who were referred to a rheumatology clinic.\n\n\nMETHODS\nConsecutive South Texas veterans of the Persian Gulf War who were referred for evaluation of rheumatic manifestations underwent a comprehensive evaluation of their musculoskeletal symptoms, pain, and health related quality of life.\n\n\nRESULTS\nOf 928 veterans evaluated in a screening clinic for unexplained symptoms, 145 had rheumatic manifestations (15.6%) and were referred to a rheumatology clinic. The most common diagnosis was fibromyalgia, present in 49 patients (33.8%), followed by various soft tissue problems in 25 (17.2%), nonspecific arthralgias in 14 (9.6%), and clinical or radiographic osteoarthritis in 16 (11.0%). In 39 patients (26.9%), no symptoms were present at the time of the evaluation, a careful musculoskeletal examination and laboratory tests were normal, and no diagnosis was possible. Two patients had Reiter's syndrome. Four had a positive rheumatoid factor and 3 had antinuclear antibodies, but none of these had clinical evidence of rheumatoid arthritis or systemic lupus erythematosus. Pain was present in nearly all patients and was widely distributed, with no body area spared in this group of patients. The most frequent painful areas were the knees in > 65%, the lower back in > 60%, the shoulders in 50%, and the hands and wrists in 35%. Widespread body pain was present in 65.1% of the veterans. Average values of all 8 scales measured by the SF-36 health survey were below the 25th percentile of published national norms, with pain and the number of nonarticular rheumatic symptoms explaining most of the decreased health related quality of life in the veterans we evaluated.\n\n\nCONCLUSION\nNo specific rheumatic diagnosis is characteristic of Gulf War veterans with unexplained illness referred to a rheumatology clinic. However, pain is common and widespread in these patients, and their health related quality of life is poor. Further research is necessary to determine the cause of the symptoms of veterans of the Gulf War.", "corpus_id": 41053440, "score": 0 }, { "doc_id": "19944574", "title": "Chronic multisymptom illness affecting Air Force veterans of the Gulf War.", "abstract": "CONTEXT\nGulf War (GW) veterans report nonspecific symptoms significantly more often than their nondeployed peers. However, no specific disorder has been identified, and the etiologic basis and clinical significance of their symptoms remain unclear.\n\n\nOBJECTIVES\nTo organize symptoms reported by US Air Force GW veterans into a case definition, to characterize clinical features, and to evaluate risk factors.\n\n\nDESIGN\nCross-sectional population survey of individual characteristics and symptoms and clinical evaluation (including a structured interview, the Medical Outcomes Study Short Form 36, psychiatric screening, physical examination, clinical laboratory tests, and serologic assays for antibodies against viruses, rickettsia, parasites, and bacteria) conducted in 1995.\n\n\nPARTICIPANTS AND SETTING\nThe cross-sectional questionnaire survey included 3723 currently active volunteers, irrespective of health status or GW participation, from 4 air force populations. The cross-sectional clinical evaluation included 158 GW veterans from one unit, irrespective of health status.\n\n\nMAIN OUTCOME MEASURES\nSymptom-based case definition; case prevalence rate for GW veterans and nondeployed personnel; clinical and laboratory findings among veterans who met the case definition.\n\n\nRESULTS\nWe defined a case as having 1 or more chronic symptoms from at least 2 of 3 categories (fatigue, mood-cognition, and musculoskeletal). The prevalence of mild-to-moderate and severe cases was 39% and 6%, respectively, among 1155 GW veterans compared with 14% and 0.7% among 2520 nondeployed personnel. Illness was not associated with time or place of deployment or with duties during the war. Fifty-nine clinically evaluated GW veterans (37%) were noncases, 86 (54%) mild-to-moderate cases, and 13 (8%) severe cases. Although no physical examination, laboratory, or serologic findings identified cases, veterans who met the case definition had significantly diminished functioning and well-being.\n\n\nCONCLUSIONS\nAmong currently active members of 4 Air Force populations, a chronic multisymptom condition was significantly associated with deployment to the GW. The condition was not associated with specific GW exposures and also affected nondeployed personnel.", "corpus_id": 19944574, "score": 1 }, { "doc_id": "20264975", "title": "Prevalence of chronic benign pain disorder among adults: a review of the literature", "abstract": "Abstract In this review epidemiological studies concerning chronic benign pain among adults are discussed. To this end, studies focusing on chronic pain, reporting prevalences at a population or primary health care level, including subjects aged between 18 and 75 years have been collected and analyzed. Focus of analysis was on research methods, definitions of chronic benign pain used, and reported prevalences. Prevalences varied between 2% and 40% of the population. Nor method used (telephone survey, postal survey, nor definition of chronicity (>1 month; >3 months; >6 months) clearly explained the differences in prevalence in the various studies. Implications for future research are discussed.", "corpus_id": 20264975, "score": 0 }, { "doc_id": "29359348", "title": "Epidemiology of illness and injury among U.S. Navy and Marine Corps female training populations.", "abstract": "Evidence suggests that female military populations are at greater risk than their male counterparts for certain training- and combat-related illnesses and injuries. The objective of this prospective, multisite, epidemiological study was to define the patterns of illness and injury in military women during training. We developed a computer-based outpatient tracking system for prospective data collection of all outpatient encounters for use at (1) Officer Candidate School (OCS), Quantico; (2) Marine Corps Recruit Depot (MCRD), Parris Island; and (3) Recruit Training Command (RTC), Great Lakes. During the study period, 85.8% of OCS candidates (260 of 303), 72.4% of MCRD recruits (2,002 of 2,766), and 83.4% of RTC recruits (7,395 of 8,865) had at least one medical encounter during training. The most common category of medical encounters at all three sites was musculoskeletal injury, followed by respiratory and dermatological disorders. This study establishes high morbidity rates and identifies medical priorities for preventive interventions in Marine Corps and Navy female trainees.", "corpus_id": 29359348, "score": 0 }, { "doc_id": "20046959", "title": "Gulf War unexplained illnesses: persistence and unexplained nature of self-reported symptoms.", "abstract": "Most published reports of health symptoms among Gulf War (GW) veterans have been based on self-reported questionnaire data. The presence of these symptoms at the time of a clinical evaluation and the unexplained nature of the symptoms have not been described. We report the findings of a sample of symptomatic veterans that were examined as part of a population-based case-control study of GW unexplained illnesses. Participants in the case-control study were selected from responders to a cross-sectional survey of a random sample of GW veterans residing in the northwestern United States. The initial survey questionnaire solicited information on the presence of fatigue and psychological/cognitive, gastrointestinal, musculoskeletal, and dermatological problems. The persistence of the symptoms and possible explanatory diagnoses were explored at the time of the clinical evaluation. Findings from the first 225 participants who completed clinical examinations indicate significant differences between self-reported symptoms on the survey questionnaire and those confirmed at the time of clinical exam. The agreement between symptoms reported both on the survey and at the time of examination varies across the symptom groups. While self-reported unexplained fatigue was confirmed at the time of clinical encounter in 79% of participants, self-reported gastrointestinal symptoms were confirmed at the clinical encounter in only 20% of participants. Differences between symptoms reported on the survey questionnaire and those confirmed at the time of clinical encounter were attributable to finding a clinical diagnosis for the symptom, resolution of symptom(s) between time of questionnaire and clinical exam, and inadvertent endorsement of the symptom on the questionnaire. These findings suggest that due to the possibility of outcome misclassification, inappropriate conclusions may be drawn about the association between exposures and unexplained illnesses in GW veterans from data derived solely from self-administered questionnaires.", "corpus_id": 20046959, "score": 0 }, { "doc_id": "41039510", "title": "Psychiatric disorder in veterans of the Persian Gulf War of 1991", "abstract": "Background Veterans of the Persian Gulf War of 1991 have reported symptoms attributed to their military service. Aims To review all studies comparing the prevalence of psychiatric disorders in Gulf War veterans and in a comparison group of service personnel not deployed to the Gulf War. Method Studies of military personnel deployed to the Gulf published between 1990 and 2001 were identified from electronic databases. Reference lists and websites were searched and key researchers were contacted for information. Atotal of 2296 abstracts and 409 complete articles were reviewed and data were extracted independently by two members of the research team. Results The prevalence of psychiatric disorder in 20 studies of Gulf War veterans was compared with the prevalence in the comparison group. Prevalence of post-traumatic stress disorder (PTSD) and common mental disorder were higher in the Gulf War veterans. Heterogeneity between studies was significant, but all reported this increased prevalence. Conclusions Veterans of the Persian Gulf War reported an increased prevalence of PTSD and common mental disorder compared with other active service personnel not deployed to the Gulf. These findings are attributable to the increase in psychologically traumatic events in wartime.", "corpus_id": 41039510, "score": 0 }, { "doc_id": "39392469", "title": "Meta-analysis: Potentials and promise", "abstract": "The number of papers published on meta-analyses in medical research has increased sharply in the past 10 years (fig 1). The merits and perils of the somewhat mysterious procedure of meta-analysis, however, continue to be debated in the medical community.1 23 What, then, is meta-analysis? A useful definition was given by Huque: “A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be ‘combinable.’” 4 The terminology, however, is still debated, and expressions used concurrently include “overview,” “pooling,” and “quantitative synthesis.” We believe that the term meta-analysis should be used to describe the statistical integration of separate studies, whereas “systematic review” is most appropriate for denoting any review of a body of data that uses clearly defined methods and criteria (box). Systematic reviews can include meta-analyses, appraisals of single trials, and other sources of evidence.6 In this article we examine the potentials and promise of meta-analysis of randomised controlled trials. In later articles of this series we will consider the practical steps involved in meta-analysis,7 examine various extensions beyond the calculation of a combined estimate,8 address potential biases and discuss strategies to detect and minimise the influence of these in meta-analysis of randomised trials9 and of observational studies.10 We will conclude with a discussion of unresolved issues and future developments.11 Details of relevant software will appear on the BMJ's website at the end of the series.\n\n\n\nFig 1 \nNumber of publications about meta-analysis, 1987–96 (results from Medline search using text word and medical subject heading “meta-analysis”)\n\n\n\n#### What's in a name? The case for “meta-analysis”\n\nThe term meta-analysis for statistically combining and analysing data from separate studies is appropriate because:", "corpus_id": 39392469, "score": 0 }, { "doc_id": "1086172", "title": "Meta-analysis in clinical trials.", "abstract": "This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.", "corpus_id": 1086172, "score": 0 }, { "doc_id": "143526183", "title": "War‐Zone Trauma and Stress‐Related Symptoms in Operation Desert Shield/Storm (ODS) Returnees", "abstract": "A growing literature suggests that human beings are often negatively impacted by participation in military combat, but there have been few attempts to document the psychological effects of war stress in the masses of troops deployed to action. We chose to study the relationship of Operation Desert Shield/Storm (ODS) participation and symptoms of psychological distress in a comparison of 215 Army National Guard and Army Reserve troops who were activated to service in the Persian Gulf and returned to the States without seeking mental health treatment services and 60 troops from these same units who were activated but not deployed overseas. Negative psychological outcomes were measured within four to ten months from homecoming in three domains: negative mood states, symptoms of posttraumatic stress disorder (PTSD), and physical health complaints. Results indicated that as war-zone stress exposure increased, the frequency and severity of psychological symptoms were enhanced, providing correlational evidence of the adverse impact of war stress, at least among a subset of ODS returnees. As many as 16–24% of war zone exposed troops exhibited levels of distress symptomatology sufficiently exaggerated to suggest the presence of mental disorders, specifically clinical depression and PTSD. Psychological symptoms were less frequently reported among troops classified in the lower war-zone stress exposure subset and those activated but not deployed to the Persian Gulf.", "corpus_id": 143526183, "score": 1 }, { "doc_id": "23964253", "title": "Is there a Persian Gulf War syndrome? Evidence from a large population-based survey of veterans and nondeployed controls.", "abstract": "PURPOSE\nConcerns have been raised about whether veterans of the Gulf War have a medical illness of uncertain etiology. We surveyed veterans to look for evidence of an illness that was unique to those deployed to the Persian Gulf and was not seen in comparable military controls.\n\n\nSUBJECTS AND METHODS\nA population-based sample of veterans (n = 1,896 from 889 units) deployed to the Persian Gulf and other Gulf War-era controls (n = 1799 from 893 units) who did not serve in the Gulf were surveyed in 1995-1996. Seventy-six percent of eligible subjects, including 91% of located subjects, answered questions about commonly reported and potentially important symptoms. We used factor analysis, a statistical technique that can identify patterns of related responses, on a random subset of the deployed veterans to identify latent patterns of symptoms. The results from this derivation sample were compared with those obtained from a separate validation sample of deployed veterans, as well as the nondeployed controls, to determine whether the results were replicable and unique.\n\n\nRESULTS\nOne half (50%) of the deployed veterans and 14% of the nondeployed controls reported health problems that they attributed to military service during 1990-1991. Compared with the nondeployed controls, the deployed veterans had significantly greater prevalences of 123 of 137 (90%) symptoms; none was significantly lower. Factor analysis identified three replicable symptom factors (or patterns) in the deployed veterans (convergent correlations > or =0.85). However, these patterns were also highly replicable in the nondeployed controls (convergent correlations of 0.95 to 0.98). The three factors also accounted for similar proportions of the common variance among the deployed veterans (35%) and nondeployed controls (30%).\n\n\nCONCLUSIONS\nThe increased prevalence of nearly every symptom assessed from all bodily organ systems among the Gulf War veterans is difficult to explain pathophysiologically as a single condition. Identification of the same patterns of symptoms among the deployed veterans and nondeployed controls suggests that the health complaints of Gulf War veterans are similar to those of the general military population and are not consistent with the existence of a unique Gulf War syndrome.", "corpus_id": 23964253, "score": 0 }, { "doc_id": "21401396", "title": "Health-related quality of life in Gulf War era military personnel.", "abstract": "The Gulf War's impact on veterans' health-related quality of life (HRQL) remains unclear. The authors examined the HRQL of military personnel deployed to the Gulf War Theater compared with those not deployed. In 1995-1996, a structured, population-based telephone survey was conducted 5 years postconflict among a cohort originally from Iowa on active duty during the conflict. The sample included 4,886 eligible subjects stratified by deployment and military status and proportionately distributed within five substrata. The Medical Outcome Study Short Form-36 (SF-36) assessed HRQL, and multivariable linear regression identified pre- and perideployment risk factors. A total of 3,695 respondents (76%) participated. Nondeployed participants reported excellent health more often than deployed participants (31% vs. 21%, p < 0.01). SF-36 scores for deployed participants were poorer than those for nondeployed controls across all health domains. Modifiable factors such as smoking and military preparedness, and other factors such as predeployment physical and mental health morbidity, were independent risk factors for poorer HRQL after deployment. Deployed veterans reported slightly poorer HRQL even after the authors adjusted for other risk factors. Further investigation of factors influencing postdeployment HRQL is needed. Routine collection of health information by using standardized instruments pre- and perideployment should be implemented.", "corpus_id": 21401396, "score": 0 }, { "doc_id": "25395676", "title": "Health-related quality of life in Persian Gulf War Veterans.", "abstract": "OBJECTIVE\nThe objective of this investigation is to describe the health-related quality of life of Persian Gulf War (GW) veterans and to examine the effects of current chronic medical conditions and psychiatric status on physical functioning.\n\n\nMETHODS\nTo measure health-related quality of life, the Medical Outcomes Short Form Survey (SF36) was administered approximately 4 years after the GW to a stratified, random sample of New England-area GW-deployed veterans and a group of military personnel deployed to Germany during the GW. The SF36 scores for the GW-deployed study population (N = 141) were compared with those for the Germany-deployed group (N = 46) and with published U.S. population norms. Multiple linear regression analyses were performed to identify risk factors associated with lower physical health functioning in the GW-deployed study group.\n\n\nRESULTS\nFunctional health status was significantly lower in the GW-deployed group compared with the Germany-deployed group for each of the SF36 subscales and the two summary scores (Physical Component Summary [PCS] and Mental Component Summary). Compared with the general U.S. population, the GW-deployed group median was between the 25th and 50th percentile for the Physical Functioning subscale and the PCS score. Within the GW-deployed group, lower education, psychological symptomatology, and a higher number of chronic self-reported medical conditions were significant predictors of the PCS score.\n\n\nCONCLUSION\nGW-deployed veterans report lower functional health status compared with a group of Germany-deployed veterans and published general U.S. population norms. Within the group of GW-deployed veterans, several current medical and psychological conditions predictive of lower physical functioning levels were identified.", "corpus_id": 25395676, "score": 0 }, { "doc_id": "23783502", "title": "State of health after deployment in the Persian Gulf. The Danish Gulf War Study.", "abstract": "BACKGROUND\nMultiple symptoms have been reported in American Gulf War Veterans including headache, fatigue, impaired short-term memory, sleep disturbances, agitation, respiratory symptoms, muscle and joint pain, diseases of the skin, and intermittent fever. The Danish Gulf War Study was performed to clarify if a corresponding pattern existed among Danes having served in the Persian Gulf during and mainly after the conflict.\n\n\nMATERIAL AND METHODS\nA cross-sectional study was performed during the period January 1997 to January 1998 which included 821 subjects who had been deployed in the Persian Gulf within the period August 2 1990 until December 31 1997. Of 686 (83.6%) subjects who participated in the study, 95% had been engaged in peace keeping operations after the war. A group consisting of randomly selected age- and gender matched controls, comprised 231 of 400 potential participants (57.7%). All participants underwent clinical and paraclinical examinations, and had an interview based on a previously completed questionnaire.\n\n\nRESULTS\nUnspecific symptoms such as repeated fits of headache, fatigue, memory and concentration difficulties, sleep disturbances, agitation, dyspnea, diseases of the skin, and intermittent fever, were significantly more frequent among Danish Gulf War Veterans, p < 0.05, than among controls; no association was found with respect to muscle and joint pain. The higher symptom prevalence among Gulf War Veterans was observed for conditions which had made their first appearance during or after the Gulf War. The prevalence of symptoms which made their first appearance before August 2 1990 was similar for both groups.\n\n\nCONCLUSION\nExcept for musculo-skeletal symptoms, this study demonstrated a pattern of symptoms among Danish Gulf War Veterans consistent with the findings among American Gulf War Veterans. Considering that American Gulf War Veterans were predominantly deployed during the armament phase and the brief war phase, and that Danish Gulf War Veterans were predominantly deployed after the war in peace keeping missions, the results indicate the existence of some common risk factors independent of war action.", "corpus_id": 23783502, "score": 1 }, { "doc_id": "20129981", "title": "Health of UK servicemen who served in Persian Gulf War", "abstract": "BACKGROUND\nVarious symptoms in military personnel in the Persian Gulf War 1990-91 have caused international speculation and concern. We investigated UK servicemen.\n\n\nMETHODS\nWe did a cross-sectional postal survey on a random sample of Gulf War veterans (Gulf War cohort, n=4248) and, stratified for age and rank, servicemen deployed to the Bosnia conflict (Bosnia cohort, n=4250) and those serving during the Gulf War but not deployed there (Era cohort, n=4246). We asked about deployment, exposures, symptoms, and illnesses. We analysed men only. Our outcome measures were physical health, functional capacity (SF-36), the general health questionnaire, the Centers for Disease Control and Prevention (CDC) multisymptom criteria for Gulf War illness, and post-traumatic stress reactions.\n\n\nFINDINGS\nThere were 8195 (65.1%) valid responses. The Gulf War cohort reported symptoms and disorders significantly more frequently than those in the Bosnia and Era cohorts, which were similar. Perception of physical health and ability were significantly worse in the Gulf War cohort than in the other cohorts, even after adjustment for confounders. Gulf War veterans were more likely than the Bosnia cohort to have substantial fatigue (odds ratio 2.2 [95% CI 1.9-2.6]), symptoms of post-traumatic stress (2.6 [1.9-3.4]), and psychological distress (1.6 [1.4-1.8]), and were nearly twice as likely to reach the CDC case definition (2.5 [2.2-2.8]). In the Gulf War, Bosnia, and Era cohorts, respectively, 61.9%, 36.8%, and 36.4% met the CDC criteria, which fell to 25.3%, 11.8%, and 12.2% for severe symptoms. Potentially harmful exposures were reported most frequently by the Gulf War cohort. All exposures showed associations with all of the outcome measures in the three cohorts. Exposures specific to the Gulf were associated with all outcomes. Vaccination against biological warfare and multiple routine vaccinations were associated with the CDC multisymptom syndrome in the Gulf War cohort.\n\n\nINTERPRETATION\nService in the Gulf War was associated with various health problems over and above those associated with deployment to an unfamiliar hostile environment. Since associations of ill health with adverse events and exposures were found in all cohorts, however, they may not be unique and causally implicated in Gulf-War-related illness. A specific mechanism may link vaccination against biological warfare agents and later ill health, but the risks of illness must be considered against the protection of servicemen.", "corpus_id": 20129981, "score": 1 }, { "doc_id": "89528", "title": "Women in the Persian Gulf: lack of gender differences in long-term health effects of service in United Kingdom Armed Forces in the 1991 Persian Gulf War.", "abstract": "A cross-sectional postal survey was conducted to evaluate the health of a random sample of United Kingdom Armed Forces personnel who were deployed to the 1990-1991 Persian Gulf conflict compared with nondeployed controls and controls deployed to Bosnia. The health of service women was examined and compared with that of United Kingdom service men. The main outcome measures were physical symptoms and ailments, functional capacity on the 36-item Short-Form Health Survey, the 12-item General Health Questionnaire, the Centers for Disease Control and Prevention multisymptom criteria for Gulf War illness, and post-traumatic stress reactions. There were 645 (65.3%) valid responses. The women from the Gulf cohort reported each symptom and the majority of health outcomes more frequently than either control group. No gender differences were found for 32 of the 50 symptoms assessed. Of the remaining 18 symptoms, women reported significantly more than men for only 6 of them, and there were no gender differences in 5 of the 6 principal health outcome measures. Women deployed to the Persian Gulf had similar rates of ill health as their male counterparts. Nothing was found to suggest that, other than for gender-specific health effects, any special considerations need to be made on health grounds for service women in any future deployments.", "corpus_id": 89528, "score": 1 }, { "doc_id": "21175543", "title": "Illnesses among United States veterans of the Gulf War: a population-based survey of 30,000 veterans.", "abstract": "Despite numerous studies on veterans of the 1990 to 1991 Gulf War, the fundamental questions of how healthy they are and how their health compares with that of their military peers who were not deployed to the Gulf have not been fully answered. We conducted a health survey in which the health outcomes of a population-based sample of 15,000 Gulf veterans representing various military branches and unit components (regular, reserve, National Guard) were compared with those of 15,000 non-Gulf veterans who were randomly sampled to mirror the number in the same military strata in the Gulf veteran group. In comparison with their peers, Gulf veterans had a higher prevalence of functional impairment, health care utilization, symptoms, and medical conditions and a higher rate of low general health perceptions. A longitudinal follow-up of the health of these veterans will be needed to detect changes in health status and to detect diseases with a long latency period.", "corpus_id": 21175543, "score": 1 }, { "doc_id": "122325", "title": "Factor analysis of self-reported symptoms: does it identify a Gulf War syndrome?", "abstract": "Active duty US Naval mobile construction battalion personnel (Seabees) were surveyed in 1994 for the presence of a variety of symptoms. Questions were drawn from the Hopkins Symptom Checklist and from a collection of symptoms either defining clinical depression or commonly reported by Persian Gulf War veterans. Of those surveyed, 524 were Gulf War veterans and 935 were nondeployed Gulf War-era veterans. Factor analysis applied to Gulf War veterans yielded five factors, three deriving from the Hopkins Symptom Checklist, one suggesting clinical depression, and one containing symptoms commonly reported by Gulf War veterans. Factor analysis applied to nondeployed veterans yielded five similar factors. Three of the factors yielded statistically significantly greater standardized factor scores for Gulf War veterans than for nondeployed veterans. Four of the factors resembled factors resulting from a previous analysis on a sample of similar Gulf War veterans. Gulf War veterans and nondeployed era veterans reported similar clusters of symptoms and illnesses. However, Gulf War veterans reported these same clusters with greater frequencies than did nondeployed veterans. The authors conclude that, in contrast to a previous report, factor analysis did not identify a unique Gulf War syndrome.", "corpus_id": 122325, "score": 1 }, { "doc_id": "34846131", "title": "Health and exposures of United Kingdom Gulf war veterans. Part I: The pattern and extent of ill health", "abstract": "OBJECTIVES To assess the health of United Kingdom Gulf war veterans, to compare their health to that of similar personnel not deployed, to describe patterns of ill health in both groups, and to estimate their extent. METHODS Main Gulf (n=4795) and validation Gulf (n=4793) cohorts were randomly selected within strata from the population deployed to the Gulf and a non-Gulf cohort (n=4790) from those who were not sent. Seven years after the war subjects completed a questionnaire about their health in the past month, including 95 symptom questions and two manikins on which to shade areas of pain or numbness and tingling. Responses were subjected to a principal component analysis with rotation and to a cluster analysis within each cohort. Mean symptom score was used as a measure of severity. Areas shaded on the manikins were coded to indicate widespread pain and possible toxic neuropathy. RESULTS A response of 85.5% was achieved. Those who had been to the Gulf were more troubled by every symptom with a mean severity score (3.0) substantially greater than in the non-Gulf cohort (1.7). Seven factors were extracted accounting for 48% of the variance. The scores on five factors (labelled psychological, peripheral, respiratory, gastrointestinal, and concentration) were significantly worse in those who had been to the Gulf. Symptoms suggestive of peripheral neuropathy were found more often (12.5%) in the Gulf than the non-Gulf (6.8%) cohorts. Widespread pain was also found more often (12.2% Gulf; 6.5% non-Gulf). Those who had been to the Gulf were found disproportionately (23.8%) in three clusters with high mean severity scores; only 9.8% of non-Gulf respondents were in these clusters. There was no evidence of an important excess in the use of alcohol, tobacco, or referral to hospital specialists by those who had been to the Gulf. For the same level of reported ill health those who had been to the Gulf were less likely to be referred to specialists than non-Gulf veterans. CONCLUSION 7 Years after the war, the Gulf war veterans were more troubled about their health than those who had not been sent, with a substantial subgroup reporting a pattern of symptoms suggestive of a significant decline in health.", "corpus_id": 34846131, "score": 1 }, { "doc_id": "1570114", "title": "Self-reported ill health in male UK Gulf War veterans: a retrospective cohort study", "abstract": "BackgroundForces deployed to the first Gulf War report more ill health than veterans who did not serve there. Many studies of post-Gulf morbidity are based on relatively small sample sizes and selection bias is often a concern. In a setting where selection bias relating to the ill health of veterans may be reduced, we: i) examined self-reported adult ill health in a large sample of male UK Gulf War veterans and a demographically similar non-deployed comparison group; and ii) explored self-reported ill health among veterans who believed that they had Gulf War syndrome.MethodsThis study uses data from a retrospective cohort study of reproduction and child health in which a validated postal questionnaire was sent to all UK Gulf War veterans (GWV) and a comparison cohort of Armed Service personnel who were not deployed to the Gulf (NGWV). The cohort for analysis comprises 42,818 males who responded to the questionnaire.ResultsWe confirmed that GWV report higher rates of general ill health. GWV were significantly more likely to have reported at least one new medical symptom or disease since 1990 than NGWV (61% versus 37%, OR 2.7, 95% CI 2.5–2.8). They were also more likely to report higher numbers of symptoms. The strongest associations were for mood swings (OR 20.9, 95%CI 16.2–27.0), memory loss/lack of concentration (OR 19.6, 95% CI 15.5–24.8), night sweats (OR 9.9, 95% CI 6.5–15.2), general fatigue (OR 9.6, 95% CI 8.3–11.1) and sexual dysfunction (OR 4.6, 95%CI 3.2–6.6). 6% of GWV believed they had Gulf War syndrome (GWS), and this was associated with the highest symptom reporting.ConclusionsIncreased levels of reported ill health among GWV were confirmed. This study was the first to use a questionnaire which did not focus specifically on the veterans' symptoms themselves. Nevertheless, the results are consistent with those of other studies of post-Gulf war illness and thus strengthen overall findings in this area of research. Further examination of the mechanisms underlying the reporting of ill health is required.", "corpus_id": 1570114, "score": 1 }, { "doc_id": "27229436", "title": "Symptoms and medical conditions in Australian veterans of the 1991 Gulf War: relation to immunisations and other Gulf War exposures", "abstract": "Aims: To investigate whether Australian Gulf War veterans have a higher than expected prevalence of recent symptoms and medical conditions that were first diagnosed in the period following the 1991 Gulf War; and if so, whether these effects were associated with exposures and experiences that occurred in the Gulf War. Methods: Cross-sectional study of 1456 Australian Gulf War veterans and a comparison group who were in operational units at the time of the Gulf War, but were not deployed to that conflict (n = 1588). A postal questionnaire was administered and the likelihood of the diagnosis of self-reported medical conditions was assessed and rated by a medical practitioner. Results: Gulf War veterans had a higher prevalence of all self-reported health symptoms than the comparison group, and more of the Gulf War veterans had severe symptoms. Increased symptom reporting was associated with several exposures, including having more than 10 immunisations, pyridostigmine bromide tablets, anti-biological warfare tablets, pesticides, insect repellents, reportedly being in a chemical weapons area, and stressful military service experiences in a strong dose-response relation. Gulf War veterans reported psychological (particularly post-traumatic stress disorder), skin, eye, and sinus conditions first diagnosed in 1991 or later more commonly than the comparison group. Over 90% of medical conditions reported by both study groups were rated by a medical practitioner as having a high likelihood of diagnosis. Conclusion: More than 10 years after the 1991 Gulf War, Australian veterans self-report all symptoms and some medical conditions more commonly than the comparison group. Further analysis of the severity of symptoms and likelihood of the diagnosis of medical conditions suggested that these findings are not due to over-reporting or to participation bias.", "corpus_id": 27229436, "score": 1 }, { "doc_id": "41102864", "title": "Increased postwar symptoms and psychological morbidity among U.S. Navy Gulf War veterans.", "abstract": "To investigate reports on war-related morbidity, 527 active-duty Gulf War veterans and 970 nondeployed veterans from 14 Seabee commands were studied in 1994 with a questionnaire, sera collection, handgrip strength, and pulmonary function testing. The questionnaire assessed postwar symptoms, war exposures, and screened for chronic fatigue syndrome, post-traumatic stress disorder, and psychological symptoms suggesting neurosis (Hopkins Symptom Checklist). Sera were tested with four nonspecific reactant assays: C-reactive protein, transferrin, ferritin, and haptoglobin. Gulf War veterans reported a higher prevalence for 35 of 41 symptoms, scored higher on psychological symptom scales, were more likely to screen for post-traumatic stress disorder, had lower handgrip strength, and had higher serum ferritin assay results. Numerous comparisons of these morbidity outcomes with 30 self-reported exposures demonstrated many associations, but no unique exposure or group of exposures were implicated. Morbidity data are consistent with other postwar observations, but the etiology for morbidity findings remains uncertain.", "corpus_id": 41102864, "score": 0 }, { "doc_id": "23915114", "title": "Relationship of psychiatric status to Gulf War veterans' health problems.", "abstract": "OBJECTIVE\nA growing body of research has shown that there are important links between certain psychiatric disorders and health symptom reporting. Two disorders in particular (posttraumatic stress disorder (PTSD) and major depression) have been the most widely implicated to date, and this association has sometimes been used to explain the occurrence of ill-defined medical problems and increased somatic symptoms in certain groups, most recently Gulf War veterans.\n\n\nMETHODS\nStructured psychiatric diagnostic interviews were used to examine the presence of major psychiatric (axis I) disorders and their relation to health symptom reporting in a well-characterized, stratified subset of Gulf War veterans and a non-Gulf-deployed veteran comparison group.\n\n\nRESULTS\nRates of most psychiatric disorders were substantially lower than national comorbidity estimates, consistent with prior studies showing heightened physical and emotional well-being among active-duty military personnel. Rates of PTSD and major depression, however, were significantly elevated relative to the veteran comparison group. The diagnosis of PTSD showed a small but significant association with increased health symptom reports. However, nearly two-thirds of Gulf participants reporting moderate to high health symptoms had no axis I psychiatric diagnosis.\n\n\nCONCLUSIONS\nResults suggest that rates of psychiatric illness were generally low with the exception of PTSD and major depression. Although PTSD was associated with higher rates of reported health problems, this disorder did not entirely account for symptoms reported by participants. Factors other than psychiatric status may play a role in Gulf War health problems.", "corpus_id": 23915114, "score": 0 }, { "doc_id": "22741984", "title": "Deployment stressors and a chronic multisymptom illness among Gulf War veterans.", "abstract": "Unusual health problems have been reported by Gulf War (GW) veterans, but no single etiology has been linked to these illnesses. This study was conducted to determine the association between self-reported GW deployment stressors and an illness defined by a combination of fatigue, mood-cognition, and musculoskeletal symptoms. A total of 1002 GW veterans from this cross-sectional survey of four Air Force units completed a self-administered questionnaire that asked about symptoms, demographic and military characteristics, and stressors during deployment. Severe and mild-moderate illness was positively associated with self-reports of pyridostigmine bromide use, insect repellent use and belief in a threat from biological or chemical weapons. Injuries requiring medical attention were only associated with severe illness. These results suggest a link between self-reported chemical, emotional, and physical exposures, and GW veterans' illness. Further research is needed to determine physiological and psychological mechanisms through which such stressors could have contributed to this symptom complex.", "corpus_id": 22741984, "score": 0 }, { "doc_id": "1220925", "title": "Severely disabling chronic pain in young adults: prevalence from a population-based postal survey in North Staffordshire", "abstract": "BackgroundSeverely disabling chronic pain in the adult population is strongly associated with a range of negative health consequences for individuals and high health care costs, yet its prevalence in young adults is less clear.MethodsAll adults aged 18–25 years old registered with three general practices in North Staffordshire were invited to complete a postal questionnaire containing questions on pain within the last 6 months, pain location and duration. Severity of chronic pain was assessed by the Chronic Pain Grade. Severely disabling chronic pain was defined as pain within the last six months that had lasted for three months or more and was highly disabling-severely limiting (Grade IV).Results858 responses from 2,389 were received (adjusted response = 37.0%). The prevalence of any pain within the previous six months was 66.9% (95%CI: 63.7%, 70.1%). Chronic pain was reported by 14.3% (95%CI: 12.0%, 16.8%) of respondents with severely disabling chronic pain affecting 3.0% (95%CI: 2.0%, 4.4%) of this population. Late responders were very similar to early responders in their prevalence of pain. Cross-checking the practice register against the electoral roll suggested register inaccuracies contributed to non-response.ConclusionPain is a common phenomenon encountered by young adults, affecting 66.9% of this study population. Previously observed age-related trends in severely disabling chronic pain in older adults extend to younger adults. Although a small minority of younger adults are affected, they are likely to represent a group with particularly high health care needs. High levels of non-response in the present study means that these estimates should be interpreted cautiously although there was no evidence of non-response bias.", "corpus_id": 1220925, "score": 0 }, { "doc_id": "205380602", "title": "Relationship of Physical Symptoms to Posttraumatic Stress Disorder Among Veterans Seeking Care for Gulf War-Related Health Concerns", "abstract": "Objectives Studies of the relationship of posttraumatic stress disorder (PTSD) to physical symptoms in war veterans consistently show a positive relationship. However, traumatic experiences causing PTSD may correlate with other war exposures and medical illnesses potentially accounting for those symptoms. Methods We analyzed data obtained from 21,244 Gulf War veterans seeking care for war-related health concerns to assess the relationship of PTSD to physical symptoms independent of environmental exposure reports and medical illness. At assessment, veterans provided demographic information and checklists of 15 common physical symptoms and 20 wartime environmental exposures. Up to seven ICD-9 provider diagnoses were ranked in order of estimated clinical significance. The relationship of provider-diagnosed PTSD to various physical symptoms and to the total symptom count was then determined in bivariate and multivariate analyses. Results Veterans diagnosed with PTSD endorsed an average of 6.7 (SD = 3.9) physical symptoms, those with a non-PTSD psychological condition endorsed 5.3 (3.5), those with medical illness endorsed 4.3 (3.4), and a group diagnosed as “healthy” endorsed 1.2 (2.2). For every symptom, the proportion of veterans reporting the symptom was highest in those with PTSD, second highest in those with any psychological condition, third highest in those with any medical illness, and lowest in those labeled as healthy. The PTSD–symptom count relationship was independent of demographic characteristics, veteran-reported environmental exposures, and comorbid medical conditions, even when symptoms overlapping with those of PTSD were excluded. Conclusions PTSD diminishes the general health perceptions of care-seeking Gulf War veterans. Clinicians should carefully consider PTSD when evaluating Gulf War veterans with vague, multiple, or medically unexplained physical symptoms.", "corpus_id": 205380602, "score": 0 }, { "doc_id": "35677845", "title": "Systematic review of multi-symptom conditions in Gulf War veterans", "abstract": "Background. Gulf War veterans have a number of health complaints. We therefore decided to carry out a systematic review to identify and summarize the findings from studies that have assessed multi-symptom conditions in Gulf War veterans and in an unexposed comparison group. Method. Studies published between January 1990 and May 2004 were identified by searching a large number of electronic databases. Reference lists and websites were also searched and key researchers were contacted. Studies were included if they compared the prevalence of chronic fatigue syndrome, multiple chemical sensitivity, CDC-defined chronic multi-symptom illness, fibromyalgia, or symptoms of either fatigue or numbness and tingling in Gulf War veterans and non-Gulf veterans. A total of 2401 abstracts were independently reviewed by two authors. Results. Twenty-three publications fulfilled the inclusion criteria. Gulf deployment was most strongly associated with chronic fatigue syndrome (OR 3·8, 95% CI 2·2–6·7). Gulf War veterans were also approximately three and a half times more likely than non-Gulf veterans to report multiple chemical sensitivity or chronic multi-symptom illness as defined by CDC. The methodological quality of the studies varied but the later and larger studies were of a high methodological standard with robust sampling strategies, adequate response rates and good adjustment for confounders. Conclusions. The results support the hypothesis that deployment to the Gulf War is associated with greater reporting of multi-symptom conditions.", "corpus_id": 35677845, "score": 0 } ]

{ "doc_id": "17916690", "title": "Learning-Induced Plasticity in Deep Cerebellar Nucleus", "abstract": "Evidence that cerebellar learning involves more than one site of plasticity comes from, in part, pavlovian eyelid conditioning, where disconnecting the cerebellar cortex abolishes one component of learning, response timing, but spares the expression of abnormally timed short-latency responses (SLRs). Here, we provide evidence that SLRs unmasked by cerebellar cortex lesions are mediated by an associative form of learning-induced plasticity in the anterior interpositus nucleus (AIN) of the cerebellum. We used pharmacological inactivation and/or electrical microstimulation of various sites afferent and efferent to the AIN to systematically eliminate alternative candidate sites of plasticity upstream or downstream from this structure. Collectively, the results suggest that cerebellar learning is mediated in part by plasticity in target nuclei downstream of the cerebellar cortex. These data demonstrate an instance in which an aspect of associative learning, SLRs, can be used as an index of plasticity at a specific site in the brain.", "corpus_id": 17916690 }

[ { "doc_id": "12178572", "title": "A primary acoustic startle circuit: lesion and stimulation studies", "abstract": "The latency of the acoustic startle reflex in the rat is 8 msec, measured from tone onset to the beginning of the electromyographic response in the hindleg. This extremely short latency indicates that only a few synapses could be involved in some primary acoustic startle circuit. Acoustic startle is being used as a model system for studying habituation, sensitization, prepulse inhibition, classical conditioning, fear or anxiety, and drug effects on behavior. The present study attempted to delineate a short latency acoustic startle circuit, since this would provide critical information for further study in all of these areas. Bilateral lesions of the ventral cochlear nucleus, which receives the primary auditory input, abolish acoustic startle. Electrical, single pulse stimulation of the ventral cochlear nucleus elicits startle-like responses with a latency of about 7 msec. Bilateral lesions of the dorsal and ventral nuclei of the lateral lemniscus, which receive direct input from the ventral cochlear nuclei, abolish acoustic startle. Electrical stimulation of these nuclei elicits startle-like responses with a latency of about 6 msec. Bilateral lesions of ventral regions of the nucleus reticularis pontis caudalis, which contain cell bodies that give rise to the reticulospinal tract, abolish acoustic startle. Electrical stimulation of these points elicits startle-like responses with a latency of about 5 msec. Reaction product from horseradish peroxidase iontophoresed into this area is found in the nuclei of the lateral lemniscus. In contrast, lesions of the dorsal cochlear nuclei, vestibular nuclei, nucleus reticularis pontis oralis, nucleus reticularis gigantocellularis, and dorsal regions of the nucleus reticularis pontis caudalis fail to abolish acoustic startle. Also, “startle” cannot be elicited electrically from these areas. The data suggest that a primary acoustic startle circuit in the rat consists of auditory nerve, ventral cochlear nucleus, nuclei of the lateral lemniscus, nucleus reticularis pontis caudalis, spinal interneuron, lower motor neuron, and muscles. Hence, five synapses, plus the neuromuscular junction, are probably involved.", "corpus_id": 12178572, "score": 0 }, { "doc_id": "37698260", "title": "Classical conditioning using stimulation of the inferior olive as the unconditioned stimulus.", "abstract": "We show that conditioned eyelid responses develop when the unconditioned stimulus is electrical stimulation of the dorsal accessory nucleus of the inferior olive. When compared to conditioning using a standard unconditioned stimulus (air puff), the conditioning produced in this manner appears quite normal: the responses develop at a similar rate, are of comparable magnitude and topography, and demonstrate a steep interstimulus interval function; and response topography varies according to the interstimulus interval. These data indicate that activation of neurons in the dorsal accessory olive is a sufficient condition for a stimulus to be an effective unconditioned stimulus. Previous experiments indicate the dorsal accessory olive is necessary in that lesions have effects functionally equivalent to removal of the unconditioned stimulus. These data indicate that the dorsal accessory olive forms a portion of the pathway conveying information about the occurrence of an unconditioned stimulus to sites of synaptic plasticity responsible for conditioning.", "corpus_id": 37698260, "score": 0 }, { "doc_id": "8153356", "title": "Classical conditioning in rabbits using pontine nucleus stimulation as a conditioned stimulus and inferior olive stimulation as an unconditioned stimulus", "abstract": "Classical conditioning of skeletal muscle responses was accomplished by pairing microstimulation of the pontine nuclei as a conditioned stimulus (CS) with microstimulation of the dorsal accessory olive as an unconditioned stimulus (US). A conditioned response identical in form to the behavioral response elicited by the olivary stimulation was established when the CS was forward paired with the US, and behavioral extinction occurred with CS‐alone presentations or unpaired CS‐US presentations. Conditioned responding could not be established or maintained when the CS and US were simultaneously presented or when the US preceded the CS (i.e., backward paired). Complete lesions of the interpositus nucleus abolished both conditioned and unconditioned responses. These findings support the idea that plasticity associated with classical conditioning of skeletal muscle responses occurs in regions of the cerebellum that receive convergent CS and US input.", "corpus_id": 8153356, "score": 0 }, { "doc_id": "10773278", "title": "Learned Movements Elicited by Direct Stimulation of Cerebellar Mossy Fiber Afferents", "abstract": "Definitive evidence is presented that the conditioned stimulus (CS) in classical conditioning reaches the cerebellum via the mossy fiber system. Decerebrate ferrets received paired forelimb and periocular stimulation until they responded with blinks to the forelimb stimulus. When direct mossy fiber stimulation was then given, the animals responded with conditioned blinks immediately, that is, without ever having been trained to the mossy fiber stimulation. Antidromic activation was prevented by blocking mossy fibers with lignocaine ventral to the stimulation site. It could be excluded that cerebellar output functioned as the CS. Analysis of latencies suggests that conditioned responses (CRs) are not generated by mossy fiber collaterals to the deep nuclei. Hence, the memory trace is probably located in the cerebellar cortex.", "corpus_id": 10773278, "score": 0 }, { "doc_id": "10147240", "title": "Cerebellum: essential involvement in the classically conditioned eyelid response.", "abstract": "Classical conditioning of the eyelid response in the rabbit was used to investigate the neuronal structures mediating basic associative learning of discrete, adaptive responses. Lesions of the ipsilateral dentate-interpositus nuclei, but not of the cerebellar cortex, abolished the learned eyeblink response. Recordings from these nuclei have revealed neuronal responses related to the learning of the response. Stimulating these recording sites produced the eyelid response. The dentate-interpositus nuclei were concluded to be critically involved in the learning and production of classically conditioned responses.", "corpus_id": 10147240, "score": 0 }, { "doc_id": "19050990", "title": "Cerebellar neuronal activity expresses the complex topography of conditioned eyeblink responses.", "abstract": "Pavlovian eyeblink conditioning is a useful model system for studying how the temporal relationship between a conditioned stimulus and an unconditioned stimulus is represented in the brain. As an example, the response topography formed under a complex conditioning paradigm, involving 2 randomly alternating interstimulus intervals (ISIs), manifests a conditioned response (CR) with 2 distinctive peaks that correspond to the 2 ISIs. The authors present the first full report of neuronal activities in the cerebellar interpositus nucleus of rabbits performing bimodal responses. All CR-related activities exhibited firing patterns that highly correlated with and preceded eyeblink responses. The striking similarity between the time course of bimodal CRs and neuronal responses indicates that neuronal activities in the cerebellum are causally related to the production of behavioral CRs.", "corpus_id": 19050990, "score": 0 }, { "doc_id": "16944655", "title": "Cerebellar cortex lesions disrupt learning-dependent timing of conditioned eyelid responses", "abstract": "Among the many issues surrounding the involvement of the cerebellum in motor learning, the relative roles of the cerebellar cortex and cerebellar nuclei in Pavlovian conditioning have been particularly difficult to assess. While previous studies have investigated the effects of cerebellar cortex lesions on the acquisition and retention of conditioned movements, we have examined the effects of these lesions on the timing of Pavlovian eyelid responses. The rationale for this approach arises from previous studies indicating that this timing is a component of Pavlovian eyelid responses that is learned and that involves temporal discrimination. To permit within-animal comparisons, rabbits were trained to produce differently timed responses to high- and low-frequency auditory conditioned stimuli (CSs). Before the lesion the conditioned responses to both CSs were appropriately timed--each peaked near the time at which the unconditioned stimulus was presented for that CS. However, after the lesion both CSs could elicit similarly timed conditioned responses that peaked inappropriately at very short latencies. The changes in responses timing were sensitive to the size of the lesion, particularly its rostral-caudal extent. Similar results were obtained in animals trained with one CS, indicating that the disruption of response timing is not related to impaired auditory discrimination. Because response timing is learned and therefore requires synaptic plasticity, these data suggest that there are at least two sites of plasticity involved in the motor expression of Pavlovian eyelid responses. Plasticity at one site is necessary for the learned timing of conditioned responses, while plasticity at another site is revealed by the inappropriately timed responses observed following removal of the cerebellar cortex. This lesion-induced dissociation of the expression of motor responses and their learned timing supports a synthesis of competing views by suggesting that motor learning involves both the cerebellar cortex and cerebellar nuclei. We hypothesize that motor learning involves a decrease in strength of the granule cell-Purkinje cell synapses (e.g., Ito and Kano, 1982) in the cerebellar cortex and an increase in strength of the mossy fiber- cerebellar nuclei synapses (e.g., Racine et al., 1986). Finally, these data suggest that the cerebellar cortex may mediate the temporal discriminations that are necessary for the learned timing of conditioned responses.", "corpus_id": 16944655, "score": 0 }, { "doc_id": "7454340", "title": "Extinction of conditioned eyelid responses requires the anterior lobe of cerebellar cortex", "abstract": "We test the hypothesis that the cerebellar cortex is required for the extinction of conditioned eyelid responses in rabbits trained using standard Pavlovian delay procedures. Following 10 daily training sessions during which rabbits achieved asymptotic performance, lesions of the ipsilateral hemisphere of the cerebellar cortex were made by aspiration. The target of these lesions was the anterior lobe, as suggested by previous observations that this region is necessary for the learning-dependent timing of conditioned eyelid responses (Perrett et al., 1993). We report that anterior lobe damage, as indicated by disrupted response timing and confirmed by tissue analysis, produces severe deficits in conditioned response extinction. Postlesion responses show no significant decline over ten training sessions, whereas response timing and extinction are unaffected by lesions that do not include the anterior lobe. These conditioned responses that do not extinguish display stimulus specificity, excluding the possibility that they are unlearned responses unmasked by cerebellar cortex lesions. These observations suggest that Pavlovian eyelid conditioning is mediated by synaptic plasticity in at least two sites and the anterior lobe of the cerebellar cortex influences one of these sites during extinction. Based on these and previous data, we propose the hypothesis that eyelid conditioning can involve plasticity in both the cerebellar cortex and interpositus nucleus and that plasticity in the nucleus is controlled by input from Purkinje cell activity in the cortex. This hypothesis is consistent with observations that the cerebellar cortex may not always be required for the expression of conditioned responses, but it is necessary for response timing and for extinction.", "corpus_id": 7454340, "score": 0 }, { "doc_id": "12899157", "title": "Cerebellar Cortex Lesions Prevent Acquisition of Conditioned Eyelid Responses", "abstract": "We have used aspiration and electrolytic lesions to investigate the contributions of cerebellar cortex to the acquisition and expression of conditioned eyelid responses. We show that lesions of the anterior lobe of rabbit cerebellar cortex disrupt the timing of previously learned conditioned eyelid responses. These short-latency responses were used as an indication that the cerebellar cortex was sufficiently damaged and that the underlying pathways necessary for the expression of responses were sufficiently intact to support responses. Rabbits were subsequently trained for 15 daily sessions using a new conditioned stimulus. Whereas rabbits in which lesions had no significant effect on response timing showed rapid acquisition of appropriately timed eyelid responses to the new conditioned stimulus, animals with lesions that disrupt timing showed no significant increases in either amplitude or probability of responses. Histological analysis suggests that damage to the anterior lobe of the cerebellar cortex is necessary and sufficient to abolish timing and prevent acquisition. These data indicate that the cerebellar cortex is necessary for the acquisition of conditioned eyelid responses and are consistent with the hypotheses that (1) eyelid conditioning results in plasticity in both the anterior lobe of the cerebellar cortex and in the anterior interpositus nucleus and (2) induction of plasticity in the interpositus requires intact input from the cerebellar cortex.", "corpus_id": 12899157, "score": 0 }, { "doc_id": "1723021", "title": "Timing Mechanisms in the Cerebellum: Testing Predictions of a Large-Scale Computer Simulation", "abstract": "We used large-scale computer simulations of eyelid conditioning to investigate how the cerebellum generates and makes use of temporal information. In the simulations the adaptive timing displayed by conditioned responses is mediated by two factors: (1) different sets of granule cells are active at different times during the conditioned stimulus (CS), and (2) responding is not only amplified at reinforced times but also suppressed at unreinforced times during the CS. These factors predict an unusual pattern of responding after partial removal of the cerebellar cortex that was confirmed using small, electrolytic lesions of cerebellar cortex. These results are consistent with timing mechanisms in the cerebellum that are similar to Pavlov's “inhibition of delay” hypothesis.", "corpus_id": 1723021, "score": 0 }, { "doc_id": "14274092", "title": "Pharmacological analysis of cerebellar contributions to the timing and expression of conditioned eyelid responses", "abstract": "Contradictory results have been reported regarding the effects of cerebellar cortex lesions on the expression of conditioned eyelid responses--either no effect, partial to complete abolition of responses, or disruption of response timing. This uncertainty is increased by debates regarding the region(s) of cerebellar cortex that are involved, by the likelihood that cortex lesions can inadvertently include damage to the interpositus nucleus or other pathways necessary for response expression, and by potential confounds from the degeneration of climbing fibers produced by cerebellar cortex lesions. We have addressed these issues by reversibly blocking cerebellar cortex output via infusion of the GABA antagonist picrotoxin into the interpositus nucleus. After picrotoxin infusion, conditioned responses are spared but their timing is disrupted and their amplitude diminished. In the same animals, conditioned responses were abolished by infusion of the GABA agonist muscimol and were unaffected by infusion of saline vehicle. These results are consistent with the hypothesis that (i) plasticity in the interpositus nucleus contributes to the expression of conditioned responses, as suggested by the responses seen with the cortex disconnected, and (ii) plasticity in the cerebellar cortex also contributes to conditioned response expression, as suggested by disruption of response timing.", "corpus_id": 14274092, "score": 1 }, { "doc_id": "14616263", "title": "A Mechanism for Savings in the Cerebellum", "abstract": "The phenomenon of savings (the ability to relearn faster than the first time) is a familiar property of many learning systems. The utility of savings makes its underlying mechanisms of special interest. We used a combination of computer simulations and reversible lesions to investigate mechanisms of savings that operate in the cerebellum during eyelid conditioning, a well characterized form of motor learning. The results suggest that a site of plasticity outside the cerebellar cortex (possibly in the cerebellar nucleus) can be protected from the full consequences of extinction and that the residual plasticity that remains can later contribute to the savings seen during relearning.", "corpus_id": 14616263, "score": 1 }, { "doc_id": "9608418", "title": "Latent Acquisition of Timed Responses in Cerebellar Cortex", "abstract": "Evidence indicates that rabbit eyelid conditioning is mediated by plasticity in the interpositus cerebellar nucleus and in cerebellar cortex. Although the relative contributions of these sites are not fully characterized, evidence suggests that plasticity in the cerebellar cortex influences conditioned response amplitude and timing, whereas plasticity in the interpositus nucleus is necessary or permissive for conditioned response expression. Recent empirical and computational analyses suggest that, during training, plasticity is initially established in the cerebellar cortex, whereas conditioned response expression begins later as plasticity is induced in the interpositus nucleus. We used the dependence of response timing on the interstimulus interval (ISI) to test this latent learning hypothesis. Rabbits were initially trained using a tone conditioned stimulus (CS) with a relatively long ISI to a low-criterion threshold. The relative absence of plasticity in the interpositus nucleus was then examined via reversible disconnection of the cerebellar cortex. Later, to induce plasticity in the interpositus nucleus, subjects were trained to robust levels of conditioned response expression using a shorter ISI. Reversible disconnection of the cerebellar cortex at this time confirmed the presence of robust interpositus nucleus plasticity after the second phase. Subsequent probe trials with the long CS alone then revealed double-peaked responses whose peaks were appropriately timed to the two ISIs. The results are consistent with the hypothesis that temporally specific learning occurs first in the cerebellar cortex before the appearance of conditioned responses. This latent learning is expressed only after plasticity is induced in the interpositus nucleus.", "corpus_id": 9608418, "score": 0 }, { "doc_id": "10857224", "title": "Cerebellar cortical inhibition and classical eyeblink conditioning", "abstract": "The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning/memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a γ-aminobutyric acid type A receptor (GABAAR) agonist and a noncompetitive GABAAR antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABAARs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.", "corpus_id": 10857224, "score": 0 }, { "doc_id": "14597440", "title": "Stimulus generalization of conditioned eyelid responses produced without cerebellar cortex: implications for plasticity in the cerebellar nuclei.", "abstract": "In Pavlovian eyelid conditioning and adaptation of the vestibulo-ocular reflex, cerebellar cortex lesions fail to completely abolish previously acquired learning, indicating an additional site of plasticity in the deep cerebellar or vestibular nucleus. Three forms of plasticity are known to occur in the deep cerebellar nuclei: formation of new synapses, plasticity at existing synapses, and changes in intrinsic excitability. Only a cell-wide increase in excitability predicts that learning should generalize broadly from a training stimulus to other stimuli capable of supporting learning, whereas the alternatives predict that learning should be relatively specific to the training stimulus. Here we show that deep nucleus plasticity, as assessed by conditioned eyelid responses produced without input from the cerebellar cortex, is relatively specific to the training conditioned stimulus (CS). We trained rabbits to a tone or light CS with periorbital stimulation as the unconditioned stimulus (US), and pharmacologically disconnected the cerebellar cortex during a posttraining generalization test. The short-latency conditioned responses unmasked by this treatment showed strong decrement along the dimension of auditory frequency and did not generalize across stimulus modalities. These results cannot be explained solely by a cell-wide increase in the excitability of deep nucleus neurons, and imply that an input-specific mechanism in the deep cerebellar nucleus operates as well.", "corpus_id": 14597440, "score": 1 }, { "doc_id": "20919394", "title": "GABA neurotransmission in the cerebellar interposed nuclei: involvement in classically conditioned eyeblinks and neuronal activity.", "abstract": "The cerebellar interposed nuclei (IN) are an essential part of circuits that control classically conditioned eyeblinks in the rabbit. The function of the IN is under the control of GABAergic projections from Purkinje cells of the cerebellar cortex. The exact involvement of cerebellar cortical input into the IN during eyeblink expression is not clear. While it is known that the application of gamma-aminobutyric acid-A (GABA(A)) agonists and antagonists affects the performance of classically conditioned eyeblinks, the effects of these drugs on IN neurons in vivo are not known. The purpose of the present study was to measure the effects of muscimol and picrotoxin on the expression of conditioned eyeblinks and the activity of IN cells simultaneously. Injections of muscimol abolished conditioned responses and either silenced or diminished the activity of IN cells. Two injections were administered in each picrotoxin experiment. The first injection of picrotoxin slightly modified the timing and amplitude of the eyeblink, produced mild tonic eyelid closure, increased tonic activity of IN cells, and reduced the amplitude of the neural responses. The second injection of picrotoxin abolished conditioned responses, further increased tonic eyelid closure, dramatically elevated the tonic activity of IN cells, and in most cases, abolished neuronal responses. These results demonstrate that both GABA(A)-mediated inactivation and tonic up-regulation of IN cells can interrupt the expression of conditioned eyeblinks and that this behavioral effect is accompanied by the suppression of the neuronal activity correlates of the conditioned stimulus and response.", "corpus_id": 20919394, "score": 0 }, { "doc_id": "41155462", "title": "The Cerebellum: A Neuronal Learning Machine?", "abstract": "Comparison of two seemingly quite different behaviors yields a surprisingly consistent picture of the role of the cerebellum in motor learning. Behavioral and physiological data about classical conditioning of the eyelid response and motor learning in the vestibulo-ocular reflex suggest that (i) plasticity is distributed between the cerebellar cortex and the deep cerebellar nuclei; (ii) the cerebellar cortex plays a special role in learning the timing of movement; and (iii) the cerebellar cortex guides learning in the deep nuclei, which may allow learning to be transferred from the cortex to the deep nuclei. Because many of the similarities in the data from the two systems typify general features of cerebellar organization, the cerebellar mechanisms of learning in these two systems may represent principles that apply to many motor systems.", "corpus_id": 41155462, "score": 0 }, { "doc_id": "14010419", "title": "A model of Pavlovian eyelid conditioning based on the synaptic organization of the cerebellum.", "abstract": "We present a model based on the synaptic and cellular organization of the cerebellum to derive a diverse range of phenomena observed in Pavlovian eyelid conditioning. These phenomena are addressed in terms of critical pathways and network properties, as well as the sites and rules for synaptic plasticity. The theory is based on four primary hypotheses: (1) Two cerebellar sites of plasticity are involved in conditioning: (a) bidirectional long-term depression/potentiation at granule cell synapses onto Purkinje cells (gr-->Pkj) in the cerebellar cortex and (b) bidirectional plasticity in the interpositus nucleus that is controlled by inhibitory inputs from Purkinje cells; (2) climbing fiber activity is regulated to an equilibrium level at which the net strength of gr-->Pkj synapses remains constant unless an unexpected unconditioned stimulus (US) is presented or an expected US is omitted; (3) a time-varying representation of the conditioned stimulus (CS) in the cerebellar cortex permits the temporal discrimination required for conditioned response timing; and (4) the ability of a particular segment of the CS to be represented consistently across trials varies as a function of time since CS onset. This variation in across-trials consistency is thought to contribute to the ISI function. The model suggests several empirically testable predictions, some of which have been tested recently.", "corpus_id": 14010419, "score": 0 }, { "doc_id": "27963067", "title": "Long-term potentiation in the interpositus and vestibular nuclei in the rat", "abstract": "SummaryPrevious unpublished experiments from this laboratory had revealed only post-activation depression effects in the cerebellar cortex when its inputs were activated by high frequency trains. In the experiments reported in this paper, we found reliable long-term potentiation (LTP) effects in the deep nuclei (interpositus and vestibular) when stimulation trains were applied to the white matter at the point where inferior peduncle fibers enter the cerebellum. LTP effects were found in both acute and chronic preparations. In the chronic preparations, LTP lasted for at least 8 days in all but one animal.", "corpus_id": 27963067, "score": 0 }, { "doc_id": "7679970", "title": "Synapse formation is associated with memory storage in the cerebellum", "abstract": "The idea that memory is encoded by means of synaptic growth is not new. However, this idea has been difficult to demonstrate in the mammalian brain because of both the complexity of mammalian behavior and the neural circuitry by which it is supported. Here we examine how eyeblink classical conditioning affects synapse number within the cerebellum; the brain region essential for long-term retention of the conditioned response. Results showed eyeblink-conditioned rats to have significantly more synapses per neuron within the cerebellar interpositus nucleus than both explicitly unpaired and untrained controls. Further analysis showed that the increase was caused by the addition of excitatory rather than inhibitory synapses. Thus, development of the conditioned eyeblink response is associated with a strengthening of inputs from precerebellar nuclei rather than from cerebellar cortex. These results demonstrate that the modifications of specific neural pathways by means of synaptogenesis contributes to formation of a specific memory within the mammalian brain.", "corpus_id": 7679970, "score": 1 }, { "doc_id": "1732215", "title": "Potentiation of Mossy Fiber EPSCs in the Cerebellar Nuclei by NMDA Receptor Activation followed by Postinhibitory Rebound Current", "abstract": "Behavioral and computational studies predict that synaptic plasticity of excitatory mossy fiber inputs to cerebellar nuclear neurons is required for associative learning, but standard tetanization protocols fail to potentiate nuclear cell EPSCs in mouse cerebellar slices. Nuclear neurons fire action potentials spontaneously unless strongly inhibited by Purkinje neurons, raising the possibility that plasticity-triggering signals in these cells differ from those at classical Hebbian synapses. Based on predictions of neuronal activity during delay eyelid conditioning, we developed quasi-physiological induction protocols consisting of high-frequency mossy fiber stimulation and postsynaptic hyperpolarization. Robust, NMDA receptor-dependent potentiation of nuclear cell EPSCs occurred with protocols including a 150-250 ms hyperpolarization in which mossy fiber stimulation preceded a postinhibitory rebound depolarization. Mossy fiber stimulation potentiated EPSCs even when postsynaptic spiking was prevented by voltage-clamp, as long as rebound current was evoked. These data suggest that Purkinje cell inhibition guides the strengthening of excitatory synapses in the cerebellar nuclei.", "corpus_id": 1732215, "score": 1 }, { "doc_id": "42444466", "title": "Long-Term Depression at the Mossy Fiber–Deep Cerebellar Nucleus Synapse", "abstract": "Several lines of evidence have indicated that the deep cerebellar nuclei (DCN) are a site of memory storage for certain forms of motor learning, most notably associative eyelid conditioning. In particular, these experiments, together with network models, have implicated the excitatory glutamatergic synapse between mossy fibers and DCN neurons in this memory trace. However, to date, evidence for persistent use-dependent change in the strength of this synapse has been almost entirely absent. Here, we report that high-frequency burst stimulation of mossy fibers, either alone or paired with postsynaptic depolarization, gives rise to long-term depression (LTD) of the mossy fiber–DCN synapse. This form of LTD is not associated with changes in the paired-pulse ratio and is blocked by loading with a postsynaptic Ca2+ chelator but not by bath application of an NMDA receptor antagonist. Mossy fiber–DCN LTD requires activation of a group I metabotropic glutamate receptor (mGluR) and protein translation. Unlike mGluR/translation-dependent LTD in other brain regions, this form of LTD requires mGluR1 and is mGluR5 independent.", "corpus_id": 42444466, "score": 0 }, { "doc_id": "206631305", "title": "Localization of a memory trace in the mammalian brain.", "abstract": "The localization of sites of memory formation within the brain has proven to be a formidable task even for simple forms of learning and memory. In order to localize a particular site of memory formation within the brain, the rabbit eyeblink response was classically conditioned while regions of the cerebellum or red nucleus were temporarily inactivated by microinfusions of the gamma-aminobutyric acid agonist muscimol. Cerebellar inactivation completely blocked learning but had no effect on subsequent learning after inactivation, whereas red nucleus inactivation did not prevent learning but did block the expression of conditioned responses. The site of memory formation for this learned response thus appears to be localized within the cerebellum.", "corpus_id": 206631305, "score": 1 }, { "doc_id": "13386685", "title": "Effects of lidocaine injection in the interpositus nucleus and red nucleus on conditioned behavioral and neuronal responses", "abstract": "The role of the cerebellum and the red nucleus in the conditioned eyeblink response was assessed, using a combination of reversible lesions and multiple-unit extracellular recording in the awake, behaving rabbit. Lesion, recording, and stimulation experiments have indicated that both of these structures are involved in the performance of learned skeletal muscle responses. The present study sought to distinguish the relative contributions of the interpositus nucleus and the red nucleus to the expression of the learned response by recording behavior-related multiple unit activity in one structure while reversibly inactivating the other via injections of local anesthetic. Results indicate that inactivating either the interpositus or the red nucleus temporarily abolishes the learned eyeblink response. Injection of lidocaine into the interpositus also abolishes the neuronal unit model of the conditioned response in the red nucleus, while injection into the red nucleus does not affect the model in the interpositus. These results are consistent with the hypothesis that the red nucleus acts as a relay for motor commands from the cerebellum, and that the plasticity that generates conditioned responses occurs in the cerebellum or an afferent structure.", "corpus_id": 13386685, "score": 0 }, { "doc_id": "17715456", "title": "Rapid, synaptically driven increases in the intrinsic excitability of cerebellar deep nuclear neurons", "abstract": "The neurons of the cerebellar deep nuclei are implicated in certain forms of motor learning such as associative eyeblink conditioning, partly because increases in their firing rates parallel acquisition of the conditioned response. Here we demonstrate that these neurons can show persistent increases in their intrinsic excitability following a Ca2+ load imposed by synaptic activation of NMDA receptors or direct current injection. This phenomenon, together with use-dependent alterations in synaptic strength, may provide a flexible and informationally rich engram for cerebellar motor learning.", "corpus_id": 17715456, "score": 1 }, { "doc_id": "22706587", "title": "Persistent changes in the intrinsic excitability of rat deep cerebellar nuclear neurones induced by EPSP or IPSP bursts", "abstract": "The deep cerebellar nuclei (DCN) are the major output of the cerebellum, and have been proposed as a site of memory storage for certain forms of motor learning. Microelectrode and whole‐cell patch recordings were performed on DCN neurones in acute slices of juvenile rat cerebellum. DCN neurones display tonic and bursting basal firing patterns. In tonically firing neurones, a stimulus consisting of EPSP bursts produced a brief increase in dendritic Ca2+ concentration and a persistent increase in the number of spikes elicited by a depolarizing test pulse, along with a decrease in spike threshold. In intrinsically bursting DCN neurones, EPSP bursts induced an increase in the number of depolarization‐evoked spikes in some neurones, but in others produced a change to a more tonic firing pattern. Application of IPSP bursts evoked a large number of rebound spikes and an associated dendritic Ca2+ transient, which also produced a persistent increase in the number of spikes elicited by a test pulse. Intracellular perfusion of the Ca2+ chelator BAPTA prevented the increase in intrinsic excitability. Thus, rapid changes in intrinsic excitability in the DCN may be driven by bursts of both EPSPs and IPSPs, and may result in persistent changes to both firing frequency and pattern.", "corpus_id": 22706587, "score": 1 }, { "doc_id": "34686603", "title": "Cerebellar Mechanisms in Eyeblink Conditioning", "abstract": "Abstract: A recent model of cerebellar learning in eyeblink conditioning predicts two sites of plasticity, the cerebellar cortex and cerebellar nuclei, which store information relating to timing and driving the movement, respectively. Consistent with this idea, lesions of the cortex or reversible “disconnections” of Purkinje cell output to the nuclei have been shown to disrupt response timing to produce short‐latency conditioned eyeblinks. To better characterize potential cortical and nuclear plasticities, we analyzed the effects upon nictitating membrane (NM) and eyeblink conditioned responses (CRs) of different drugs administered to the cortex and to the nuclei. When either excitatory or inhibitory inputs to the cerebellar cortical lobule HVI were blocked by infusions of the AMPA receptor antagonist CNQX or the GABA‐A receptor antagonists picrotoxin or SR95531, CRs were abolished. Similarly GABA‐A receptor antagonists in the cerebellar nuclei abolished CRs. CR latencies were never shortened. However, blockade of AMPA/kainate receptor‐mediated excitatory transmission to the nuclei had no effect upon CR frequencies or latencies. These results suggest that normal cortical and nuclear function is required for performance of NM and eyeblink CRs. We saw no evidence that CRs can be driven by AMPA/kainate receptor‐mediated transmission from mossy fiber afferents to the cerebellar nuclei. So, although plasticity in the cerebellar nuclei is not ruled out, it is unlikely that a long‐term change in AMPA receptor‐mediated transmission from mossy fiber inputs to the nuclei is an essential mechanism in eyeblink conditioning. Our findings indicate that a fully functional olivo‐cortico‐nuclear loop is required to express all characteristics of associatively conditioned responses.", "corpus_id": 34686603, "score": 0 }, { "doc_id": "10479443", "title": "Evidence of plasticity in the pontocerebellar conditioned stimulus pathway during classical conditioning of the eyeblink response in the rabbit.", "abstract": "Electrical stimulation thresholds required to elicit eyeblinks with either pontine or cerebellar interpositus stimulation were measured before and after classical eyeblink conditioning with paired pontine stimulation (conditioned stimulus, CS) and corneal airpuff (unconditioned stimulus, US). Pontine stimulation thresholds dropped dramatically after training and returned to baseline levels following extinction, whereas interpositus thresholds and input-output functions remained stable across training sessions. Learning rate, magnitude of threshold change, and electrode placements were correlated. Pontine projection patterns to the cerebellum were confirmed with retrograde labeling techniques. These results add to the body of literature suggesting that the pons relays CS information to the cerebellum and provide further evidence of synaptic plasticity in the cerebellar network.", "corpus_id": 10479443, "score": 0 }, { "doc_id": "5798044", "title": "Glutamate neurotransmission in the cerebellar interposed nuclei: involvement in classically conditioned eyeblinks and neuronal activity.", "abstract": "The cerebellar interposed nuclei (IN) are critical components of a neural network that controls the expression of classically conditioned eyeblinks. The IN receive 2 major inputs: the massive, gamma-aminobutyric acid (GABA)-mediated input from the Purkinje cells of the cerebellar cortex and the relatively weaker, glutamate-mediated input from collaterals of mossy and climbing fiber cerebellar afferent systems. To elucidate the role of IN glutamate neurotransmission in conditioned response (CR) expression, effects of blocking fast glutamatergic neurotransmission in the IN with gamma-d-glutamylglycine (DGG) on the expression of conditioned eyeblinks and on cerebellar nuclear neuronal activity were examined. Surprisingly, blocking fast glutamate receptors in the IN did not abolish CRs. DGG decreased CR incidence and slightly increased CR latency. In contrast, identical amounts of DGG applied to the cerebellar cortex abolished CRs. Similar to the behavioral effects, DGG had unexpectedly mild effects on IN neurons. At the population level, the baseline firing frequency of IN cells was not affected. After DGG injections, the incidence of excitatory modulation of cell activity in the interstimulus interval decreased but was not abolished. A combined block of fast glutamate and GABA(A) neurotransmission using a mixture of DGG and picrotoxin dramatically reduced CR incidence, increased the firing frequency of all cell types, and virtually abolished all modulation of neuronal activity. These results indicate that fast glutamate neurotransmission in the IN plays only an accessory role both in the expression of behavioral CRs and in the generation of associated neuronal activity in the IN.", "corpus_id": 5798044, "score": 0 }, { "doc_id": "7157466", "title": "A Theory of Cerebellar Function", "abstract": "Abstract A comprehensive theory of cerebellar function is presented, which ties together the known anatomy and physiology of the cerebellum into a pattern-recognition data processing system. The cerebellum is postulated to be functionally and structurally equivalent to a modification of the classical Perceptron pattern-classification device. It is suggested that the mossy fiber → granule cell → Golgi cell input network performs an expansion recoding that enhances the pattern-discrimination capacity and learning speed of the cerebellar Purkinje response cells. Parallel fiber synapses of the dendritic spines of Purkinje cells, basket cells, and stellate cells are all postulated to be specifically variable in response to climbing fiber activity. It is argued that this variability is the mechanism of pattern storage. It is demonstrated that, in order for the learning process to be stable, pattern storage must be accomplished principally by weakening synaptic weights rather than by strengthening them.", "corpus_id": 7157466, "score": 0 }, { "doc_id": "24159883", "title": "Plasticity in the vestibulo-ocular reflex: a new hypothesis.", "abstract": "The vestibulo-ocular reflex functions to prevent head movements from disturbing retinal images by generating compensatory eye movements to offset the head movements. In the monkey--the species mainly under consideration here--this reflex is machine-like and very effective. In the short-term, the VOR operates as an open-loop control system without the benefit of feedback and its performance is fixed and immutable: No matter what pattern of eye-head coordination the animal uses to view external objects, there is a continuing need for the VOR and it continues to operate; however, should the VOR consistently fail to stabilize the retinal images during head turns, it will gradually undergo long-term adaptive gain changes that restore, that stability. This adaptive capability is ultimately dependent upon vision, and a variety of optical devices that disturb the visual input normally associated with lead turns have been used to induce large changes in the reflex. Insofar as the monkey is concerned, all of the available evidence suggests to us that the modifiable elements underlying these long-term adjustments are located in the brainstem vestibular pathways and not, as previously suggested by others, in the floccular lobes of the cerebellum. However, the flocculus does appear to have an important, inductive role in the adaptive process providing at least part of the error signal guiding the long-term adjustments in the brainstem. In our view, the VOR is a particularly well-defined example of a plastic system and promises to be a most useful model for studying the cellular mechanisms underlying memory and learning the central nervous system.", "corpus_id": 24159883, "score": 0 }, { "doc_id": "24139184", "title": "Neural basis for motor learning in the vestibuloocular reflex of primates. III. Computational and behavioral analysis of the sites of learning.", "abstract": "1. We have used a combination of eye movement recordings and computer modeling to study long-term adaptive modification (motor learning) in the vestibuloocular reflex (VOR). The eye movement recordings place constraints on possible sites for motor learning. The computer model abides by these constraints, as well as constraints provided by data in previous papers, to formalize a new hypothesis about the sites of motor learning. The model was designed to reproduce as much of the existing neural and behavioral data as possible. 2. Motor learning was induced in monkeys by fitting them with spectacles that caused the gain of the VOR (eye speed divided by head speed) to increase to values > 1.6 or to decrease to values < 0.4. We elicited pursuit by providing ramp motion of a small target at 30 degrees/s along the horizontal axis. Changes in the gain of the VOR caused only small and inconsistent changes in the eye acceleration in the first 100 ms after the onset of pursuit and had no effect on the eye velocity during tracking of steady target motion. Electrical stimulation in the flocculus and ventral paraflocculus with single pulses or trains of pulses caused smooth eye movement toward the side of stimulation after latencies of 9-11 ms. Neither the latency, the peak eye velocity, nor the initial eye acceleration varied as a consistent function of the gain of the VOR. 3. The computer model contained nodes that represented position-vestibular-pause cells (PVP-cells) and flocculus target neurons (FTNs) in the vestibular nucleus, and horizontal gaze-velocity Purkinje cells (HGVP-cells) in the cerebellar flocculus and ventral paraflocculus. Node FTN represented only the \"E-c FTNs,\" which show increased firing for eye motion away from the side of recording. The transfer functions in the model included dynamic elements (filters) as well as static elements (summing junctions, gain elements, and time delays). Except for the transfer functions that converted visual motion inputs into commands for smooth eye movement, the model was linear. 4. The performance of the model was determined both by computer simulation and, for the VOR in the dark, by analytic solution of linear equations. For simulation, we adjusted the parameters by hand to match the output of the model to the eye velocity of monkeys and to match the activity of the relevant nodes in the model to the firing of HGVP-cells, FTNs, and PVP-cells when the gain of the VOR was 0.4, 1.0, and 1.6.(ABSTRACT TRUNCATED AT 400 WORDS)", "corpus_id": 24139184, "score": 0 }, { "doc_id": "3169647", "title": "Learning and memory in the vestibulo-ocular reflex.", "abstract": "Studies of the neural basis of learning and memory in intact animals must, by their nature, start \"from the top\" by choosing a behavior that can be modified through learning, revealing how iaeuronal activity gives rise to that behavior, and then investigating, in the awake, behaving animal, changes in neural signaling that are associated with learning. Such studies also must recognize that the learning and memory expressed in the behavior of an animal will reflect both the properties of the neural network that mediates the behavior and the nature of the underlying changes in the operation of cells or synapses. In the past 10 years, there has been an explosion of information about learning and memory in the vestibulo-ocular reflex (VOR) of the awake, behaving monkey. At the same time, there have been unprecedented advances in understanding mechanisms of cellular plasticity such as long-term potentiation (LTP) in the hippocampus and long-term depression (LTD) in the cerebellum. A prerequisite for understanding learning and memory is to elevate specific mechanisms of cellular plasticity into cellular mechanisms of learning by establishing their function in the context of a neural system that mediates learning and memory in a particular behavior. Our review synthesizes the", "corpus_id": 3169647, "score": 0 }, { "doc_id": "13288680", "title": "Roles of Cerebellar Cortex and Nuclei in Motor Learning: Contradictions or Clues?", "abstract": "population of granule cells, whose activity is also influThe cerebellum, with its relatively simple and regular enced by the inhibitory Golgi cells. One numeric fact synaptic organization, has yielded much about its contriillustrates these dramatic differences in computing bution to brain function and its internal information propower; each nucleus cell receives around 10 mossy cessing. A central theme that has emerged is the cerefiber synapses (mf→nuc) and is influenced by 10 granbellum’s role in the adaptation or learning of movements. ule cell synapses onto Purkinje cells (gr→Pkj). Ideas about cerebellar-mediated motor learning began Early ideas about cerebellar-mediated motor learning in the 1960s, most notably with the seminal theory prowere based on thesenotable anatomicalcharacteristics. posed by Marr (1969). The basic tenets of this theory In 1969, Marr proposed a theory suggesting how plasticare supported by numerous studies. In particular, analyity in the cerebellar cortex at the gr→Pkj synapses could sis of two forms of motor learning, adaptation of the mediate motor learning. Three basic components of this vestibulo-ocular reflex (VOR) and Pavlovian eyelid contheory were: (i) the mossy fiber/granule cell system enditioning (EC), has revealed much about cerebellar concodes the contexts in which movements occur, with the tributions to motor learning and the cerebellar informaabundance of granule cells providing a rich representation processing involved. tion; (ii) climbing fibers signal that the movement conThe cerebellum is comprised of two anatomical comtrolled by its Purkinje cell should change, and (iii) these ponents, the cerebellar cortex and nuclei. Despite much climbing fiber inputs induce plasticity at coactive gr→Pkj progress, their relative contributions to motor learning synapses, improving subsequent movement perforremain a fundamentally important issue that is largely mance in the context encoded by that pattern of granule", "corpus_id": 13288680, "score": 0 }, { "doc_id": "10658357", "title": "Long-Lasting Increases in Intrinsic Excitability Triggered by Inhibition", "abstract": "Although experience-dependent changes in neural circuits are commonly assumed to be mediated by synaptic plasticity, modifications of intrinsic excitability may serve as a complementary mechanism. In whole-cell recordings from spontaneously firing vestibular nucleus neurons, brief periods of inhibitory synaptic stimulation or direct membrane hyperpolarization triggered long-lasting increases in spontaneous firing rates and firing responses to intracellular depolarization. These increases in excitability, termed firing rate potentiation, were induced by decreases in intracellular calcium and expressed as reductions in the sensitivity to the BK-type calcium-activated potassium channel blocker iberiotoxin. Firing rate potentiation is a novel form of cellular plasticity that could contribute to motor learning in the vestibulo-ocular reflex.", "corpus_id": 10658357, "score": 0 }, { "doc_id": "16659326", "title": "Decreases in CaMKII Activity Trigger Persistent Potentiation of Intrinsic Excitability in Spontaneously Firing Vestibular Nucleus Neurons", "abstract": "Calcium/calmodulin-dependent protein kinase II (CaMKII) has been described as a biochemical switch that is turned on by increases in intracellular calcium to mediate synaptic plasticity. Here, we show that reductions in CaMKII activity trigger persistent increases in intrinsic excitability. In spontaneously firing vestibular nucleus neurons, CaMKII activity is near maximal, and blockade of CaMKII activity increases excitability by reducing BK-type calcium-activated potassium currents. Firing rate potentiation, a form of plasticity in which synaptic inhibition induces long-lasting increases in excitability, is occluded by prior blockade of CaMKII and blocked by addition of constitutively active CaMKII. Reductions in CaMKII activity are necessary and sufficient to induce firing rate potentiation and may contribute to motor learning in the vestibulo-ocular reflex.", "corpus_id": 16659326, "score": 0 }, { "doc_id": "17397545", "title": "The other side of the engram: experience-driven changes in neuronal intrinsic excitability", "abstract": "Modern theories of memory storage have largely focused on persistent, experience-dependent changes in synaptic function such as long-term potentiation and depression. But in addition to these synaptic changes, certain learning tasks produce enduring changes in the intrinsic excitability of neurons by changing the function of voltage-gated ion channels, a change that can produce broader, even neuron-wide changes in synaptic throughput. We will consider the evidence for persistent changes in intrinsic neuronal excitability — what we will call intrinsic plasticity — that is produced by training in behaving animals and by artificial patterns of activation in brain slices and neuronal cultures. These intrinsic changes might function as part of the engram itself, or as a related phenomenon such as a trigger for the consolidation or adaptive generalization of memories.", "corpus_id": 17397545, "score": 0 }, { "doc_id": "17345075", "title": "Simulations of Cerebellar Motor Learning: Computational Analysis of Plasticity at the Mossy Fiber to Deep Nucleus Synapse", "abstract": "We question the widely accepted assumption that a molecular mechanism for long-term expression of synaptic plasticity is sufficient to explain the persistence of memories. Instead, we show that learning and memory require that these cellular mechanisms be correctly integrated within the architecture of the neural circuit. To illustrate this general conclusion, our studies are based on the well characterized synaptic organization of the cerebellum and its relationship to a simple form of motor learning. Using computer simulations of cerebellar-mediated eyelid conditioning, we examine the ability of three forms of plasticity at mossy fiber synapses in the cerebellar nucleus to contribute to learning and memory storage. Results suggest that when the simulation is exposed to reasonable patterns of “background” cerebellar activity, only one of these three rules allows for the retention of memories. When plasticity at the mossy fiber synapse is controlled by nucleus or climbing fiber activity, the circuit is unable to retain memories because of interactions within the network that produce spontaneous drift of synaptic strength. In contrast, a plasticity rule controlled by the activity of the Purkinje cell allows for a memory trace that is resistant to ongoing activity in the circuit. These results suggest specific constraints for theories of cerebellar motor learning and have general implications regarding the mechanisms that may contribute to the persistence of memories.", "corpus_id": 17345075, "score": 0 }, { "doc_id": "21952075", "title": "Suppression of cerebellar Purkinje cells during conditioned responses in ferrets.", "abstract": "Decerebrate ferrets were conditioned, using electrical stimulation of the forelimb as conditioned stimulus and periorbital stimulation as unconditioned stimulus, until they produced conditioned eyeblink responses. The latency of these was 125-250 ms. Microelectrode recordings were made from single Purkinje cells in an eyeblink controlling area in the c3 zone of the cerebellar cortex. Whereas Purkinje cells in animals, which had only received unpaired stimulus presentations, responded weakly or not at all to the conditioned stimulus, some cells in conditioned animals responded with a powerful suppression of simple spike firing. The latency of this suppression was 50-200 ms. The results support the hypothesis that classical conditioning involves plastic changes in cerebellar Purkinje cells.", "corpus_id": 21952075, "score": 0 }, { "doc_id": "12040645", "title": "The Site of a Motor Memory Shifts with Consolidation", "abstract": "The basis for the consolidation of memory is a controversial topic, particularly in the case of motor memory. One view is that motor memory is transferred, partially or completely, to a new location during the consolidation process (“systems consolidation”). We investigated this possibility in a primitive motor system, the vestibulo-ocular reflex (VOR). In the simple circuitry of the VOR, there are relatively few possible storage sites for memory. We partially blocked excitatory neurotransmission in the cerebellar cortex of cats with the glutamate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). If CNQX was injected immediately after 60 min of rotation under conditions that induced a learned decrease in the gain of the VOR, gain was returned to its baseline value. Expression of the new memory could also be disrupted by rotation in darkness, suggesting that consolidation had not taken place; however, after learning had continued for 3 d, expression of the learned change was diminished only slightly by blockade and was unaffected by rotation in darkness. Our interpretation of these results is that learning may take place initially in the cerebellar cortex and that during consolidation, motor memories are converted to a more distributed representation that includes the cerebellar cortex and another site.", "corpus_id": 12040645, "score": 0 }, { "doc_id": "15363087", "title": "Memory trace of motor learning shifts transsynaptically from cerebellar cortex to nuclei for consolidation", "abstract": "Adaptation of ocular reflexes is a prototype of motor learning. While the cerebellum is acknowledged as the critical site for motor learning, the functional differences between the cerebellar cortex and nuclei in motor memory formation are not precisely known. Two different views are proposed: one that the memory is formed within the cerebellar flocculus, and the other that the memory is formed within vestibular nuclei. Here we developed a new paradigm of long-term adaptation of mouse horizontal optokinetic response eye movements and examined the location of its memory trace. We also tested the role of flocculus and inferior olive in long-term adaptation by chronic lesion experiments. Reversible bilateral flocculus shutdown with local application of 0.5 microl-5% lidocaine extinguished the memory trace of day-long adaptation, while it very little affected the memory trace of week-long adaptation. The responsiveness of vestibular nuclei after week-long adaptation was examined by measuring the extracellular field responses to the electrical stimulation of vestibular nerve under trichloroacetaldehyde anesthesia. The amplitudes and slopes of evoked monosynaptic field response (N1) of week-long adapted mice were enhanced around the medial vestibular nucleus compared with those of control mice. Chronic flocculus or inferior olive lesions abolished both day and week-long adaptations. These results suggest that the functional memory trace of short-term adaptation is formed initially within the cerebellar cortex, and later transferred to vestibular nuclei to be consolidated to a long-term memory. Both day and week-long adaptations were markedly depressed when neural nitric oxide was pharmacologically blocked locally and when neuronal nitric oxide synthase was ablated by gene knockout, suggesting that cerebellar long-term depression underlies both acquisition and consolidation of motor memory.", "corpus_id": 15363087, "score": 0 }, { "doc_id": "27679504", "title": "Cholinergic innervation and receptors in the cerebellum.", "abstract": "We have studied the source and ultrastructural characteristics of ChAT-immunoreactive fibers in the cerebellum of the rat, and the distribution of muscarinic and nicotinic receptors in the cerebellum of the rat, rabbit, cat and monkey, in order to define which of the cerebellar afferents may use ACh as a neurotransmitter, what target structures are they, and which cholinergic receptor mediate the actions of these pathways. Our data confirm and extend previous observations that cholinergic markers occur at relatively low density in the cerebellum and show not only interspecies variability, but also heterogeneity between cerebellar lobules in the same species. As previously demonstrated by Barmack et al. (1992a,b), the predominant fiber system in the cerebellum that might use ACh as a transmitter or a co-transmitter is formed by mossy fibers originating in the vestibular nuclei and innervating the nodulus and ventral uvula. Our results show that these fibers innervate both granule cells and unipolar brush cells, and that the presumed cholinergic action of these fibers most likely is mediated by nicotinic receptors. In addition to cholinergic mossy fibers, the rat cerebellum is innervated by beaded ChAT-immunoreactive fibers. We have demonstrated that these fibers originate in the pedunculopontine tegmental nucleus (PPTg), the lateral paragigantocellular nucleus (LPGi), and to a lesser extent in various raphe nuclei. In both the cerebellar cortex and the cerebellar nuclei these fibers make asymmetric synaptic junctions with small and medium-sized dendritic profiles. Both muscarinic and nicotinic receptor could mediate the action of these diffuse beaded fibers. In the cerebellar nuclei the beaded cholinergic fibers form a moderately dense network, and could in principle have a significant effect on neuronal activity. For instance, the cholinergic fibers arising in the PPTg may modulate the excitability of the cerebellonuclear neurons in relation to sleep and arousal (e.g. McCormick, 1989). Studies on the distribution of cholinergic markers in the cerebellum have proven valuable besides the issue whether cholinergic mechanism play a role in the cerebellar circuitry, because they illustrate a complexity of the cerebellar anatomy that extends beyond its regular trilaminar and foliar arrangement. For instance, AChE histochemistry has been shown to preferentially stain the borders of white matter compartments (the 'raphes', Voogd, 1967), and therefore is useful in topographical analysis of the cortico-nuclear and olivocerebellar projections (Hess and Voogd, 1986; Tan et al., 1995; Voogd et al., 1996; see Voogd and Ruigrok, 1997, this Volume). ChAT-immunoreactivity, at least in rat, appears to be a good marker to outline the morphological heterogeneity of mossy fibers, and m2-immunocytochemistry could be used to label (subpopulations of) Golgi cells, subsets of mossy fibers and, in the rabbit, a specific subset of Purkinje cells (Jaarsma et al., 1995).", "corpus_id": 27679504, "score": 0 }, { "doc_id": "24492883", "title": "Firing activities of identified posterior interpositus nucleus neurons during associative learning in behaving cats", "abstract": "On the basis of stimulation and permanent or transient lesions of putatively involved structures, and using transgenic mice with defective functional circuits, it has been proposed that cerebellar cortex and/or nuclei could be the sites where classically conditioned nictitating membrane/eyelid responses are acquired and stored. Here, we review recent information regarding the electrical activities of deep cerebellar nuclei neurons recorded during the performance of reflex and acquired eyeblinks. In particular, the rostral pole of the dorsolateral region of the posterior interpositus nucleus contains neurons significantly related to reflexively evoked and classically conditioned eyelid responses. Thus, type A interpositus neurons increase their discharge rate during eyelid movements, modulating it depending upon eyelid motorics. In contrast, type B neurons decrease their firing, even to a stop, during the same eyelid responses. However, as these changes in firing start after the onset of eyelid conditioned responses (CRs), and because they do not seem to encode eyelid position and velocity during the CR, the interpositus nucleus cannot be conclusively considered the site where eyelid learned responses are generated and stored. Additional microstimulation and pharmacological blockage of the recorded sites support the suggestion that posterior interpositus neurons contribute to the enhancement of CRs. Moreover, interpositus neurons probably contribute to the proper damping of newly acquired eyelid responses. The contributing role of other neuronal centers and circuits related to the eyelid motor system are also discussed.", "corpus_id": 24492883, "score": 0 }, { "doc_id": "42477355", "title": "Cerebellar LTD and Learning-Dependent Timing of Conditioned Eyelid Responses", "abstract": "Mammals can be trained to make a conditioned movement at a precise time, which is correlated to the interval between the conditioned stimulus and unconditioned stimulus during the learning. This learning-dependent timing has been shown to depend on an intact cerebellar cortex, but which cellular process is responsible for this form of learning remains to be demonstrated. Here, we show that protein kinase C–dependent long-term depression in Purkinje cells is necessary for learning-dependent timing of Pavlovian-conditioned eyeblink responses.", "corpus_id": 42477355, "score": 0 }, { "doc_id": "15284834", "title": "Deletion of FMR1 in Purkinje Cells Enhances Parallel Fiber LTD, Enlarges Spines, and Attenuates Cerebellar Eyelid Conditioning in Fragile X Syndrome", "abstract": "Absence of functional FMRP causes Fragile X syndrome. Abnormalities in synaptic processes in the cerebral cortex and hippocampus contribute to cognitive deficits in Fragile X patients. So far, the potential roles of cerebellar deficits have not been investigated. Here, we demonstrate that both global and Purkinje cell-specific knockouts of Fmr1 show deficits in classical delay eye-blink conditioning in that the percentage of conditioned responses as well as their peak amplitude and peak velocity are reduced. Purkinje cells of these mice show elongated spines and enhanced LTD induction at the parallel fiber synapses that innervate these spines. Moreover, Fragile X patients display the same cerebellar deficits in eye-blink conditioning as the mutant mice. These data indicate that a lack of FMRP leads to cerebellar deficits at both the cellular and behavioral levels and raise the possibility that cerebellar dysfunctions can contribute to motor learning deficits in Fragile X patients.", "corpus_id": 15284834, "score": 0 }, { "doc_id": "20094165", "title": "Building new motor responses: eyelid conditioning revisited", "abstract": "Neural processes underlying memory and learning should be studied under the best possible physiological conditions - namely, in alert behaving animals. The classical conditioning of the nictitating membrane and eyelid response is a widely used experimental model for studying the neural bases of motor learning in mammals. Nevertheless, information is still needed on the functional aspects, taking place simultaneously in different cerebral structures, that underlie acquisition, extinction and recall of new motor and cognitive abilities. Here, we review recent data on the neural activity generated in selected brain sites (facial motor nuclei, deep cerebellar nuclei and the hippocampus) in simultaneity with the process of learning. The use of modern technologies for the proper recording of eyelid movements, for the identification of the recorded units, and for the activation of selective synaptic processes during the learning situation enables a precise redefinition of the role played by these neural structures in such associative learning. This review is part of the TINS special issue on The Neural Substrates of Cognition.", "corpus_id": 20094165, "score": 0 }, { "doc_id": "8093388", "title": "In vitro classical conditioning of the turtle eyeblink reflex: approaching cellular mechanisms of acquisition", "abstract": "The classically conditioned eyeblink reflex is the best studied model for understanding the neural mechanisms that underlie learning and memory. Here, data from an in vitro model of the conditioned eyeblink reflex are summarized with the aim of shedding some light on potential cellular mechanisms that may underlie eyeblink classical conditioning. An isolated brainstem-cerebellum preparation from turtles was developed in which to study the synaptic circuitry of pathways involving the cerebellum, red nucleus and brainstem nuclei. A neural correlate of an eyeblink response recorded in the abducens nerve can be conditioned entirely in vitro by pairing trigeminal and auditory nerve stimulation. Conditioned abducens nerve responses (CRs) are not generated or sustained by unpaired stimuli and their long latencies, on the order of hundreds of milliseconds, support the Interpretation that the CRs are not unconditioned responses. Ablation experiments show that CRs can be generated in brainstem preparations lacking a cerebellum or the medulla. However, the timing of the CRs are disrupted by removal of the cerebellar circuitry. Thus, a highly reduced in vitro brainstem preparation demonstrates acquisition of CRs but poor timing features. Recent experiments have focused on elucidating cellular mechanisms for CR acquisition in the brainstem blink circuitry. These studies show that NMDA-mediated synaptic mechanisms are required to generate CRs and that the level of conditioning is associated with the upregulation of GluR4-containing AMPA receptors in the abducens motor nuclei. Data from immunocytochemistry and physiological experiments using the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 suggest that CaMKII does not have a key role in mediating the induction or expression of abducens nerve CRs. It is hypothesized that GluR4-containing AMPA receptors In the abducens motor nuclei are targeted to auditory nerve synapses by an NMDA receptor-dependent process to strengthen the CS input during conditioning which results in the generation of CRs. Future studies will examine the synaptic localization of GluR4 and potential signal transduction pathways involved in in vitro conditioning. Moreover, the role feedback loops through the cerebellum and their role in CR timing will be a key issue to address using this preparation.", "corpus_id": 8093388, "score": 0 } ]

{ "doc_id": "62820129", "title": "The Influence of Superstars on Organizational Identification of External Stakeholders: Empirical Findings from Professional Soccer", "abstract": "This paper examines the effect of superstars on external stakeholders’ organizational identification through the lens of sport. Drawing on social identity theory and the concept of organizational identification, as well as on role model theories and superstar economics, we develop several hypotheses regarding the influence of soccer stars on their fans’ degree of team identification. Using a proprietary dataset including archival data on professional German soccer players and clubs as well as survey data of more than 1,400 soccer fans, we find evidence for a positive effect of superstar characteristics and role model perception. We further find that players who measure up to the definition of a superstar are more important to fans of established teams than to fans of unsuccessful teams. The player’s club tenure, however, seems to have no influence on fans’ team identification. We argue that the effect of soccer stars on their fans is comparable to that of CEOs on their organizations’ external stakeholders and consequently apply our results to the business domain. Our results contribute to organizational identification research by extending the list of determinants related to individual persons.", "corpus_id": 62820129 }

[ { "doc_id": "153108988", "title": "Stardom and Talent", "abstract": "The Economics of Superstars sets out to explain the relationship between talent and success in the arts, but there is no agreement about what this relationship is. But whatever its other features may be, superstardom means that market output is concentrated on just a few artists. Concentration always raises the question of efficiency. Superstardom may be inefficient not only because it raises prices for consumers but also because it deprives other artists of the opportunity to practice art. Artists who do not practice art lose psychic income. Because psychic income cannot be transferred from one person to another, the loss of this income may be inefficient. This chapter reviews theories of superstardom and theories about the emergence of stars. The efficiency of superstardom is discussed in terms of effects on consumers and the use of publicity rights by the star. The chapter goes on to deal with the loss of opportunities to practice art that are caused by superstardom and suggests ways to alleviate the problem. Finally the empirical literature that tests the different theories of superstardom is reviewed.", "corpus_id": 153108988, "score": 1 }, { "doc_id": "41960418", "title": "The risky business of hiring stars.", "abstract": "With the battle for the best and brightest people heating up again, you're most likely out there looking for first-rate talent in the ranks of your competitors. Chances are, you're sold on the idea of recruiting from outside your organization, since developing people within the firm takes time and money. But the authors, who have tracked the careers of high-flying CEOs, researchers, software developers, and leading professionals, argue that top performers quickly fade after leaving one company for another. To study this phenomenon in greater detail, the authors analyzed the ups and downs of more than 1,000 star stock analysts, a well-defined group for which there are abundant data. The results were striking. After a star moves, not only does her performance plunge, but so does the effectiveness of the group she joins--and the market value of her new company. Moreover, transplanted stars don't stay with their new organizations for long, despite the astronomical salaries firms pay to lure them from rivals. Most companies that hire stars overlook the fact that an executive's performance is not entirely transferable because his personal competencies inevitably include company-specific skills. When the star leaves the old company for the new, he cannot take with him many of the resources that contributed to his achievements. As a result, he is unable to repeat his performance in another company--at least not until he learns to work the new system, which could take years. The authors conclude that companies cannot gain a competitive advantage or successfully grow by hiring stars from outside. Instead, they should focus on cultivating talent from within and do everything possible to retain the stars they create. Firms shouldn't fight the star wars, because winning could be the worst thing that happens to them.", "corpus_id": 41960418, "score": 0 }, { "doc_id": "154988844", "title": "Star CEOs Benefit or burden", "abstract": "magine that one day you get a call from anationalnewsmagazinesayingthey wantto write an article proÞling the great job youare doing as CEO. They might even make thearticle the cover story! In encouraging you toparticipate, they tell you the article willincrease the visibility and reputation of bothyou and your Þrm and is likely to lead tomore recognition in the future.How should you feel about this impend-ing wave of media attention? Should younonchalantly recognize this as part of whatit means to be a successful CEO? Should yoube excited and embrace your new fame, per-haps writing a book to elaborate on yourrecipe for success and mounting a speakingtour? Or, should you be leery that fame maybring withitthe burdenofincreasedscrutinyand higher performance expectations thatyour Þrm may or may not be able to meet?At one time or another, these questionsare likely to confront any CEO of a large,high-performing corporation. Given thepressure put on media outlets by 24-hournews cycles, coupled with our celebrity-obsessed culture, it is little wonder that thebusiness press has turned the powerful butheretofore largely anonymous CEOs ofAmericaOs most successful corporations intocelebrities in their own right. Thus, top man-agers would do well to consider these ques-tions, because more and more researchsuggests that media attention and adorationbrings with it both beneÞts and burdens. Onthe one hand, certain CEOs are recognizedand gloriÞed by the media and are given adisproportionateshareofthecreditforfavor-able Þrm outcomes during their tenure. Butbeneath the surface of the mediaOs glare is atangle of burdens that can make it difÞcultfor star CEOs to stay on top. And when acelebrity CEO falls from grace, the fall can berapid and complete.Before the collapse of Enron Corp., forexample,KennethLaywashailedasavision-ary who was revolutionizing how the publicutility industry did business. In less than afew months time, however, these accoladesturned to jeers and Lay was cruciÞed in thebusiness pressfor hiscompanyOsshoddyandmisleading accounting practices. Similarly,Dennis Kozlowski was widely praised for", "corpus_id": 154988844, "score": 1 }, { "doc_id": "9758470", "title": "Believing one's own press: the causes and consequences of CEO celebrity", "abstract": "This theoretical article introduces the construct of CEO celebrity in order to explain how the tendency of journalists to attribute a firm's actions and outcomes to the volition of its CEO affects such firm. In the model developed here, journalists celebrate a CEO whose firm takes strategic actions that are distinctive and consistent by attributing such actions and performance to the firm's CEO. In so doing, journalists over-attribute a firm's actions and outcomes to the disposition of its CEO rather than to broader situational factors. A CEO who internalizes such celebrity will also tend to believe this over-attribution and become overconfident about the efficacy of her past actions and future abilities. Hubris arises when CEO overconfidence results in problematic firm decisions, including undue persistence with actions that produce celebrity. Copyright © 2004 John Wiley & Sons, Ltd.", "corpus_id": 9758470, "score": 0 }, { "doc_id": "142613120", "title": "Identity Economics: How Our Identities Shape Our Work, Wages, and Well-Being", "abstract": "Identity Economics provides an important and compelling new way to understand human behavior, revealing how our identities--and not just economic incentives--influence our decisions. In 1995, economist Rachel Kranton wrote future Nobel Prize-winner George Akerlof a letter insisting that his most recent paper was wrong. Identity, she argued, was the missing element that would help to explain why people--facing the same economic circumstances--would make different choices. This was the beginning of a fourteen-year collaboration--and of Identity Economics. The authors explain how our conception of who we are and who we want to be may shape our economic lives more than any other factor, affecting how hard we work, and how we learn, spend, and save. Identity economics is a new way to understand people's decisions--at work, at school, and at home. With it, we can better appreciate why incentives like stock options work or don't; why some schools succeed and others don't; why some cities and towns don't invest in their futures--and much, much more. Identity Economics bridges a critical gap in the social sciences. It brings identity and norms to economics. People's notions of what is proper, and what is forbidden, and for whom, are fundamental to how hard they work, and how they learn, spend, and save. Thus people's identity--their conception of who they are, and of who they choose to be--may be the most important factor affecting their economic lives. And the limits placed by society on people's identity can also be crucial determinants of their economic well-being.", "corpus_id": 142613120, "score": 1 }, { "doc_id": "5574290", "title": "Antecedents and consequences of customer-company identification: expanding the role of relationship marketing.", "abstract": "This article presents an empirical test of organizational identification in the context of customer-company (C-C) relationships. It investigates whether customers identify with companies and what the antecedents and consequences of such identification are. The model posits that perceived company characteristics, construed external image, and the perception of the company's boundary-spanning agent lead to C-C identification. In turn, such identification is expected to impact both in-role behavior (i.e., product utilization) as well as extra-role behavior (i.e., citizenship). The model was tested in a consultative selling context of pharmaceutical sales reps calling on physicians. Results from the empirical test indicated that customers do indeed identify with organizations and that C-C identification positively impacts both product utilization behavior and extra-role behavior even when the effect of brand perception is accounted for. Second, the study found that the organization's characteristics as well as the salesperson's characteristics contributed to the development of C-C identification.", "corpus_id": 5574290, "score": 1 }, { "doc_id": "10912226", "title": "Corporate Marketing in the Stock Market: The Impact of Company Identification on Individuals’ Investment Behaviour", "abstract": "Purpose – The purpose of this article is to contribute to corporate marketing literature by examining how an individual’s identification with a company influences their willingness to invest in the company’s shares.Methodology/Approach – A set of hypotheses were developed based on theory, and survey data were obtained from 440 individuals in order to test the hypotheses. The data pertained to the individuals’ recent decisions to invest in particular companies’ shares, and to the degree of their identification with the companies’ identities. The analysis method was PLS path modelling.Findings – Firstly, an individual’s identification with a company was found to have a positive effect on their determination to invest in the company’s shares rather than in other companies’ shares that have approximately similar expected financial returns/risks. Secondly, company identification was found to elicit preparedness to invest in the company’s shares with lower financial returns expected from the shares than from other shares. Both influences were partly mediated by the individual’s willingness to give support to a company which they identify with.Research limitations/implications – The study pertains to company identification of individual investors; institutional (and professional) investors are beyond the scope of the article. Also, the sample focuses on investors in a single country (Finland), and the data may involve some self-reporting and retrospection biases.Practical implications – Considering corporate marketing in the stock markets, individuals who identify with the company are identified as worthwhile targets when the company seeks to attract new investors. Originality/Value of the paper – The article provides theoretical grounding for and empirical evidence of the positive influence of company identification on individuals’ willingness to invest in companies’ shares. It is a novel finding for corporate marketing literature that individuals express their identification with a corporate brand also through investing in its shares.", "corpus_id": 10912226, "score": 1 }, { "doc_id": "167710267", "title": "Consumer–Company Identification: A Framework for Understanding Consumers’ Relationships with Companies", "abstract": "In this article, the authors try to determine why and under what conditions consumers enter into strong, committed, and meaningful relationships with certain companies, becoming champions of these companies and their products. Drawing on theories of social identity and organizational identification, the authors propose that strong consumer–company relationships often result from consumers’ identification with those companies, which helps them satisfy one or more important self-definitional needs. The authors elaborate on the nature of consumer–company identification, including the company identity, and articulate a consumer-level conceptual framework that offers propositions regarding the key determinants and consequences of such identification in the marketplace.", "corpus_id": 167710267, "score": 1 }, { "doc_id": "145466253", "title": "Beauty is in the Eye of the Beholder: The Impact of Organizational Identification, Identity, and Image on the Cooperative Behaviors of Physicians", "abstract": "We use an established model of organizational identification to try to understand the voluntary cooperative behavior of professionals in organizations. We examined the relationships among physicians' assessments of the attractiveness of a health care system's perceived identity and construed external image, strength of system identification, and cooperative behaviors. We surveyed 1,504 physicians affiliated with three health care systems and collected follow-up data from 285 physicians a year later. Attractiveness of perceived identity and construed external image were positively related to physicians' identification with the system, which in turn was positively related to cooperative behavior. Extensions to the model of organizational identification are suggested.", "corpus_id": 145466253, "score": 1 }, { "doc_id": "167909205", "title": "ORGANIZATIONAL IDENTITY CHANGE: MANAGERIAL REGULATION AND MEMBER IDENTIFICATION IN AN ACCOUNTING FIRM ACQUISITION.", "abstract": "This article presents a study that investigates the organizational identity of accountants and how it affects their behavior. The article states that the study has two objectives: to explore the in...", "corpus_id": 167909205, "score": 0 }, { "doc_id": "20512231", "title": "Organizational identification: Extending our understanding of social identities through social networks†", "abstract": "Summary Although organizational identification is founded on social identity and symbolic interactionist theories, current theories emphasize a social identity whereby organizational members categorize themselves and others based on roles and membership in an organization or work unit. In contrast symbolic interactionism, which resides in interpersonal relationships, is rarely theorized or empirically assessed in studies of organizational identification. We use survey data collected at an academic institution to explore how the strength and structure of an individual’s social network both directly influences organizational identification as well as moderates the relation between social identity, or categorical, antecedents and organizational identification. Our results show that the size of an individual’s network as well as the interaction between relationship strength and prestige better explain organizational identification than do antecedents based solely on categorization and social comparison processes. Thus networks of relationships, which have been a foundational but much neglected premise and process for organizational identification, are brought back into a theory of organizational identification. Copyright # 2010 John Wiley & Sons, Ltd.", "corpus_id": 20512231, "score": 0 }, { "doc_id": "8932757", "title": "Identification with the retail organization and customer-perceived employee similarity: effects on customer spending.", "abstract": "Two constructs important to academicians and managers are the degree to which employees and customers identify with an organization, employee organizational identification (employee OI) and customer-company identification (customer identification), respectively. This research examines the effects of these identification constructs and the related construct of customer perceived similarity to employees on customer spending. Via a 1-year multilevel study of 12,047 customers and 1,464 store employees (sales associates) covering 212 stores of a specialty apparel retailer, our study contributes to the literature in 2 critical ways. First, we expand the theoretical network of employee OI and customer identification by examining the related construct of a customer's perceived similarity to store employees. We examine the incremental (not fully mediated) main and interaction effects of customer-perceived similarity to employees and employee OI on customer spending. Second, we examine the effect of customer identification on customer spending relative to the effect of customer satisfaction on customer spending. Thus, our study also contributes by demonstrating a potential complementary route to achieve customer spending (customer identification), a route that may be more readily affected by management than the efforts required for a sustained increase in customer satisfaction. Implications for academics and managers are offered.", "corpus_id": 8932757, "score": 0 }, { "doc_id": "1675985", "title": "Unethical behavior in the name of the company: the moderating effect of organizational identification and positive reciprocity beliefs on unethical pro-organizational behavior.", "abstract": "We examined the relationship between organizational identification and unethical pro-organizational behavior (UPB)-unethical behaviors conducted by employees to potentially benefit the organization. We predicted that organizational identification would be positively related to UPB and that positive reciprocity beliefs would moderate and strengthen this relationship. The results from 2 field studies support the interaction effect and show that individuals who strongly identify with their organization are more likely to engage in UPB when they hold strong positive reciprocity beliefs. Given the nature of reciprocity, our findings may suggest that highly identified employees who hold strong reciprocity beliefs may conduct UPB with an anticipation of a future reward from their organization. Theoretical and managerial implications of our results for understanding unethical behaviors are discussed.", "corpus_id": 1675985, "score": 0 }, { "doc_id": "168003853", "title": "Understanding the Bond of Identification: An Investigation of its Correlates among Art Museum Members:", "abstract": "Identification is defined as the “perceived oneness with or belongingness to an organization” of which the person is a member. The authors propose that customers, in their role as members, identify...", "corpus_id": 168003853, "score": 1 }, { "doc_id": "144792828", "title": "Corporate sponsorship of a cause: the role of identification in purchase intent", "abstract": "Abstract Nonprofit organizations (NPOs) have attracted significant levels of support from corporate sponsors over the past decade. Despite this significant and continuing interest, very little is known about how consumers perceive and respond to corporate sponsors of NPOs. Drawing on social identity theory, the authors propose that willingness to purchase sponsoring firms' products be related to consumers' identification with an NPO. Possible antecedents of identification with an NPO are also modeled, including the prestige of an NPO, consumers' affiliation with an NPO, and their motivation to support a cause. As predicted, the results find a positive relationship between consumers' identification with an NPO and their intentions to purchase sponsors' products. The results also suggest an important role for identification with an NPO in mediating the relationships between the antecedents studied here and consumers' purchase intentions. Finally, the moderating effects of biodata (life experiences) on several modeled relationships are examined.", "corpus_id": 144792828, "score": 0 }, { "doc_id": "144582451", "title": "Bringing Out Charisma: CEO Charisma and External Stakeholders", "abstract": "We present a theory detailing the processes through which CEO charisma affects participants outside the organization. In order to reach this goal, the model extends the range of current theory beyond internal organizational members, linking CEO charisma to those outsiders key to organizational effectiveness: institutional intermediaries and external stakeholders. We discuss several implications suggested by this framework to facilitate future research in this area.", "corpus_id": 144582451, "score": 0 }, { "doc_id": "30446420", "title": "Lend me your wallets: the effect of charismatic leadership on external support for an organization", "abstract": "We argue that charismatic leadership can influence external support for the organization, particularly in making the company more attractive to outside investors. Two studies were conducted to test this general hypothesis. First, an archival study demonstrated that the stock of companies headed by charismatic leaders appreciated more than the stock of comparable companies, even after differences in corporate performance were controlled. It was also found that the effect of charismatic leadership was heightened under more difficult economic conditions. Second, an experiment was conducted in which the salience of charismatic leadership was manipulated, along with information about the prospects for an organization's turnaround. Results showed that appeals from a charismatic leader led to increased investment in the firm, and the leader's influence was greater when the prospects for an organizational turnaround were more difficult. It was also found that an endowment of stock enhanced the influence of charismatic appeals and that charismatic leadership may have affected the general risk propensities of followers. These findings were interpreted in terms of an external perspective on leadership, illustrating how leaders can manage the firm's economic and social environment. Copyright © 2004 John Wiley & Sons, Ltd.", "corpus_id": 30446420, "score": 0 }, { "doc_id": "144556150", "title": "Factors leading to group identification: A field study of winners and losers", "abstract": "Why do fans of losing sports teams, alumni of poorly ranked educational programs, and patrons of charities that are rocked by scandal maintain or even increase their support? The present research investigates this issue by examining how differences in group success affect the factors that lead to identification and ultimately the incidence of group-supportive behaviors. The results of a two-group field study of professional sports fans suggest that members of unsuccessful groups identify on the basis of their involvement with the domain in which the group operates and the attractiveness of group members. Also, whereas perceived group performance is the most important factor leading to identification for members of successful groups, this factor is irrelevant to members of unsuccessful groups. In addition, the study finds a strong association between the strength of identification and the incidence of group-supportive consumption behaviors for members of both types of groups. The research has important implications for organizations that depend upon member support, such as sports teams, educational institutions, musical groups, and charities.", "corpus_id": 144556150, "score": 1 }, { "doc_id": "43698616", "title": "A model of fan identification: antecedents and sponsorship outcomes", "abstract": "This study examines the impact of fan identification on four distinct sponsorship outcomes: sponsor recognition, attitude toward the sponsor, sponsor patronage, and satisfaction with the sponsor. In addition, consistent with the identification literature we investigate the antecedents of prestige, domain involvement, and fan associations for predicting fan identification among sports spectators. Utilizing structural equation modeling the findings support the premise that highly identified fans are more likely to exhibit the investigated sponsorship outcomes. In addition, we found that the investigated antecedents may aid in predicting fan identification. Our findings are discussed, managerial implications presented, and future research directions provided.", "corpus_id": 43698616, "score": 1 }, { "doc_id": "18662094", "title": "The impact of managerial quality on organizational performance: evidence from German soccer", "abstract": "Although a considerable literature exists on the determinants of managerial compensation, much of it focussing on the role of incentives, there is much less known about the impact of managerial remuneration and quality upon attainment of organizational goals. In this paper we apply two distinct econometric methods to panel data on head coach quality and team performance in Germany’s premier soccer league. We find that, given a particular amount of spending on players relative to the rest of the league, a team that hires a better quality head coach can expect to achieve improved performance.", "corpus_id": 18662094, "score": 0 }, { "doc_id": "143638061", "title": "The Sporting Life: Exploring Organizations through the Lens of Sport", "abstract": "We selectively review the literature from the fields of organizational behavior and sport science with the overarching purpose of identifying and summarizing key themes and contributions. The liter...", "corpus_id": 143638061, "score": 0 }, { "doc_id": "67796232", "title": "Social Psychology of Intergroup Relations", "abstract": "INDIVIDUAL PROCESSES IN INTERGROUP BEHAVIOR 3 From Individual to Group Impressions 3 GROUP MEMBERSHIP AND INTERGROUP BEHAVIOR 7 The Scope and Range of Ethnocentrism 8 The Development of Ethnocentrism 9 Intergroup Conflict and Competition 12 Interpersonal and intergroup behavior 13 Intergroup conflict and group cohesion 15 Power and status in intergroup behavior 16 Social Categorization a d Intergroup Behavior 20 Social categorization: cognitions, values, and groups 20 Social categorization a d intergroup discrimination 23 Social identity and social comparison 24 THE REDUCTION FINTERGROUP DISCRIMINATION 27 Intergroup Cooperation and Superordinate Goals \" 28 Intergroup Contact. 28 Multigroup Membership and \"lndividualizat~’on\" of the Outgroup 29 SUMMARY 30", "corpus_id": 67796232, "score": 0 }, { "doc_id": "144349176", "title": "Social comparison and social identity: Some prospects for intergroup behaviour", "abstract": "Recent studies have reported that the variable of social categorization per se is sufficient for intergroup discrimination. This paper presents an explanation of these findings in terms of the operation of social comparison processes between groups based on the need for a positive ingroup identity. The relationship between perceived social identity and intergroup comparison is elaborated theoretically, and it is argued that social comparisons give rise to processes of mutual differentiation between groups which can be analyzed as a form of ‘social’ competition. Social competition is distinguished from realistic competition (conflict of group interests). New data is reported which strengthens this interpretation of the ‘minimal’ categorization studies. It is found that minimal intergroup discrimination takes place in the distribution of meaningless ‘points’ as well as monetary rewards and that social categorization per se does not lead to intergroup behaviour where the subjects can act directly in terms of ‘self’. Other studies on intergroup biases are reviewed to argue for the generality of social competition in intergroup situations.", "corpus_id": 144349176, "score": 0 }, { "doc_id": "145352228", "title": "Social identity theory and the organization", "abstract": "It is argued that (a) social identification is a perception of oneness with a group of persons; (b) social identification stems from the categorization of individuals, the distinctiveness and prestige of the group, the salience of outgroups, and the factors that traditionally are associated with group formation; and (c) social identification leads to activities that are congruent with the identity, support for institutions that embody the identity, stereotypical perceptions of self and others, and outcomes that traditionally are associated with group formation, and it reinforces the antecedents of identification. This perspective is applied to organizational socialization, role conflict, and intergroup relations.", "corpus_id": 145352228, "score": 1 }, { "doc_id": "144473310", "title": "Role Models in Career Development: New Directions for Theory and Research.", "abstract": "Abstract Career theory proposes the importance of role models as helping to guide individual development. Furthermore, the media often depict role models as essential to career success. However, research on role models as a construct distinct from developmental relationships with mentors and behavioral models has waned. This article makes the case for reinvigorating the role model construct. A revised definition is provided, depicting role models as cognitive constructions based on an individual’s needs, wants, and ambitions. Drawing on recent advances in social comparison and self-concept theories, a dimensional approach to role models integrates current theory and research, suggesting that role models should be construed along two cognitive dimensions (positive/negative, global/specific), and two structural dimensions (close/distant, up/across-down). The article concludes by suggesting new research directions prompted by this new view of the role model construct.", "corpus_id": 144473310, "score": 1 }, { "doc_id": "147165954", "title": "Identification as the basis for a theory of motivation.", "abstract": "R OLE theory has suffered since inception from lack of a satisfactory account of motivation. It is all very well as far as it goes to state that a person learns to recognize standard situations and to play expected roles in them according to the status defined for him in each. But this is not enough when the person encounters alternatives and must resolve conflicting definitions of his appropriate behavior.1 Nor is it enough to account for the emergence of new roles in his conduct, nor for his more or less unique variations upon conventional roles. A striking revelation of the need for some theory of motivation to back up situational analysis2 is disclosed by apathy in the performance of conventional roles, when these are on the verge of abandonment or are accepted only under duress. Roles as such do not provide their own motives. Most of the recent writers on role theory3 have recognized this deficiency and have endeavored to make it up through the expedient of eclecticism. Like a Ford car with a Chevrolet motor, each of these \"integrators\" puts on the road his own model of role theory, one powered by psychic energy, another by a system of tensions or a drivereduction apparatus, a third by some hierarchy of innate and derived needs. Also, a", "corpus_id": 147165954, "score": 1 }, { "doc_id": "146955640", "title": "Factors Affecting Fan Attendance: The Influence of Identity Salience and Satisfaction", "abstract": "The study combines disparate streams of research in order to develop a model of devoted fan behavior. The theoretical foundations for this study are based on literature examining social identity theory, involvement, attachment and satisfaction. A model of the factors that influence fan identity salience and attendance is developed and tested. First, the factors that influence fan identity salience and sporting event attendance are discussed and an integrated model is developed. Second, the proposed model is tested using a sample of college students. Third, the implications of the findings are discussed. The findings suggest that identity salience is an important factor in explaining fan-related behavior.", "corpus_id": 146955640, "score": 0 }, { "doc_id": "59374121", "title": "The Impact of Team Identification on Biased Predictions of Player Performance", "abstract": "The current investigation examined sport fans’ impressions of an athlete described as a potential member of their team or a potential member of a rival team. In Study 1, we predicted that individuals would exhibit an ingroup favoritism effect by reporting more positive evaluations of the player’s performance when he was described as a high-performing recruit for their team than when he was presented as a recruit for a rival. However, this effect was expected only among highly identified fans (i.e., fans with a strong psychological attachment to the team). College students (N = 70) classified as high or low in identification with a target team watched a videotaped basketball practice session involving a player identified as either a recruit for the target team or a rival. After completion of the videotape, participants rated the target athlete. As expected, planned contrast analyses indicated that the most positive ratings were given by highly identified persons evaluating a potential member of their team while the least positive evaluations were offered by highly identified fans rating a rival’s potential player. Lowly identified persons reported moderate evaluations of each target player. In Study 2, we examined evaluations of the target recruit when this person was described in a more negative fashion. In this instance, the target team and level of fan identification had no significant impact on player evaluations.", "corpus_id": 59374121, "score": 0 }, { "doc_id": "144602763", "title": "Comments on the motivational status of self-esteem in social identity and intergroup discrimination", "abstract": "The background and development of motivational hypotheses in social identity theory are examined, revealing two general motives for intergroup discrimination: a desire for cognitive coherence, or good structure; and a need for positive self-esteem. The latter (self-esteem hypothesis: SEH) has received most attention. Both the theoretical and empirical bases of the SEH are largely rooted in research using the minimal group paradigm. However, it remains unclear whether self-esteem is to be considered primarily as a cause or an effect of discrimination. When real social groups are considered the SEH appears to provide only a partial explanation, and a variety of more or less powerful alternative social motives may underlie discriminatory behaviour. We explore some social-structural, individual and interpersonal limits to the SEH, and we call for an awareness of these motives and a re-examination of the good-structure thesis. The SEH, as it stands, provides only a partial contribution to our understanding of the relationship between social identity and discriminatory intergroup behaviour.", "corpus_id": 144602763, "score": 0 }, { "doc_id": "144869891", "title": "Interpersonal attraction, social identification and psychological group formation", "abstract": "Two perspectives on the nature of the social group and psychological group formation are discussed. The traditional social cohesion approach traces group formation to processes of interpersonal attraction, while the social identity approach defines the group in cognitive terms and considers identification, or self-categorization, to be the mechanism of psychological group formation. On the basis of an experiment by Turner, Sachdev and Hogg (1983) it is hypothesized that interpersonal attraction (positive or negative) is related to group formation only in so far as it enhances intergroup distinctiveness. This hypothesis is experimentally tested in a 2 × 3 (interpersonal liking/disliking per se versus no explicit categorization/random categorization/criterial categorization on the basis of affect) factorial design employing the ‘minimal group’ paradigm. People who like each other and were not explicitly categorized formed a group. This effect was enhanced by criterial categorization but disappeared when categorization was random. Although the results do not support the hypothesis, they are not explicable in social cohesion terms. A social identity explanation is furnished—attraction influences group formation by acting, under certain specifiable conditions, as a cognitive criterion for common category membership. This explanation is located in current theorizing and is proposed as part of a reconceptualization of the relationship between interpersonal attraction and group formation.", "corpus_id": 144869891, "score": 0 }, { "doc_id": "145783588", "title": "Die-Hard and Fair-Weather Fans: Effects of Identification on BIRGing and CORFing Tendencies", "abstract": "Previous research has demonstrated that people are capable of strategic self-presentation; they decrease the distance between themselves and successful groups with which they have only the most trivial of associations, and strive to increase the distance between themselves and groups viewed negatively as a result of some perceived failure. These two processes, termed basking-in- reflected-glory (BIRGing) and cutting-off-reflected failure (CORFing) respectively, assist in the maintenance of self-esteem. The current study investigated the extent to which allegiance to a group would modify these general processes. In support of the hypotheses, higher fan identification resulted in increased tendencies to BIRG and decreased tendencies to CORF. In contrast, persons moderate or low in identification were less likely to BIRG and showed an increased likelihood to CORF. Discussion focuses on the role of identification with a group in terms of how it moderates coping with threats to an identity and its impact on self-esteem.", "corpus_id": 145783588, "score": 0 }, { "doc_id": "145063179", "title": "Organizational images and member identification.", "abstract": "We thank Massimo Bergami, Arthur Brief, Mason Carpenter, Brian Golden, Frances Hauge, Rod Kramer, Sharon Lobel, Reuben McDaniel, Debra Meyerson, Wendy Penner, Sandy Piderit, Linda Pike, Mlchael Pratt, Robert Quinn, Anat Rafaeli, Lance Sandelands, Bob Sutton, David Whetten, Batia Wiesenfeld, and three anonymous reviewers for comments on earlier drafts of this paper. We develop a model to explain how images of one's work organization shape the strength of his or her identification with the organization. We focus on two key organizational images: one based on what a member believes is distinctive, central, and enduring about his or her organization and one based on a member's beliefs about what outsiders think about the organization. According to the model, members assess the attractiveness of these images by how well the image preserves the continuity of their self-concept, provides distinctiveness, and enhances self-esteem. The model leads to a number of propositions about how organizational identification affects members' patterns of social interaction.'", "corpus_id": 145063179, "score": 0 }, { "doc_id": "153891143", "title": "What Do Investors Want?", "abstract": "Investments, like restaurants, offer both utilitarian and expressive benefits. Diners want more than the utilitarian benefits of low cost and high nutrition when they choose restaurants; they want the utilitarian benefits of tastiness, ambiance, and conformance to culture. And they also want the expressive benefits of status, patriotism, and social responsibility. Similarly, investors want more than the utilitarian benefits of low risk and high expected returns when they choose investments; they want additional utilitarian benefits, and they want expressive benefits as well. Food service trade periodicals discuss both the utilitarian benefits of restaurants and their expressive ones, but finance journals confine themselves to the utilitarian benefits of low risk and high expected returns. Might not the expressive benefits of investments be discussed in future finance journals?", "corpus_id": 153891143, "score": 0 }, { "doc_id": "141161441", "title": "The Relationship between Sport Team Identification and Social Well-Being: Additional Evidence Supporting the Team Identification-Social Psychological Health Model", "abstract": "The current study tested three predictions generated from Wann's (2004) Team Identification--(Social) Psychological Health Model. Specifically, it was hypothesized that social well-being would be a) positively related to identification with a local sport team, b) not related to identification with a distant team, and c) not related to mere sport fandom. The current investigation expanded on previous research by assessing social well-being through participants' satisfaction with their social life (and their collective self-esteem) and by using regression analyses simultaneously examining the impact of the three predictor variables on social psychological health. Results from 155 university students confirmed expectations and substantiated Wann's model. Discussion includes suggestions for future research. Sport team identification concerns the extent to which a fan feels a psychological connection to a team or player (see Wann, Melnick, Russell, & Pease, 2001). In recent years, Wann and his associates have presented evidence that level of identification with a local team is positively related to psychological health. For instance, Branscombe and Wann (1991) found a positive relationship between identification and personal self-esteem (i.e., one's critical evaluations of his or her personal characteristics) and the frequency of experiencing positive emotions while identification was negatively correlated with depression, alienation, and frequency of experiencing negative emotions. Wann (1994) extended these findings by demonstrating that identification was positively correlated with collective (i.e., social) self-esteem (i.e., one's critical evaluations of his or her groups). Additional findings are reported by Wann, Inman, Ensor, Gates, and Caldwell (1999) and Wann, Dunham, Byrd, and Keenan (2004). Wann et al. (1999) found that identification was positively correlated with self-esteem and vigor (i.e., energy) and negatively related to fatigue, anger, tension, confusion, and depression. Wann et al. (2004) examined the relationship between team identification and well-being through scores on the NEO PI-R questionnaire (Costa & MaCrae, 1992). They found that identification with a local team was positively related to extroversion, openness, and conscientiousness, a pattern consistent with psychological health. This body of literature led Wann (2004) to develop the Team Identification--Psychological Health Model. This model offers three predictions. First, psychological well-being is predicted to be positively related to identification with a local sport team. This prediction, supported by the aforementioned literature, is based on the notion that identifying with a local team will result in valued social relationships and a sense of connectedness with society. Certainly, it is well-established that social connections via group memberships are important for well-being (Cohen & Wills, 1985; Hogg & Abrams, 1990; Mael & Ashforth, 2001) and sport fandom may serve as one such group (Melnick, 1993; Smith, 1988, 1989). The second prediction derived from the model is that identification with a distant team will not result in well-being benefits because they do not readily result in connections with others. Third, mere sport fandom will not be related to psychological health because this will also fail to result in meaningful relationships. Similar to prediction 1, these latter two hypotheses have strong empirical support (e.g., Wann et al., 2004; Wann et al., 1999). Wann, Dimmock, and Grove (in press) were able to extend the generalizability of the Team Identification--Psychological Health Model by examining fans from a different culture (i.e., non North American). In this research investigating the well-being of Australian sport fans, support was found for each of the three predictions. However, Wann and his associates concluded that, consistent with previous work (e.g., Wann et al., 2004) identification with a local sport team appears to be more strongly related to social aspects of well-being (such as loneliness) than personal components of psychological health (such as stress). …", "corpus_id": 141161441, "score": 0 }, { "doc_id": "144213999", "title": "The Relationship between Team Identification and Willingness of Sport Fans to Consider Illegally Assisting Their Team", "abstract": "Previous researchers have indicated that a sizeable minority of sport fans admit a willingness to anonymously injure a star player or coach of a rival team. Highly identified fans were particularly likely to consider these acts. In the current investigation we aimed to extend the previous work by examining the frequency with which individuals would consider, under the protection of anonymity, engaging in antisocial acts of cheating that are either illegal or violate societal norms. A sizeable minority of the college student sample admitted a willingness to consider a number of such acts and, as hypothesized, there was a significant positive correlation between team identification and reports of willingness.", "corpus_id": 144213999, "score": 0 }, { "doc_id": "145578295", "title": "Social identity effects in a belief–attitude–intentions hierarchy: Implications for corporate sponsorship", "abstract": "Companies have increasingly turned to sponsorship as a marketing communications vehicle in the hopes that the goodwill that consumers feel toward an event, cause, or sports team will rub off on their brands. The current study tests a beliefs–attitude–intentions hierarchy in the context of the corporate sponsorship of a major university's sports teams. The direct and indirect effects of social identity with the university's teams (i.e., team identification) on intentions to purchase products from a corporate sponsor are also considered. A random-digit dialing methodology was used to collect data from 368 individuals. In general, the results supported the hypotheses. Of special interest was team identification's ability to moderate the effect of attitude on purchase intentions. As predicted, attitude toward purchasing a sponsor's products was more highly related to purchase intentions for low identifiers than for high identifiers. Specifically, among those with an unfavorable attitude, high identifiers had significantly more positive intentions to purchase than did low identifiers. For high identifiers, it appears that team identification acts as a heuristic that favorably predisposes them to want to buy products from a sponsor in spite of their evaluation of that action. Marketing implications are discussed. © 2001 John Wiley & Sons, Inc.", "corpus_id": 145578295, "score": 0 }, { "doc_id": "146548068", "title": "Perceived external prestige and internal respect: New insights into the organizational identification process", "abstract": "The group engagement model (Tyler & Blader, 2003) suggests that identification with one's organization is based not only on the individual's evaluation of the status of the organization (i.e. perceived external prestige), but also the individual's evaluation of their own status within the organization (i.e. perceived internal respect). Using data drawn from three different sources (subordinates, supervisors, and company records), results from a sample of healthcare employees (n = 205) provide support for the core relationships proposed in the group engagement model and extend the model by showing that prestige and respect have different antecedents. The perceived status of the organization's employees, the organization's perceived success in achieving its goals, the visibility of the organization, and the status level of the individual employee were all associated with perceived external prestige. The results also indicate that visibility within the organization, perceived opportunities for growth, and participation in decision-making were all related to perceived respect. Further, prestige and respect were directly related to organizational identification, but only indirectly related to organization-supportive behavior. These results extend the group engagement model in that we utilize a form of supportive behavior that focuses upon constructive change (i.e. voice behavior; Van Dyne & LePine, 1998), rather than the helpful, but status quo maintaining behavior.", "corpus_id": 146548068, "score": 0 }, { "doc_id": "166389388", "title": "An Identification and Examination of Influences That Shape the Creation of a Professional Team Fan", "abstract": "Keywords: Team Loyalty, Fan Socialization, Team Fans, Professional Football, Sport Fans Executive Summary Sport organizations recognize the importance of a strong fan base, yet little research has been done to help organizations understand how to build and maintain such a group of fans. There is ample evidence that people are readily able to form deep attachments to sports teams. A body of research has examined the level of attachment (i.e. identification) that fans have with a team (Branscombe and Wann, 1991, Wann and Branscombe, 1993, 1995; Wann and Dolan, 1994), and also the relationship between level of identification with a team and different types of fan responses. Fans' emotions, perceptions of influence on team performance and game outcomes, objective knowledge and subjective beliefs about their team, and enjoyment of sports events have all been related to identification levels among United States collegiate sport fans (e.g. Murrell and Dietz, 1992; Wann and Branscombe, 1995; Wann, Dolan, McGeorge and Allison, 1994). The small amount of work that has been done on building and maintaining a fall base has focused primarily on maintenance issues. Sutton, McDonald, Milne and Cimperman (1997) suggested that a sport franchise could foster fan relationships by having a successful team and a good organizational reputation, creating some connection with the community, and by providing as many consumption opportunities as possible for people. Mahony, Madrigal and Howard (1999) found that loyalty to professional teams in the National Football League (NFL) in the United States could be largely determined by knowing a fan's specific personality characteristic. To date, however, research has not adequately examined what factors incipiently influence a person to become a team fan. Knowing what influences people to become team fans is important because these factors are the corner stones for creating, building, and maintaining a base of loyal team fans. The current study was designed to explore a/Id identify: (1) when in their life span individuals became team fans; and (2) what people and things affect this process. A survey was conducted with long-term season ticket holders (N = 518) of a professional National Football League (NFL) team in the United States to address these issues. The results suggested that fathers were very influential in shaping team preferences, particularly among those who became fans in their preteen years and, to a somewhat lesser extent, among adolescents. The majority of respondents stated that they had become a team fan prior to age 15. Players and coaches of the team wee important influences for those who became fails as adolescents or adults. The emotional hometown connection fans made between the city in which the team plays and the team itself was influential in shaping team loyalty. Attending and experiencing the excitement of games was also a catalyst for becoming a team fan. Respondents valued being part of a \"community\" of fans (i.e. a group of people sharing a common bond -- the team). Sports marketers who wish to build the next generation of fans need to create opportunities for fathers to spend time with their children at team-related activities. Developing and promoting linkages between a team and the city in which the team is located has value in building team loyalty as well. Such linkages help fans attribute positive characteristics to both the team and city, thereby reinforcing strong feelings held about each entity. The community of fans concept can be used to build linkages to the teams. One means for creating esprit de corps among fans is to use e-mail and other team-sponsored Internet forums to encourage fans to discuss among themselves their feelings about the team. Team personnel can monitor this information to identify trends and other issues important to team fans. An Identification and Examination of Influences That Shape the Creation of a Professional Team Fan While we often speak of the interest in sports among the collective population, it is the individual fan who invests her/his time, money and self in sports. …", "corpus_id": 166389388, "score": 0 }, { "doc_id": "154887408", "title": "The Assessment: The Economics of Sport", "abstract": "The study of sports economics has expanded rapidly in recent years in response to significantly increased demand--for sport itself, for economic analysis relevant to commercial litigation in sport, for lively teaching material in schools and universities, and for research into the incentive properties of sporting contests. While much of the literature has focused on the issue of competitive balance and how to achieve it, there have still been relatively few studies that apply the lessons of the economic theory of contests to the analysis of sports. There remain huge opportunities both to develop our theoretical understanding of incentive mechanisms in sport and to conduct empirical research in the operation of incentives in sporting contests. Copyright 2003, Oxford University Press.", "corpus_id": 154887408, "score": 0 }, { "doc_id": "146421497", "title": "I Would Like to be Like Her/Him: Are Athletes Role-Models for Boys and Girls?", "abstract": "The first part of this contribution deals with theoretical considerations of the meaning of role-models and idols in general and for young people in particular. Then the results of existing studies are discussed. As research shows, the huge majority of idols, especially of sport heroes, are men, and it is boys who admire sport stars. In the second part of the article a pilot study is presented in which we asked female and male pupils about their role-models. A high percentage of boys named sporting heroes or ‘action stars’ whom they admired because of their strength, aggression and their ability to get things done. In contrast, for the girls interviewed, sport stars did not have the function of role-models. They admired the stars and starlets of the movie and music scene. At the end, the potential effects of these orientations are discussed, and the question is asked what kind of answers pedagogy can offer.", "corpus_id": 146421497, "score": 0 }, { "doc_id": "144366127", "title": "Do role models influence teenagers’ purchase intentions and behavior?", "abstract": "Attempts to determine which individual, or group of individuals, has the strongest influence on adolescent consumer purchase intentions and purchase behavior. By introducing the concepts of direct (fathers and mothers) and vicarious (favorite entertainers and favorite athletes) role models into the consumer behavior literature, the study allows greater understanding of the socialization patterns of young adult consumers. Results from this study provide significant contributions for marketing and advertising managers seeking to improve their understanding of the ever‐growing adolescent consumer market.", "corpus_id": 144366127, "score": 0 }, { "doc_id": "14068398", "title": "Sports Celebrity Influence On The Behavioral Intentions Of Generation Y", "abstract": "ABSTRACT Teenagers currently spend an estimated $153 billion a year on everything from computers to cars to clothes (Brand, 2000). Trend conscious teens are very active in utilizing the media and advertising in seeking out the latest products, services, and fashions (Zollo, 1995). A greater understanding of teens' role model influences can help organizations and their advertising agencies more effectively target and communicate to this growing market. In this study, we examine the effect of athlete role models on teenagers' purchase intentions and behaviors. Results from a survey of 218 adolescents are discussed with implications and future research directions for advertising and sports marketing researchers.", "corpus_id": 14068398, "score": 0 }, { "doc_id": "147370941", "title": "The Effect of Role Model Influence on Adolescents’ Materialism and Marketplace Knowledge", "abstract": "The goal of the present research was to analyze the consumer socialization process of adolescents, utilizing social learning theory as a conceptual guide to understand how role models influence adolescents’ materialism and marketplace knowledge. A convenience sample of 175 teenagers between the ages of 15 and 18 were surveyed in a major metropolitan area. Direct role models included in this study were mothers, fathers and teachers. Vicarious role models included athletes and entertainers. Results at the .05 level of significance show that materialism and marketplace knowledge are associated with members of both direct and vicarious role model groups. Specifically for materialism, athletes and fathers were found to have the greatest impact. Teachers and athlete role models were found to have the greatest impact on adolescents’ marketplace knowledge. Implications from the empirical analysis of these proposed relationships are provided for marketing managers and practitioners.", "corpus_id": 147370941, "score": 0 }, { "doc_id": "115720375", "title": "Superstars and me: predicting the impact of role models on the self", "abstract": "Purpose of the study. Why do superstars exist? Talent, fame and power. An economic theory behind the superstars' phenomenon. Hypothesis development. Overview through the most popular sports in the world.", "corpus_id": 115720375, "score": 0 }, { "doc_id": "145004974", "title": "Villains, fools or heroes? Sports stars as role models for young people", "abstract": "Sporting texts are designed to prioritize, personalize and sensationalize characters in an attempt to capture audience attention. The sporting hero has traditionally been perceived of as epitomizing social ideals and masculine virtues, and as embodying values that learnt on the playing fields will readily transfer into everyday life. However, growing media intrusion signifies the contemporary sports star as a ‘damaged hero’ – the male sports celebrity exemplifying contemporary laddishness, drunken exploits, wife and girlfriend beatings and gay relationships, all of which influence the image of the modern day sports hero. In contrast, female sport stars are well documented as marginalized, trivialized and objectified, to the extent which sports heroines are both invisible and questionable as role models for young girls. This article discusses ways in which sport stars are constructed as role models for young people. It cites instancing examples from the sports calendar of the ‘summer of sport’ 1996, in its discussion of the media construction of sports stars as villains, fools or heroes. It identifies the gender differentiated readings of sports stars as heroes and heroines and concludes that the ways in which media critics accord hero and role model status does not necessarily reflect the opinions of young people.", "corpus_id": 145004974, "score": 0 }, { "doc_id": "153416989", "title": "Superstars in the National Basketball Association: Economic Value and Policy", "abstract": "An econometric analysis demonstrates that television ratings for NBA games are substantially higher when certain players (“superstars”) are involved. Thus, these superstars are quite important for generating revenue, not only for their own teams but for other teams as well. Using the econometric analysis and additional information on attendance and paraphernalia sales, we estimate the value of Michael Jordan to the other NBA teams to be approximately $53 million. The positive externality superstars have on other teams can lead to an inefficient distribution of player talent. We examine several league policies that might be used to address the externality.", "corpus_id": 153416989, "score": 0 }, { "doc_id": "166541376", "title": "Linking sports sponsorship with purchase intentions: Team performance, stars, and the moderating role of team identification", "abstract": "Purpose – It is common for companies to sponsor sports teams. The aim of this paper is to examine experimentally the impact of two team attributes (team performance and the presence of a star in the team) on consumers' intention to purchase the sponsor's product. The moderating role of team identification on the relationship between these two team attributes and intention to purchase is also to be studied.Design/methodology/approach – An experiment was conducted in Hong Kong. A series of hypotheses relating to team performance, presence of stars in the team, and team identification were tested.Findings – Team performance significantly influenced consumers' intention to purchase the sponsor's product, and this influence was more pronounced for casual than for avid fans and more pronounced when the team contained a star. A winning team with a star generated the strongest purchase intention. A losing team with a star produced the lowest purchase intention.Research limitations/implications – The trade‐off bet...", "corpus_id": 166541376, "score": 0 }, { "doc_id": "143062833", "title": "Who Is the Celebrity Endorser? Cultural Foundations of the Endorsement Process", "abstract": "This article offers a new approach to celebrity endorsement. Previous explanations, especially the source credibility and source attractiveness models are criticized, and an alternative meaning transfer model is proposed. According to this model, celebrities' effectiveness as endorsers stems from the cultural meanings with which they are endowed. The model shows how meanings pass from celebrity to product and from product to consumer. The implications of this model for our understanding of the consumer society are considered. Research avenues suggested by the model are also discussed. Copyright 1989 by the University of Chicago.", "corpus_id": 143062833, "score": 0 }, { "doc_id": "143358238", "title": "Organizational identification: A meta-analysis", "abstract": "Abstract The last two decades have witnessed a surge in interest in research on organizational identification (OI). This paper presents a comprehensive meta-analysis of this research ( k  = 96). Results indicate that (a) OI is correlated with a wide range of work-related attitudes, behaviors, and context variables, (b) OI is empirically distinct from its closest conceptual neighbor, attitudinal organizational commitment (AOC), and (c) the two most common OI measures (the Mael scale and the Organizational Identification Questionnaire) produce very different results. It is argued that OI scales, especially the Mael scale, may be preferable over AOC scales for studies aimed at explaining, and partly also for studies aimed at predicting, work behavior.", "corpus_id": 143358238, "score": 0 }, { "doc_id": "167539921", "title": "The sales manager as a Role model: Effects on trust, job satisfaction, and performance of salespeople", "abstract": "This study develops a conceptual framework that relates role-modeling behavior of sales managers to a set of key outcome variables and assesses the validity of the framework using a cross-sectional sample of salespeople and sales managers drawn from a variety of business-to-business sales organizations. Findings indicate that salespeople’s perceptions of their managers’ role-modeling behavior relate positively to trust in the sales manager and relate indirectly, through trust, to both job satisfaction and overall performance of salespeople. The study provides empirical validity for practitioner suggestions that sales managers should lead by example, and thus should provide a model of the behavior managers desire their salespeople to enact.", "corpus_id": 167539921, "score": 0 }, { "doc_id": "5281538", "title": "Common method biases in behavioral research: a critical review of the literature and recommended remedies.", "abstract": "Interest in the problem of method biases has a long history in the behavioral sciences. Despite this, a comprehensive summary of the potential sources of method biases and how to control for them does not exist. Therefore, the purpose of this article is to examine the extent to which method biases influence behavioral research results, identify potential sources of method biases, discuss the cognitive processes through which method biases influence responses to measures, evaluate the many different procedural and statistical techniques that can be used to control method biases, and provide recommendations for how to select appropriate procedural and statistical remedies for different types of research settings.", "corpus_id": 5281538, "score": 0 }, { "doc_id": "167967723", "title": "A Paradigm for Developing Better Measures of Marketing Constructs", "abstract": "A critical element in the evolution of a fundamental body of knowledge in marketing, as well as for improved marketing practice, is the development of better measures of the variables with which ma...", "corpus_id": 167967723, "score": 0 }, { "doc_id": "153414402", "title": "The Labour Market in Association Football: Who Gets Transferred and For How Much?", "abstract": "This paper employs data for the 1993-94 season to estimate a hedonic equation representing the determination of the price structure in the transfer market for professional players in the English football leagues. Player transfer proneness is modelled, and the Heckman two-step procedure is employed to take account of selection bias. The paper identifies those player attributes which affect either the probability of transfer or the transfer fee and evaluates the relative influence of such variables. Copyright 1999 by Blackwell Publishing Ltd and the Board of Trustees of the Bulletin of Economic Research", "corpus_id": 153414402, "score": 0 }, { "doc_id": "145523872", "title": "The determination of player transfer fees in English professional soccer", "abstract": "Unlike most major U.S. sport teams, it is common for professional soccer clubs around the world to trade players for cash. This article develops a model of the player-transfer market in soccer in which observed transfer fees are determined by player characteristics, selling-club characteristics, buying-club characteristics, and time effects. The model is based on data on 1,350 transfer fees in English professional soccer from June 1990 to August 1996. The estimated model is used to investigate the rate of inflation in transfer fees. In addition, the determination of transfer fees is considered within different segments of the transfer market. It is found that the determination of transfer fees differs markedly among segments.", "corpus_id": 145523872, "score": 0 }, { "doc_id": "154805101", "title": "The determination of transfer fees in English nonleague football", "abstract": "In recent years a number of studies have analysed the player transfer market in English professional football. This paper examines whether similar factors operate to determine transfer fees in the semiprofessional, or nonleague, game. An empirical model of the nonleague player transfer market is developed in which observed transfer fees are determined by player characteristics, time effects, selling-club characteristics and buying-club characteristics. Using data on 114 transfer fees covering the period 1988 to 1997, we find evidence that the data generating process for transfer fees is broadly similar in both professional and nonleague football.", "corpus_id": 154805101, "score": 0 }, { "doc_id": "34604622", "title": "Local Heroes and Superstars", "abstract": "Recent studies of the demand for sports clearly indicate that stars play an important role in promoting fan interest. However, on theoretical grounds it is controversial if a star's talent superiority and/or a star's popularity drive match attendance and hence increase gate revenues. Using longitudinal match attendance data of all clubs in the first German soccer league in a 9-year period, the authors analyze star attraction of national superstars and of so-called ``local heroes'' defined as the most valued players of teams without national superstars. The authors find empirical evidence that these groups differ in the way they attract fans: whereas superstars enhance attendance both at home and on the road, the star attraction of local heroes is limited to home games. In addition, superstars attract fans by outstanding field performances, whereas local heroes facilitate fan support by mere popularity.", "corpus_id": 34604622, "score": 0 }, { "doc_id": "118490874", "title": "Multiple Regression: A Primer", "abstract": "What Is Multiple Regression? How Do I Interpret Multiple Regression Results? What Can Go Wrong with Multiple Regression? How Do I Run a Multiple Regression? How Does Bivariate Regression Work? What Are the Assumptions of Multiple Regression? What Can Be Done about Multicollinearity? How Can Multiple Regression Handle Nonlinear Relationships? How Is Multiple Regression Related to Other Statistical Techniques?", "corpus_id": 118490874, "score": 0 }, { "doc_id": "167483914", "title": "A Stakeholder Approach to Organizational Identity", "abstract": "We develop a model of organizational identity construction that reframes organizational identity within the broader context of manager-stakeholder relationships and more effectively integrates theory on organizational identity and organizational identification. We describe organizational identity as emerging from complex, dynamic, and reciprocal interactions among managers, organizational members, and other stakeholders. The model draws attention to organizational identity as negotiated cognitive images and to the embeddedness of organizational identity within different systems of organizational membership and meaning. Viewing organizational identity from the perspective of manager-stakeholder relationships provides a more parsimonious but more complete theory of organizational identity management.", "corpus_id": 167483914, "score": 0 }, { "doc_id": "168003611", "title": "EXECUTIVE SUCCESSION: ORGANIZATIONAL ANTECEDENTS OF CEO CHARACTERISTICS", "abstract": "Based on 195 succession events in Business Week 1000 firms, this study examines the organizational antecedents of CEO demographic characteristics. Study findings suggest that antecedent conditions of lower firm profits and firm growth are associated with the selection of outsider CEOs. Additionally, R&D intensity is associated with the selection of CEOs having technical functional backgrounds and higher levels of education.", "corpus_id": 168003611, "score": 0 }, { "doc_id": "168151913", "title": "CEO SUCCESSION AND STOCKHOLDER REACTION: THE INFLUENCE OF ORGANIZATIONAL CONTEXT AND EVENT CONTENT", "abstract": "In this article, we construe chief executive officer (CEO) succession events as instances of organizational change. Predictions of positive, negative, or inconsequential outcomes of succession events are contingent on two features of organizational context-presuccession organizational performance and organizational size-and three elements of the content of a succession event: the force initiating the change in CEO, the predecessor's disposition, and the origin of the new CEO. We found that poor presuccession performance was associated with boardinitiation and predecessor departure. Stockholder reactions were positive when presuccession performance was poor and either boards or, to a lesser extent, CEOs initiated successions. Successions that occurred when performance had been good resulted in negative consequences, as did those caused by CEO disability. However, most successions studied were customary retirements associated with no significant stockholder reaction. CEO succession events are of central concern in organization theory. They are universal-if organizations survive long enough, they must experience succession-and they have provided a means for assessing the efficacy of leaders in shaping organizational fortunes by demarcating eras of stewardship. After some decades of research, however, scholars have not reached consensus on the general question of whether leaders make a difference. Instead, the literature on succession has led to a focus on specifying conditions under which it is more or less possible for individuals newly placed in the seat of legitimate authority to influence important organizational outcomes. Under certain circumstances, new CEOs can have palpable effects on", "corpus_id": 168151913, "score": 0 }, { "doc_id": "24780500", "title": "On making causal claims: A review and recommendations", "abstract": "Abstract Social scientists often estimate models from correlational data, where the independent variable has not been exogenously manipulated; they also make implicit or explicit causal claims based on these models. When can these claims be made? We answer this question by first discussing design and estimation conditions under which model estimates can be interpreted, using the randomized experiment as the gold standard. We show how endogeneity – which includes omitted variables, omitted selection, simultaneity, common-method variance, and measurement error – renders estimates causally uninterpretable. Second, we present methods that allow researchers to test causal claims in situations where randomization is not possible or when causal interpretation could be confounded; these methods include fixed-effects panel, sample selection, instrumental variable, regression discontinuity, and difference-in-differences models. Third, we take stock of the methodological rigor with which causal claims are being made in a social sciences discipline by reviewing a representative sample of 110 articles on leadership published in the previous 10 years in top-tier journals. Our key finding is that researchers fail to address at least 66% and up to 90% of design and estimation conditions that make causal claims invalid. We conclude by offering 10 suggestions on how to improve non-experimental research.", "corpus_id": 24780500, "score": 0 } ]

{ "doc_id": "14514024", "title": "A New Single-Step PCR Assay for the Detection of the Zoonotic Malaria Parasite Plasmodium knowlesi", "abstract": "Background Recent studies in Southeast Asia have demonstrated substantial zoonotic transmission of Plasmodium knowlesi to humans. Microscopically, P. knowlesi exhibits several stage-dependent morphological similarities to P. malariae and P. falciparum. These similarities often lead to misdiagnosis of P. knowlesi as either P. malariae or P. falciparum and PCR-based molecular diagnostic tests are required to accurately detect P. knowlesi in humans. The most commonly used PCR test has been found to give false positive results, especially with a proportion of P. vivax isolates. To address the need for more sensitive and specific diagnostic tests for the accurate diagnosis of P. knowlesi, we report development of a new single-step PCR assay that uses novel genomic targets to accurately detect this infection. Methodology and Significant Findings We have developed a bioinformatics approach to search the available malaria parasite genome database for the identification of suitable DNA sequences relevant for molecular diagnostic tests. Using this approach, we have identified multi-copy DNA sequences distributed in the P. knowlesi genome. We designed and tested several novel primers specific to new target sequences in a single-tube, non-nested PCR assay and identified one set of primers that accurately detects P. knowlesi. We show that this primer set has 100% specificity for the detection of P. knowlesi using three different strains (Nuri, H, and Hackeri), and one human case of malaria caused by P. knowlesi. This test did not show cross reactivity with any of the four human malaria parasite species including 11 different strains of P. vivax as well as 5 additional species of simian malaria parasites. Conclusions The new PCR assay based on novel P. knowlesi genomic sequence targets was able to accurately detect P. knowlesi. Additional laboratory and field-based testing of this assay will be necessary to further validate its utility for clinical diagnosis of P. knowlesi.", "corpus_id": 14514024 }

[ { "doc_id": "13901635", "title": "Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening.", "abstract": "BACKGROUND\nUntil recently, Plasmodium knowlesi malaria in humans was misdiagnosed as Plasmodium malariae malaria. The objectives of the present study were to determine the geographic distribution of P. knowlesi malaria in the human population in Malaysia and to investigate 4 suspected fatal cases.\n\n\nMETHODS\nSensitive and specific nested polymerase chain reaction was used to identify all Plasmodium species present in (1) blood samples obtained from 960 patients with malaria who were hospitalized in Sarawak, Malaysian Borneo, during 2001-2006; (2) 54 P. malariae archival blood films from 15 districts in Sabah, Malaysian Borneo (during 2003-2005), and 4 districts in Pahang, Peninsular Malaysia (during 2004-2005); and (3) 4 patients whose suspected cause of death was P. knowlesi malaria. For the 4 latter cases, available clinical and laboratory data were reviewed.\n\n\nRESULTS\nP. knowlesi DNA was detected in 266 (27.7%) of 960 of the samples from Sarawak hospitals, 41 (83.7%) of 49 from Sabah, and all 5 from Pahang. Only P. knowlesi DNA was detected in archival blood films from the 4 patients who died. All were hyperparasitemic and developed marked hepatorenal dysfunction.\n\n\nCONCLUSIONS\nHuman infection with P. knowlesi, commonly misidentified as the more benign P. malariae, are widely distributed across Malaysian Borneo and extend to Peninsular Malaysia. Because P. knowlesi replicates every 24 h, rapid diagnosis and prompt effective treatment are essential. In the absence of a specific routine diagnostic test for P. knowlesi malaria, we recommend that patients who reside in or have traveled to Southeast Asia and who have received a \"P. malariae\" hyperparasitemia diagnosis by microscopy receive intensive management as appropriate for severe falciparum malaria.", "corpus_id": 13901635, "score": 1 }, { "doc_id": "7491591", "title": "Severe malaria - a case of fatal Plasmodium knowlesi infection with post-mortem findings: a case report", "abstract": "BackgroundZoonotic malaria caused by Plasmodium knowlesi is an important, but newly recognized, human pathogen. For the first time, post-mortem findings from a fatal case of knowlesi malaria are reported here.Case presentationA formerly healthy 40 year-old male became symptomatic 10 days after spending time in the jungle of North Borneo. Four days later, he presented to hospital in a state of collapse and died within two hours. He was hyponatraemic and had elevated blood urea, potassium, lactate dehydrogenase and amino transferase values; he was also thrombocytopenic and eosinophilic. Dengue haemorrhagic shock was suspected and a post-mortem examination performed. Investigations for dengue virus were negative. Blood for malaria parasites indicated hyperparasitaemia and single species P. knowlesi infection was confirmed by nested-PCR. Macroscopic pathology of the brain and endocardium showed multiple petechial haemorrhages, the liver and spleen were enlarged and lungs had features consistent with ARDS. Microscopic pathology showed sequestration of pigmented parasitized red blood cells in the vessels of the cerebrum, cerebellum, heart and kidney without evidence of chronic inflammatory reaction in the brain or any other organ examined. Brain sections were negative for intracellular adhesion molecule-1. The spleen and liver had abundant pigment containing macrophages and parasitized red blood cells. The kidney had evidence of acute tubular necrosis and endothelial cells in heart sections were prominent.ConclusionsThe overall picture in this case was one of systemic malaria infection that fit the WHO classification for severe malaria. Post-mortem findings in this case were unexpectedly similar to those that define fatal falciparum malaria, including cerebral pathology. There were important differences including the absence of coma despite petechial haemorrhages and parasite sequestration in the brain. These results suggest that further study of knowlesi malaria will aid the interpretation of, often conflicting, information on malaria pathophysiology in humans.", "corpus_id": 7491591, "score": 0 }, { "doc_id": "7776536", "title": "A large focus of naturally acquired Plasmodium knowlesi infections in human beings", "abstract": "BACKGROUND\nAbout a fifth of malaria cases in 1999 for the Kapit division of Malaysian Borneo had routinely been identified by microscopy as Plasmodium malariae, although these infections appeared atypical and a nested PCR assay failed to identify P malariae DNA. We aimed to investigate whether such infections could be attributable to a variant form of P malariae or a newly emergent Plasmodium species.\n\n\nMETHODS\nWe took blood samples from 208 people with malaria in the Kapit division between March, 2000, and November, 2002. The small subunit ribosomal RNA and the circumsporozoite protein genes were sequenced for eight isolates that had been microscopically identified as P malariae. All blood samples were characterised with a genus-specific and species-specific nested PCR assay together with newly designed P knowlesi-specific primers.\n\n\nFINDINGS\nAll DNA sequences were phylogenetically indistinguishable from those of P knowlesi, a malaria parasite of long-tailed macaque monkeys, but were significantly different from other malaria parasite species. By PCR assay, 120 (58%) of 208 people with malaria tested positive for P knowlesi, whereas none was positive for P malariae. P knowlesi parasites in human erythrocytes were difficult to distinguish from P malariae by microscopy. Most of the P knowlesi infections were in adults and we did not note any clustering of cases within communities. P knowlesi infections were successfully treated with chloroquine and primaquine.\n\n\nINTERPRETATION\nNaturally acquired P knowlesi infections, misdiagnosed by microscopy mainly as P malariae, accounted for over half of all malaria cases in our study. Morphological similarities between P knowlesi and P malariae necessitate the use of molecular methods for correct identification. Further work is needed to determine whether human P knowlesi infections in the Kapit division are acquired from macaque monkeys or whether a host switch to human beings has occurred.", "corpus_id": 7776536, "score": 1 }, { "doc_id": "205990205", "title": "Differential prevalence of Plasmodium infections and cryptic Plasmodium knowlesi malaria in humans in Thailand.", "abstract": "BACKGROUND\nA case of human infection with Plasmodium knowlesi has been recently discovered in Thailand. To investigate the prevalence of this malaria species, a molecular-based survey was performed.\n\n\nMETHODS\nBlood samples from 1874 patients were tested for Plasmodium species by microscopy and nested polymerase chain reaction. P. knowlesi was characterized by sequencing the merozoite surface protein 1 gene (msp-1).\n\n\nRESULTS\nOf all Plasmodium species identified, P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi contributed 43.52%, 68.08%, 1.37%, 1.03%, and 0.57%, respectively. Mixed-species infections were more common in northwestern and southwestern regions bordering Myanmar (23%-24%) than in eastern and southern areas (3%-5%). In northwestern and southwestern regions, mixed-species infections had a significantly higher prevalence in dry than in rainy seasons (P < .001). P. knowlesi was found in 10 patients, mostly from southern and southwestern areas-9 were coinfected with either P. falciparum or P. vivax. Most of the P. knowlesi Thai isolates were more closely related to isolates from macaques than to isolates from Sarawak patients. The msp-1 sequences of isolates from the same area of endemicity differed and possessed novel sequences, indicating genetic polymorphism in P. knowlesi infecting humans.\n\n\nCONCLUSIONS\nThis survey highlights the widespread distribution of P. knowlesi in Thailand, albeit at low prevalence and mostly occurring as cryptic infections.", "corpus_id": 205990205, "score": 0 }, { "doc_id": "6510862", "title": "Human Plasmodium knowlesi infections in young children in central Vietnam", "abstract": "BackgroundConsidering increasing reports on human infections by Plasmodium knowlesi in Southeast Asian countries, blood samples collected during two large cross-sectional malariometric surveys carried out in a forested area of central Vietnam in 2004 and 2005 were screened for this parasite.MethodsBlood samples collected at the 2004 survey and positive for Plasmodium malariae were randomly selected for PCR analysis detecting P. knowlesi. Blood samples collected in 2005 from the same individuals were screened again for P. knowlesi. Positive samples were confirmed by sequencing. Family members of positive cases who participated in both surveys were also screened.ResultsNinety-five samples with P. malariae mono- or mixed infections identified by species-specific PCR were screened for P. knowlesi. Among the five (5.2%) positive samples by PCR, three were confirmed to be P. knowlesi infections by sequencing, two young children (<5 years old) and a young man, all asymptomatic at the time of the survey and for the next six months after the survey. One of the two children was still positive one year later. No infection was found among the family members.ConclusionPlasmodium knowlesi infections in humans can be found in central Vietnam. A small child was positive for P. knowlesi in both surveys at one year interval, though it is unclear whether it was the same or a new infection.", "corpus_id": 6510862, "score": 1 }, { "doc_id": "3803047", "title": "Plasmodium knowlesi: Reservoir Hosts and Tracking the Emergence in Humans and Macaques", "abstract": "Plasmodium knowlesi, a malaria parasite originally thought to be restricted to macaques in Southeast Asia, has recently been recognized as a significant cause of human malaria. Unlike the benign and morphologically similar P. malariae, these parasites can lead to fatal infections. Malaria parasites, including P. knowlesi, have not yet been detected in macaques of the Kapit Division of Malaysian Borneo, where the majority of human knowlesi malaria cases have been reported. In order to extend our understanding of the epidemiology and evolutionary history of P. knowlesi, we examined 108 wild macaques for malaria parasites and sequenced the circumsporozoite protein (csp) gene and mitochondrial (mt) DNA of P. knowlesi isolates derived from macaques and humans. We detected five species of Plasmodium (P. knowlesi, P. inui, P. cynomolgi, P. fieldi and P. coatneyi) in the long-tailed and pig-tailed macaques, and an extremely high prevalence of P. inui and P. knowlesi. Macaques had a higher number of P. knowlesi genotypes per infection than humans, and some diverse alleles of the P. knowlesi csp gene and certain mtDNA haplotypes were shared between both hosts. Analyses of DNA sequence data indicate that there are no mtDNA lineages associated exclusively with either host. Furthermore, our analyses of the mtDNA data reveal that P. knowlesi is derived from an ancestral parasite population that existed prior to human settlement in Southeast Asia, and underwent significant population expansion approximately 30,000–40,000 years ago. Our results indicate that human infections with P. knowlesi are not newly emergent in Southeast Asia and that knowlesi malaria is primarily a zoonosis with wild macaques as the reservoir hosts. However, ongoing ecological changes resulting from deforestation, with an associated increase in the human population, could enable this pathogenic species of Plasmodium to switch to humans as the preferred host.", "corpus_id": 3803047, "score": 1 }, { "doc_id": "2380721", "title": "Natural transmission of Plasmodium knowlesi to humans by Anopheles latens in Sarawak, Malaysia.", "abstract": "Four species of malaria parasites are known to infect humans. A fifth species, Plasmodium knowlesi, has been reported to infect humans in Malaysian Borneo. Here we report for the first time the incrimination of Anopheles latens as the vector of P. knowlesi among humans and monkeys in Sarawak, Malaysia.", "corpus_id": 2380721, "score": 0 }, { "doc_id": "54524143", "title": "Informed decision‐making before changing to RDT: a comparison of microscopy, rapid diagnostic test and molecular techniques for the diagnosis and identification of malaria parasites in Kassala, eastern Sudan", "abstract": "Objectives  Rapid diagnostic tests (RDTs) are promoted for the diagnosis of malaria in many countries. The question arises whether laboratories where the current method of diagnosis is microscopy should also switch to RDT. This problem was studied in Kassala, Sudan where the issue of switching to RDT is under discussion.", "corpus_id": 54524143, "score": 0 }, { "doc_id": "6847091", "title": "Human Infections with Plasmodium knowlesi, the Philippines", "abstract": "Human Infections with Plasmodium knowlesi, the Philippines", "corpus_id": 6847091, "score": 0 }, { "doc_id": "14034600", "title": "Plasmodium knowlesi in humans, macaques and mosquitoes in peninsular Malaysia", "abstract": "BackgroundSince a large focus of human infection with Plasmodium knowlesi, a simian malaria parasite naturally found in long-tailed and pig tailed macaques, was reported in Sarawak, Malaysian Borneo, it was pertinent to study the situation in peninsular Malaysia. A study was thus initiated to screen human cases of Plasmodium malariae using molecular techniques, to determine the presence of P. knowlesi in non- human primates and to elucidate its vectors.MethodsNested polymerase chain reaction (PCR) was used to identify all Plasmodium species present in the human blood samples sent to the Parasitology laboratory of Institute for Medical Research. At the same time, non-human primates were also screened for malaria parasites and nested PCR was carried out to determine the presence of P. knowlesi. Mosquitoes were collected from Pahang by human landing collection and monkey-baited-traps situated on three different levels. All mosquitoes were identified and salivary glands and midguts of anopheline mosquitoes were dissected to determine the presence of malaria parasites and nested PCR was carried out on positive glands. Sequencing of the csp genes were carried on P. knowlesi samples from humans, monkeys and mosquitoes, positive by PCR.Results and DiscussionPlasmodium knowlesi was detected in 77 (69.37%) of the 111 human samples, 10 (6.90%) of the 145 monkey blood and in 2 (1.7%) Anopheles cracens. Sequence of the csp gene clustered with other P. knowlesi isolates.ConclusionHuman infection with Plasmodium knowlesi is occurring in most states of peninsular Malaysia. An. cracens is the main vector. Economic exploitation of the forest is perhaps bringing monkeys, mosquitoes and humans into increased contact. A single bite from a mosquito infected with P. knowlesi is sufficient to introduce the parasite to humans. Thus, this zoonotic transmission has to be considered in the future planning of malaria control.", "corpus_id": 14034600, "score": 0 }, { "doc_id": "89335946", "title": "Naturally Acquired Human Plasmodium knowlesi Infection", "abstract": "We report a case of naturally acquired Plasmodium knowlesi in Singapore, a malaria-free country. Diagnosis was confi rmed by PCR with validated species-specifi c primers. In industrialized countries, free-ranging primates are a potential source of P. knowlesi human infection. P. knowlesi infection is a differential diagnosis of febrile illness acquired in Singapore.", "corpus_id": 89335946, "score": 0 }, { "doc_id": "11878033", "title": "Plasmodium knowlesi: a malaria parasite of monkeys and humans.", "abstract": "Plasmodium knowlesi is a malaria parasite of monkeys of Southeast Asia that is transmitted by mosquitoes of the Anopheles leucosphyrus group. Humans are frequently infected with this parasite and misdiagnosed as being infected with Plasmodium malariae. The parasite was a major monkey animal model for developing antimalarial vaccines and investigations of the biology of parasite invasion. P. knowlesi is the first monkey malaria parasite genome to be sequenced and annotated.", "corpus_id": 11878033, "score": 0 }, { "doc_id": "5817385", "title": "Imported Plasmodium knowlesi malaria in a French tourist returning from Thailand.", "abstract": "We report a case of imported Plasmodium knowlesi malaria in a French tourist following a vacation in Thailand. This case shows, first, tourists may contract knowlesi malaria even only staying on the beach and second, the diagnosis remains difficult, even with polymerase chain reaction methods.", "corpus_id": 5817385, "score": 0 }, { "doc_id": "40263884", "title": "Plasmodium knowlesi in a traveller returning to New Zealand.", "abstract": "The recent discovery that Plasmodium knowlesi causes malaria in human populations, established it as the fifth species of plasmodium that may do so. A case of P. knowlesi malaria is described in a helicopter pilot from New Zealand, who became ill after returning from recurring visits to Malaysian Borneo in June 2010. His P. knowlesi infection was not detected using microscopic examination and a rapid diagnostic test for malaria, but was confirmed by both PCR (polymerase chain reaction) and sequence analysis showing homology with the ribosomal RNA gene for P. knowlesi. He responded rapidly to treatment with artemether & lumefantrine combination. The evolution of a rapid diagnostic kit to diagnose P. knowlesi is needed, for early identification and appropriate anti-malarial therapy of suspect cases are both critical in the prevention of the potentially life-threatening disease through P. knowlesi. Clinicians need to consider knowlesi infection in the differential diagnosis in recent-onset febrile travellers to areas of forestation in Southeast Asia.", "corpus_id": 40263884, "score": 0 }, { "doc_id": "10948259", "title": "First case of detection of Plasmodium knowlesi in Spain by Real Time PCR in a traveller from Southeast Asia", "abstract": "Previously, Plasmodium knowlesi was not considered as a species of Plasmodium that could cause malaria in human beings, as it is parasite of long-tailed (Macaca fascicularis) and pig-tailed (Macaca nemestrina) macaques found in Southeast Asia. A case of infection by P. knowlesi is described in a Spanish traveller, who came back to Spain with daily fever after his last overseas travel, which was a six-month holiday in forested areas of Southeast Asia between 2008 and 2009. His P. knowlesi infection was detected by multiplex Real time quantitative PCR and confirmed by sequencing the amplified fragment. Using nested multiplex malaria PCR (reference method in Spain) and a rapid diagnostic test, the P. knowlesi infection was negative. This patient was discharged and asymptomatic when the positive result to P. knowlesi was reported. Prior to this case, there have been two more reports of European travellers with malaria caused by P. knowlesi, a Finnish man who travelled to Peninsular Malaysia during four weeks in March 2007, and a Swedish man who did a short visit to Malaysian Borneo in October 2006. Taken together with this report of P. knowlesi infection in a Spanish traveller returning from Southeast Asia, this is the third case of P. knowlesi infection in Europe, indicating that this simian parasite can infect visitors to endemic areas in Southeast Asia. This last European case is quite surprising, given that it is an untreated-symptomatic P. knowlesi in human, in contrast to what is currently known about P. knowlesi infection. Most previous reports of human P. knowlesi malaria infections were in adults, often with symptoms and relatively high parasite densities, up to the recent report in Ninh Thuan province, located in the southern part of central Vietnam, inhabited mainly by the Ra-glai ethnic minority, in which all P. knowlesi infections were asymptomatic, co-infected with P. malariae, with low parasite densities and two of the three identified cases were very young children under five years old.", "corpus_id": 10948259, "score": 0 }, { "doc_id": "44861067", "title": "Experimental mosquito-transmission of Plasmodium knowlesi to man and monkey.", "abstract": "Summary\nThe H strain of P. knowlesi was transmitted through the bites of Anopheles balabacencis balabacensis mosquitoes from monkey to man, from man to man, and from man back to monkey. All attempts to infect man through the bites of infected mosquitoes were successful, one volunteer contracting infection after only a single infective bite. The prepatent periods in man ranged from 9 to 12 days, and in the monkey was 6 days. The infections exhibited a quotidian periodicity, and were characterized by relatively high parasitemia and moderate to severe clinical manifestations.\nThe significance of this zoonosis as it may affect a program of malaria eradication is discussed.", "corpus_id": 44861067, "score": 0 }, { "doc_id": "13910587", "title": "Morphological features and differential counts of Plasmodium knowlesi parasites in naturally acquired human infections", "abstract": "BackgroundHuman infections with Plasmodium knowlesi, a simian malaria parasite, are more common than previously thought. They have been detected by molecular detection methods in various countries in Southeast Asia, where they were initially diagnosed by microscopy mainly as Plasmodium malariae and at times, as Plasmodium falciparum. There is a paucity of information on the morphology of P. knowlesi parasites and proportion of each erythrocytic stage in naturally acquired human infections. Therefore, detailed descriptions of the morphological characteristics and differential counts of the erythrocytic stages of P. knowlesi parasites in human infections were made, photographs were taken, and morphological features were compared with those of P. malariae and P. falciparum.MethodsThick and thin blood films were made prior to administration of anti-malarial treatment in patients who were subsequently confirmed as having single species knowlesi infections by PCR assays. Giemsa-stained blood films, prepared from 10 randomly selected patients with a parasitaemia ranging from 610 to 236,000 parasites per μl blood, were examined.ResultsThe P. knowlesi infection was highly synchronous in only one patient, where 97% of the parasites were at the late trophozoite stage. Early, late and mature trophozoites and schizonts were observed in films from all patients except three; where schizonts and early trophozoites were absent in two and one patient, respectively. Gametocytes were observed in four patients, comprising only between 1.2 to 2.8% of infected erythrocytes. The early trophozoites of P. knowlesi morphologically resemble those of P. falciparum. The late and mature trophozoites, schizonts and gametocytes appear very similar to those of P. malariae. Careful examinations revealed that some minor morphological differences existed between P. knowlesi and P. malariae. These include trophozoites of knowlesi with double chromatin dots and at times with two or three parasites per erythrocyte and mature schizonts of P. knowlesi having 16 merozoites, compared with 12 for P. malariae.ConclusionPlasmodium knowlesi infections in humans are not highly synchronous. The morphological resemblance of early trophozoites of P. knowlesi to P. falciparum and later erythrocytic stages to P. malariae makes it extremely difficult to identify P. knowlesi infections by microscopy alone.", "corpus_id": 13910587, "score": 0 }, { "doc_id": "13944321", "title": "Plasmodium knowlesi from archival blood films: Further evidence that human infections are widely distributed and not newly emergent in Malaysian Borneo", "abstract": "Human infections with Plasmodium knowlesi have been misdiagnosed by microscopy as Plasmodium malariae due to their morphological similarities. Although microscopy-identified P. malariae cases have been reported in the state of Sarawak (Malaysian Borno) as early as 1952, recent epidemiological studies suggest the absence of indigenous P. malariae infections. The present study aimed to determine the past incidence and distribution of P. knowlesi infections in the state of Sarawak based on archival blood films from patients diagnosed by microscopy as having P. malariae infections. Nested PCR assays were used to identify Plasmodium species in DNA extracted from 47 thick blood films collected in 1996 from patients in seven different divisions throughout the state of Sarawak. Plasmodium knowlesi DNA was detected in 35 (97.2%) of 36 blood films that were positive for Plasmodium DNA, with patients originating from all seven divisions. Only one sample was positive for P. malariae DNA. This study provides further evidence of the widespread distribution of human infections with P. knowlesi in Sarawak and its past occurrence. Taken together with data from previous studies, our findings suggest that P. knowlesi malaria is not a newly emergent disease in humans.", "corpus_id": 13944321, "score": 0 }, { "doc_id": "206779172", "title": "Spurious Amplification of a Plasmodium vivax Small-Subunit RNA Gene by Use of Primers Currently Used To Detect P. knowlesi", "abstract": "ABSTRACT The PCR primers commonly used to detect Plasmodium knowlesi infections in humans were found to cross-react stochastically with P. vivax genomic DNA. A nested primer set that targets one of the P. knowlesi small-subunit rRNA genes was validated for specificity and for sensitivity of detection of <10 parasite genomes.", "corpus_id": 206779172, "score": 0 }, { "doc_id": "3162096", "title": "Plasmodium knowlesi malaria in Vietnam: some clarifications", "abstract": "A recently published comment on a report of Plasmodium knowlesi infections in Vietnam states that this may not accurately represent the situation in the study area because the PCR primers used may cross-hybridize with Plasmodium vivax. Nevertheless, P. knowlesi infections have been confirmed by sequencing. In addition, a neighbour-joining tree based on the 18S S-Type SSUrRNA gene shows that the Vietnamese samples clearly cluster with the P. knowlesi isolates identified in Malaysia and are distinct from the corresponding P. vivax sequences. All samples came from asymptomatic individuals who did not consult for fever during the months preceding or following the survey, indicating that asymptomatic P. knowlesi infections occur in this population, although this does not exclude the occurrence of symptomatic cases. Large-scale studies to determine the extent and the epidemiology of P. knowlesi malaria in Vietnam are further needed.", "corpus_id": 3162096, "score": 0 }, { "doc_id": "18618836", "title": "Knowlesi malaria in Vietnam", "abstract": "The simian malaria parasite Plasmodium knowlesi is transmitted in the forests of Southeast Asia. Symptomatic zoonotic knowlesi malaria in humans is widespread in the region and is associated with a history of spending time in the jungle. However, there are many settings where knowlesi transmission to humans would be expected but is not found. A recent report on the Ra-glai population of southern central Vietnam is taken as an example to help explain why this may be so.", "corpus_id": 18618836, "score": 0 }, { "doc_id": "1016058", "title": "Evaluation of a Loop-Mediated Isothermal Amplification Method as a Tool for Diagnosis of Infection by the Zoonotic Simian Malaria Parasite Plasmodium knowlesi", "abstract": "ABSTRACT Loop-mediated isothermal amplification (LAMP) is a novel method that rapidly amplifies target DNA with high specificity under isothermal conditions. It has been applied as a diagnostic tool for several infectious diseases, including viral, bacterial, and parasitic diseases. In the present study, we developed a LAMP method for the molecular diagnosis of Plasmodium knowlesi infection (PkLAMP) and evaluated its sensitivity, specificity, and clinical applicability. We designed three sets of PkLAMP primers for the species-specific β-tubulin gene. The primer sets for PkLAMP specifically amplified the autologous DNA extracts of P. knowlesi, and the sensitivity of the test was 100-fold that of single-PCR assay. These results indicate that our PkLAMP method can be used to efficiently distinguish between P. knowlesi and other malaria parasites. To evaluate the feasibility of using in vivo materials, comparisons of PkLAMP and the conventional nested PCR (nPCR) method and microscopic examination were made with blood samples from two experimentally infected monkeys. These studies showed that P. knowlesi infection can be identified much earlier with PkLAMP than with nPCR and microscopy. Moreover, the detection performance of PkLAMP using whole blood as the template was identical to that of PkLAMP when genomic DNA extracts were used. These results suggest that the PkLAMP method is a promising tool for molecular diagnosis of P. knowlesi infection in areas of endemicity.", "corpus_id": 1016058, "score": 0 }, { "doc_id": "18471626", "title": "A TaqMan real-time PCR assay for the detection and quantitation of Plasmodium knowlesi", "abstract": "BackgroundThe misdiagnosis of Plasmodium knowlesi by microscopy has prompted a re-evaluation of the geographic distribution, prevalence and pathogenesis of this species using molecular diagnostic tools. In this report, a specific probe for P. knowlesi, that can be used in a previously described TaqMan real-time PCR assay for detection of Plasmodium spp., and Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale, was designed and validated against clinical samples.MethodsA hydrolysis probe for a real-time PCR assay was designed to recognize a specific DNA sequence within the P. knowlesi small subunit ribosomal RNA gene. The sensitivity, linearity and specificity of the assay were determined using plasmids containing P. knowlesi DNA and genomic DNA of P. falciparum, P. knowlesi, P. malariae, P. ovale and P. vivax isolated from clinical samples. DNA samples of the simian malaria parasites Plasmodium cynomolgi and Plasmodium inui that can infect humans under experimental conditions were also examined together with human DNA samples.ResultsAnalytical sensitivity of the P. knowlesi-specific assay was 10 copies/μL and quantitation was linear over a range of 10-106 copies. The sensitivity of the assay is equivalent to nested PCR and P. knowlesi DNA was detected from all 40 clinical P. knowlesi specimens, including one from a patient with a parasitaemia of three parasites/μL of blood. No cross-reactivity was observed with 67 Plasmodium DNA samples (31 P. falciparum, 23 P. vivax, six P. ovale, three P. malariae, one P. malariae/P. ovale, one P. falciparum/P. malariae, one P. inui and one P. cynomolgi) and four samples of human DNA.ConclusionsThis test demonstrated excellent sensitivity and specificity, and adds P. knowlesi to the repertoire of Plasmodium targets for the clinical diagnosis of malaria by real-time PCR assays. Furthermore, quantitation of DNA copy number provides a useful advantage over other molecular assays to investigate the correlation between levels of infection and the spectrum of disease.", "corpus_id": 18471626, "score": 0 }, { "doc_id": "46273937", "title": "Detection of Plasmodium knowlesi by real-time polymerase chain reaction.", "abstract": "We previously developed a real-time polymerase chain reaction (PCR) assay for detection of the four Plasmodium species that infect humans. Recent studies have shown that natural transmission of the simian parasite Plasmodium knowlesi to humans occurs frequently in Southeast Asia. We have expanded our PCR assay to include detection of P. knowlesi.", "corpus_id": 46273937, "score": 0 }, { "doc_id": "1607084", "title": "Applied Genomics: Data Mining Reveals Species-Specific Malaria Diagnostic Targets More Sensitive than 18S rRNA", "abstract": "ABSTRACT Accurate and rapid diagnosis of malaria infections is crucial for implementing species-appropriate treatment and saving lives. Molecular diagnostic tools are the most accurate and sensitive method of detecting Plasmodium, differentiating between Plasmodium species, and detecting subclinical infections. Despite available whole-genome sequence data for Plasmodium falciparum and P. vivax, the majority of PCR-based methods still rely on the 18S rRNA gene targets. Historically, this gene has served as the best target for diagnostic assays. However, it is limited in its ability to detect mixed infections in multiplex assay platforms without the use of nested PCR. New diagnostic targets are needed. Ideal targets will be species specific, highly sensitive, and amenable to both single-step and multiplex PCRs. We have mined the genomes of P. falciparum and P. vivax to identify species-specific, repetitive sequences that serve as new PCR targets for the detection of malaria. We show that these targets (Pvr47 and Pfr364) exist in 14 to 41 copies and are more sensitive than 18S rRNA when utilized in a single-step PCR. Parasites are routinely detected at levels of 1 to 10 parasites/μl. The reaction can be multiplexed to detect both species in a single reaction. We have examined 7 P. falciparum strains and 91 P. falciparum clinical isolates from Tanzania and 10 P. vivax strains and 96 P. vivax clinical isolates from Venezuela, and we have verified a sensitivity and specificity of ∼100% for both targets compared with a nested 18S rRNA approach. We show that bioinformatics approaches can be successfully applied to identify novel diagnostic targets and improve molecular methods for pathogen detection. These novel targets provide a powerful alternative molecular diagnostic method for the detection of P. falciparum and P. vivax in conventional or multiplex PCR platforms.", "corpus_id": 1607084, "score": 1 }, { "doc_id": "41284633", "title": "PCR as a Confirmatory Technique for Laboratory Diagnosis of Malaria", "abstract": "ABSTRACT We compared a nested PCR assay and microscopic examination of Giemsa-stained blood films for detection and identification of Plasmodium spp. in blood specimens. PCR was more sensitive than microscopy and capable of identifying malaria parasites at the species level when microscopy was equivocal.", "corpus_id": 41284633, "score": 0 }, { "doc_id": "4805748", "title": "Redefining the expressed prototype SICAvar gene involved in Plasmodium knowlesi antigenic variation", "abstract": "AbstractBackgroundThe SICAvar gene family, expressed at the surface of infected erythrocytes, is critical for antigenic variation in Plasmodium knowlesi. When this family was discovered, a prototypic SICAvar gene was characterized and defined by a 10-exon structure. The predicted 205-kDa protein lacked a convincing signal peptide, but included a series of variable cysteine-rich modules, a transmembrane domain encoded by the penultimate exon, and a cytoplasmic domain encoded by the final highly conserved exon. The 205 SICAvar gene and its family with up to 108 possible family members, was identified prior to the sequencing of the P. knowlesi genome. However, in the published P. knowlesi database this gene remains disjointed in five fragments. This study addresses a number of structural and functional questions that are critical for understanding SICAvar gene expression.MethodsDatabase mining, bioinformatics, and traditional genomic and post-genomic experimental methods including proteomic technologies are used here to confirm the genomic context and expressed structure of the prototype 205 SICAvar gene.\n Results\n This study reveals that the 205 SICAvar gene reported previously to have a 10-exon expressed gene structure has, in fact, 12 exons, with an unusually large and repeat-laden intron separating two newly defined upstream exons and the bona fide 5'UTR from the remainder of the gene sequence. The initial exon encodes a PEXEL motif, which may function to localize the SICA protein in the infected erythrocyte membrane. This newly defined start of the 205 SICAvar sequence is positioned on chromosome 5, over 340 kb upstream from the rest of the telomerically positioned SICAvar gene sequence in the published genome assembly. This study, however, verifies the continuity of these sequences, a 9.5 kb transcript, and provides evidence that the 205 SICAvar gene is located centrally on chromosome 5.ConclusionThe prototype 205 SICAvar gene has been redefined to have a 12-exon structure. These data are important because they 1) address questions raised in the P. knowlesi genome database regarding SICAvar gene fragments, numbers and structures, 2) show that this prototype gene encodes a PEXEL motif, 3) emphasize the need for further refinement of the P. knowlesi genome data, and 4) retrospectively, provide evidence for recombination within centrally located SICAvar sequences.", "corpus_id": 4805748, "score": 0 }, { "doc_id": "2541070", "title": "Jumbled Genomes: Missing Apicomplexan Synteny", "abstract": "Whole-genome comparisons provide insight into genome evolution by informing on gene repertoires, gene gains/losses, and genome organization. Most of our knowledge about eukaryotic genome evolution is derived from studies of multicellular model organisms. The eukaryotic phylum Apicomplexa contains obligate intracellular protist parasites responsible for a wide range of human and veterinary diseases (e.g., malaria, toxoplasmosis, and theileriosis). We have developed an in silico protein-encoding gene based pipeline to investigate synteny across 12 apicomplexan species from six genera. Genome rearrangement between lineages is extensive. Syntenic regions (conserved gene content and order) are rare between lineages and appear to be totally absent across the phylum, with no group of three genes found on the same chromosome and in the same order within 25 kb up- and downstream of any orthologous genes. Conserved synteny between major lineages is limited to small regions in Plasmodium and Theileria/Babesia species, and within these conserved regions, there are a number of proteins putatively targeted to organelles. The observed overall lack of synteny is surprising considering the divergence times and the apparent absence of transposable elements (TEs) within any of the species examined. TEs are ubiquitous in all other groups of eukaryotes studied to date and have been shown to be involved in genomic rearrangements. It appears that there are different criteria governing genome evolution within the Apicomplexa relative to other well-studied unicellular and multicellular eukaryotes.", "corpus_id": 2541070, "score": 0 }, { "doc_id": "4411221", "title": "Genome sequence of the human malaria parasite Plasmodium falciparum", "abstract": "The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host–parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria.", "corpus_id": 4411221, "score": 0 }, { "doc_id": "3542073", "title": "Comparative genomics of the neglected human malaria parasite Plasmodium vivax", "abstract": "The human malaria parasite Plasmodium vivax is responsible for 25–40% of the ∼515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.", "corpus_id": 3542073, "score": 0 }, { "doc_id": "11542997", "title": "Diagnostic Difficulties with Plasmodium knowlesi Infection in Humans", "abstract": "To the Editor: Studies conducted in Malaysia have raised questions about Plasmodium knowlesi as the fifth human pathogenic malaria parasite (1,2); additional cases of P. knowlesi malaria have subsequently been reported from other Asian countries (3–5). Microscopic diagnosis is hindered because P. knowlesi morphologically resembles P. falciparum or P. malariae, depending on blood stage (6). Singh et al. has designed a nested PCR assay for identification of P. knowlesi infections (1). \n \nAs part of an ongoing research project focusing on characterizing genes from malaria isolates in Indonesia (E. Sulistyanisih, unpub. data), during December 2008–February 2009, blood samples from 22 gold miners with uncomplicated malaria were collected in South Kalimantan Province in Indonesia. Ring forms typical for P. falciparum were seen during microscopy. DNA was extracted and species were identified by nested PCR by using Plasmodium genus- and species-specific primers derived from the small subunit ribosomal RNA gene described elsewhere (1). PCR products were directly sequenced and verified by 2 independent amplifications of the same DNA sample. PCR using P. knowlesi–specific primers yielded a 153-bp product in samples from 4 of the 22 malaria cases. Sequencing showed perfect matching with the recently published P. knowlesi S-type from Malaysian Borneo for 1 of the 4 samples. The other sequences were repeatedly consistent with the small subunit ribosomal RNA gene of sporozoite P. vivax (S-type), and random blasting (http://blast.ncbi.nlm.nih.gov) showed higher homology (93%–100%) with various P. vivax strains than with different P. knowlesi (<84%) or other Plasmodium strains. The vivax-specific PCR showed the expected bands in each case, and sequencing confirmed P. vivax A-type DNA that matched perfectly with a strain from Thailand. Of the miners with malaria, 3 case-patients were coinfected with P. falciparum. All 22 samples from the case-patients were negative for P. malariae. One case-patient (P 15) infected with P. knowlesi (4,000 parasite ring forms/μL) had a mixed infection with P. vivax and was successfully treated with chloroquine-primaquine (Table). \n \n \n \nTable \n \nProfile of Plasmodium knowlesi–positive patients, South Kalimantan Province, Indonesia, December 2008–February 2009* \n \n \n \nThe results of this study indicate the geographic distribution of natural P. knowlesi human infections includes Indonesian Borneo, although this detection is no surprise because many P. knowlesi isolates are found in Malaysian Borneo (1,2). However, the diagnosis would have been unrecognized without molecular techniques, and even those techniques posed a problem. \n \nThe species-specific nested PCR assay repeatedly showed bands of 153 bp, indicating 4 P. knowlesi cases, but sequencing confirmed P. knowlesi in only 1 sample. There was no indication of contamination of the samples tested by PCR, and the other 18 samples and the negative control remained negative for P. knowlesi. All 3 samples showed molecularly confirmed mixed infections with P. falciparum and P. vivax in the case-patients. As P. vivax was only molecularly detected, low parasitemia was assumed. \n \nThe reverse primer sequence (pmkr 9) is found in P. vivax S-type strains and other Plasmodium spp., especially those related to P. vivax, thus, amplification from this site should be theoretically possible. The forward primer pmk 8, on the other hand, seemed to be highly specific. \n \nOne Plasmodium strain (GenBank accession no. {\"type\":\"entrez-nucleotide\",\"attrs\":{\"text\":\"DQ660817\",\"term_id\":\"110084549\",\"term_text\":\"DQ660817\"}}DQ660817) found in orangutans in Kalimantan, Indonesia, and classified as P. vivax, seemed to be more likely to bind to pmk 8 (7). However, this classification was recently disproved by Singh and Divis (8), and the parasite was categorized as probably being P. pitheci or P. silvaticum, where human infections are not described. Other primate malaria parasites, such as P. hylobati, P. inui, P. cynomolgi, P. simium, P. fieldi, and P. simiovale, showed better binding sites for pmk 8 than P. vivax S- or A-strains. Regarding the theory of P. vivax originating in macaques in Southeast Asia and the close relationship to other primate malaria parasites (9), one might imagine that P. vivax strains in Indonesia differ slightly from the strains described so far. A P. vivax isolate from Indonesia, recently sequenced in cooperation with the University of Heidelberg (GenBank accession no. {\"type\":\"entrez-nucleotide\",\"attrs\":{\"text\":\"GU233452\",\"term_id\":\"283443763\",\"term_text\":\"GU233452\"}}GU233452), showed 2 point mutations; the patient had been in Flores, Bali, and Lembata. However, the 3 P. vivax samples presented no mutations at the pmk 8 binding sites. Notably, pmk 8 and pmkr 9 seem always to amplify the S-type and the rVIV 1 and rVIV 2 primers, the A-type DNA, respectively. The genus-specific DNA amplified both types at random. \n \nSome colleagues have experienced similar difficulties with the primers pmk 8 and pmkr 9 in samples from Vietnam (5); 2 of 5 samples gave false positive results for P. knowlesi. Unfortunately, their report did not mention which species was actually amplified (5). \n \nUntil recently, we had no satisfying explanation for the 3 assumed false-positive results. Then, in 2009, Imwong et al. reported that these P. knowlesi primers stochastically cross-react with P. vivax genomic DNA. No polymorphisms alleviating the binding of pmk8 were found; however, a new PCR for P. knowlesi was introduced (10). \n \nGiven the large distribution of the vector and the natural host of P. knowlesi in Southeast Asia, it is likely that P. knowlesi will be found in other parts of Indonesia. As microscopic and molecular diagnosis of this parasite seems difficult, the underestimation of its distribution and clinical relevance can be assumed.", "corpus_id": 11542997, "score": 0 }, { "doc_id": "6131863", "title": "Improved performance with saliva and urine as alternative DNA sources for malaria diagnosis by mitochondrial DNA-based PCR assays.", "abstract": "Saliva and urine from malaria-infected individuals contain trace amounts of Plasmodium DNA, and therefore, could be used as alternative specimens for diagnosis. A nested PCR targeting the mitochondrial cytochrome b gene (Cytb-PCR) of four human malaria species and Plasmodium knowlesi was developed and tested with 693 blood samples from febrile patients living in diverse malaria-endemic areas of Thailand, and compared with microscopy and nested PCR targeting small-subunit rRNA (18S-PCR). Cytb-PCR was 16% and 39.8% more sensitive than 18S-PCR and microscopy, respectively, in detecting all of these malarial species in blood samples. Importantly, 34% and 17% of Plasmodium falciparum and Plasmodium vivax mono-infections, respectively, detected by microscopy were, in fact, mixed P. falciparum and P. non-falciparum infections. Analysis of matched blood, saliva and urine from 157 individuals showed that microscopy and Cytb-PCR of saliva yielded no significant difference in detecting P. falciparum and P. vivax. However, Cytb-PCR of saliva was more sensitive than microscopy for diagnosis of mixed-species infections. A combination of Cytb-PCR of saliva and of urine significantly outperformed microscopy (p 0.0098 for P. falciparum, p 0.006 for P. vivax, and p 0.0002 for mixed infections). Furthermore, Plasmodium malariae and P. knowlesi could also be identified in saliva and urine with this method. Therefore, the Cytb-PCR developed herein offers a high potential for the use of both saliva and urine for malaria diagnosis, with a sensitivity comparable with or superior to that of microscopy.", "corpus_id": 6131863, "score": 0 }, { "doc_id": "38038054", "title": "Monkey malaria in humans: a diagnostic dilemma with conflicting laboratory data.", "abstract": "Plasmodium knowlesi has recently been recognized as the fifth Plasmodium species causing malaria in humans. Diagnosis is difficult morphologically, and currently, available rapid tests have not been comprehensively evaluated with this pathogen. We report a case of P. knowlesi malaria that was confirmed after the initial clue of discordant microscopy and immunochromatographic results, highlighting the importance of molecular diagnostics in cases with the relevant clinical and epidemiologic history.", "corpus_id": 38038054, "score": 0 }, { "doc_id": "25536577", "title": "Circos: an information aesthetic for comparative genomics.", "abstract": "We created a visualization tool called Circos to facilitate the identification and analysis of similarities and differences arising from comparisons of genomes. Our tool is effective in displaying variation in genome structure and, generally, any other kind of positional relationships between genomic intervals. Such data are routinely produced by sequence alignments, hybridization arrays, genome mapping, and genotyping studies. Circos uses a circular ideogram layout to facilitate the display of relationships between pairs of positions by the use of ribbons, which encode the position, size, and orientation of related genomic elements. Circos is capable of displaying data as scatter, line, and histogram plots, heat maps, tiles, connectors, and text. Bitmap or vector images can be created from GFF-style data inputs and hierarchical configuration files, which can be easily generated by automated tools, making Circos suitable for rapid deployment in data analysis and reporting pipelines.", "corpus_id": 25536577, "score": 0 } ]

{ "doc_id": "14673837", "title": "Corticosterone Acts in the Nucleus Accumbens to Enhance Dopamine Signaling and Potentiate Reinstatement of Cocaine Seeking", "abstract": "Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may “set the stage” for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induced increases in extracellular dopamine in the nucleus accumbens (NAc), and pharmacological blockade of NAc dopamine receptors blocked corticosterone-induced potentiation of reinstatement. Intra-accumbens administration of corticosterone reproduced the behavioral effects of stress and systemic corticosterone. Corticosterone treatment acutely decreased NAc dopamine clearance measured by fast-scan cyclic voltammetry, suggesting that inhibition of uptake2-mediated dopamine clearance may underlie corticosterone effects. Consistent with this hypothesis, intra-accumbens administration of the uptake2 inhibitor normetanephrine potentiated cocaine-induced reinstatement. Expression of organic cation transporter 3, a corticosterone-sensitive uptake2 transporter, was detected on NAc neurons. These findings reveal a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake.", "corpus_id": 14673837 }

[ { "doc_id": "11052298", "title": "Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states", "abstract": "RationaleEnvironmental stimuli associated with cocaine are known to elicit drug craving and increase the likelihood of relapse. However, the psychobiological changes that occur with exposure to these stimuli and in episodes of drug craving are not well understood. This study examined the response of brain stress circuits to environmental stimuli that are known to increase cocaine craving in cocaine dependent individuals.MethodsFifty-four treatment seeking cocaine dependent individuals, who were admitted to an inpatient treatment research unit for 2–4 weeks, participated in three laboratory sessions. Subjects were exposed to a brief 5-min guided imagery procedure that involved imagining a recent personal stressful situation, a drug-related situation and a neutral-relaxing situation, one imagery per session presented in random order. Subjective ratings of craving and anxiety, cardiovascular measures, and plasma levels of adrenocorticotrophic hormone (ACTH), cortisol, prolactin, norepinephrine (NE) and epinephrine (EPI) were assessed.ResultsExposure to stress and to drug cues each resulted in significant increases in cocaine craving and subjective anxiety, pulse rate, systolic blood pressure, ACTH, cortisol, prolactin and NE as compared to the response to neutral imagery. In addition, stress imagery also increased diastolic blood pressure and plasma EPI as compared to responses to the drug cue imagery and neutral-relaxing imagery.ConclusionsThe findings indicate a significant activation of the CRF-HPA axis and noradrenergic/sympatho-adreno-medullary (SAM) system response during stress-induced and drug cue induced cocaine craving states in cocaine dependent individuals. The role of stress system activation in cocaine craving and in cocaine use is discussed.", "corpus_id": 11052298, "score": 1 }, { "doc_id": "15139406", "title": "Neural mechanisms of addiction: the role of reward-related learning and memory.", "abstract": "Addiction is a state of compulsive drug use; despite treatment and other attempts to control drug taking, addiction tends to persist. Clinical and laboratory observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. The major substrates of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (involving the ventral and dorsal striatum and prefrontal cortex) that receive input from midbrain dopamine neurons. Here we review progress in identifying candidate mechanisms of addiction.", "corpus_id": 15139406, "score": 0 }, { "doc_id": "5984933", "title": "Correlation between behavior and extracellular dopamine levels in rat striatum: comparison of microdialysis and fast-scan cyclic voltammetry", "abstract": "Recently, fast-scan cyclic voltammetry (FSCV) has been adapted for real-time measurements of evoked dopamine (DA) release and uptake in freely moving rats. Using the advantages of this experimental design in combination with behavioral measures, we examined the effect of GBR 12909 (20 mg/kg, i.p.), a selective DA uptake inhibitor, on striatal extracellular DA dynamics and compared these data to that obtained by microdialysis. These studies established that both techniques report changes in DA that correlate with the kinetics of GBR 12909-induced behavioral effects. However, the time course of changes in evoked DA levels detected by FSCV was more closely linked with the changes in stereotypy than microdialysis measurements.", "corpus_id": 5984933, "score": 1 }, { "doc_id": "18659140", "title": "Corticosterone-Sensitive Monoamine Transport in the Rat Dorsomedial Hypothalamus: Potential Role for Organic Cation Transporter 3 in Stress-Induced Modulation of Monoaminergic Neurotransmission", "abstract": "Glucocorticoid hormones act within the brain to alter physiological and behavioral responses to stress-related stimuli. Previous studies indicated that acute stressors can increase serotonin [5-hydroxytryptamine (5-HT)] concentrations in the dorsomedial hypothalamus (DMH), a midline hypothalamic structure involved in the integration of physiological and behavioral responses to stress. The current study tests the hypothesis that rapid, stress-induced accumulation of 5-HT is attributable to the inhibition of 5-HT transport via organic cation transporters (OCTs). OCTs are a family of high-capacity, bidirectional, multispecific transporters of organic cations (including 5-HT, dopamine, and norepinephrine) only recently described in brain. In peripheral tissues, organic cation transport via some OCTs is inhibited by corticosterone. We examined the expression and function of OCTs in the periventricular medial hypothalamus of male Sprague Dawley rats using reverse-transcriptase (RT)-PCR, immunohistochemistry, and in vitro transport assays. RT-PCR revealed expression of OCT3 mRNA, but not OCT1 or OCT2 mRNA, in the medial hypothalamus. OCT3-like immunoreactivity was observed in ependymal and glial-like cells in the DMH. Acutely prepared minces of rat medial hypothalamic tissue accumulated the OCT substrates [3H]-histamine and [3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+). Consistent with the pharmacological profile of OCT3, corticosterone, 5-HT, estradiol, and the OCT inhibitor decynium22 dose-dependently inhibited histamine accumulation. Corticosterone and decynium22 also inhibited efflux of [3H]-MPP+ from hypothalamic minces. These data support the hypothesis that corticosterone-induced inhibition of OCT3 mediates stress-induced accumulation of 5-HT in the DMH and suggest that corticosterone may acutely modulate physiological and behavioral responses to stressors by altering serotonergic neurotransmission in this brain region.", "corpus_id": 18659140, "score": 1 }, { "doc_id": "8532334", "title": "Surgical Adrenalectomy with Diurnal Corticosterone Replacement Slows Escalation and Prevents the Augmentation of Cocaine-Induced Reinstatement in Rats Self-Administering Cocaine Under Long-Access Conditions", "abstract": "The loss of control over cocaine use and persistently heightened susceptibility to drug relapse that define human cocaine addiction are consequences of drug-induced neuroplasticity and can be studied in rats self-administering cocaine under conditions of daily long access (LgA) as escalating patterns of drug intake and heightened susceptibility to reinstatement. This study investigated the potential contribution of elevated glucocorticoids at the time of LgA cocaine self-administration (SA) to these behavioral indices of addiction-related neuroplasticity. Rats provided 14 days of 6-h access (LgA) to cocaine showed a progressive escalation of SA and were more susceptible to cocaine-induced reinstatement (10 mg/kg, i.p.) compared to rats self-administering under short-access (ShA; 2 h) conditions. A surgical adrenalectomy and corticosterone replacement (ADX/C) regimen that eliminated SA-induced increases in corticosterone (CORT) while maintaining the diurnal pattern of secretion failed to alter SA or reinstatement in ShA rats but slowed escalation and attenuated later reinstatement in LgA rats when applied before but not after chronic LgA SA testing. Although the contribution of other adrenal hormones cannot be ruled out, these data suggest that elevated glucocorticoids at the time of cocaine exposure may be required for the effects of LgA SA on cocaine intake and later reinstatement. The inability of daily CORT administration before daily ShA SA, at a dose that reproduced the response during LgA SA, to mimic the effects of LgA SA suggests that elevated glucocorticoids during SA may play a permissive role in cocaine-induced neuroplasticity that contributes to addiction.", "corpus_id": 8532334, "score": 1 }, { "doc_id": "14817995", "title": "Adrenal Activity during Repeated Long-Access Cocaine Self-Administration is Required for Later CRF-Induced and CRF-Dependent Stressor-Induced Reinstatement in Rats", "abstract": "Understanding the neurobiological processes that contribute to the establishment and expression of stress-induced regulation of cocaine use in addicted individuals is important for the development of new and better treatment approaches. It has been previously shown that rats self-administering cocaine under long-access conditions (6 h daily) display heightened susceptibility to the reinstatement of extinguished cocaine seeking by a stressor, electric footshock, or i.c.v. administration of the stressor-responsive neuropeptide, corticotropin-releasing factor (CRF). This study tested the hypothesis that adrenal responsiveness during earlier long-access cocaine self-administration (SA) is necessary for the establishment of later CRF-dependent stress-induced reinstatement. Reinstatement by footshock, but not a cocaine challenge (10 mg/kg, i.p.) following long-access SA, was blocked by i.c.v. administration of the CRF receptor antagonist, α-helical CRF9−41 (10 μg). Elimination of SA-induced adrenal responses through surgical adrenalectomy and diurnal corticosterone replacement (ADX/C) before 14 days of SA under long-access conditions had minimal impact on cocaine SA, but blocked later footshock-induced reinstatement. By contrast, ADX/C after SA, but before extinction and reinstatement testing, failed to reduce footshock-induced reinstatement. Likewise, ADX/C before 14 days long-access SA prevented later reinstatement by i.c.v. CRF (0.5 or 1.0 μg). However, significant CRF-induced reinstatement was observed when rats underwent ADX/C following SA, but before extinction and reinstatement testing, although a modest but statistically nonsignificant reduction in sensitivity to CRF's reinstating effects was observed. Taken together, these findings suggest that adrenal-dependent neuroadaptations in CRF responsiveness underlie the increased susceptibility to stress-induced relapse that emerges with repeated cocaine use.", "corpus_id": 14817995, "score": 1 }, { "doc_id": "45208576", "title": "Organic cation transporter 3 is densely expressed in the intercalated cell groups of the amygdala: Anatomical evidence for a stress hormone-sensitive dopamine clearance system", "abstract": "The intercalated cell groups of the amygdala (ITCs) are clusters of GABAergic neurons which exert powerful modulatory control of amygdala output, and are thought to play key roles in the extinction of conditioned fear responses. Dopamine, acting through D1 receptors, inhibits ITC neuronal activity, an action that has the potential to disinhibit amygdala activity, leading to changes in behavioral responses. Dopaminergic neurotransmission in the ITC occurs through a combination of synaptic and volume transmission. Thus, mechanisms, including transport mechanisms, that regulate extracellular dopamine concentrations in the ITC, are likely to be important determinants of amygdala function. We have recently demonstrated the expression of organic cation transporter 3 (OCT3), a high-capacity transporter for dopamine and other monoamines, throughout the rat brain. In this study, we used immunohistochemical and immunofluorescence techniques to examine the distribution of OCT3 in the ITC, to identify the phenotype of OCT3-expressing cells, and to describe the spatial relationships of OCT3 to dopaminergic terminals and dopamine D1 receptors in these areas. We observed high densities of OCT3-immunoreactive perikarya and punctae throughout the D1 receptor-rich main, anterior and paracapsular ITCs, in contrast with the basolateral amygdala, where OCT3 immunoreactive perikarya and puncta were observed at much lower density. OCT3-immunoreactive perikarya in the ITC were identified as neurons. Tyrosine hydroxylase-immunoreactive fibers in the ITC were immunonegative for OCT3, though OCT3-immunoreactive punctae were observed in close proximity to TH+ terminals. Punctate OCT3-immunoreactivity in the ITCs was observed in very close proximity (<1 μm) to D1 receptor immunoreactivity. These anatomical data are consistent with the hypothesis that OCT3 plays a central role in regulating dopaminergic neurotransmission in the ITC, and that it represents a post- or peri-synaptic dopamine clearance mechanism. Inhibition of OCT3-mediated transport by corticosterone may represent a mechanism by which acute stress alters dopaminergic neurotransmission in the amygdala, leading to alterations in fear and anxiety-like behavior.", "corpus_id": 45208576, "score": 0 }, { "doc_id": "16776760", "title": "Nongenomic Glucocorticoid Inhibition via Endocannabinoid Release in the Hypothalamus: A Fast Feedback Mechanism", "abstract": "Glucocorticoid negative feedback in the brain controls stress, feeding, and neural-immune interactions by regulating the hypothalamic—pituitary—adrenal axis, but the mechanisms of inhibition of hypothalamic neurosecretory cells have never been elucidated. Using whole-cell patch-clamp recordings in an acute hypothalamic slice preparation, we demonstrate a rapid suppression of excitatory glutamatergic synaptic inputs to parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) by the glucocorticoids dexamethasone and corticosterone. The effect was maintained with dexamethasone conjugated to bovine serum albumin and was not seen with direct intracellular glucocorticoid perfusion via the patch pipette, suggesting actions at a membrane receptor. The presynaptic inhibition of glutamate release by glucocorticoids was blocked by postsynaptic inhibition of G-protein activity with intracellular GDP-β-S application, implicating a postsynaptic G-protein-coupled receptor and the release of a retrograde messenger. The glucocorticoid effect was not blocked by the nitric oxide synthesis antagonist NG-nitro-l-arginine methyl ester hydrochloride or by hemoglobin but was blocked completely by the CB1 cannabinoid receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] and AM281 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide] and mimicked and occluded by the cannabinoid receptor agonist WIN55,212-2 [(β)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate], indicating that it was mediated by retrograde endocannabinoid release. Several peptidergic subtypes of parvocellular neuron, identified by single-cell reverse transcripton-PCR analysis, were subject to rapid inhibitory glucocorticoid regulation, including corticotropin-releasing hormone-, thyrotropin-releasing hormone-, vasopressin-, and oxytocin-expressing neurons. Therefore, our findings reveal a mechanism of rapid glucocorticoid feedback inhibition of hypothalamic hormone secretion via endocannabinoid release in the PVN and provide a link between the actions of glucocorticoids and cannabinoids in the hypothalamus that regulate stress and energy homeostasis.", "corpus_id": 16776760, "score": 0 }, { "doc_id": "35895801", "title": "Transition from moderate to excessive drug intake: change in hedonic set point.", "abstract": "Differential access to cocaine self-administration produced two patterns of drug intake in rats. With 1 hour of access per session, drug intake remained low and stable. In contrast, with 6 hours of access, drug intake gradually escalated over days. After escalation, drug consumption was characterized by an increased early drug loading and an upward shift in the cocaine dose-response function, suggesting an increase in hedonic set point. After 1 month of abstinence, escalation of cocaine intake was reinstated to a higher level than before. These findings may provide an animal model for studying the development of excessive drug intake and the basis of addiction.", "corpus_id": 35895801, "score": 0 } ]

{ "doc_id": "58009915", "title": "Diagnosis of Bacterial Pathogens in the Urine of Urinary-Tract-Infection Patients Using Surface-Enhanced Raman Spectroscopy", "abstract": "(1) Background: surface-enhanced Raman spectroscopy (SERS) is a novel method for bacteria identification. However, reported applications of SERS in clinical diagnosis are limited. In this study, we used cylindrical SERS chips to detect urine pathogens in urinary tract infection (UTI) patients. (2) Methods: Urine samples were retrieved from 108 UTI patients. A 10 mL urine sample was sent to conventional bacterial culture as a reference. Another 10 mL urine sample was loaded on a SERS chip for bacteria identification and antibiotic susceptibility. We concentrated the urine specimen if the intensity of the Raman spectrum required enhancement. The resulting Raman spectrum was analyzed by a recognition software to compare with spectrum-form reference bacteria and was further confirmed by principal component analysis (PCA). (3) Results: There were 97 samples with single bacteria species identified by conventional urine culture and, among them, 93 can be successfully identified by using SERS without sample concentration. There were four samples that needed concentration for bacteria identification. Antibiotic susceptibility can also be found by SERS. There were seven mixed flora infections found by conventional culture, which can only be identified by the PCA method. (4) Conclusions: SERS can be used in the diagnosis of urinary tract infection with the aid of the recognition software and PCA.", "corpus_id": 58009915 }

[ { "doc_id": "39706914", "title": "Multidrug-Resistant Urinary Tract Isolates ofEscherichia coli: Prevalence and Patient Demographics in the United States in 2000", "abstract": "ABSTRACT Concurrent resistance to antimicrobials of different structural classes has arisen in a multitude of bacterial species and may complicate the therapeutic management of infections, including those of the urinary tract. To assess the current breadth of multidrug resistance among urinary isolates of Escherichia coli, the most prevalent pathogen contributing to these infections, all pertinent results in The Surveillance Network Database—USA from 1 January to 30 September 2000 were analyzed. Results were available for 38,835 urinary isolates of E. coli that had been tested against ampicillin, cephalothin, ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole. Of these isolates, 7.1% (2,763 of 38,835) were resistant to three or more agents and considered multidrug resistant. Among the multidrug-resistant isolates, 97.8% were resistant to ampicillin, 92.8% were resistant to trimethoprim-sulfamethoxazole, 86.6% were resistant to cephalothin, 38.8% were resistant to ciprofloxacin, and 7.7% were resistant to nitrofurantoin. The predominant phenotype among multidrug-resistant isolates (57.9%; 1,600 of 2,793) included resistance to ampicillin, cephalothin, and trimethoprim-sulfamethoxazole. This was the most common phenotype regardless of patient age, gender, or inpatient-outpatient status and in eight of the nine U.S. Bureau of the Census regions. Rates of multidrug resistance were demonstrated to be higher among males (10.4%) than females (6.6%), among patients >65 years of age (8.7%) than patients ≤17 (6.8%) and 18 to 65 (6.1%) years of age, and among inpatients (7.6%) than outpatients (6.9%). Regionally, the rates ranged from 4.3% in the West North Central region to 9.2% in the West South Central region. Given the current prevalence of multidrug resistance among urinary tract isolates ofE. coli in the United States (7.1%), continued local, regional, and national surveillance is warranted.", "corpus_id": 39706914, "score": 0 }, { "doc_id": "26834221", "title": "Bacteriuria in representative population samples of persons aged 72-79 years.", "abstract": "Screening for bacteriuria was performed between 1984 and 1988 in persons aged 72-79 years representative of the general population in Göteborg, Sweden. The frequency of bacteriuria (greater than or equal to 10(5)/ml) at a single screening was 6% and 16% at age 72 years and 6% and 14% at age 79 years for the screened men (n = 235 and 259) and women (n = 259 and 297), respectively. By repeated screening after one month and 30 months of those previously negative at age 72 years, an additional 4% and 3% of men and 3% and 7% of women with bacteriuria were detected. Bacteriuric persons were excluded from further screening and controlled by frequent cultures during several years, with careful monitoring of clinical interventions. The persistence of untreated bacteriuria was analyzed in relation to bacterial species and number in the untreated subgroup of bacteriuric individuals. Nine of 10 Escherichia coli (E. coli) with less than 10(6)/ml and 22/22 non-E. coli strains disappeared spontaneously. In contrast, 20/26 (77%, p less than 0.01) with greater than or equal to 10(6) E. coli/ml persisted. Of 17 persons with bacteriuria persisting at least 12 months, 16 were women and 16 had E. coli. Of 201 E. coli cultures obtained from this group, 94% had greater than or equal to 10(6)/ml, and 99% had greater than or equal to 5 x 10(5)/ml. The results indicate that screening for high counts (greater than 10(6)/ml) of E. coli most effectively detects persisting bacteriuria in the general elderly population.", "corpus_id": 26834221, "score": 0 }, { "doc_id": "46702756", "title": "WIDESPREAD DISTRIBUTION OF URINARY TRACT INFECTIONS CAUSED BY A MULTIDRUG-RESISTANT ESCHERICHIA COLI CLONAL GROUP", "abstract": "A BSTRACT Background The management of urinary tract infections is complicated by the increasing prevalence of antibiotic-resistant strains of Escherichia coli. We studied the clonal composition of E. coli isolates that were resistant to trimethoprim–sulfamethoxazole from women with community-acquired urinary tract infections. Methods Prospectively collected E. coli isolates from women with urinary tract infections in a university community in California were evaluated for antibiotic susceptibility, O:H serotype, DNA fingerprinting, pulsed-field gel electrophoretic pattern, and virulence factors. The prevalence and characteristics of an antibiotic-resistant clone were evaluated in this group of isolates and in those from comparison cohorts in Michigan and Minnesota. Results Fifty-five of the 255 E. coli isolates (22 percent) from the California cohort were resistant to trimethoprim–sulfamethoxazole as well as other antibiotics. There was a common pattern of DNA fingerprinting, suggesting that the isolates belonged to the same clonal group (clonal group A), in 28 of 55 isolates with trimethoprim–sulfamethoxazole resistance (51 percent) and in 2 of 50 randomly selected isolates that were susceptible to trimethoprim–sulfamethoxazole (4 percent, P<0.001). In addition, 11 of 29 resistant isolates (38 percent) from the Michigan cohort and 7 of 18 (39 percent) from the Minnesota cohort belonged to clonal group A. Most of the clonal group A isolates were serotype O11:H(nt) or O77:H(nt), with similar patterns of virulence factors, antibiotic susceptibility, and electrophoretic features. Conclusions In three geographically diverse communities, a single clonal group accounted for nearly half of community-acquired urinary tract infections in women that were caused by E. coli strains with resistance to trimethoprim–sulfamethoxazole. The widespread distribution and high prevalence of E. coli clonal group A have major public health implications. (N Engl J Med 2001;345:1007-13.)", "corpus_id": 46702756, "score": 0 }, { "doc_id": "79024721", "title": "The laboratory diagnosis of urinary tract infection", "abstract": "Urinary tract infection is common, and it is not surprising that urine specimens make up a large proportion of those samples submitted to the routine diagnostic laboratory. Many of these specimens will show no evidence of infection and several methods can be used to screen out negative samples. Those that grow bacteria need to be carefully assessed to quantify the degree of bacteriuria and hence clinical relevance. To influence treatment, a final report should be produced within 24 hours of specimen receipt, with turnaround times continuously monitored. Much work needs to be done to determine the cost effectiveness involved in processing urine specimens and the evidence base for the final report provided.", "corpus_id": 79024721, "score": 0 }, { "doc_id": "45994494", "title": "Identification of Rare Pathogenic Bacteria in a Clinical Microbiology Laboratory: Impact of Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry", "abstract": "ABSTRACT During the past 5 years, matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry (MS) has become a powerful tool for routine identification in many clinical laboratories. We analyzed our 11-year experience in routine identification of clinical isolates (40 months using MALDI-TOF MS and 91 months using conventional phenotypic identification [CPI]). Among the 286,842 clonal isolates, 284,899 isolates of 459 species were identified. The remaining 1,951 isolates were misidentified and required confirmation using a second phenotypic identification for 670 isolates and using a molecular technique for 1,273 isolates of 339 species. MALDI-TOF MS annually identified 112 species, i.e., 36 species/10,000 isolates, compared to 44 species, i.e., 19 species/10,000 isolates, for CPI. Only 50 isolates required second phenotypic identifications during the MALDI-TOF MS period (i.e., 4.5 reidentifications/10,000 isolates) compared with 620 isolates during the CPI period (i.e., 35.2/10,000 isolates). We identified 128 bacterial species rarely reported as human pathogens, including 48 using phenotypic techniques (22 using CPI and 37 using MALDI-TOF MS). Another 75 rare species were identified using molecular methods. MALDI-TOF MS reduced the time required for identification by 55-fold and 169-fold and the cost by 5-fold and 96-fold compared with CPI and gene sequencing, respectively. MALDI-TOF MS was a powerful tool not only for routine bacterial identification but also for identification of rare bacterial species implicated in human infectious diseases. The ability to rapidly identify bacterial species rarely described as pathogens in specific clinical specimens will help us to study the clinical burden resulting from the emergence of these species as human pathogens, and MALDI-TOF MS may be considered an alternative to molecular methods in clinical laboratories.", "corpus_id": 45994494, "score": 0 }, { "doc_id": "12229134", "title": "Sensitive cylindrical SERS substrate array for rapid microanalysis of nucleobases.", "abstract": "In this work, a cylindrical-substrate array for surface-enhanced Raman scattering (SERS) measurements was developed to enable analysis of nucleobases in a few microliters of liquid. To eliminate uncertainties associated with SERS detection of aqueous samples, a new type of cylindrical SERS substrate was designed to confine the aqueous sample at the tip of the SERS probe. Poly(methyl methacrylate) (PMMA) optical fibers in a series of different diameters were used as the basic substrate. A solution of poly(vinylidene fluoride)/dimethylformamide (PVDF/DMF) was used to coat the tip of each fiber to increase the surface roughness and facilitate adsorption of silver nanoparticles (AgNPs) for enhancing Raman signals. A chemical reduction method was used to form AgNPs in and on the PVDF coating layer. The reagents and reaction conditions were systematically examined with the aim of estimating the optimum parameters. Unlike the spreading of aqueous sample on most SERS substrates, particularly flat ones, the new SERS substrates showed enough hydrophobicity to restrict aqueous sample to the tip area, thus enabling quantitative analysis. The required volume of sample could be as low as 1 μL with no need for a drying step in the procedure. By aligning the cylindrical SERS substrates into a solid holder, an array of cylindrical substrates was produced for mass analysis of aqueous samples. This new substrate improves both reproducibility and sensitivity for detection in aqueous samples. The enhancement factor approaches 7 orders in magnitude with a relative standard error close to 8%. Using the optimized conditions, nucleobases of adenine, cytosine, thymine, and uracil could be detected with limits approaching a few hundreds nanomolar in only a few microliters of solution.", "corpus_id": 12229134, "score": 1 }, { "doc_id": "36643503", "title": "Raman's “Effect” on Molecular Imaging", "abstract": "Raman spectroscopy is an optical technique that offers unsurpassed sensitivity and multiplexing capabilities to the field of molecular imaging. In the past, Raman spectroscopy had predominantly been used as an analytic tool for routine chemical analysis, but more recently, researchers have been able to harness its unique properties for imaging and spectral analysis of molecular interactions in cell populations and preclinical animal models. Additionally, researchers have already begun to translate this optical technique into a novel clinical diagnostic tool using various endoscopic strategies.", "corpus_id": 36643503, "score": 0 }, { "doc_id": "33777781", "title": "Controlled plasmonic nanostructures for surface-enhanced spectroscopy and sensing.", "abstract": "After its discovery more than 30 years ago, surface-enhanced Raman spectroscopy (SERS) was expected to have major impact as a sensitive analytical technique and tool for fundamental studies of surface species. Unfortunately, the lack of reliable and reproducible fabrication methods limited its applicability. In recent years, SERS has enjoyed a renaissance, and there is renewed interest in both the fundamentals and applications of SERS. New techniques for nanofabrication, the design of substrates that maximize the electromagnetic enhancement, and the discovery of single-molecule SERS are driving the resurgence of this field. This Account highlights our group's recent work on SERS. Initially, we discuss SERS substrates that have shown proven reproducibility, stability, and large field enhancement. These substrates enable many analytical applications, such as anthrax detection, chemical warfare agent stimulant detection, and in vitro and in vivo glucose sensing. We then turn to a detailed study of the wavelength and distance dependence of SERS, which further illustrate predictions obtained from the electromagnetic enhancement mechanism. Last, an isotopic labeling technique applied to the rhodamine 6G (R6G)/silver system serves as an additional proof of the existence of single-molecule SERS and explores the dynamical features of this process. This work, in conjunction with theoretical calculations, allows us to comment on the possible role of charge transfer in the R6G/silver system.", "corpus_id": 33777781, "score": 0 }, { "doc_id": "31157493", "title": "Diagnosis of bacterial pathogens in the dialysate of peritoneal dialysis patients with peritonitis using surface-enhanced Raman spectroscopy.", "abstract": "BACKGROUND\nBacterial peritonitis is the most common cause of peritoneal dialysis (PD) therapy drop-out. A quick and accurate diagnosis of the bacterial pathogen can reduce the PD drop-out rate. Surface-enhanced Raman spectroscopy (SERS) can rapidly identify bacteria using chips coated with nano-sized metal particles.\n\n\nMETHODS\nKnown bacteria were loaded in the SERS-chips and illuminated with laser light to establish a reference Raman spectra library. Dialysate from PD peritonitis patients was concentrated by centrifuge and examined with the same SERS, and the resulting Raman spectra were compared with library spectra for bacteria identification. Principal component analysis was used for further confirmation. The same batches of dialysate were sent to routine culture as a reference bacteria identification method. The results of the 2 identification methods were compared.\n\n\nRESULTS\nA total of 43 paired-samples were sent for study. There were 37 samples with bacteria identified but 6 were culture-negative by the reference method. 31 bacteria were identified in paired-samples by SERS, among which, 29 bacteria were exactly the same as those identified by the reference method. Bacteria not included in the reference library spectra cannot be identified.\n\n\nCONCLUSIONS\nSERS techniques can rapidly identify bacterial pathogens in the dialysate of PD peritonitis patients.", "corpus_id": 31157493, "score": 1 }, { "doc_id": "16256382", "title": "Rapid bacterial antibiotic susceptibility test based on simple surface-enhanced Raman spectroscopic biomarkers", "abstract": "Rapid bacterial antibiotic susceptibility test (AST) and minimum inhibitory concentration (MIC) measurement are important to help reduce the widespread misuse of antibiotics and alleviate the growing drug-resistance problem. We discovered that, when a susceptible strain of Staphylococcus aureus or Escherichia coli is exposed to an antibiotic, the intensity of specific biomarkers in its surface-enhanced Raman scattering (SERS) spectra drops evidently in two hours. The discovery has been exploited for rapid AST and MIC determination of methicillin-susceptible S. aureus and wild-type E. coli as well as clinical isolates. The results obtained by this SERS-AST method were consistent with that by the standard incubation-based method, indicating its high potential to supplement or replace existing time-consuming methods and help mitigate the challenge of drug resistance in clinical microbiology.", "corpus_id": 16256382, "score": 0 }, { "doc_id": "3332015", "title": "A novel method for discrimination of beef and horsemeat using Raman spectroscopy.", "abstract": "A new approach, based on the usage of Raman spectroscopy in combination with chemometrics, was developed for the rapid determination of beef adulteration with horsemeat. The data mining process of collected Raman spectra was performed with principal component analysis (PCA). Pure fat samples, extracted from forty-nine meat beef and horsemeat samples, were analysed using the Raman spectroscopy. All meat samples were classified successfully according to their origins. The presence of different concentrations (25%, 50%, 75%, w/w) of horsemeat in beef was also differentiated using the developed model system. This study offers a rapid assay for determination of meat adulteration by discriminating beef and horsemeat with high accuracy, a short analysis time (30s) and no requirement for time-consuming sample preparation procedures.", "corpus_id": 3332015, "score": 1 }, { "doc_id": "5252172", "title": "Single-molecule surface-enhanced Raman spectroscopy of nonresonant molecules.", "abstract": "Single-molecule surface-enhanced Raman scattering (SERS) detection of nonresonant molecules is demonstrated experimentally using the bianalyte SERS method. To this end, bianalyte SERS is performed at 633 nm excitation using the nonresonant molecule 1,2-di-(4-pyridyl)-ethylene (BPE) in combination with a benzotriazole derivative as a partner. The results are then extended to the even more challenging case of a small nonresonant molecule, adenine, using an isotopically substituted adenine as bianalyte SERS partners. In addition, SERS cross sections of single-molecule events are quantified, thus providing estimates of the enhancement factors needed to see them. It turns out that an enhancement factor on the order of approximately 5 x 10(9) was sufficient for single-molecule detection of BPE, while maximum enhancement factors of approximately 5 x 10(10) were observed in extreme cases. In the case of adenine, single-molecule detection was only possible in the rare cases with enhancement factors of approximately 10(11). This study constitutes a quantitative fundamental test into the lowest detection limits (in terms of differential cross sections) for single-molecule SERS.", "corpus_id": 5252172, "score": 0 }, { "doc_id": "137353585", "title": "Functionalized arrays of raman-enhancing nanoparticles for capture and culture-free analysis of bacteria in human blood", "abstract": "Detecting bacteria in clinical samples without the time-consuming culture process is most desired for rapid diagnosis. Such a culture-free detection needs to capture and analyze bacteria from a body fluid usually containing complicate constituents. Here we show that vancomycin (Van) coating of a special substrate with arrays of Ag-nanoparticles, which can provide label-free analysis of bacteria via surface enhanced Raman spectroscopy (SERS), leads to 1000 folds increase in its capability to capture bacteria without introducing significant spectral interference. Bacteria spiked in human blood can be concentrated onto a microscopic Van-coated area while blood cells are excluded. Furthermore, A Van-coated substrate provides distinctly different SERS spectra of Van-susceptible and Van-resistant Enterococcus, indicating its potential use for drug-resistance test. Our results represent a critical step towards the creation of SERS-based multifunctional biochips for rapid culture/label-free detection and drug-resistant testing of microorganisms in clinical samples.", "corpus_id": 137353585, "score": 0 }, { "doc_id": "206360637", "title": "Combined dielectrophoresis-Raman setup for the classification of pathogens recovered from the urinary tract.", "abstract": "Rapid and effective methods of pathogen identifications are of major interest in clinical microbiological analysis to administer timely tailored antibiotic therapy. Raman spectroscopy as a label-free, culture-independent optical method is suitable to identify even single bacteria. However, the low bacteria concentration in body fluids makes it difficult to detect their characteristic molecular fingerprint directly in suspension. Therefore, in this study, Raman spectroscopy is combined with dielectrophoresis, which enables the direct translational manipulation of bacteria in suspensions with spatial nonuniform electrical fields so as to perform specific Raman spectroscopic characterization. A quadrupole electrode design is used to capture bacteria directly from fluids in well-defined microsized regions. With live/dead fluorescence viability staining, it is verified, that the bacteria survive this procedure for the relevant range of field strengths. The dielectrophoretic enrichment of bacteria allows for obtaining high quality Raman spectra in dilute suspensions with an integration time of only one second. As proof-of-principle study, the setup was tested with Escherichia coli and Enterococcus faecalis, two bacterial strains that are commonly encountered in urinary tract infections. Furthermore, to verify the potential for dealing with real world samples, pathogens from patients' urine have been analyzed. With the additional help of multivariate statistical analysis, a robust classification model could be built and allowed the classification of those two strains within a few minutes. In contrast, the standard microbiological diagnostics are based on very time-consuming cultivation tests. This setup holds the potential to reduce the crucial parameter diagnosis time by orders of magnitude.", "corpus_id": 206360637, "score": 0 }, { "doc_id": "22369040", "title": "Development of a Loop Mediated Isothermal Amplification (LAMP) - Surface Enhanced Raman spectroscopy (SERS) Assay for the Detection of Salmonella Enterica Serotype Enteritidis", "abstract": "As a major foodborne pathogen, Salmonella enterica serotype Enteritidis is increasingly rising as a global health concern. Here, we developed an integrated assay that combines loop mediated isothermal amplification (LAMP) and surface enhanced Raman spectroscopy (SERS) for DNA detection of S. Enteritidis using specifically designed Raman active Au-nanoprobes. The target DNA was amplified by LAMP and then labeled with Au-nanoprobes comprised of gold nanoparticle-modified with specific cy5/DNA probes to allow the detection by SERS. The sensitivity of the developed LAMP-SERS detection assay (66 CFU/mL) was ~100-fold higher than the conventional polymerase chain reaction (PCR) method. Significantly, this technique allowed highly specific detection of the target DNA of S. Enteritidis and could differentiate it from the DNA of closely related bacterial species or non-specific contamination, making it more accurate and reliable than the standard LAMP technique. The applicability of detection of S. Enteritidis in milk samples using LAMP-SERS assay was validated as well. In sum, the developed LAMP-SERS assay is highly specific and sensitive, and has the potential to be applied for rapid detection of different foodborne pathogens and other microbial contaminants.", "corpus_id": 22369040, "score": 0 }, { "doc_id": "4323103", "title": "Surface enhanced Raman spectroscopy of Chlamydia trachomatis and Neisseria gonorrhoeae for diagnostics, and extra-cellular metabolomics and biochemical monitoring", "abstract": "SERS spectra excited at 785 nm of the bacteria Chlamydia trahomatis (elementary bodies, EB) and Neisseria gonorrheoae, the causative pathogens for the two most common sexually transmitted diseases (STD), chlamydia and gonorrhea, respectively, are reported. Although both are Gram-negative bacteria, the SERS signatures of C. trachomatis and N. gonorrheoae are completely different. N. gonorrheoae SERS spectra are due to the starvation induced nucleotide metabolites adenine and guanine, and the surface associated co-enzyme nicotinamide adenine dinucleotide and are very similar on Au and Ag although the spectrum appears more rapidly on Ag. The C. trachomatis SERS spectrum is dominated by the vibrational features of cell surface proteins. While features attributable to specific residues and the amide backbone characterize the C. trachomatis spectrum on Ag, the corresponding SERS spectrum on Au substrates displays vibrational characteristics of aggregated proteins. The prospects for the development of a SERS based platform for rapid (<one hour), low-cost bacterial STD diagnostics are promising based on these initial studies. Furthermore, this biomedical application demonstrates the potential for SERS to be a sensitive real time probe of the dynamics of biochemical activity in the cell wall and extracellular regions of microorganisms.", "corpus_id": 4323103, "score": 0 }, { "doc_id": "27786171", "title": "Nanotools and molecular techniques to rapidly identify and fight bacterial infections.", "abstract": "Reducing the emergence and spread of antibiotic-resistant bacteria is one of the major healthcare issues of our century. In addition to the increased mortality, infections caused by multi-resistant bacteria drastically enhance the healthcare costs, mainly because of the longer duration of illness and treatment. While in the last 20years, bacterial identification has been revolutionized by the introduction of new molecular techniques, the current phenotypic techniques to determine the susceptibilities of common Gram-positive and Gram-negative bacteria require at least two days from collection of clinical samples. Therefore, there is an urgent need for the development of new technologies to determine rapidly drug susceptibility in bacteria and to achieve faster diagnoses. These techniques would also lead to a better understanding of the mechanisms that lead to the insurgence of the resistance, greatly helping the quest for new antibacterial systems and drugs. In this review, we describe some of the tools most currently used in clinical and microbiological research to study bacteria and to address the challenge of infections. We discuss the most interesting advancements in the molecular susceptibility testing systems, with a particular focus on the many applications of the MALDI-TOF MS system. In the field of the phenotypic characterization protocols, we detail some of the most promising semi-automated commercial systems and we focus on some emerging developments in the field of nanomechanical sensors, which constitute a step towards the development of rapid and affordable point-of-care testing devices and techniques. While there is still no innovative technique that is capable of completely substituting for the conventional protocols and clinical practices, many exciting new experimental setups and tools could constitute the basis of the standard testing package of future microbiological tests.", "corpus_id": 27786171, "score": 0 }, { "doc_id": "21964491", "title": "Label-free highly sensitive detection of proteins in aqueous solutions using surface-enhanced Raman scattering.", "abstract": "We detected concentration-dependent surface-enhanced Raman scattering (SERS) spectra of several label-free proteins (lysozyme, ribonuclease B, avidin, catalase, and hemoglobin) for the first time in aqueous solutions. Acidified sulfate was used as an aggregation agent to induce high electromagnetic enhancement in SERS. Strong SERS spectra of simple and conjugated protein samples could easily be accessed after the pretreatment with the aggregation agent. The detection limits of the proposed method for lysozyme and catalase were as low as 5 microg/mL and 50 ng/mL, respectively. This detection protocol for label-free proteins has combined simplicity, sensitivity, and reproducibility and allows routine qualitative and relatively quantitative detections. Thus, it has great potential in practical high-throughput protein detections.", "corpus_id": 21964491, "score": 1 }, { "doc_id": "44849967", "title": "Detection of bacteria by surface-enhanced Raman spectroscopy", "abstract": "AbstractThe detection and identification of dilute bacterial samples by surface-enhanced Raman spectroscopy has been explored by mixing aqueous suspensions of bacteria with a suspension of nanocolloidal silver particles. An estimate of the detection limit of E. coli was obtained by varying the concentration of bacteria. By correcting the Raman spectra for the broad librational OH band of water, reproducible spectra were obtained for E. coli concentrations as low as approximately 103 cfu/mL. To aid in the assignment of Raman bands, spectra for E. coli in D2O are also reported.\n FigureLight scattering apparatus used to detect bacteria", "corpus_id": 44849967, "score": 1 }, { "doc_id": "206427811", "title": "Extended spectrum beta lactamase (ESBL) producing bacteria urinary tract infections and complex pediatric urology.", "abstract": "AIM OF THE STUDY\nExtended spectrum beta lactamase (ESBL) producing bacteria are resistant to most beta-lactam antibiotics including third-generation cephalosporins, quinolones and aminoglycosides. This resistance is plasmid-borne and can spread between species. Management of ESBL is challenging in children with recurrent urinary tract infections (UTIs) and complex urological abnormalities. We aim to quantify the risk in children and specifically in urological patients.\n\n\nMETHODS\nRetrospective review of a microbiology database (April 2014 to November 2015). This identified urine isolates, pyuria, ESBL growth and patient demographics. Data analysis was by Chi square, Mann-Whitney U-test and ANOVA. A P value of <0.05 was taken as significant.\n\n\nMAIN RESULTS\nAnalysis of 9418 urine samples showed 2619 with pure isolates, of which 1577 had pyuria (>10×106 WC/L). 136 urine cultures (n=79 patients) grew purely ESBL. Overall, 5.2% of urine isolates were ESBL and 9.5% isolates with pyuria (>100×106 WC/L) had ESBL, whereas only 22/1032 (2.1%) with no pyuria, (P<0.0001). Urology patients had 86/136 (63%) ESBL positive cultures. These represented 86/315 (27%) of all positive cultures for urology patients vs. 50/2267 (2.2%) for all other specialties (P<0.0001). Potential ESBL transmission between organisms occurred in 3 (all on prophylactic antibiotics). Over the study period, there was no significant rise of the monthly incidence between 2014 and 2015 (ANOVA P=0.1).\n\n\nCONCLUSION\nThis study is the first to document the incidence of ESBL in children (5%), and estimate the frequency of possible plasmid transmission between bacterial species in children. This quantifies the risk of ESBL, especially to urology patients, and mandates better antibiotic stewardship.\n\n\nLEVEL OF EVIDENCE\nLevel IIc.", "corpus_id": 206427811, "score": 0 }, { "doc_id": "11465062", "title": "Bacteremic Urinary Tract Infection Caused by Multidrug-Resistant Enterobacteriaceae Are Associated With Severe Sepsis at Admission", "abstract": "Abstract The purpose of this study is to compare the clinical features and treatment outcomes among patients with bacteremic urinary tract infection (UTI) caused by multidrug-resistant (MDR) and non-MDR Enterobacteriaceae and to identify whether MDR pathogens were independently associated with severe sepsis or septic shock at presentation. The clinical data of adult patients visiting and being treated at Chia-Yi Christian Hospital due to bacteremic UTI caused by Enterobacteriaceae from January 2006 to August 2015 were retrospectively analyzed. A total of 585 patients were enrolled. Among them, 220 (37.6%) were caused by the MDR Enterobacteriaceae. A total of 206 patients (35.2%) developed severe sepsis or septic shock at presentation. Patients in the MDR group tend to be male and have a past history of gout, recurrent UTI, prior hospitalization, hydronephrosis, renal stone, ureteral stone, indwelling urinary catheter, newly development of renal dysfunction, severe sepsis or septic shock, intensive care unit (ICU) admission, receipt of ineffective empirical therapy, longer hospital stay, and higher in-hospital mortality (2.7% vs 1.9%, P = 0.569). Using multivariate logistic regression analysis, it is revealed that independent predictors associated with severe sepsis or septic shock at presentation were liver cirrhosis (OR 2.868; 95% CI 1.439–5.716; P = 0.003), indwelling urinary catheter (OR 1.936; 95% CI 1.238–3.027; P = 0.004), and MDR Enterobacteriaceae (OR 1.447; 95% CI 1.002–2.090; P = 0.049). Multidrug resistance was associated with the development of severe sepsis or septic shock upon presentation among patients with bacteremic UTI caused by Enterobacteriaceae. Therefore, empirical antibiotics therapy for patients with UTI presented with severe sepsis and/or septic shock should be more broad-spectrum to effectively cover MDR Enterobacteriaceae.", "corpus_id": 11465062, "score": 0 }, { "doc_id": "51889837", "title": "Risk for subsequent infection and mortality after hospitalization among patients with multidrug-resistant gram-negative bacteria colonization or infection", "abstract": "BackgroundRisks for subsequent multidrug-resistant gram-negative bacteria (MDRGNB) infection and long-term outcome after hospitalization among patients with MDRGNB colonization remain unknown.MethodsThis observational study enrolled 817 patients who were hospitalized in the study hospital in 2009. We defined MDRGNB as a GNB resistant to at least three different antimicrobial classes. Patients were classified into MDRGNB culture-positive (MDRGNB-CP; 125 patients) and culture-negative (MDRGNB-CN; 692 patients) groups based on the presence or absence of any MDRGNB identified from either active surveillance or clinical cultures during index hospitalization. Subsequent MDRGNB infection and mortality within 12 months after index hospitalization were recorded. We determined the frequency and risk factors for subsequent MDRGNB infection and mortality associated with previous MDRGNB culture status.ResultsIn total, 129 patients had at least one subsequent MDRGNB infection (MDRGNB-CP, 48.0%; MDRGNB-CN, 10.0%), and 148 patients died (MDRGNB-CP, 31.2%; MDRGNB-CN, 15.9%) during the follow-up period. MDR Escherichia coli and Acinetobacter baumannii were the predominant colonization microorganisms; patients with Proteus mirabilis and Pseudomonas aeruginosa had the highest hazard risk for developing subsequent infection. After controlling for other confounders, MDRGNB-CP during hospitalization independently predicted subsequent MDRGNB infection (hazard ratio [HR], 5.35; 95% confidence interval [CI], 3.72–7.71), all-cause mortality (HR, 2.42; 95% CI, 1.67–3.50), and subsequent MDRGNB infection-associated mortality (HR, 4.88; 95% CI, 2.79–8.52) after hospitalization.ConclusionsHarboring MDRGNB significantly increases patients’ risk for subsequent MDRGNB infection and mortality after hospitalization, justifying the urgent need for developing effective strategies to prevent and eradicate MDRGNB colonization.", "corpus_id": 51889837, "score": 0 }, { "doc_id": "5953699", "title": "Rapid (<5 min) Identification of Pathogen in Human Blood by Electrokinetic Concentration and Surface-Enhanced Raman Spectroscopy", "abstract": "This study reports a novel microfluidic platform for rapid and long-ranged concentration of rare-pathogen from human blood for subsequent on-chip surface-enhanced Raman spectroscopy (SERS) identification/discrimination of bacteria based on their detected fingerprints. Using a hybrid electrokinetic mechanism, bacteria can be concentrated at the stagnation area on the SERS-active roughened electrode, while blood cells were excluded away from this region at the center of concentric circular electrodes. This electrokinetic approach performs isolation and concentration of bacteria in about three minutes; the density factor is increased approximately a thousand fold in a local area of ~5000 μm2 from a low bacteria concentration of 5 × 103 CFU/ml. Besides, three genera of bacteria, S. aureus, E. coli, and P. aeruginosa that are found in most of the isolated infections in bacteremia were successfully identified in less than one minute on-chip without the use of any antibody/chemical immobilization and reaction processes.", "corpus_id": 5953699, "score": 0 }, { "doc_id": "33976438", "title": "Isolation and identification of bacteria by means of Raman spectroscopy.", "abstract": "Bacterial detection is a highly topical research area, because various fields of application will benefit from the progress being made. Consequently, new and innovative strategies which enable the investigation of complex samples, like body fluids or food stuff, and improvements regarding the limit of detection are of general interest. Within this review the prospects of Raman spectroscopy as a reliable tool for identifying bacteria in complex samples are discussed. The main emphasis of this work is on important aspects of applying Raman spectroscopy for the detection of bacteria like sample preparation and the identification process. Several approaches for a Raman compatible isolation of bacterial cells have been developed and applied to different matrices. Here, an overview of the limitations and possibilities of these methods is provided. Furthermore, the utilization of Raman spectroscopy for diagnostic purposes, food safety and environmental issues is discussed under a critical view.", "corpus_id": 33976438, "score": 0 }, { "doc_id": "6439350", "title": "Increasing local density and purity of molecules/bacteria on a sensing surface from diluted blood using 3D hybrid electrokinetics.", "abstract": "We present a long-range and selective nanocolloid/molecular/bacteria concentrator based on 3D hybrid AC electrokinetics (ACEK) that includes AC dielectrophoresis (DEP) and biased AC electroosmosis (ACEO). Through a convergency comb-shaped electrode design, this long-range ACEO allows the effective transport of a high number of targets into the centre of the detection zone. In the proposed 3D hybrid electrokinetics model, 3D ACEO provides long-range transportation, and the 3D DEP provides an effective separation mechanism. Thus, detection targets ranging from nanoscale to micrometers could be selectively concentrated long-range from diluted blood. The proposed design was used for selectively concentrating nanocolloids and bacteria in the diluted blood sample, respectively. Compared to a 3D short-range dipolar electrode configuration, the detection limit of long-range 3D convergency tripolar electrode configuration is one order of magnitude higher. The result also shows that the 3D hybrid ACEK demonstrated a higher purity of any plane above the electrode, which compared positively to the same design of a 2D hybrid ACEK. The concentration factor of the proposed 3D hybrid electrokinetics device increased by several orders of local density and raised the local purity at least 6 orders (from 0.05% to greater than 99.9%). The chip is capable of making a DNA/protein/bacterial aggregate characterized by high local density and purity for further molecular and bacteria detection/analysis.", "corpus_id": 6439350, "score": 0 }, { "doc_id": "38346184", "title": "Microfluidic concentration of bacteria by on-chip electrophoresis.", "abstract": "In this contribution, we present a system for efficient preconcentration of pathogens without affecting their viability. Development of miniaturized molecular diagnostic kits requires concentration of the sample, molecule extraction, amplification, and detection. In consequence of low analyte concentrations in real-world samples, preconcentration is a critical step within this workflow. Bacteria and viruses exhibit a negative surface charge and thus can be electrophoretically captured from a continuous flow. The concept of phaseguides was applied to define gel membranes, which enable effective and reversible collection of the target species. E. coli of the strains XL1-blue and K12 were used to evaluate the performance of the device. By suppression of the electroosmotic flow both strains were captured with efficiencies of up to 99%. At a continuous flow of 15 μl/min concentration factors of 50.17 ± 2.23 and 47.36 ± 1.72 were achieved in less than 27 min for XL1-blue and K12, respectively. These results indicate that free flow electrophoresis enables efficient concentration of bacteria and the presented device can contribute to rapid analyses of swab-derived samples.", "corpus_id": 38346184, "score": 0 }, { "doc_id": "25094229", "title": "Correlation of virulence genes to clinical manifestations and outcome in patients with Streptococcus dysgalactiae subspecies equisimilis bacteremia.", "abstract": "BACKGROUND/PURPOSE\nStreptococcus dysgalactiae subsp. equisimilis (SDSE) is increasingly recognized as a human pathogen responsible for invasive infection and streptococcal toxic shock syndrome (STSS). The pathogen possesses virulence genes that resemble those found in Streptococcus pyogenes (GAS). We analyzed the association between these specific toxic genes, clinical presentations, and outcome in patients with SDSE infections.\n\n\nMETHODS\nPatients (older than 18 years) with community-acquired invasive bacteremia caused by SDSE bacteremia who were undergoing treatment at China Medical University Hospital from June 2007 to December 2010 were included in this study. Multiplex polymerase chain reaction was performed to identify virulence genes of the SDSE isolates. Demographic data, clinical presentations, and outcome in patients with SDSE infections were reviewed and analyzed.\n\n\nRESULTS\nForty patients with 41 episodes of SDSE bacteremia were reviewed. The median age of the patients with SDSE infection was 69.7 years; 55% were female and 78% had underlying diseases. Malignancy (13, 33%) and diabetes mellitus (13, 33%) were the most common comorbidities. The 30-day mortality rate was 12%. Compared with the survivors, the non-survivors had a higher rate of diabetes mellitus (80% vs. 26%), liver cirrhosis (60% vs.11%), shock (60% vs.17%), STSS (60% vs. 8%), and a high Pittsburgh bacteremia score >4 (40% vs. 6%). Most isolates had scpA, ska, saga, and slo genes, whereas speC, speG, speH, speI, speK, smez, and ssa genes were not detected. speA gene was identified only in one patient with STSS (1/6, 17%). All isolates were susceptible to penicillin, cefotaxime, levofloxacin, moxifloxacin, vancomycin, and linezolid.\n\n\nCONCLUSION\nIn invasive SDSE infections, most isolates carry putative virulence genes, such as scpA, ska, saga, and slo. Clinical SDSE isolates in Taiwan remain susceptible to penicillin cefotaxime, and levofloxacin.", "corpus_id": 25094229, "score": 0 }, { "doc_id": "37830227", "title": "Sepsis Pathogen Identification", "abstract": "Sepsis is a rapidly progressing, severe inflammatory response to infection, causing more than 200 000 deaths per year. Rapid, specific pathogen identification is important to guide sepsis treatment. In this review, we describe and compare currently available commercial products for sepsis diagnosis and pathogen identification, based on microbiological, molecular, and mass spectrometric technologies. Microbiological techniques, the current “gold standard” in sepsis pathogen identification, include blood culture followed by subculturing and pathogen identification via biochemical or microscopic means. These methods have been automated but nevertheless require several days to generate results. Alternative technologies, including highly multiplexed PCR-based methods and mass spectrometric approaches, can decrease the required turnaround time. Matrix-assisted laser-desorption ionization time-of-flight–based systems have recently become an attractive option to rapidly identify a broad spectrum of sepsis pathogens with good sensitivity and specificity. Effectively integrating rapid sepsis pathogen identification into the hospital workflow can improve patient outcomes and can reduce the length of hospitalization and cost per patient.", "corpus_id": 37830227, "score": 0 }, { "doc_id": "24028800", "title": "Determination of minimum inhibitory concentrations.", "abstract": "Minimum inhibitory concentrations (MICs) are defined as the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation, and minimum bactericidal concentrations (MBCs) as the lowest concentration of antimicrobial that will prevent the growth of an organism after subculture on to antibiotic-free media. MICs are used by diagnostic laboratories mainly to confirm resistance, but most often as a research tool to determine the in vitro activity of new antimicrobials, and data from such studies have been used to determine MIC breakpoints. MBC determinations are undertaken less frequently and their major use has been reserved for isolates from the blood of patients with endocarditis. Standardized methods for determining MICs and MBCs are described in this paper. Like all standardized procedures, the method must be adhered to and may not be adapted by the user. The method gives information on the storage of standard antibiotic powder, preparation of stock antibiotic solutions, media, preparation of inocula, incubation conditions, and reading and interpretation of results. Tables giving expected MIC ranges for control NCTC and ATCC strains are also supplied.", "corpus_id": 24028800, "score": 0 } ]

{ "doc_id": "54636408", "title": "Transition scenario to turbulence in thin vibrating plates", "abstract": "A thin plate, excited by a harmonic external forcing of increasing amplitude, shows transitions from a periodic response to a chaotic state of wave turbulence. By analogy with the transition to turbulence observed in fluid mechanics as the Reynolds number is increased, a generic transition scenario for thin vibrating plates, first experimentally observed, is here numerically studied. The von Karman equations for thin plates, which include geometric non-linear effects, are used to model large amplitude vibrations, and an energy-conserving finite difference scheme is employed for discretisation. The transition scenario involves two bifurcations separating three distinct regimes. The first regime is the periodic, weakly non-linear response. The second is a quasiperiodic state where energy is exchanged between internally resonant modes. It is observed only when specific internal resonance relationships are fulfilled between the eigenfrequencies of the structure and the forcing frequency; otherwise a direct transition to the last turbulent state is observed. This third, or turbulent, regime is characterized by a broadband Fourier spectrum and a cascade of energy from large to small wavelengths. For perfect plates including cubic non-linearity, only third-order internal resonances are likely to exist. For imperfect plates displaying quadratic nonlinearity, the energy exchanges and the quasiperiodic states are favored and thus are more easily obtained. Finally, the turbulent regime is characterized in the light of available theoretical results from wave turbulence theory.", "corpus_id": 54636408 }

[ { "doc_id": "120882372", "title": "Dissipative Structures and Weak Turbulence", "abstract": "We present a brief overview of the current understanding of temporal and spatio-temporal chaos, both termed weak turbulence according to the context [1]. The process which allows one to reduce the primitive problem to a low-dimensional dynamical system is discussed. It turns out to be appropriate as long as confinement effects are sufficiently strong to freeze the space dependence of unstable modes, hence temporal chaos only. Otherwise modulated patterns arise, yielding genuine space-time chaos. The corresponding theory rests on envelope equations providing a useful framework for weak turbulence in a globally super-critical setting. spatio-temporal intermittency analyzed next is the relevant scenario in the sub-critical case. Finally, the connection with hydrodynamic turbulence and the more general relevance of some of the ideas developed here are examined.", "corpus_id": 120882372, "score": 0 }, { "doc_id": "52036028", "title": "Wave turbulence and intermittency", "abstract": "In the early 1960s, it was established that the stochastic initial value problem for weakly coupled wave systems has a natural asymptotic closure induced by the dispersive properties of the waves and the large separation of linear and nonlinear time scales. One is thereby led to kinetic equations for the redistribution of spectral densities via three- and four-wave resonances together with a nonlinear renormalization of the frequency. The kinetic equations have equilibrium solutions which are much richer than the familiar thermodynamic, Fermi–Dirac or Bose–Einstein spectra and admit in addition finite flux (Kolmogorov–Zakharov) solutions which describe the transfer of conserved densities (e.g. energy) between sources and sinks. There is much one can learn from the kinetic equations about the behavior of particular systems of interest including insights in connection with the phenomenon of intermittency. What we would like to convince you is that what we call weak or wave turbulence is every bit as rich as the macho turbulence of 3D hydrodynamics at high Reynolds numbers and, moreover, is analytically more tractable. It is an excellent paradigm for the study of many-body Hamiltonian systems which are driven far from equilibrium by the presence of external forcing and damping. In almost all cases, it contains within its solutions behavior which invalidates the premises on which the theory is based in some spectral range. We give some new results concerning the dynamic breakdown of the weak turbulence description and discuss the fully nonlinear and intermittent behavior which follows. These results may also be important for proving or disproving the global existence of solutions for the underlying partial differential equations. Wave turbulence is a subject to which many have made important contributions. But no contributions have been more fundamental than those of Volodja Zakharov whose 60th birthday we celebrate at this meeting. He was the first to appreciate that the kinetic equations admit a far richer class of solutions than the fluxless thermodynamic solutions of equilibrium systems and to realize the central roles that finite flux solutions play in non-equilibrium systems. It is appropriate, therefore, that we call these Kolmogorov–Zakharov (KZ) spectra. © 2001 Elsevier Science B.V. All rights reserved.", "corpus_id": 52036028, "score": 0 }, { "doc_id": "23823161", "title": "Turbulence of capillary waves.", "abstract": "A numerical model for direct simulation of the surface of ideal fluid based on the expansion of theHamiltonian of the surface up to terms of fourth order is developed. For the case of capillary wavewe observe the formation of powerlike spectrum of spatial elevations close to one predicted by weak-turbulent theory", "corpus_id": 23823161, "score": 0 }, { "doc_id": "12419937", "title": "Weak turbulent Kolmogorov spectrum for surface gravity waves.", "abstract": "We study the long-time evolution of surface gravity waves on deep water excited by a stochastic external force concentrated in moderately small wave numbers. We numerically implemented the primitive Euler equations for the potential flow of an ideal fluid with free surface written in Hamiltonian canonical variables, using the expansion of the Hamiltonian in powers of nonlinearity of terms up to fourth order. We show that because of nonlinear interaction processes a stationary Fourier spectrum of a surface elevation close to <|eta(k)|(2)> approximately k(-7/2) is formed. The observed spectrum can be interpreted as a weak-turbulent Kolmogorov spectrum for a direct cascade of energy.", "corpus_id": 12419937, "score": 0 }, { "doc_id": "12849511", "title": "Observation of gravity-capillary wave turbulence.", "abstract": "We report the observation of the crossover between gravity and capillary wave turbulence on the surface of mercury. The probability density functions of the turbulent wave height are found to be asymmetric and thus non-Gaussian. The surface wave height displays power-law spectra in both regimes. In the capillary region, the exponent is in fair agreement with weak turbulence theory. In the gravity region, it depends on the forcing parameters. This can be related to the finite size of the container. In addition, the scaling of those spectra with the mean energy flux is found in disagreement with weak turbulence theory for both regimes.", "corpus_id": 12849511, "score": 0 }, { "doc_id": "49266088", "title": "Weak Langmuir turbulence", "abstract": "Abstract Weak turbulence theory presents a regular method for a statistical description of nonlinear wave interactions. The present review deals with an application of weak turbulence theory to Langmuir wave turbulence. Our main attention is devoted to a plasma with comparable ion and electron temperatures, both magnetized and unmagnetized. In this practically important situation ion-sound motions are heavily damped, which simplifies the physics of nonlinear phenomena. We will demonstrate that the turbulence spectra are highly anisotropic and take the form of “jets” in k-space, and that the onset of a steady state is nontrivial and sometimes does not occur at all. On the base of the jet-like spectra approach it is possible to find the turbulence spectra, to evaluate the anomalous absorption rate and to determine the comparable role of the different absorption mechanisms for a number of practical problems: the excitation of waves by powerful electromagnetic radiation or by electron and ion beams. We demonstrate also that the range in which pure weak turbulence is valid is pretty narrow. The jet-like spectra structure stimulates a modulation instability and after that wave self-focusing and collapse. Then, weak and strong turbulence coexist. The final part of the review deals with the turbulence of nonisothermal plasmas when additional degrees of freedom are excited. We demonstrate that the ideas, models and methods, presented in this review, give us a chance to advance greatly in the understanding of turbulence patterns.", "corpus_id": 49266088, "score": 0 }, { "doc_id": "122504946", "title": "Optical turbulence: weak turbulence, condensates and collapsing filaments in the nonlinear Schro¨dinger equation", "abstract": "The nonlinear Schrodinger (NLS) equation iΨt + ∇2Ψ + α⋎Ψ⋎sΨ = 0 is a canonical and universal equation which is of major importance in continuum mechanics, plasma physics and optics. This paper argues that much of the observed solution behavior in the critical case sd = 4, where d is dimension and s is the order of nonlinearity, can be understood in terms of a combination of weak turbulence theory and condensate and collapse formation. The results are derived in the broad context of a class of Hamiltonian systems of which NLS is a member, so that the reader can gain a perspective on the ingredients important for the realization of the various equilibrium spectra, thermodynamic, pure Kolmogorov and combinations thereof. We also present time-dependent, self-similar solutions which describe the relaxation of the system towards these equilibrium states. We show that the number of particles lost in an individual collapse event is virtually independent of damping. Our numerical simulation of the full governing equations is the first to show the validity of the weak turbulence approximation. We also present a mechanism for intermittency which should have widespread application. It is caused by strongly nonlinear collapse events which are nucleated by a flow of particles towards the origin in wavenumber space. These highly organized events result in a cascade of particle number towards high wavenumbers and give rise to an intermittency and a behavior which violates many of the usual Kolmogorov assumptions about the loss of statistical information and the statistical independence of large and small scales. We discuss the relevance of these ideas to hydrodynamic turbulence in the conclusion.", "corpus_id": 122504946, "score": 0 }, { "doc_id": "55425956", "title": "Non-local MHD turbulence", "abstract": "We consider an example of strongly non-local interaction in incompressible magnetohydrodynamic (MHD) turbulence which corresponds to the case where the Alfven waves travelling in the opposite directions have essentially different characteristic wavelengths. We use two approaches to the dynamics of turbulent Alfvenic wavepackets: the first is a geometrical WKB theory [Phys. Lett. A 165 (1992) 330] and the second one is a three-wave kinetic equation derived for weakly turbulent waves [J. Plasma Phys., in press]. We show that these theories have a common limit of weak turbulence with scale separation in which they both predict the same Fokker–Planck equation for the wave power spectrum. In both cases the packet wavenumbers (and therefore the Lagrangian field-line separations) are allowed to experience order 1 changes. The WKB theory developed here formalises an intuitive geometrical argument of Goldreich and Sridhar [ApJ 485 (1997) 680] and allows one to see where such an intuition leads to a wrong conclusion about the inapplicability of the three-wave kinetic equation for order 1 wavepacket distortions. We show that the exponent of the constant flux non-local spectrum matches the value previously found for local turbulence at the boundary of the locality interval. The relationship between the WKB theory and the weak turbulence theory found in this paper for an ensemble of Alfven waves seems to be general for three-wave systems. © 2001 Elsevier Science B.V. All rights reserved.", "corpus_id": 55425956, "score": 0 }, { "doc_id": "73618530", "title": "Lyapunov exponents from experimental time series. Application to cymbal vibrations", "abstract": "Lyapunov exponents are among the most relevant and most informative invariants for detecting and quantifying chaos in a dynamical system. This method is applied here to the analysis of cymbal vibrations. The advantage of using a quadratic fit for determining the Jacobian of the dynamics is presented. In addition, the interest of using a time step for the evolution of the neighbourhood not equal to the timelag used for the reconstruction of the phase space is underlined. The robustness of the algorithm used yields a high degree of confidence in the characterization and in the quantification of the chaotic state. \nTo illustrate these features in the case of cymbal vibrations, transitions from quasiperiodicity to chaos are exhibited. The quasiperiodic state of the system is characterized together by the power spectrum of the experimental signal and by calculation of the Lyapunov spectrum.", "corpus_id": 73618530, "score": 1 }, { "doc_id": "121292656", "title": "Nonlinear vibrations and chaos in gongs and cymbals", "abstract": "This paper summarizes some results obtained in the last few years for the modeling of nonlinear vibrating instruments such as gongs and cymbals. Linear, weakly nonlinear and chaotic regimes are successively examined. A theoretical mechanical model is presented, based on the nonlinear von Karman equations for thin shallow spherical shells. Modal projection and Nonlinear Normal Mode (NNM) formulation leads to a subset of coupled nonlinear oscillators. Current developments are aimed at using this subset for sound synthesis purpose.", "corpus_id": 121292656, "score": 1 }, { "doc_id": "59882402", "title": "Numerical Sound Synthesis: Finite Difference Schemes and Simulation in Musical Acoustics", "abstract": "Digital sound synthesis has long been approached using standard digital filtering techniques. Newer synthesis strategies, however, make use of physical descriptions of musical instruments, and allow for much more realistic and complex sound production and thereby synthesis becomes a problem of simulation. This book has a special focus on time domain finite difference methods presented within an audio framework. It covers time series and difference operators, and basic tools for the construction and analysis of finite difference schemes, including frequency-domain and energy-based methods, with special attention paid to problems inherent to sound synthesis. Various basic lumped systems and excitation mechanisms are covered, followed by a look at the 1D wave equation, linear bar and string vibration, acoustic tube modelling, and linear membrane and plate vibration. Various advanced topics, such as the nonlinear vibration of strings and plates, are given an elaborate treatment. Key features: Includes a historical overview of digital sound synthesis techniques, highlighting the links between the various physical modelling methodologies. A pedagogical presentation containing over 150 problems and programming exercises, and numerous figures and diagrams, and code fragments in the MATLAB programming language helps the reader with limited experience of numerical methods reach an understanding of this subject. Offers a complete treatment of all of the major families of musical instruments, including certain audio effects. Numerical Sound Synthesis is suitable for audio and software engineers, and researchers in digital audio, sound synthesis and more general musical acoustics. Graduate students in electrical engineering, mechanical engineering or computer science, working on the more technical side of digital audio and sound synthesis, will also find this book of interest.", "corpus_id": 59882402, "score": 1 }, { "doc_id": "45802670", "title": "Nonlinearity, chaos, and the sound of shallow gongs", "abstract": "Experimental studies on several orchestral gongs of the tamtam and cymbal families suggest that two separate nonlinear mechanisms contribute to the evolution of the sound. The first mechanism is an upward cascade of energy from the low‐frequency modes initially excited into high‐frequency modes, caused by coupling between tension and shear stresses at regions of sharp change in shape of the gong. The second is a transition from simple periodic nonlinear modal motion to multiple fractional subharmonics, or even chaotic motion, which fills out the radiated spectrum at frequencies between those of the normal linear modes. Each of these mechanisms has considerable hysteresis, so that the spectrum of the radiated sound evolves over a period of several seconds. Measurements using high‐level sinusoidal excitation have elucidated some of the features of this behavior.", "corpus_id": 45802670, "score": 0 }, { "doc_id": "2364674", "title": "Spatio-Temporal Chaos and solitons Exhibited by von kÁrmÁn Model", "abstract": "Forced oscillations of flexible plates with a longitudinal, time dependent load acting on one plate side are investigated. Regular (harmonic, subharmonic and quasi-periodic) and irregular (chaotic) oscillations appear depending on the system parameters as well as initial and boundary conditions. In order to achieve highly reliable results, an effective algorithm has been applied to convert a problem of finding solutions to the hybrid type partial differential equations (the so-called von Karman form) to that of the ordinary differential equations (ODEs) and algebraic equations (AEs). The obtained equations are solved using finite difference method with the approximations 0(h4) and 0(h2) (in respect to the spatial coordinates). The ODEs are solved using the Runge–Kutta fourth order method, whereas the AEs are solved using either the Gauss or relaxation methods. The analysis and identification of spatio-temporal oscillations are carried out by investigation of the series wij(t), wt,ij(t), phase portraits wt,ij (wij) and wtt,ij(wt,ij, wij) and the mode portraits in the planes wx,ij(wij), wy,ij (wij) and in the space wxx(wx,ij,wij), FFT as well as the Poincare sections and pseudo-sections.", "corpus_id": 2364674, "score": 0 }, { "doc_id": "120786918", "title": "Chaotic Vibrations of Sector-Type Spherical Shells", "abstract": "In this work, chaotic vibrations of shallow sector-type spherical shells are studied. A sector-type shallow shell is understood as a shell defined by a sector with associated boundary conditions and obtained by cutting a spherical shell for a given angle θ k , or it is a sector of a shallow spherical cap associated with the mentioned angle. Both static stability and complex nonlinear dynamics of the mentioned mechanical objects subjected to transversal uniformly distributed sign-changeable load are analyzed, and the so-called vibration charts and scales regarding the chosen control parameters are reported. In particular, scenarios of transition from regular to chaotic dynamics of the mentioned shells are investigated. A novel method to control chaotic dynamics of the studied flexible spherical shells driven by transversal sign-changeable load via synchronized action of the sign-changeable antitorque is proposed and applied. All investigations are carried out within the fields of qualitative theory of differential equations and nonlinear dynamics.", "corpus_id": 120786918, "score": 0 }, { "doc_id": "122080519", "title": "Chaotic oscillations of a shallow cylindrical shell with a concentrated mass under periodic excitation", "abstract": "This paper presents effects of a concentrated mass on chaotic oscillations of a shallow cylindrical shell under gravity and periodic acceleration. The rectangular shell is simply supported and is elastically in-plane constrained. Assuming mode functions, the Donnell equation with inertia force is reduced to non-linear coupled differential equations by the Galerkin method. The chaotic response is calculated numerically and is examined by the maximum Lyapunov exponent. Dominant chaotic responses are generated within restricted frequency regions of sub-harmonic resonance of 1/2 order. As the concentrated mass increases, the chaotic response is shifted to the lower frequency region. The increment of the concentrated mass decreases the maximum Lyapunov exponent.", "corpus_id": 122080519, "score": 0 }, { "doc_id": "122168436", "title": "Experiments and analysis on chaotic vibrations of a shallow cylindrical shell-panel", "abstract": "Abstract Detailed experimental results and analytical results are presented on chaotic vibrations of a shallow cylindrical shell-panel subjected to gravity and periodic excitation. The shallow shell-panel with square boundary is simply supported for deflection. In-plane displacement at the boundary is elastically constrained by in-plain springs. In the experiment, the cylindrical shallow shell-panel with thickness 0.24 mm, square form of length 140 mm and mean radius 5150 mm is used for the test specimen. All edges around the shell boundary are simply supported by adhesive flexible films. First, to find fundamental properties of the shell-panel, linear natural frequencies and characteristics of restoring force of the shell-panel are measured. These results are compared with the relevant analytical results. Then, geometrical parameters of the shell-panel are identified. Exciting the shell-panel with lateral periodic acceleration, nonlinear frequency responses of the shell-panel are obtained by sweeping the frequency of periodic acceleration. In typical ranges of the exciting frequency, predominant chaotic responses are generated. Time histories of the responses are recorded for inspection of the chaos. In the analysis, the Donnell equation with lateral inertia force is introduced. Assuming mode functions, the governing equation is reduced to a set of nonlinear ordinary differential equations by the Galerkin procedure. Periodic responses are calculated by the harmonic balance method. Chaotic responses are integrated numerically by the Runge–Kutta–Gill method. The chaotic responses, which are obtained by the experiment and the analysis, are inspected with the Fourier spectra, the Poincare projections, the maximum Lyapunov exponents and the Lyapunov dimension. It is found that the dominant chaotic responses of the shell-panel are generated from the responses of the sub-harmonic resonance of 1 2 order and of the ultra-sub-harmonic resonance of 2 3 order. By the convergence of the maximum Lyapunov exponent to the embedding dimension, the number of predominant vibration modes which contribute to the chaos is found to be three or four. Fairly good agreements are obtained between the experimental results and the analytical results.", "corpus_id": 122168436, "score": 0 }, { "doc_id": "123329958", "title": "Modal interaction in chaotic vibrations of a shallow double-curved shell-panel", "abstract": "Abstract Experimental results and analytical results are presented on chaotic vibrations of a shallow double-curved shell-panel subjected to gravity and periodic excitation. Modal interactions in the chaotic responses are discussed. The shell-panel with square boundary is simply supported for deflection. In-plane displacement at the boundary is elastically constrained. In the experiment, time histories of the chaotic responses at the spatial multiple positions of the shell-panel are measured for the inspection of modal interaction. In the analysis, the shallow shell-panel is assumed to have constant curvatures along to orthogonal directions and geometric initial imperfection. The Donnell–Mushtari–Vlasov type equation is used as governing equation with lateral inertia force. Assuming deflection with multiple modes of vibration, the governing equation is reduced to a set of nonlinear ordinary differential equations by the Bubnov–Galerkin procedure. Chaotic responses are integrated numerically. The chaotic responses, which are obtained by the experiment and the analysis, are inspected with the Fourier spectra, the Poincare projections, the maximum Lyapunov exponents and the Lyapunov dimension. Contribution of modes of vibration to the chaotic responses is analyzed by the principal component analysis, i.e., Karhunen–Loeve transformation.", "corpus_id": 123329958, "score": 0 }, { "doc_id": "3092630", "title": "Characterizing the Dynamic Response of a Thermally Loaded, Acoustically Excited Plate", "abstract": "Abstract In this work the dynamic response is considered of a homogeneous, fully clamped rectangular plate subject to spatially uniform thermal loads and narrow-band acoustic excitation. In both the pre-and post-buckled regimes, the small amplitude, linear response is confirmed. However, the primary focus is on the large amplitude, non-linear, snap-through response, because of the obvious implications for fatigue in aircraft components. A theoretical model is developed which uses nine spatial modes and incorporates initial imperfections and non-ideal boundary conditions. Because of the higher order nature of this model, it is inherently more complicated than a one-mode buckled beam equation (Duffing's equation). An experimental system was developed to complement the theoretical results, and also to measure certain system parameters for the model which are not available theoretically. Several analysis techniques are used to characterize the response. These include time series, power spectra and autocorrelation functions. In addition, the fractal dimension and Lyapunov exponents for the response are computed to address the issue of spatial dimension and temporal complexity (chaos), respectively. Comparisons between theory and experiment are made and show considerable agreement. However, these comparisons also serve to point out difficulties in computing the fractal dimension and Lyapunov exponents from experimental data.", "corpus_id": 3092630, "score": 0 }, { "doc_id": "120763886", "title": "Transition to chaotic vibrations for harmonically forced perfect and imperfect circular plates", "abstract": "The transition from periodic to chaotic vibrations in free-edge, perfect and imperfect circular plates, is numerically studied. A pointwise harmonic forcing with constant frequency and increasing amplitude is applied to observe the bifurcation scenario. The von Karman equations for thin plates, including geometric non-linearity, are used to model the large-amplitude vibrations. A Galerkin approach based on the eigenmodes of the perfect plate allows discretizing the model. The resulting ordinary-differential equations are numerically integrated. Bifurcation diagrams of Poincare maps, Lyapunov exponents and Fourier spectra analysis reveal the transitions and the energy exchange between modes. The transition to chaotic vibration is studied in the frequency range of the first eigenfrequencies. The complete bifurcation diagram and the critical forces needed to attain the chaotic regime are especially addressed. For perfect plates, it is found that a direct transition from periodic to chaotic vibrations is at hand. For imperfect plates displaying specific internal resonance relationships, the energy is first exchanged between resonant modes before the chaotic regime. Finally, the nature of the chaotic regime, where a high-dimensional chaos is numerically found, is questioned within the framework of wave turbulence. These numerical findings confirm a number of experimental observations made on shells, where the generic route to chaos displays a quasiperiodic regime before the chaotic state, where the modes, sharing internal resonance relationship with the excitation frequency, appear in the response.", "corpus_id": 120763886, "score": 1 }, { "doc_id": "9924414", "title": "Weak turbulence for a vibrating plate: can one hear a Kolmogorov spectrum?", "abstract": "We study the long-time evolution of waves of a thin elastic plate in the limit of small deformation so that modes of oscillations interact weakly. According to the theory of weak turbulence (successfully applied in the past to plasma, optics, and hydrodynamic waves), this nonlinear wave system evolves at long times with a slow transfer of energy from one mode to another. We derive a kinetic equation for the spectral transfer in terms of the second order moment. We show that such a theory describes the approach to an equilibrium wave spectrum and represents also an energy cascade, often called the Kolmogorov-Zakharov spectrum. We perform numerical simulations that confirm this scenario.", "corpus_id": 9924414, "score": 1 }, { "doc_id": "375112", "title": "Observation of wave turbulence in vibrating plates.", "abstract": "The nonlinear interaction of waves in a driven medium may lead to wave turbulence, a state such that energy is transferred from large to small length scales. Here, wave turbulence is observed in experiments on a vibrating plate. The frequency power spectra of the normal velocity of the plate may be rescaled on a single curve, with power-law behaviors that are incompatible with the weak turbulence theory of Düring et al. [Phys. Rev. Lett. 97, 025503 (2006)10.1103/PhysRevLett.97.025503]. Alternative scenarios are suggested to account for this discrepancy -- in particular the occurrence of wave breaking at high frequencies. Finally, the statistics of velocity increments do not display an intermittent behavior.", "corpus_id": 375112, "score": 0 }, { "doc_id": "16618456", "title": "Statistics of power injection in a plate set into chaotic vibration", "abstract": "A vibrating plate is set into a chaotic state of wave turbulence by either a periodic or a random local forcing. Correlations between the forcing and the local velocity response of the plate at the forcing point are studied. Statistical models with fairly good agreement with the experiments are proposed for each forcing. Both distributions of injected power have a logarithmic cusp for zero power, while the tails are Gaussian for the periodic driving and exponential for the random one. The distributions of injected work over long time intervals are investigated in the framework of the fluctuation theorem, also known as the Gallavotti-Cohen theorem. It appears that the conclusions of the theorem are verified only for the periodic, deterministic forcing. Using independent estimates of the phase space contraction, this result is discussed in the light of available theoretical framework.", "corpus_id": 16618456, "score": 0 }, { "doc_id": "18590088", "title": "Are there waves in elastic wave turbulence?", "abstract": "An thin elastic steel plate is excited with a vibrator and its local velocity displays a turbulentlike Fourier spectrum. This system is believed to develop elastic wave turbulence. We analyze here the motion of the plate with a two-point measurement in order to check, in our real system, a few hypotheses required for the Zakharov theory of weak turbulence to apply. We show that the motion of the plate is indeed a superposition of bending waves following the theoretical dispersion relation of the linear wave equation. The nonlinearities seem to efficiently break the coherence of the waves so that no modal structure is observed. Several hypotheses of the weak turbulence theory seem to be verified, but nevertheless the theoretical predictions for the wave spectrum are not verified experimentally.", "corpus_id": 18590088, "score": 0 }, { "doc_id": "123088324", "title": "Fourier analysis of wave turbulence in a thin elastic plate", "abstract": "The spatio-temporal dynamics of the deformation of a vibrated plate is measured by a high speed Fourier transform profilometry technique. The space-time Fourier spectrum is analyzed. It displays a behavior consistent with the premises of the Weak Turbulence theory. A isotropic continuous spectrum of waves is excited with a non linear dispersion relation slightly shifted from the linear dispersion relation. The spectral width of the dispersion relation is also measured. The non linearity of this system is weak as expected from the theory. Finite size effects are discussed. Despite a qualitative agreement with the theory, a quantitative mismatch is observed which origin may be due to the dissipation that ultimately absorbs the energy flux of the Kolmogorov-Zakharov casade.", "corpus_id": 123088324, "score": 0 }, { "doc_id": "122825779", "title": "A family of conservative finite difference schemes for the dynamical von Karman plate equations", "abstract": "Numerical methods for nonlinear plate dynamics play an important role across many disciplines. In this article, the focus is on numerical stability for numerical methods for the von Karman system, through the use of energy-conserving methods. It is shown that one may take advantage of structure particular to the system to construct numerical methods, which are provably numerically stable, and for which computer implementation is simplified. Numerical results are presented. © 2007 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq, 2007", "corpus_id": 122825779, "score": 1 }, { "doc_id": "54712898", "title": "Asymmetric non-linear forced vibrations of free-edge circular plates. Part II: Experiments", "abstract": "This article is devoted to an experimental validation of a theoretical model presented in an earlier contribution by the same authors. The non-linear forced vibrations of circular plates, with the excitation frequency close to the natural frequency of an asymmetric mode, are investigated. The experimental set-up, which allows one to perform precise measurements of the vibration amplitudes of the two preferential configurations, is presented. Experimental resonance curves showing the amplitude and the phase of each configuration as functions of the driving frequency are compared to the theoretical ones, leading to a quantitative validation of the predictions given by the model. Finally, all the approximations used are systematically discussed, in order to show the scope and relevance of the approach. © 2003 Elsevier Science Ltd. All rights reserved.", "corpus_id": 54712898, "score": 0 }, { "doc_id": "122717335", "title": "Non-linear vibrations of free-edge thin spherical shells: Experiments on a 1:1:2 internal resonance", "abstract": "This study is devoted to the experimental validation of a theoretical model of large amplitude vibrations of thin spherical shells described in a previous study by the same authors. A modal analysis of the structure is first detailed. Then, a specific mode coupling due to a 1:1:2 internal resonance between an axisymmetric mode and two companion asymmetric modes is especially addressed. The structure is forced with a simple-harmonic signal of frequency close to the natural frequency of the axisymmetric mode. The experimental setup, which allows precise measurements of the vibration amplitudes of the three involved modes, is presented. Experimental frequency response curves showing the amplitude of the modes as functions of the driving frequency are compared to the theoretical ones. A good qualitative agreement is obtained with the predictions given by in the model. Some quantitative discrepancies are observed and discussed, and improvements of the model are proposed.", "corpus_id": 122717335, "score": 0 }, { "doc_id": "5068330", "title": "Non-linear vibrations of imperfect free-edge circular plates and shells", "abstract": "Large-amplitude, geometrically non-linear vibrations of free-edge circular plates with geometric imperfections are addressed in this work. The dynamic analog of the von Karman equations for thin plates, with a stress-free initial deflection, is used to derive the imperfect plate equations of motion. An expansion onto the eigenmode basis of the perfect plate allows discretization of the equations of motion. The associated non-linear coupling coefficients for the imperfect plate with an arbitrary shape are analytically expressed as functions of the cubic coefficients of a perfect plate. The convergence of the numerical solutions are systematically addressed by comparisons with other models obtained for specific imperfections, showing that the method is accurate to handle shallow shells, which can be viewed as imperfect plate. Finally, comparisons with a real shell are shown, showing good agreement on eigenfrequencies and mode shapes. Frequency-response curves in the non-linear range are compared in a very peculiar regime displayed by the shell with a 1:1:2 internal resonance. An important improvement is obtained compared to a perfect spherical shell model, however some discrepancies subsist and are discussed.", "corpus_id": 5068330, "score": 0 }, { "doc_id": "59332203", "title": "Non-linear vibrations of free-edge thin spherical shells: modal interaction rules and 1:1:2 internal resonance", "abstract": "This paper is devoted to the derivation and the analysis of vibrations of shallow spherical shell subjected to large amplitude transverse displacement. The analog for thin shallow shells of von Karman's theory for large deflection of plates is used. The validity range of the approximations is assessed by comparing the analytical modal analysis with a numerical solution. The specific case of a free edge is considered. The governing partial differential equations are expanded onto the natural modes of vibration of the shell. The problem is replaced by an infinite set of coupled second-order differential equations with quadratic and cubic non-linear terms. Analytical expressions of the non-linear coefficients are derived and a number of them are found to vanish, as a consequence of the symmetry of revolution of the structure. Then, for all the possible internal resonances, a number of rules are deduced, thus predicting the activation of the energy exchanges between the involved modes. Finally, a specific mode coupling due to a 1:1:2 internal resonance between two companion modes and an axisymmetric mode is studied. © 2004 Elsevier Ltd. All rights reserved.", "corpus_id": 59332203, "score": 0 }, { "doc_id": "28388197", "title": "ASYMMETRIC NON-LINEAR FORCED VIBRATIONS OF FREE-EDGE CIRCULAR PLATES. PART 1: THEORY", "abstract": "In this article, a detailed study of the forced asymmetric non-linear vibrations of circular plates with a free edge is presented. The dynamic analogue of the von Karman equations is used to establish the governing equations. The plate displacement at a given point is expanded on the linear natural modes. The forcing is harmonic, with a frequency close to the natural frequency $\\omega_n$ of one asymmetric mode of the plate. Thus, the vibration is governed by the two degenerated modes corresponding to $\\omega_n$, which are one-to-one internally resonant. An approximate analytical solution, using the method of multiple scales, is presented. Attention is focused on the case where one configuration which is not directly excited by the load gets energy through non-linear coupling with the other configuration. Slight imperfections of the plate are taken into account. Experimental validations are presented in the second part of this paper.", "corpus_id": 28388197, "score": 0 }, { "doc_id": "120513655", "title": "Nonlinear Vibrations and Stability of Shells and Plates", "abstract": "Introduction. 1. Nonlinear theories of elasticity of plates and shells 2. Nonlinear theories of doubly curved shells for conventional and advanced materials 3. Introduction to nonlinear dynamics 4. Vibrations of rectangular plates 5. Vibrations of empty and fluid-filled circular cylindrical 6. Reduced order models: proper orthogonal decomposition and nonlinear normal modes 7. Comparison of different shell theories for nonlinear vibrations and stability of circular cylindrical shells 8. Effect of boundary conditions on a large-amplitude vibrations of circular cylindrical shells 9. Vibrations of circular cylindrical panels with different boundary conditions 10. Nonlinear vibrations and stability of doubly-curved shallow-shells: isotropic and laminated materials 11. Meshless discretization of plates and shells of complex shapes by using the R-functions 12. Vibrations of circular plates and rotating disks 13. Nonlinear stability of circular cylindrical shells under static and dynamic axial loads 14. Nonlinear stability and vibrations of circular shells conveying flow 15. Nonlinear supersonic flutter of circular cylindrical shells with imperfections.", "corpus_id": 120513655, "score": 0 }, { "doc_id": "118129164", "title": "Vibration of Plates", "abstract": "Abstract : Contents: Fundamental Equations of Classical Plate Theory; Circular Plates; Elliptical Plates; Rectangular Plates; Parallelogram Plates; Other Quadrilateral Plates; Triangular Plates; Plates of Other Shapes; Anisotropic Plates; Plates With Inplane Forces; Plates With Variable Thickness; and Other Considerations.", "corpus_id": 118129164, "score": 0 }, { "doc_id": "122702757", "title": "Geometrically nonlinear flexural vibrations of plates: In-plane boundary conditions and some symmetry properties", "abstract": "Abstract This study is devoted to the derivation of some properties of the von Karman equations for geometrically nonlinear models of plates, with a boundary of arbitrary shape, for applications to nonlinear vibration and buckling. An intrinsic formulation of the local partial differential equations in terms of the transverse displacement and an Airy stress function as unknowns is provided. Classical homogeneous boundary conditions—with vanishing prescribed forces and displacements—are derived in terms of the Airy stress function in the case of a boundary of arbitrary geometry. A special property of this operator, crucial for some energy-conserving numerical schemes and called “triple self-adjointness”, is derived in the case of an edge of arbitrary shape. It is shown that this property takes a simple form for some classical boundary conditions, so that the calculations in some practical cases are also simplified. The applications of this work are either semi-analytical methods of solution, using an expansion of the solution onto an eigenmode basis of the associated linear problem, or special energy-conserving numerical methods.", "corpus_id": 122702757, "score": 0 }, { "doc_id": "121562322", "title": "Computational formulation for periodic vibration of geometrically nonlinear structures—part 1: Theoretical background", "abstract": "Abstract A general computational formulation for geometrically nonlinear structures excited by harmonic forces and executing periodic motion in a steady-state is presented. The equations of both continuous and discretized models are reformulated to obtain the motion equation in a more suitable form to a further analysis. The multi-harmonic solution of motion equation is written in a form of truncated Fourier series. Next, the Galerkin, Ritz and the harmonic balance method are discussed in a context of their equivalency in derivation of the matrix amplitude equation. The matrix amplitude equation as well as the associated tangent matrix are given in an explicit form. The stability of steady-state solution is discussed by using the Floquet theory. The numerical algorithm and an example application are described in a companion paper by Lewandowski [Lewandowski, R. Computational formulation for periodic vibration of geometrically nonlinear structures—Part 2: Numerical strategy and numerical examples. International Journal of Solids and Structures . (in preparation)].", "corpus_id": 121562322, "score": 0 }, { "doc_id": "121641221", "title": "Computational formulation for periodic vibration of geometrically nonlinear structures—part 2: Numerical strategy and examples", "abstract": "Abstract In this paper the numerical strategy for solving the matrix amplitude equation with parameter is discussed in detail. The matrix amplitude equation is the result of application of the Galerkin method for analysis of periodic solutions of the geometrically nonlinear structures. A theoretical background of the proposed method of analysis is given in a companion paper by Lewandowski [Lewandowski, R. (1996). Computational formulation for periodic vibration of geometrically nonlinear structures—Part 1: theoretical background. International Journal of Solids and Structures34(15), 1925–1947]. An example application of general theory is also presented. Numerical results are given and discussed to show some interesting behaviors of nonlinear structures and to illustrate the numerical efficiency and validity of the suggested method.", "corpus_id": 121641221, "score": 0 }, { "doc_id": "34493719", "title": "Nonlinear normal modes, Part I: A useful framework for the structural dynamicist", "abstract": "The concept of nonlinear normal modes (NNMs) is discussed in the present paper and its companion, Part II. Because there is virtually no application of the NNMs to large-scale engineering structures, these papers are an attempt to highlight several aspects that might drive their development in the future. Specifically, we support that (i) numerical methods for the continuation of periodic solutions pave the way for an effective and practical computation of NNMs, and (ii) time–frequency analysis is particularly suitable for the analysis of the resulting dynamics. Another objective of the present paper is to describe, in simple terms, and to illustrate the fundamental properties of NNMs. This is achieved to convince the structural dynamicist not necessarily acquainted with them that they are a useful framework for the analysis of nonlinear vibrating structures.", "corpus_id": 34493719, "score": 0 }, { "doc_id": "53979325", "title": "Nonlinear normal modes, Part II: Toward a practical computation using numerical continuation techniques", "abstract": "The concept of nonlinear normal modes (NNMs) is discussed in the present paper and its companion, Part I. One reason of the still limited use of NNMs in structural dynamics is that their computation is often regarded as impractical. However, when resorting to numerical algorithms, we show that the NNM computation is possible with limited implementation effort, which paves the way to a practical method for determining the NNMs of nonlinear mechanical systems. The proposed algorithm relies on two main techniques, namely a shooting procedure and a method for the continuation of NNM motions. The algorithm is demonstrated using four different mechanical systems, a weakly and a strongly nonlinear two-degree-of-freedom system, a simplified discrete model of a nonlinear bladed disk and a nonlinear cantilever beam discretized by the finite element method.", "corpus_id": 53979325, "score": 0 }, { "doc_id": "118174323", "title": "Nonlinear Targeted Energy Transfer in Mechanical and Structural Systems", "abstract": "Volume I: Preface Abbreviations 1 Introduction 2 Preliminary Concepts, Methodologies and Techniques 2.1 Nonlinear Normal Modes (NNMs) 2.2 Energy Localization in Nonlinear Systems 2.3 Internal Resonances, Transient and Sustained Resonance Captures 2.4 Averaging, Multiple Scales and Complexification 2.5 Methods of Advanced Signal Processing 2.5.1 NumericalWavelet Transforms 2.5.2 Empirical Mode Decompositions and Hilbert Transforms 2.6 Perspectives on Hardware Development and Experiments 3 Nonlinear Targeted Energy Transfer in Discrete Linear Oscillators with Single-DOF Nonlinear Energy Sinks 3.1 Configurations of Single-DOF NESs 3.2 Numerical Evidence of TET in a SDOF Linear Oscillator with a SDOF NES 3.3 SDOF Linear Oscillators with SDOF NESs: Dynamics of the Underlying Hamiltonian Systems 3.3.1 Numerical Study of Periodic Orbits (NNMs) 3.3.2 Analytic Study of Periodic Orbits (NNMs) 3.3.3 Numerical Study of Periodic Impulsive Orbits (IOs) 3.3.4 Analytic Study of Periodic and Quasi-Periodic IOs 3.3.5 Topological Features of the Hamiltonian Dynamics 3.4 SDOF Linear Oscillators with SDOF NESs: Transient Dynamics of the Damped Systems 3.4.1 Nonlinear Damped Transitions Represented in the FEP 3.4.2 Dynamics of TET in the Damped System 3.5 Multi-DOF (MDOF) Linear Oscillators with SDOF NESs: Resonance Capture Cascades and Multi-frequency TET 3.5.1 Two-DOF Linear Oscillator with a SDOF NES 3.5.2 Semi-Infinite Chain of Linear Oscillators with an End SDOF NES 4 Targeted Energy Transfer in Discrete Linear Oscillators with Multi-DOF NESs 4.1 Multi-Degree-of-Freedom(MDOF) NESs 4.1.1 An AlternativeWay for Passive Multi-frequency Nonlinear Energy Transfers 4.1.2 Numerical Evidence of TET in MDOF NESs 4.2 The Dynamics of the Underlying Hamiltonian System 4.2.1 System I: NES with O(1) Mass 4.2.2 System II: NES with O(e) Mass 4.2.3 Asymptotic Analysis of Nonlinear Resonant Orbits 4.2.4 Analysis of Resonant Periodic Orbits 4.3 TRCs and TET in the Damped and Forced System 4.3.1 Numerical Wavelet Transforms 4.3.2 Damped Transitions on the Hamiltonian FEP 4.4 Concluding Remarksl Index. Volume 2: 5 Targeted Energy Transfer in Linear Continuous Systems with Singlean Multi-DOF NESs 5.1 Beam of Finite Length with SDOF NES 5.1.1 Formulation of the Problem and Computational Procedure 5.1.2 Parametric Study of TET 5.2 Rod of Finite Length with SDOF NES 5.2.1 Formulation of the Problem, Computational Procedure and Post-Processing Algorithms 5.2.2 Computational Study of TET 5.2.3 Damped Transitions on the Hamiltonian FEP 5.3 Rod of Semi-Infinite Length with SDOF NES 5.3.1 Reduction to Integro-differential Form 5.3.2 Numerical Study of Damped Transitions 5.3.3 Analytical Study 5.4 Rod of Finite Length with MDOF NES 5.4.1 Formulation of the Problem and FEPs 5.4.2 Computational Study of TET 5.4.3 Multi-Modal Damped Transitions and Multi-Scale Analysis 5.5 Plate with SDOF and MDOF NESs 5.5.1 Case of a SDOF NES 5.5.2 Case of Multiple SDOF NESs 5.5.3 Case of a MDOF NES 5.5.4 Comparative Study with Linear Tuned Mass Damper 6 Targeted Energy Transfer in Systems with Periodic Excitations 6.1 Steady State Responses and Generic Bifurcations 6.1.1 Analysis of Steady State Motions 6.1.2 Numerical Verification of the Analytical Results 6.2 Strongly Modulated Responses (SMRs) 6.2.1 General Formulation and Invariant Manifold Approach 6.2.2 Reduction to One-DimensionalMaps and Existence Conditions for SMRs 6.2.3 Numerical Simulations 6.3 NESs as Strongly Nonlinear Absorbers for Vibration Isolation 6.3.1 Co-existent Response Regimes 6.3.2 Efficiency and Broadband Features of the Vibration Isolation 6.3.3 Passive Self-tuning Capacity of the NES 7 NESs with Non-Smooth Stiffness Characteristics 7.1 Systems with Multiple NESs Possessing Clear", "corpus_id": 118174323, "score": 0 }, { "doc_id": "32019158", "title": "Modulation instability: The beginning", "abstract": "Abstract We discuss the early history of an important field of “sturm and drang” in modern theory of nonlinear waves. It is demonstrated how scientific demand resulted in independent and almost simultaneous publications by many different authors on modulation instability, a phenomenon resulting in a variety of nonlinear processes such as envelope solitons, envelope shocks, freak waves, etc. Examples from water wave hydrodynamics, electrodynamics, nonlinear optics, and convection theory are given.", "corpus_id": 32019158, "score": 0 }, { "doc_id": "7227838", "title": "Modulational instability: first step towards energy localization in nonlinear lattices", "abstract": "We study the modulational instability in discrete lattices and we show how the discreteness drastically modifies the stability condition. Analytical and numerical results are in very good agreement. We predict also the evolution of a linear wave in the presence of noise and we show that modulational instability is the first step towards energy localization.", "corpus_id": 7227838, "score": 0 }, { "doc_id": "32103952", "title": "Modulation instability and capillary wave turbulence", "abstract": "Formation of turbulence of capillary waves is studied in laboratory experiments. The spectra show multiple exponentially decreasing harmonics of the parametrically excited wave which nonlinearly broaden with the increase in forcing. Spectral broadening leads to the development of the spectral continuum which scales as ∝f− 2.8, in agreement with the weak turbulence theory (WTT). Modulation instability of capillary waves is shown to be responsible for the transition from discrete to broadband spectrum. The instability leads to spectral broadening of the harmonics, randomization of their phases, it isolates the wave field from the wall, eventually allows the transition from 4- to 3-wave interactions as the dominant nonlinear process, thus creating the prerequisites assumed in WTT.", "corpus_id": 32103952, "score": 0 }, { "doc_id": "40718746", "title": "Space-time resolved wave turbulence in a vibrating plate.", "abstract": "Wave turbulence in a thin elastic plate is experimentally investigated. By using a Fourier transform profilometry technique, the deformation field of the plate surface is measured simultaneously in time and space. This enables us to compute the wave-vector-frequency (k, omega) Fourier spectrum of the full space-time deformation velocity. In the 3D (k, omega) space, we show that the energy of the motion is concentrated on a 2D surface that represents a nonlinear dispersion relation. This nonlinear dispersion relation is close to the linear dispersion relation. This validates the usual wave-number-frequency change of variables used in many experimental studies of wave turbulence. The deviation from the linear dispersion, which increases with the input power of the forcing, is attributed to weak nonlinear effects. Our technique opens the way for many new extensive quantitative comparisons between theory and experiments of wave turbulence.", "corpus_id": 40718746, "score": 0 }, { "doc_id": "10159687", "title": "Linear versus nonlinear response of a forced wave turbulence system.", "abstract": "A vibrating plate is set into a chaotic state of wave turbulence by a forcing having periodic and random components. Both components are weighted in order to explore continuously intermediate forcing from the periodic to the random one, but keeping constant its rms value. The transverse velocity of the plate is measured at the application point of the force. It is found that whatever the detail of the forcing is, the velocity spectra exhibit a universal cascade for frequencies larger than the forcing frequency range. In contrast, the velocity spectra strongly depend on the nature of the forcing within the range of forcing frequencies. The coherence function is used to extract the contribution of the velocity fluctuations that display a linear relationship with the forcing. The nonlinear contribution to the velocity fluctuations is found to be almost constant, about 55% of the total velocity fluctuations whatever the nature of the forcing from random to periodic. On the other hand, the nonlinear contribution to the fluctuations of the injected power depends on the nature of the forcing; it is significantly larger for the periodic forcing (60%) and decreases continuously as the randomness is increased, reaching a value of 40% for the pure random forcing. For all the cases of intermediate forcing from random to periodic, a simple model of the velocity response recovers in a fairly good agreement the probability density function of the injected power. The consequence of the existence of a linear-response component is discussed in the context of the fluctuation-dissipation theorem validation in experiments of out-of-equilibrium systems.", "corpus_id": 10159687, "score": 0 }, { "doc_id": "2719333", "title": "Effective dissipation and turbulence in spectrally truncated euler flows.", "abstract": "A new transient regime in the relaxation towards absolute equilibrium of the conservative and time-reversible 3D Euler equation with a high-wave-number spectral truncation is characterized. Large-scale dissipative effects, caused by the thermalized modes that spontaneously appear between a transition wave number and the maximum wave number, are calculated using fluctuation dissipation relations. The large-scale dynamics is found to be similar to that of high-Reynolds number Navier-Stokes equations and thus obeys (at least approximately) Kolmogorov scaling.", "corpus_id": 2719333, "score": 0 } ]

{ "doc_id": "2793551", "title": "Effusion rate controls on lava flow length and the role of heat loss: a review", "abstract": "Walker (1973; Phil. Trans. R. Soc. Lond., 274, 107) argued that, for a limited set of compositions and flow types, effusion rate (E) was the principal influence on flow length, sparking a series of studies into the volume and cooling limits on flow extension. We here review these works, as well as the role of heat loss in controlling flow length. We also explore the applicability of Walker's idea to a larger compositional and morphological range. Heat loss plays a fundamental role in determining flow core cooling rates, thereby influencing cooling-limited flow length. Field measurements allow classification of four flow types with respect to heat loss. In this classification as we move from poorly insulated to well insulated regimes, decreased heat losses increase the length that a flow can extend for a given E, composition, morphology, or amount of cooling: (1) immature tube-contained, basalt - thin tube roofs provide minimal insulation, allowing cooling rates of c .1 0 22 8 Cs 21 so that at low E, these flows extend only a few hundred metres; (2) poorly crusted, basalt - open channels with hot surface crusts also exhibit cooling rates of c .1 0 22 8 Cs 21 so such flows extend a few kilometres at E , 1m 3 s 21 ; (3) heavily crusted, dacite - heat losses are reduced when thick crusts form, reducing core cooling rates to c .1 0 24 8 Cs 21 so these flows can potentially extend several kilometres even at low E and despite very high viscosities (10 9 -10 10 Pa s); (4) master tube-contained, basalt - thick tube roofs insulate flow, reducing heat losses and cooling rates to c .1 0 23 8 Cs 21 . These cooling rates mean that at low E, tube-contained flows can extend tens to hundreds of kilometres. Basically, if composition, insulation, and morphology are held constant flow length will increase with effusion rate. Our aim is to review G. P. L. Walker's pioneering work into the emplacement of lava flows, focusing on his studies of the relationship between effusion rate and eventual flow length, and the subsequent work that this inspired. Walker's ideas on this topic followed observations of active lava flow emplacement during a terminal (summit) effusive eruption at Mt Etna (Italy) during 1966, and the work was completed during 1967-1973. The work comprised a series of three papers. The first, 'Thick- ness and viscosity of etnean lavas' (Walker 1967), was published in Nature and examined the influence of viscosity and slope on flow emplacement, dimen- sions and morphology. The second, 'Compound and simple lava flows and flood basalts' (Walker 1972), published in Bulletin of Volcanology, set up stan- dard definitions and nomenclature for lava flow units and compound lava flows, and examined the conditions under which different flow architectures are built. Finally, 'Lengths of lava flows' (Walker 1973; in the Philosophical Transactions of the Royal Society of London) rounded the series off by demonstrating that effusion rate is the principal factor that influences not only flow length, but also flow field type, with viscosity being a secondary factor. With higher effusion rates, long simple flows tend to be emplaced, whereas at lower effu- sion rates, multiple short flows pile up around a vent to build compound flow fields. We focus on the main theme of this third paper and the influence that this has had on subsequent study and debate, before examining the role of thermal insulation and heat loss on determining and modifying effusion rate-flow length relation- ships. A relationship that governs the interplay between flow length, heat loss and effusion rate was recognized by Walker (1973). In the conclusion of the 'Lengths of lava flows' paper he stated:", "corpus_id": 2793551 }

[ { "doc_id": "129675420", "title": "Compound and simple lava flows and flood basalts", "abstract": "Compound lava flows, defined as those lavas which are divisible into flowunits, commonly have a shield-like form and are thought to develop when the rate of extrusion of lava is relatively low.Simple lava flows, defined as those lavas which are not divisible into flow-units, are thought to form when the rate of extrusion of lava is relatively high. A logical definition oflava flow must embrace both simple lava sheets and substantial lava shields (compound lava flows) up to 600 m high. Flood basalt piles include both compound and simple flows, but the most extensive and far-reaching flows are simple and they are believed to form when the rate of extrusion of lava is particularly high.", "corpus_id": 129675420, "score": 1 }, { "doc_id": "53139481", "title": "Flow-Units in Basalt", "abstract": "Basalt flows in the San José Valley, Valencia County, New Mexico, are of pahoehoe type and are characterized by flow-units. A \"flow-unit\" may be defined as a tongue-shaped structure within a flow. In transverse cross section flow-units are small lenses from ioo to more than 300 feet long and from 10 to more than 20 feet thick. As many as five flow-units, one on top of the other, may occur in a flow. As there is no evidence of erosion, weathering, or deposition between flow-units, the time-interval between them must be short. The simplest flow mechanism for lava is one in which the lava moves as a single unit. The existence of the flow-units, however, indicates a greater complexity in the mechanism of these flows. At the front of the flow and also on its margins tongues a few hundred feet wide break out and flow for considerable distances. A number of tongues form, crusts appear on them, and these tongues are buried by later tongues, which in turn are buried by others. In this way multiple flows are formed. Such flows differ from single flows of pahoehoe type in their greater proportion of vesicles and other cavities, a fact of importance in the movement of solutions through them.", "corpus_id": 53139481, "score": 0 }, { "doc_id": "129778596", "title": "The variation of magma discharge during basaltic eruptions", "abstract": "Abstract The rate at which basaltic magma is discharged varies substantially during many eruptions. An individual eruption has an eruption rate (Qe), the volumetric rate of discharge averaged over the whole or a major part of an eruption, and an effusion rate (Qf), the volumetric flux rate at any given time. In many examples Qf soon reaches a maximum value after a short period of waxing flow, partly because of magmatic expansion, and then falls more slowly in the later parts of the eruption. The release of elastic strain energy from stored magma and the sub-volcanic reservoir during eruption can produce an exponential form of such waning flow. Comparison of the eruption rates of the historic eruptions of Mauna Loa, Kilauea and Etna shows that for each volcano there is a trend of decreasing Qe with increasing duration of eruption. This relationship is not predicted by a simple elastic model of magma release. Two additional processes are invoked to explain the eruptive histories of these volcanoes: modification of the eruptive conduits, and the continued supply of magma from depth during eruption. Conduits evolving from dikes to plugs by wall-rock erosion or freezing of magma can result in increased early values of Qf and the maintenance of very low values of Qf values for long periods later in the eruption. Discharge variations during three specific eruptions are discussed in detail. Paricutin (1943–1952) had exponentially waning flow, with a time constant of about three years, that is consistent with a deep reservoir. The waning flow of Hekla's 1947–1948 eruption showed some of the characteristics of conduit modification, whilst the 1959 Kilauea Iki eruption is interpreted in terms of a closed system with varying magma rheology.", "corpus_id": 129778596, "score": 0 }, { "doc_id": "48361928", "title": "Pahoehoe and aa in Hawaii: volumetric flow rate controls the lava structure", "abstract": "The historical records of Kilauea and Mauna Loa volcanoes reveal that the rough-surfaced variety of basalt lava called aa forms when lava flows at a high volumetric rate (>5–10 m3/s), and the smooth-surfaced variety called pahoehoe forms at a low volumetric rate (<5–10 m3/s). This relationship is well illustrated by the 1983–1990 and 1969–1974 eruptions of Kilauea and the recent eruptions of Mauna Loa. It is also illustrated by the eruptions that produced the remarkable paired flows of Mauna Loa, in which aa formed during an initial short period of high discharge rate (associated with high fountaining) and was followed by the eruption of pahoehoe over a sustained period at a low discharge rate (with little or no fountaining). The finest examples of paired lava flows are those of 1859 and 1880–1881. We attribute aa formation to rapid and concentrated flow in open channels. There, rapid heat loss causes an increase in viscosity to a threshold value (that varies depending on the actual flow velocity) at which, when surface crust is torn by differential flow, the underlying lava is unable to move sufficiently fast to heal the tear. We attribute pahoehoe formation to the flowage of lava at a low volumetric rate, commonly in tubes that minimize heat loss. Flow units of pahoehoe are small (usually <1 m thick), move slowly, develop a chilled skin, and become virtually static before the viscosity has risen, to the threshold value. We infer that the high-discharge-rate eruptions that generate aa flows result from the rapid emptying of major or subsidiary magma chambers. Rapid near-surface vesiculation of gas-rich magma leads to eruptions with high discharge rates, high lava fountains, and fast-moving channelized flows. We also infer that long periods of sustained flow at a low discharge rate, which favor pahoehoe, result from the development of a free and unimpeded pathway from the deep plumbing system of the volcano and the separation of gases from the magma before eruption. Achievement of this condition requires one or more episodes of rapid magma excursion through the rift zone to establish a stable magma pathway.", "corpus_id": 48361928, "score": 0 }, { "doc_id": "128477633", "title": "Mapping lava flow hazards using computer simulation", "abstract": "Computer simulations of the paths of flowing lava are achieved using a program, FLOWFRONT, that describes the behavior of flow and digital models of the terrain. Two methods of application of simulations to the hazards posed by lava flows are described. The first, deterministic, method requires that program parameters such as vent position, minimum flow thickness, and thickness/slope relationship be based on the ambient eruptive conditions so that the future course of a specific lava flow can be simulated. This is illustrated using retrospective modeling of the first 21 days of the eruption of an andesitic lava flow at Lonquimay volcano, Chile, in 1988–1989. The usefulness of this method for real-time predictive modeling is likely to be limited by the lack of accurate field data on flow characteristics, the simple nature of the model, and the sensitivity to parameter choice of the final planimetric form of the model flow. The second application is probabilistic in nature and creates a map of the likelihood of inundation by lava flows that is useful for long-term land use planning. This method uses the historical record of past eruptions to constrain a series of Monte Carlo simulations and is illustrated using data from Etna volcano in Sicily. A multivariate statistical analysis of nine parameters for the 1763–1989 eruption catalog using simulated annealing permitted a classification of Etna's flank eruptions into two types: A and B. Type A eruptions are short-lived and produce linear lava flows; type B eruptions are long-lived, and produce lava flows that are much broader in shape, and their vents are restricted to the eastern flank of the volcano. The simulation method consists of creating a probability surface of the location of future eruption vents and segmenting the region according to the most likely historical eruption on which to base the simulation. Analysis of the autocorrelation of the historical eruptions shows that type A eruptions are strongly autocorrelated but type B eruptions are only weakly autocorrelated. A library is created of simulation parameters that give reasonable retrospective fits to each of the historical lava flows. Monte Carlo sampling of the simulation space using this library and the above spatial constraints produces a map of probability of lava inundation.", "corpus_id": 128477633, "score": 0 }, { "doc_id": "140634066", "title": "A preliminary thermal budget for lava tubes on the Earth and planets", "abstract": "Lava tubes are a very common and important feature in mafic lava flows. The insulation provided by lava tubes allows molten lava to travel large distances from the vent with little cooling. This paper presents the first attempt to quantify the processes that control this cooling. The resulting thermal budget balances heat loss by (1) conduction, (2) convection of air in the wall rocks, (3) vaporization of rainwater, and (4) radiation out of skylights against (1) viscous dissipation, (2) latent heat released during crystallization, and (3) the cooling of the lava. When applied to the Waha'ula tube on Kilauea Volcano, Hawaii, this thermal budget reproduces the observed ∼1°C/km cooling of the lava inside the active tube. The thermal budget is also used to compare the insulating ability of hypothetical lava tubes in a continental flood basalt setting, on the ocean floor, Venus, the Moon, and Mars. This analysis demonstrates the large effect of rainfall and atmospheric convection, the importance of the volumetric flux of lava through the tube, and the overwhelming importance of compositional (i.e., rheological) differences. This work suggests that basaltic tube-fed flows several hundred kilometers long can be produced by eruptions with effusion rates of only a few tens of cubic meters per second. Thus even the longest lava flows observed in our solar system could have been produced by low to moderate effusion rate eruptions, if they were tube-fed.", "corpus_id": 140634066, "score": 1 }, { "doc_id": "129231024", "title": "Kīlauea summit overflows: their ages and distribution in the Puna District, Hawai'i", "abstract": "Abstract The tube-fed pāhoehoe lava flows covering much of the northeast flank of Kīlauea Volcano are named the 'Ailā'au flows. Their eruption age, based on published and six new radiocarbon dates, is approximately AD 1445. The flows have distinctive paleomagnetic directions with steep inclinations (40°–50°) and easterly declinations (0°–10°E). The lava was transported ∼40 km from the vent to the coast in long, large-diameter lava tubes; the longest tube (Kazumura Cave) reaches from near the summit to within several kilometers of the coast near Kaloli Point. The estimated volume of the 'Ailā'au flow field is 5.2±0.8 km3, and the eruption that formed it probably lasted for approximately 50 years. Summit overflows from Kīlauea may have been nearly continuous between approximately AD 1290 and 1470, during which time a series of shields formed at and around the summit. The 'Ailā'au shield was either the youngest or the next to youngest in this series of shields. Site-mean paleomagnetic directions for lava flows underlying the 'Ailā'au flows form only six groups. These older pāhoehoe flows range in age from 2750 to <18,000 BP, and the region was inundated by lava flows only three times in the past 5000 years. The known intervals between eruptive events average ∼1600 years and range from ∼1250 years to >2200 years. Lava flows from most of these summit eruptions also reached the coast, but none appears as extensive as the 'Ailā'au flow field. The chemistry of the melts erupted during each of these summit overflow events is remarkably similar, averaging approximately 6.3 wt.% MgO near the coast and 6.8 wt.% MgO near the summit. The present-day caldera probably formed more recently than the eruption that formed the 'Ailā'au flows (estimated termination ca. AD 1470). The earliest explosive eruptions that formed the Keanakāko'i Ash, which is stratigraphically above the 'Ailā'au flows, cannot be older than this age.", "corpus_id": 129231024, "score": 0 }, { "doc_id": "128775845", "title": "Lengths of Hawaiian lava flows", "abstract": "Comparison of length, volume, and effusion rate for 87 historic Hawaiian basaltic lava flows shows little support for a direct relationship between flow length and effusion rate. A statistically more significant relationship exists between flow length and total volume of material extruded. Cross-sectional area, effusion rate, and volume all play important roles in governing the emplacement of lava flows in Hawaii; no single factor appears most important. One reason for the observed relationships in Hawaii may be that tube-fed flows, with approximately constant cross-sectional area, advance farther than other types of flows for similar effusion rates and volumes.", "corpus_id": 128775845, "score": 1 }, { "doc_id": "129457391", "title": "Effusion rate and the shape of aa lava flow-fields on Mount Etna", "abstract": "The maximum distance attained by lava flows on Mount Etna increases linearly with an increasing effusion rate for flows greater than 1 km long. By considering lava as a Bingham fluid, a simple model of the shape of a lava flow-field in terms of flows and conduits can be constructed. Calibration of this model using the flow distance-effusion rate relationship enables the variation of effusion rate during the eruption that produced the flow-field to be calculated. Analysis of the historical flank eruptions of Etna indicates a favored range of effusion rate from 15 to 45 m3/s.", "corpus_id": 129457391, "score": 1 }, { "doc_id": "129422358", "title": "The 1983 Etna eruption: Event chronology and morphological evolution of the lava flow", "abstract": "The event chronology of the 1983 Etna eruption is summarized, and the development of a compound lava field at different time intervals during the eruption is described as observed from aerial photographs.The morphological evolution of the lava fronts has been compared with effusion rate and principal modifications occurring in the main channel, and it has been inferred that the development of the lava flow units is related to the formation of lava tunnels and particularly of lava channels. The total volume of lava emitted has been estimated to be 100±20×106 m3 according to two different methods. Finally, the comparison with previous historical eruptive activity shows a good correlation to other quiet eruptions.", "corpus_id": 129422358, "score": 0 }, { "doc_id": "129367487", "title": "Formation of lava tubes and extensive flow field during the 1991–1993 eruption of Mount Etna", "abstract": "Detailed mapping during the 1991–1993 eruption of Mount Etna has shown that there is a relationship between tumuli, ephemeral vents, lava tubes, and their parent lava flows. During this eruption, many tubes formed in stationary, inflated ‘a’a lava flows. Ephemeral vents at the fronts of these stationary flows and above lava tubes fed secondary lava flows, many of which subsequently developed new tubes. The resulting complex network of tubes, ephemeral vents, and secondary flows was responsible for most of the widening, thickening, and lengthening of the 1991–1993 Etna lava flow field. The supply of relatively uncooled lava via tubes to distal parts of this flow field allowed lava to flow 3 km farther from the vent than the longest channel-fed lava flow. Our observations suggest that lava tubes play a more important role in the formation of extensive ‘a’a flow fields on Etna than has previously been recognized.", "corpus_id": 129367487, "score": 0 }, { "doc_id": "128681928", "title": "Lava flow cooling estimated from Landsat Thematic Mapper infrared data: The Lonquimay Eruption (Chile, 1989)", "abstract": "Surface temperatures of a 1989 andesite lava flow at Volcan Lonquimay, Chile, derived from an analysis of Landsat Thematic Mapper (TM) infrared data, show a progressive cooling of crusted lava from 250°C to 170°C down a 1.5 km segment of the flow. These results are obtained by solving “dual-band” equations for the two short-wavelength infrared TM bands, assuming that the lava surface can be represented by two thermal components, exposed core and chilled crust, and unlike previous investigations, by predetermining the temperature of the hot component rather than the cool component. This approach is consistent with both observational data and theoretical models, and shows that any exposed core of the flow occupies tiny fractions, possibly less than 0.03%, of the surface area. As a result, the crust made by far the greatest contribution to radiative heat losses, estimated at between 1 and 3 MW per 30×30 m pixel, along most of the flow's length. Convective heat transfer into the air above the flow is about two thirds the corresponding radiative flux. These estimated surface heat losses suggest thicknesses of less than 1 m for a conductive thermal boundary layer component of the crust. Radiance values in the thermal infrared band 6 of the TM image are consistent with temperatures derived from the short-wavelength infrared data and reveal the thermal manifestation of a topographic step beneath the flow.", "corpus_id": 128681928, "score": 0 }, { "doc_id": "128567196", "title": "Modeling of the steady-state temperature field in lava flow levées", "abstract": "The rationale of lava flow deviation is to prevent major damage, and, among the possible techniques, the opening of the flow levees has often been demonstrated to be suitable and reliable. The best way to open the levees in the right point, in order to obtain the required effect, is to produce an explosion in situ, and it is then necessary to map with the highest precision the temperature field inside the levees, in order to design a safe and successful intervention. The levees are formed by lava flows due to their non-Newtonian rheology, where the shear stress is lower than the yield stress. The levees then cool and solidify due to heat loss into the atmosphere. In this work we present analytical solutions of the steady-state heat conduction problem in a levee using the method of conformal mapping for simple geometrical shapes of the levee cross-section (triangular or square). Numerical solutions are obtained with a finite-element code for more complex, realistic geometries.", "corpus_id": 128567196, "score": 0 }, { "doc_id": "121233932", "title": "A method for estimating eruption rates of planetary lava flows", "abstract": "Abstract A model that accounts for radiative losses from a partially crusted hotter core can be used to constrain eruption rates of single-lobed planetary lava flows by assuming thermal characteristics are similar to terrestrial flows. Eruption rate can be expressed as a function of the area fraction of core exposed, initial core temperature, core temperature when the flow stops advancing, crust thickness, flow thickness, and the density and heat capacity of the lava.", "corpus_id": 121233932, "score": 0 }, { "doc_id": "55016208", "title": "Cooling and crystallization of lava in open channels, and the transition of Pāhoehoe Lava to 'A'ā", "abstract": "Abstract Samples collected from a lava channel active at Kīlauea Volcano during May 1997 are used to constrain rates of lava cooling and crystallization during early stages of flow. Lava erupted at near-liquidus temperatures (∼1150  °C) cooled and crystallized rapidly in upper parts of the channel. Glass geothermometry indicates cooling by 12–14  °C over the first 2 km of transport. At flow velocities of 1–2 m/s, this translates to cooling rates of 22–50  °C/h. Cooling rates this high can be explained by radiative cooling of a well-stirred flow, consistent with observations of non-steady flow in proximal regions of the channel. Crystallization of plagioclase and pyroxene microlites occurred in response to cooling, with crystallization rates of 20–50% per hour. Crystallization proceeded primarily by nucleation of new crystals, and nucleation rates of ∼104/cm3s are similar to those measured in the 1984 open channel flow from Mauna Loa Volcano. There is no evidence for the large nucleation delays commonly assumed for plagioclase crystallization in basaltic melts, possibly a reflection of enhanced nucleation due to stirring of the flow. The transition of the flow surface morphology from pāhoehoe to 'a'ā occurred at a distance of 1.9 km from the vent. At this point, the flow was thermally stratified, with an interior temperature of ∼1137  °C and crystallinity of ∼15%, and a flow surface temperature of ∼1100  °C and crystallinity of ∼45%. 'A'ā formation initiated along channel margins, where crust was continuously disrupted, and involved tearing and clotting of the flow surface. Both observations suggest that the transition involved crossing of a rheological threshold. We suggest this threshold to be the development of a lava yield strength sufficient to prevent viscous flow of lava at the channel margin. We use this concept to propose that 'a'ā formation in open channels requires both sufficiently high strain rates for continued disruption of surface crusts and sufficient groundmass crystallinity to generate a yield strength equivalent to the imposed stress. In Hawai'i, where lava is typically microlite poor on eruption, these combined requirements help to explain two common observations on 'a'ā formation: (a) 'a'ā flow fields are generated when effusion rates are high (thus promoting crustal disruption); and (b) under most eruption conditions, lava issues from the vent as pāhoehoe and changes to 'a'ā only after flowing some distance, thus permitting sufficient crystallization.", "corpus_id": 55016208, "score": 0 }, { "doc_id": "28098534", "title": "Viscosity of hydrous rhyolitic melts inferred from kinetic experiments, and a new viscosity model", "abstract": "Abstract Viscosity of hydrous silicate melts is a critical property for understanding magma transport, bubble growth, volcanic eruption, and magma fragmentation. We report new inferred viscosity for hydrous rhyolitic melt in the viscosity range of 109 to 1015 Pa·s based on the kinetics of hydrous species reactions in the melt upon cooling (i.e., based on the equivalence between the glass-transition temperature and the apparent equilibrium temperature), as well as data from bubble-growth experiments. By combining viscosity data of rhyolitic melts containing from 6 ppm to about 8.0 wt% total H2O (both our own data and literature data), we propose the following relation for the dependence of viscosity on total H2O content at a given temperature and pressure: where η is viscosity and 1/η is fluidity, η1 is the viscosity of the dry melt, x is the mole fraction of total dissolved H2O, n and η2 are two fitting parameters, and η2 can be interpreted to be the viscosity of the hypothetical melt consisting of pure H2O. The above simple equation appears to work well in modeling viscosity of hydrous rhyolitic melts. Using the above functional form and a weighted nonlinear regression, experimental data covering 570 to 1920 K and 0.0006 to 8.2 wt% total H2O are used to obtain the following non-Arrhenian model for the viscosity of Mono Crater rhyolitic melts: logη = -log{exp(18.5611 - 49584/T) + exp[1.47517 - (1795.5/T)1.9448]x1+ (1812.2/T)2} where T is in K, and x is the mole fraction of total dissolved H2O on a single oxygen basis. The 2σ uncertainty in the above 6-parameter formula is 0.36 in terms of logη (for experimental data with errors smaller than 1 log unit), much less than uncertainties in all previous models for hydrous rhyolitic melt. We hence recommend its use for predicting the viscosity of high-SiO2 and calc-alkaline rhyolitic melts. Our model shows that a minute H2O content can still affect the melt viscosity significantly, especially at low temperatures (i.e., high viscosity). For example, at 973 K, the viscosity of rhyolitic melt increases by 1.2 orders of magnitude from a melt with 0.1 wt% total H2O to a melt with less than 100 ppm total H2O. Because a nominally “dry” melt may still contain some H2O, such as several hundred ppm, it is critical for experimentalists to report its total H2O content for viscosity measurements. Some inconsistency in literature viscosity data might be attributable to small variations in H2O content in the samples.", "corpus_id": 28098534, "score": 0 }, { "doc_id": "129589130", "title": "Dynamics of lava flows", "abstract": "Extensive lava flows, like those of the Columbia plateau of Washington state, require thicknesses only of the order of meters and temperatures only slightly above the melting point to spread over distances of the order of hundreds of kilometers. Other things being equal, the spreading distance is proportional to the cube of the thickness of the flow.", "corpus_id": 129589130, "score": 0 }, { "doc_id": "62732018", "title": "Simulating lava flows by an improved cellular automata method", "abstract": "Abstract Lava-flow morphology is determined by cooling rate, viscosity, yield strength, eruption rate, topography, total mass, and other various factors. We have made a numerical flow model, assuming nonisothermal laminar Bingham flow, in which we take the self-gravity and cooling mechanisms into account. Because the calculation method is a type of cellular automata on square meshes, we can apply our numerical model on any actual topography based on a dense-grid digital elevation model. A method of eliminating the mesh shape dependence, which is a well-known problem of cellular automata, is also presented. This reduced random space method enables us to calculate large-scale lava flows in a short time without numerical instability, and obtain mesh-free reliable results. This method is applicable to any other cellular automata type algorithm with ease. We validate our simulation code using data from a real lava flow.", "corpus_id": 62732018, "score": 0 }, { "doc_id": "51517703", "title": "FLOWGO: a kinematic thermo-rheological model for lava flowing in a channel", "abstract": "Abstract. We present a kinematic, self-adaptive, numerical model to describe the down-flow thermal and rheological evolution of channel-contained lava. As our control volume of lava advances down a channel it cools and crystallizes, an increasingly thick and extensive surface crust grows, and its heat budget and rheology evolve. By estimating down-flow heat and velocity loss, our model calculates the point at which the control volume becomes stationary, giving the maximum distance lava flowing in the channel can extend. Modeled effusion rates, velocities, widths, surface crust parameters, heat budget, cooling, temperature, crystallinity, viscosity, and yield strength all compare well with field data collected during eruptions at Mauna Loa, Kĩlauea, and Etna. Modeled lengths of 25–27, 2.5–5.7, and 0.59–0.83 km compare with measured lengths of 25–27, 4, and 0.75 km for the three flows, respectively. Over proximal flow portions we calculate cooling, crystallization, viscosity, and yield strength of 1–10°C km–1, 0.001–0.01 volume fraction km–1, 103–104 Pa s, and 10–3–102 Pa, respectively. At the flow front, cooling, crystallization, viscosity, and yield strength increase to >100°C km–1, 0.1 volume fraction km–1, 106–107 Pa s, and 103–104 Pa, respectively, all of which combine to cause the lava to stop flowing. Our model presents a means of (a) analyzing lava flow thermo-rheological relationships; (b) identifying important factors in determining how far a channel-fed flow can extend; (c) assessing lava flow hazard; and (d) reconstructing flow regimes at prehistoric, unobserved, or remote flows.", "corpus_id": 51517703, "score": 1 }, { "doc_id": "128422159", "title": "The simulation model SCIARA: the 1991 and 2001 lava flows at Mount Etna", "abstract": "Abstract Cellular Automata (CA), a paradigm of parallel computing, represent an alternative to differential equations for modelling and simulating very complex phenomena, whose evolution is based on local interactions of their constituent parts. A CA model for lava flow simulations, SCIARA (‘Simulation by Cellular Interactive Automata of the Rheology of Aetnean lava flows’) was developed and improved according to an empirical CA method for simulating macroscopic phenomena. Its last version, SCIARA-hex1, was applied to the 1991 lava flow of the 1991–1993 eruption of Etna. The simulation results are satisfying within limits to forecast the lava flow path. It was also applied during the eruption of Etna in the summer of 2001, when a new eruption threatened the town of Nicolosi. This ‘real time’ application proved that SCIARA is a reliable and flexible tool for forecasting lava flow paths and for assessing hazard in the Etnean area.", "corpus_id": 128422159, "score": 0 }, { "doc_id": "128878098", "title": "The 1975 sub-terminal lavas, mount etna: a case history of the formation of a compound lava field", "abstract": "The 1975 sub-terminal activity was characterised by low effusion rates (0.3–0.5 m3 s−1) and the formation of a compound lava field composed of many thousands of flow units. Several boccas were active simultaneously and effusion rates from individual boccas varied from about 10−4 to 0.25 m3s−1. The morphology of lava flows was determined by effusion rate (E): aa flows with well-developed channels and levees formed when E > 2 × 10−3 m3 s−1, small pahoehoe flows formed when 2 × 10−3 m3 s−1 >E > 5 > 10−4 m3 s−1 and pahoehoe toes formed when E < 5 × 10−4 m3 s−1. There was very little variation with time in the effusion temperature, composition or phenocryst content of the lava. \n \nNew boccas were commonly formed at the fronts of mature lava flows which had either ceased to flow or were moving slowly. These secondary boccas developed when fluid lava in the interior of mature aa flows either found a weakness in the flow front or was exposed by avalanching of the moving flow front. The resulting release of fluid lava was accompanied by either partial drainage of the mature flow or by the formation of a lava tube in the parent flow. The temperature of the lava forming the new bocca decreased with increasing distance from the source bocca (0.035°C m−1). It is demonstrated from the rate of temperature decrease and from theoretical considerations that many of the Etna lavas still contained a substantial proportion of uncooled material in their interior as they came to rest. The formation of secondary boccas is postulated to be one reason why direct measurements of effusion rates tend, in general, to overestimate the total effusion rates of sub-terminal Etna lava fields.", "corpus_id": 128878098, "score": 0 }, { "doc_id": "129523976", "title": "Some physical requirements for the emplacement of long basaltic lava flows", "abstract": "Long basaltic lava flows (over 100 km in length) require specific emplacement conditions to prevent the lava from freezing as it is transported to the flow front. The minimum dimensions of the lava transport systems (tubes, channels, or sheets) require that the flow have a volume greater than several cubic kilometers. Long lava flows are emplaced on slopes less than 10% (∼5°) and the lava being transported must cool at a rate less than 0.5°C/km. We show that there are two modes by which thermally efficient, long distance lava transport can be achieved: (1) “rapid” emplacement in which the lava flows so quickly that it does not cool excessively despite large heat losses and (2) “insulated” emplacement in which heat loss is minimized. We here estimate cooling in the rapid mode using a modified version of a previously published thermal model for aa flows and find that, for a range of inputs appropriate for subaerial terrestrial condition, effusion rates of at least 3100 to 11000 m3/s, channel flow velocities in excess of 4–12 m/s, and minimum channel depths of 3–17 m are required for basaltic flows >100 km in length. For emplacement in the insulated mode, we construct a very simple heat balance model for roofed sheet flows which shows that extremely long sheet-fed flows are possible with velocities as low as 0.2–1.4 m/s, flow thickness of 6–23 m, and minimum effusion rates of the order of 50–7100 m3/s. Also, earlier work has suggested that tube-fed flows more than 100 km long can be produced at effusion rates as low as several tens of m3/s and with tube diameters of a few tens of meters. We argue that flows emplaced in the rapid mode should be morphologically similar to channel-fed aa flows while those emplaced in the insulated mode should be similar to tube-fed or sheet-like inflated pahoehoe flows. This leads to several field criteria for distinguishing these two modes of emplacement in ancient lava sequences. Additional constraints on the emplacement of long lava flows are expected from the continued study of the formation and evolution of lava channels, tubes, and sheets.", "corpus_id": 129523976, "score": 1 }, { "doc_id": "59128914", "title": "Terrestrial analogs and thermal models for Martian flood lavas", "abstract": "The recent flood lavas on Mars appear to have a characteristic “platy-ridged” surface morphology different from that inferred for most terrestrial continental flood basalt flows. The closest analog we have found is a portion of the 1783–1784 Laki lava flow in Iceland that has a surface that was broken up and transported on top of moving lava during major surges in the eruption rate. We suggest that a similar process formed the Martian flood lava surfaces and attempt to place constraints on the eruption parameters using thermal modeling. Our conclusions from this modeling are (1) in order to produce flows >1000 km long with flow thicknesses of a few tens of meters, the thermophysical properties of the lava should be similar to fluid basalt, and (2) the average eruption rates were probably of the order of 104 m3/s, with the flood-like surges having flow rates of the order of 105–106 m3/s. We also suggest that these high eruption rates should have formed huge volumes of pyroclastic deposits which may be preserved in the Medusae Fossae Formation, the radar “stealth” region, or even the polar layered terrains.", "corpus_id": 59128914, "score": 0 }, { "doc_id": "48358286", "title": "Effects of Martian conditions on numerically modeled, cooling‐limited, channelized lava flows", "abstract": "[1] We used the FLOWGO thermorheological model to examine the effects of Martian gravitational and environmental conditions on the cooling-limited behavior of lava flowing in a channel. The largest effect is due to the lower gravity on Mars as compared to Earth, which causes lava to flow more slowly. The lower velocity means that heat loss per distance down a Mars channel is greater even though the lower velocity also produces a higher percentage cover of insulating crust. Gravity alone causes the Mars flow to be >65 km shorter than an Earth flow with an equivalent volumetric flow rate. The cooler ambient Mars atmosphere causes a slight increase in heat loss by forced convection. This slows the flow a bit more, resulting in a very slight increase in heat loss per distance by all mechanisms, and decreases the modeled flow length by ∼1 km, a difference well below our model uncertainty. Replacing terrestrial values of atmospheric density, viscosity, thermal conductivity, heat capacity, and cubic expansivity makes convection less efficient and increases flow length by ∼15 km. Nevertheless, at the same volumetric flow rate, lava flows ∼50 km less far under Martian conditions than under terrestrial conditions. Our specific model flow has a volumetric flow rate of ∼5000 m3 s−1 and traveled ∼190 km down a channel on a constant 7° slope. This volumetric flow rate is slightly less than the maximum rates during the 1783–1785 Laki eruption and is 5–10 times greater than those of typical Mauna Loa eruptions.", "corpus_id": 48358286, "score": 0 }, { "doc_id": "140542548", "title": "The effect of crystallization on the rheology and dynamics of lava flows", "abstract": "Abstract The dynamics of a lava flow is studied by a two-dimensional model describing a viscous fluid with Bingham rheology, flowing down a slope. The temperature in the flow is calculated assuming that heat is transferred through the plug by conduction and is lost by radiation to the atmosphere at the top of the flow. Taken into account is that the increasing crystallization takes place in the flow as a consequence of cooling. The lava viscosity and yield stress are expressed as a function of crystallization degree as well as of temperature: in particular it is assumed that yield stress reaches a maximum value above the solidus temperature, according to experimental data. Dynamical variables, such as velocity and thickness of the flow, are calculated for different values of the maximum crystallization degree and the flow rate. The model shows how the lava flow dynamics is affected by cooling and crystallization. The cooling of the flow is controlled by the increase of yield stress, which produces a thicker plug and makes the heat loss slower. The increasing crystallization has two opposing effects on viscosity: it produces an increase of viscosity, but at the same time produces an increase of yield stress and hence reduces the heat loss and keeps the internal temperature high. As a consequence, lava flows are significantly affected by the dependence of yield stress on temperature and scarcely by the maximum crystallization degree.", "corpus_id": 140542548, "score": 0 }, { "doc_id": "129377211", "title": "Influence of crystallization and entrainment of cooler material on the emplacement of basaltic aa lava flows", "abstract": "A theoretical model is used to describe and investigate the effects of simultaneous crystallization, radiation loss, and entrainment of cooler material on the temperature of a well-mixed core of an active aa lava flow. Entrainment of crust, levee debris, and base material into the interior of active flows has been observed, but the degree of assimilation and the thermal consequences are difficult to quantify. The rate of entrainment can be constrained by supplementing the theoretical model with information on the crystallization along the path of the flow and estimation of the radiative loss from the flow interior. Application of the model is demonstrated with the 1984 Mauna Loa flow, which was erupted about 30°C undercooled. Without any entrainment of cooler material, the high crystallization rates would have driven temperatures in the core well above temperatures measured by thermocouple and estimated from glass geothermometry. One plausible scenario for this flow, which agrees with available temperature and crystallinity measurements, has a high initial rate of entrainment during the first 8 hours of travel (a mass ratio of entrained material to fluid core of about 15% if the average temperature of the entrained material was 600°C), which counterbalances the latent heat from approximately 40% crystallization. In this scenario, the model suggests an additional 5% crystallization and a 5% entrainment mass ratio over the subsequent 16-hour period. Measurements of crystallization, radiative losses, and entrainment factors are necessary for understanding the detailed thermal histories of active lava flows.", "corpus_id": 129377211, "score": 0 }, { "doc_id": "129519862", "title": "Heat loss measured at a lava channel and its implications for down-channel cooling and rheology", "abstract": "During May 2001 we acquired 2016 thermal images over an ~8-h-long period for a section of active lava channel on Mount Etna (Italy). We used these to extract surface temperature and heat-loss profi les and thereby calculate core cooling rates. Flow surface temperatures declined from ~1070 K at the vent to ~930 K at 70 m. Heat losses were dominated by radiation (5 × 10 W m) and convection (~10 W/m). These compare with a heat gain from crystallization of 6 × 10 W/m. The imbalance between sinks and sources gives core cooling (δT/δx) of ~110 K/km. However, cooling rate per unit distance also depends on fl ow conditions, where we distinguished: (1) unimpeded, high-velocity (~0.2 m/s) fl ow with low δT/δx (0.3 K/m); (2) unimpeded, low-velocity (~0.1 m/s) fl ow with higher δT/δx (0.5 K/m); (3) waning, insulated fl ow at low velocity (~0.1 m/s) with low δT/δx (0.3 K/m); and (4) impeded fl ow at low velocity (<0.1 m/s) with higher δT/δx (0.4 K/m). Our data allow us to defi ne three thermal states of fl ow emplacement: insulated, rapid, and protected. Insulated is promoted by the formation of hanging blockages and coherent roofs. During rapid emplacement, higher velocities suppress cooling rates, and δT/δx can be tied to mean velocity (V mean ) by δT/δx = aV mean . In the protected case, deeper, narrow channels present a thermally effi cient channel, where δT/δx can be assessed using the ratio of channel width (w) to depth (d) in w/d = aδT/δx.", "corpus_id": 129519862, "score": 0 }, { "doc_id": "129077414", "title": "Flow and convective cooling in lava tubes", "abstract": "Tube-fed basaltic lava flows with lengths ranging from 10 to 200 km are inferred to exhibit similar amounts of cooling. To explain the wide range of implied cooling rates, we consider forced convection as a dominant cooling process in lava tubes and present solutions that express mean temperature versus distance down the tube as a function of flow rate and flow cross section. Our models treat forced convective thermal losses in steady laminar flow through a lava tube with constant temperature walls and constant material properties. We explore the effects of different wall temperature and heat flux rate boundary conditions for circular tube and parallel plate flows over a range of tube sizes, plate spacings, eruption temperatures, and volume flow rates. Results show that nonlinear cooling rates over distance are characteristic of constant wall temperature for a piecewise parallel plate/circular tube model. This provides the best fit to temperature observations for Hawaiian tubes. Such a model may also provide an explanation for the very low (∼10°C) cooling observed in ∼10 km long Hawaii tube flows and inferred in longer ∼50 to 150 km tube-fed flows in Queensland. The forced convective cooling model may also explain similar flow morphologies for long tube-fed basaltic lava flows in a wide variety of locations, since small variations in eruption temperature or flow rate can accommodate the entire range of flow lengths and cooling rates considered. Our results are consistent with previous suggestions that long basaltic flows may be a reflection of low slopes, a particularly steady moderate eruption rate, and well-insulated flow, rather than of high discharge rates.", "corpus_id": 129077414, "score": 0 }, { "doc_id": "132297501", "title": "Thermal efficiency of lava tubes in the Pu'u 'ō'Ō-Kupaianaha eruption", "abstract": "We have applied glass geothermometry to a suite of 37 pairs of glassy lava samples collected on Kilauea's east - rift zone, from the upper and lower ends of the episode 48 lava-tube system, when the Kupaianaha pond was active (1986-90). We also present data on a small suite of skylight samples collected from 1986 through the end of episode 48 (in 1991), plus some data on skylight-coast sample pairs from episodes 51 and 53. The results for the pond-coast pairs are as follows: (1) From November 1986 through January 1988 (15 months), the average change in inferred quenching temperature from pond to coast (for 12 sample pairs) is 12.4°C, and the average increase in crystal content (inferred from the observed enrichment of TiO 2 and K 2 O in glasses in coastal samples) is 11 to 12 weight percent. (2) From February 1988 through November 1989 (23 months), the average change in inferred quenching temperature from pond to coast (for 25 sample pairs) is 8.4°C, and the average increase in crystal content is 4 to 5 weight percent. Within this part of the data set, pond and coastal temperatures rise and fall together much of the time, even though these temporal fluctuations are at or below the limit of resolution of glass geothermometry ΔT≤3°C). (3) The minimum temperature difference for any pond-coast pair is 7°C. Of 37 sample pairs, 24 have ΔT=7-9°C, over the entire 3-year period. In about half of the skylight samples, the enclosed glasses have MgO contents consistent with the location at which the samples were collected along the lava-tube system. Glasses in the rest of the skylight samples are displaced to lower MgO contents; such samples may not be consistently as well quenched as the pond and littoral spatter samples. The data from episodes 51 and 53 are from a new tube system that was somewhat shorter than the episode 48 (Kupaianaha) lava tubes. The best-documented temperature difference observed for this 10-km long lava tube (6°C) gives exactly the same rate of temperature decrease with distance (0.6°/km) as the limiting ΔT value of 7°C observed for the 12-km-long Kupaianaha lava-tube systems. This cooling rate may represent the limiting thermal efficiency of tubes of the current eruption.", "corpus_id": 132297501, "score": 0 }, { "doc_id": "128879618", "title": "Field measurements of heat loss from skylights and lava tube systems", "abstract": "[1] We present temperature measurements made at skylights in the active flow field of Kilauea Volcano between 1995 and 2000. Spot temperature measurements of the lava stream within the lava tube revealed surface temperatures of 1017–1132°C. This compared with lava core temperatures of 1161 ± 3°C. The difference is the result of surface cooling due to radiation at the skylights. A FLIR thermal imager recorded a down-tube lava surface temperature decrease followed by a surface temperature recovery due to entrainment of the crust down flow of the skylight. The temperature of hot air expelled from skylights reached a maximum of 600°C. From these field data, we place constraints on heat loss from the skylight and lava tube. Heat losses due to conduction and circulation of air in wall rocks around the tube are 103–104 and 104–106 W m−1 down tube, respectively. At skylights, heat losses due to radiation and forced convection are 1.5 × 105 W m−1 over the skylight length and 5 × 105 W per skylight, respectively. For a 10-km-long tube, the total heat loss is between 5 × 108 and 1 × 1010 W for a fully roofed tube with an additional 1.1 × 106 W lost per 4 m × 1 m skylight. In terms of cooling rates, 1.2°C km−1 is a minimum resulting from heat losses at fully roofed tubes with no skylights. Heat loss and cooling rate will, however, increase with skylight area.", "corpus_id": 128879618, "score": 0 }, { "doc_id": "48357085", "title": "The changing morphology of an open lava channel on Mt. Etna", "abstract": "An open channel lava flow on Mt. Etna (Sicily) was observed during May 30–31, 2001. Data collected using a forward looking infrared (FLIR) thermal camera and a Minolta-Land Cyclops 300 thermal infrared thermometer showed that the bulk volume flux of lava flowing in the channel varied greatly over time. Cyclic changes in the channel's volumetric flow rate occurred over several hours, with cycle durations of 113–190 min, and discharges peaking at 0.7 m3 s−1 and waning to 0.1 m3 s−1. Each cycle was characterized by a relatively short, high-volume flux phase during which a pulse of lava, with a well-defined flow front, would propagate down-channel, followed by a period of waning flow during which volume flux lowered. Pulses involved lava moving at relatively high velocities (up to 0.29 m s−1) and were related to some change in the flow conditions occurring up-channel, possibly at the vent. They implied either a change in the dense rock effusion rate at the source vent and/or cyclic-variation in the vesicle content of the lava changing its bulk volume flux. Pulses would generally overspill the channel to emplace pāhoehoe overflows. During periods of waning flow, velocities fell to 0.05 m s–1. Blockages forming during such phases caused lava to back up. Occasionally backup resulted in overflows of slow moving ‘a‘ā that would advance a few tens of meters down the levee flank. Compound levees were thus a symptom of unsteady flow, where overflow levees were emplaced as relatively fast moving pāhoehoe sheets during pulses, and as slow-moving ‘a‘ā units during backup. Small, localized fluctuations in channel volume flux also occurred on timescales of minutes. Volumes of lava backed up behind blockages that formed at constrictions in the channel. Blockage collapse and/or enhanced flow under/around the blockage would then feed short-lived, wave-like, down-channel surges. Real fluctuations in channel volume flux, due to pulses and surges, can lead to significant errors in effusion rate calculations.", "corpus_id": 48357085, "score": 0 }, { "doc_id": "129040672", "title": "Lava tube morphology on Etna and evidence for lava flow emplacement mechanisms", "abstract": "Lava tubes play a pivotal role in the formation of many lava flow fields. A detailed examination of several compound ‘a‘a lava flow fields on Etna confirmed that a complex network of tubes forms at successively higher levels within the flow field, and that tubes generally advance by processes that include flow inflation and tube coalescence. Flow inflation is commonly followed by the formation of major, first-order ephemeral vents which, in turn, form an arterial tube network. Tube coalescence occurs when lava breaks through the roof or wall of an older lava tube; this can result in the unexpected appearance of vents several kilometers downstream. A close examination of underground features allowed us to distinguish between ephemeral vent formation and tube coalescence, both of which are responsible for abrupt changes in level or flow direction of lava within tubes on Etna. Ephemeral vent formation on the surface is frequently recorded underground by a marked increase in size of the tube immediately upstream of these vents. When the lining of an inflated tube has collapsed, ‘a‘a clinker is commonly seen in the roof and walls of the tube, and this is used to infer that inflation has taken place in the distal part of an ‘a‘a lava flow. Tube coalescence is recognised either from the compound shape of tube sections, or from breached levees, lava falls, inclined grooves or other structures on the walls and roof. Our observations confirm the importance of lava tubes in the evolution of extensive pahoehoe and ‘a‘a flow fields on Etna.", "corpus_id": 129040672, "score": 0 }, { "doc_id": "129910155", "title": "Extended cooling and viscous flow of large, hot rhyolite lavas: implications of numerical modeling results", "abstract": "Abstract A common misconception about rhyolite lava flows is that they cannot advance far from their vents and are constrained to be small due to their high viscosities. Although a high-viscosity lava will indeed flow quite slowly, it may advance a great distance if the lava efficiently retains heat and thus mobility, and if the available magma supply is large. To evaluate this possibility, a finite-difference numerical model was used to determine the rate of heat loss from units interpreted to be large rhyolite lavas. Cooling of such 100–300 m-thick units is very slow and is further retarded by a vesicular carapace and by evolution of latent heat. Thermal history alone suggests that large, thick lava flows could remain active for several decades. To constrain the duration of flow advance of these units, their inferred apparent viscosities are compared with those of active lava flows. Mean flow velocity of some large rhyolites in southwestern Idaho, USA, was estimated based on the observation that the units must still have been advancing by viscous flow at the start of spherulite crystallization, indicating perhaps a 10- to 18-year flow duration, based on studies of Obsidian Dome, California. Mean flow velocities would have been roughly 0.59 to 2.5 km/yr, and calculated average apparent viscosities of the flows ranged from 1.8 to 3.6 orders of magnitude greater than the viscosity of the lava itself. This relationship also holds for active andesite and basaltic andesite block lava flows, which have apparent viscosities 2.7 to 4 orders of magnitude greater than lava viscosities. This implies that large rhyolites may indeed have been emplaced in the same manner as less-silicic block lavas, and that long distance viscous flow is not unrealistic for rhyolite lavas. A good example of a large-volume lava is the 15-km 3 Rhyolite of the Badlands (SW Idaho), where vent relations show that lava effused from a fissure and advanced up to 9 km. More extensive rhyolites could also be emplaced solely by effusion. Extended flow of these lavas may lead to the remelting and removal of basal crumble breccias, and to the formation of welded shard textures in their margins, both processes tending to obscure the lava flow origin of the units. The great dimensions of lava-like rhyolitic units with volumes of 10 to at least 200 km 3 are not a sufficient reason to assume they erupted as ignimbrites.", "corpus_id": 129910155, "score": 0 } ]

{ "doc_id": "119298244", "title": "Holomorphic Embeddings and Immersions of Stein Manifolds: A Survey", "abstract": "In this paper we survey results on the existence of holomorphic embeddings and immersions of Stein manifolds into complex manifolds. Most of them pertain to proper maps into Stein manifolds. We include a new result saying that every continuous map \\(X\\rightarrow Y\\) between Stein manifolds is homotopic to a proper holomorphic embedding provided that \\(\\dim Y>2\\dim X\\) and we allow a homotopic deformation of the Stein structure on X.", "corpus_id": 119298244 }

[ { "doc_id": "124035982", "title": "MAPPINGS OF PARTIALLY ANALYTIC SPACES.", "abstract": "1. Introduction. We study a mapping f of a partially analytic space K into n-dimensional complex affine space Cn. A partially analytic space K is a Hausdorff topological space which is a countable union of conditionally compact open sets, which is locally connected, and which is endowed, at least partially, with an analytic structure. This means that a countable family {Ma} of subsets of K is given, each with the structure of a complex analytic manifold. An algebra A of continuous functions on K, called the analytic functions on K, is also given, with the property that each function in A is analytic on each Ml,a. The algebra A is closed in the topology of uniform coiivergence on compact subsets of K. The coordinates of the mapping f are required to lie in A. The purpose of this paper is to show that for certain spaces K the mapping f can be chosen to have certain properties. For instance, sufficient conditions are given foi there to exist an f which is proper, or which separates points, or which has a certain rank at certain points. Since the", "corpus_id": 124035982, "score": 0 }, { "doc_id": "117402231", "title": "Stein Manifolds and Holomorphic Mappings: The Homotopy Principle in Complex Analysis", "abstract": "Preliminaries. - Stein Manifolds. - Stein Neighborhoods and Holomorphic Approximation. - Automorphisms of Complex Euclidean Spaces. - Oka Manifolds. - Elliptic Complex Geometry and Oka Principle. - Applications. - Embeddings, Immersions and Submersions.- Topological Methods in Stein Geometry. - References. - Index.", "corpus_id": 117402231, "score": 1 }, { "doc_id": "118894044", "title": "Theory Of Stein Spaces", "abstract": "A. Sheaf Theory.- B. Cohomology Theory.- I. Coherence Theory for Finite Holomorphic Maps.- II. Differential Forms and Dolbeault Theory.- III. Theorems A and B for Compact Blocks ?m.- IV. Stein Spaces.- V. Applications of Theorems A and B.- VI. The Finiteness Theorem.- VII. Compact Riemann Surfaces.- Table of Symbols.- Addendum.- Errors and Misprints.", "corpus_id": 118894044, "score": 0 }, { "doc_id": "118335201", "title": "Analytic Functions of Several Complex Variables", "abstract": "The Jacobi inversion theorem leads to functions of several variables with many periods. So, we are led to the problem of developing a theory of them which is analogous to the theory of elliptic functions. First of all, we need to give an introduction to the theory of functions of several complex variables. In this chapter, we give an elementary introduction which essentially follows Weierstrass. One of the main topics will be the proof of the theorem that any meromorphic function on ℂn can be written as a quotient of two entire functions. Weierstrass called this a very difficult problem. The first proof was given by Poincare. In the case n = 1, it is not difficult to show this by means of the theory of Weierstrass products, even for arbitrary domains D ⊂ ℂ instead of ℂ. The case n > 1 is more involved, since the zero sets and pole sets of analytic functions of several complex variables are not discrete.", "corpus_id": 118335201, "score": 0 }, { "doc_id": "122821814", "title": "An introduction to complex analysis in several variables", "abstract": "I. Analytic Functions of One Complex Variable. II. Elementary Properties of Functions of Several Complex Variables. III. Applications to Commutative Banach Algebras. IV. L2 Estimates and Existence Theorems for the Operator. V. Stein Manifolds. VI. Local Properties of Analytic Functions. VII. Coherent Analytic Sheaves on Stein Manifolds. Bibliography. Index.", "corpus_id": 122821814, "score": 0 }, { "doc_id": "59421037", "title": "Complete complex hypersurfaces in the ball come in foliations.", "abstract": "In this paper we prove that every smooth complete closed complex hypersurface in the open unit ball $\\mathbb{B}_n$ of $\\mathbb{C}^n$ $(n\\ge 2)$ is a level set of a noncritical holomorphic function on $\\mathbb{B}_n$ all of whose level sets are complete. This shows that $\\mathbb{B}_n$ admits a nonsingular holomorphic foliation by smooth complete closed complex hypersurfaces and, what is the main point, that every hypersurface in $\\mathbb{B}_n$ of this type can be embedded into such a foliation. We establish a more general result in which neither completeness nor smoothness of the given hypersurface is required. \nFurthermore, we obtain a similar result for complex submanifolds of arbitrary positive codimension and prove the existence of a nonsingular holomorphic submersion foliation of $\\mathbb{B}_n$ by smooth complete closed complex submanifolds of any pure codimension $q\\in\\{1,\\ldots,n-1\\}$.", "corpus_id": 59421037, "score": 1 }, { "doc_id": "117940141", "title": "Every bordered Riemann surface is a complete conformal minimal surface bounded by Jordan curves", "abstract": "In this paper we find approximate solutions of certain Riemann-Hilbert boundary value problems for minimal surfaces in $\\mathbb{R}^n$ and null holomorphic curves in $\\mathbb{C}^n$ for any $n\\ge 3$. With this tool in hand we construct complete conformally immersed minimal surfaces in $\\mathbb{R}^n$ which are normalized by any given bordered Riemann surface and have Jordan boundaries. We also furnish complete conformal proper minimal immersions from any given bordered Riemann surface to any smoothly bounded, strictly convex domain of $\\mathbb{R}^n$ which extend continuously up to the boundary; for $n\\ge 5$ we find embeddings with these properties.", "corpus_id": 117940141, "score": 0 }, { "doc_id": "119129424", "title": "Proper holomorphic embeddings into stein manifolds with the density property", "abstract": "We prove that a Stein manifold of dimension d admits a proper holomorphic embedding into any Stein manifold of dimension at least 2d + 1 satisfying the holomorphic density property. This generalizes classical theorems of Remmert, Bishop and Narasimhan, pertaining to embeddings into complex euclidean spaces, as well as several other recent results.", "corpus_id": 119129424, "score": 0 }, { "doc_id": "119155995", "title": "Proper holomorphic immersions into Stein manifolds with the density property", "abstract": "In this paper we prove that every Stein manifold S admits a proper holomorphic immersion into any Stein manifold of dimension 2 dimS enjoying the density property or the volume density property.", "corpus_id": 119155995, "score": 0 }, { "doc_id": "53136158", "title": "The density property for complex manifolds and geometric structures", "abstract": "Definition Let g be a Lie algebra of holomorphic vector fields. We say that g has the density property if the Lie subalgebra of g generated by the complete vector fields in g is dense in g. When the Lie algebra XO(M) of all holomorphic vector fields on a complex manifold M has the density property, we say that M has the density property. If (M,ω) is a calibrated complex manifold, i.e., ω is a nondegenerate holomorphic n-form (n = dimCM) on M , we say that (M,ω) has the volume density property if the Lie algebra XO(M,ω) of all holomorphic vector fields with vanishing ω-divergence has the density property.", "corpus_id": 53136158, "score": 0 }, { "doc_id": "53136158", "title": "The density property for complex manifolds and geometric structures", "abstract": "Definition Let g be a Lie algebra of holomorphic vector fields. We say that g has the density property if the Lie subalgebra of g generated by the complete vector fields in g is dense in g. When the Lie algebra XO(M) of all holomorphic vector fields on a complex manifold M has the density property, we say that M has the density property. If (M,ω) is a calibrated complex manifold, i.e., ω is a nondegenerate holomorphic n-form (n = dimCM) on M , we say that (M,ω) has the volume density property if the Lie algebra XO(M,ω) of all holomorphic vector fields with vanishing ω-divergence has the density property.", "corpus_id": 53136158, "score": 0 }, { "doc_id": "118317956", "title": "Lectures on Harmonic Maps", "abstract": "A presentation of research on harmonic maps, based on lectures given at the University of California, San Diego. Schoen has worked to use the Fells/Sampson theorem to reprove the rigidity theorem of Masfow and superrigidity theorem of Marqulis. Many of these developments are recorded here.", "corpus_id": 118317956, "score": 0 }, { "doc_id": "124274146", "title": "On the Density and the Volume Density Property", "abstract": "This article gives a short introduction into the notions of density property (DP) and volume density property (VDP). Moreover we develop an effective criterion of verifying whether a given X has VDP. As an application of this method we give a new proof of the basic fact that the product of two Stein manifolds with VDP admits VDP.", "corpus_id": 124274146, "score": 0 }, { "doc_id": "17001843", "title": "A pr 2 00 6 HOLOMORPHIC CURVES IN COMPLEX SPACES", "abstract": "We study the existence of closed complex curves normalized by bordered Riemann surfaces in complex spaces. Our main result is that such curves abound in any non compact complex space admitting an exhaustion function whose Levi form has at least two positive eigenvalues at every point outside a compact set, and this condition is essential. We also construct a Stein neighborhood basis of any compact complex curve with C 2 boundary in a complex space.", "corpus_id": 17001843, "score": 1 }, { "doc_id": "16428953", "title": "Strongly pseudoconvex domains as subvarieties of complex manifolds", "abstract": "In this paper we obtain existence and approximation results for closed complex subvarieties that are normalized by strongly pseudoconvex Stein domains. Our sufficient condition for the existence of such subvarieties in a complex manifold $X$ is expressed in terms of the Morse indices and the number of positive Levi eigenvalues of an exhaustion function on $X$. Examples show that our conditions cannot be weakened in general. We obtain optimal results for subvarieties of this type in complements of compact complex submanifolds with Griffiths positive normal bundle; in the projective case these generalize classical theorems of Remmert, Bishop and Narasimhan concerning proper holomorphic maps and embeddings to ${\\Bbb C}^n ={\\Bbb P}^n \\backslash {\\Bbb P}^{n-1}$..", "corpus_id": 16428953, "score": 1 }, { "doc_id": "119622686", "title": "On the Hodge conjecture for $q$-complete manifolds", "abstract": "We establish the Hodge conjecture for the top dimensional cohomology group with integer coefficients of any $q$-complete complex manifold $X$ with $q<\\dim X$. This holds in particular for the complement $X=\\mathbb{C}\\mathbb{P}^n\\setminus A$ of any complex projective manifold defined by $q", "corpus_id": 119622686, "score": 0 }, { "doc_id": "15928068", "title": "DEFORMATIONS OF STEIN STRUCTURES AND EXTENSIONS OF HOLOMORPHIC MAPPINGS", "abstract": "Assume that A is a closed complex subvariety of a Stein manifold X and that f : X ! Y is a continuous map to a complex manifold Y such that the restriction f|A: A ! Y is holomorphic on A. After a homotopic deformation of the Stein structure outside a neighborhood of A in X we find a holomorphic map e f : X ! Y which agrees with f on A and which is homotopic to f relative to A. When dimC X = 2 we must also change the C1 structure on X\\A.", "corpus_id": 15928068, "score": 0 }, { "doc_id": "12969940", "title": "Stein structures and holomorphic mappings", "abstract": "We prove that every continuous map from a Stein manifold X to a complex manifold Y can be made holomorphic by a homotopic deformation of both the map and the Stein structure on X. In the absence of topological obstructions, the holomorphic map may be chosen to have pointwise maximal rank. The analogous result holds for any compact Hausdorff family of maps, but it fails in general for a noncompact family. Our main results are actually proved for smooth almost complex source manifolds (X,J) with the correct handlebody structure. The paper contains another proof of Eliashberg’s (Int J Math 1:29–46, 1990) homotopy characterization of Stein manifolds and a slightly different explanation of the construction of exotic Stein surfaces due to Gompf (Ann Math 148(2): 619–693, 1998; J Symplectic Geom 3:565–587, 2005).", "corpus_id": 12969940, "score": 1 }, { "doc_id": "120085133", "title": "Proper Holomorphic Embeddings of Riemann Surfaces with Arbitrary Topology into ℂ2", "abstract": "We prove that given an open Riemann surface $\\mathcal{N}$ of arbitrary (finite or infinite) topology, there exists an open domain $\\mathcal{M}\\subset \\mathcal{N}$ homeomorphic to $\\mathcal{N}$ which properly holomorphically embeds in ℂ2. Furthermore, $\\mathcal{M}$ can be chosen with hyperbolic conformal type.In particular, any open orientable surface M admits a complex structure $\\mathcal{C}$ such that $(M,\\mathcal{C})$ can be properly holomorphically embedded into ℂ2.", "corpus_id": 120085133, "score": 0 }, { "doc_id": "62893679", "title": "Embedding some bordered Riemann surfaces int the affine plane", "abstract": "We study the existence of proper holomorphic embeddings of bordered Riemann surfaces into the complex plane C^2. Denote by M(R) the moduli space consisting of all equivalence classes of complex structures J on a given smooth oriented bordered surface R. We introduce a class F(R) in M(R)with the following properties: (1) F(R) is nonempty and open (in a natural topology on M(R)); (2) The interior of any Riemann surface (R,J) in the class F(R) admits a proper holomorphic embedding in C^2; (3) If R is a finitely connected planar domain then F(R)=M(R); (4) Each hyperelliptic bordered Riemann surface (R,J) belongs to the class F(R) and hence admits a proper holomorphic embedding in C^2. Part (3) above is equivalent to the theorem of Globevnik and Stensones (Holomorphic embeddings of planar domains into C^2, Math. Ann. 303, 579-597, 1995). Our approach builds upon the earlier work of Cerne and Globevnik (On holomorphic embedding of planar domains into C^2, J. d'Analyse Math. 8, 269-282, 2000).", "corpus_id": 62893679, "score": 0 }, { "doc_id": "119570058", "title": "Some aspects of holomorphic mappings: A survey", "abstract": "This expository paper is concerned with the properties of proper holomorphic mappings between domains in complex affine spaces. We discuss some of the main geometric methods of this theory, such as the reflection principle, the scaling method, and the Kobayashi–Royden metric. We sketch the proofs of certain principal results and discuss some recent achievements. Several open problems are also stated.", "corpus_id": 119570058, "score": 0 }, { "doc_id": "129939502", "title": "Proper Holomorphic Mappings : A Survey *", "abstract": "A continuous mapping I: X --> Y is called proper if 11(K) is a compact subset of X whenever K is a compact subset of Y. If X and Y are complex spaces and I: X --> Y is a proper holomorphic mapping, then 1-(y) is a compact subvariety of X for all points y E Y. Consequently, if the space X is Stein, the preimage 1(y) is finite for all y E Y. A special class of proper holomorphic maps are the biholomorphic maps, i.e. , the bijective holomorphic maps with a holomorphic inverse. Proper holomorphic mappings between complex spaces were studied in the 1950s and early 1960s; (see Remmert-Stein (RS]). Perhaps the most important result from this time is the Grauert's theorem on the coherence of direct images of a coherent analytic sheaves (Nar2]. A special but important case of this result is the Proper Mapping Theorem of Remmert (GR): If I: X _, Y is a proper holomorphic mapping of complex spaces, and if A C X is a complex subvariety of X, then its image f (A) is a complex subvariety of Y. If both X and Y are Stein spaces and A C X is an irreducible subvariety of dimension k, then B = l(A) is an irreducible subvariety of Y of dimension k. Moreover, there exists a proper, nowhere dense subvari-", "corpus_id": 129939502, "score": 0 }, { "doc_id": "31184272", "title": "A tranversality theorem for holomorphic mappings and stability of Eisenman-Kobayashi measures", "abstract": "We show that Thom’s Transversality Theorem is valid for holomorphic mappings from Stein manifolds. More precisely, given such a mapping f : S → M from a Stein manifold S to a complex manifold M and given an analytic subset A of the jet space Jk(S,M), f can be approximated in neighborhoods of compacts by holomorphic mappings whose k-jet extensions are transversal to A. As an application the stability of Eisenman-Kobayshi intrinsic k-measures with respect to deleting analytic subsets of codimension > k is proven. This is a generalization of the Campbell-Howard-Ochiai-Ogawa theorem on stability of Kobayashi pseudodistances.", "corpus_id": 31184272, "score": 0 }, { "doc_id": "126057839", "title": "A relative embedding theorem for Stein spaces.", "abstract": "L’accès aux archives de la revue « Annali della Scuola Normale Superiore di Pisa, Classe di Scienze » (http://www.sns.it/it/edizioni/riviste/annaliscienze/) implique l’accord avec les conditions générales d’utilisation (http://www.numdam.org/conditions). Toute utilisation commerciale ou impression systématique est constitutive d’une infraction pénale. Toute copie ou impression de ce fichier doit contenir la présente mention de copyright.", "corpus_id": 126057839, "score": 0 }, { "doc_id": "120780245", "title": "Oka’s principle for holomorphic sections of elliptic bundles", "abstract": "2. The h-principle for locally trivial fibrations 2.1. The h-principle over small subsets 2.2. The h-principle over totally real submanifolds 2.3. Local extension of the h-principle 2.4. Localizable extensions 2.5. The h-principle for Cm-bundles 2.6. Manifolds with totally real souls 2.7. Totally real extensions 2.8. Nicely localizable extensions 2.9. The basic h-principle for Z -* X 2.10. Homomorphisms and holomorphic maps of rank > r", "corpus_id": 120780245, "score": 0 }, { "doc_id": "13338106", "title": "Survey of Oka theory", "abstract": "Oka theory has its roots in the classical Oka principle in complex analysis. It has emerged as a subfield of complex geometry in its own right since the appearance of a seminal paper of M. Gromov in 1989. Following a brief review of Stein manifolds, we discuss the recently introduced category of Oka manifolds and Oka maps. We consider geometric sufficient conditions for being Oka, the most important of which is ellipticity, introduced by Gromov. We explain how Oka manifolds and maps naturally fit into an abstract homotopy-theoretic framework. We describe recent applications and some key open problems. This article is a much expanded version of the lecture given by the first-named author at the conference RAFROT 2010 in Rincon, Puerto Rico, on March 22, 2010, and of a brief survey article by the second-named author in Notices Amer. Math. Soc., January 2010.", "corpus_id": 13338106, "score": 0 }, { "doc_id": "9613825", "title": "Optimality for totally real immersions and independent mappings of manifolds into C^N", "abstract": "The optimal target dimensions are determined for totally real immersions and for independent mappings into complex affine spaces. Our arguments are similar to those given by Forster, but we use orientable manifolds as far as possible and so are able to obtain improved results for orientable manifolds of even dimension. This leads to new examples showing that the known immersion and submersion dimensions for holomorphic mappings from Stein manifolds to affine spaces are best possible.", "corpus_id": 9613825, "score": 0 }, { "doc_id": "119173387", "title": "Oka properties of ball complements", "abstract": "Let $$n>1$$n>1 be an integer. We prove that holomorphic maps from Stein manifolds $$X$$X of dimension $${<}n$$<n to the complement $$\\mathbb {C}^n{\\setminus } L$$Cn\\L of a compact convex set $$L\\subset \\mathbb {C}^n$$L⊂Cn satisfy the basic Oka property with approximation and interpolation. If $$L$$L is polynomially convex then the same holds when $$2\\dim X \\le n$$2dimX≤n. We also construct proper holomorphic maps, immersions and embeddings $$X\\rightarrow \\mathbb {C}^n$$X→Cn with additional control of the range, thereby extending classical results of Remmert, Bishop and Narasimhan.", "corpus_id": 119173387, "score": 0 }, { "doc_id": "118963833", "title": "Principles of Algebraic Geometry", "abstract": "A comprehensive, self-contained treatment presenting general results of the theory. Establishes a geometric intuition and a working facility with specific geometric practices. Emphasizes applications through the study of interesting examples and the development of computational tools. Coverage ranges from analytic to geometric. Treats basic techniques and results of complex manifold theory, focusing on results applicable to projective varieties, and includes discussion of the theory of Riemann surfaces and algebraic curves, algebraic surfaces and the quadric line complex as well as special topics in complex manifolds.", "corpus_id": 118963833, "score": 0 }, { "doc_id": "16942650", "title": "Proper holomorphic embeddings of finitely and some infinitely connected subsets of into", "abstract": "We show that any finitely connected domain can be properly embedded into . For some sequences can also be properly embedded into .", "corpus_id": 16942650, "score": 0 }, { "doc_id": "119593373", "title": "Embedding Riemann Surfaces Properly into $\\CC^2$", "abstract": "For certain bordered submanifolds $M\\subset\\CC^2$ we show that $M$ can be embedded properly and holomorphically into $\\CC^2$. An application is that any subset of a torus with two boundary components can be embedded properly into $\\CC^2$.", "corpus_id": 119593373, "score": 0 }, { "doc_id": "16711757", "title": "Embedding Subsets of Tori Properly into C", "abstract": "Let T be a torus. We prove that all subsets of T with finitely many boundary components (none of them being points) embed properly into C 2. We also show that the algebras of analytic functions on certain countably connected subsets of T are doubly generated.", "corpus_id": 16711757, "score": 0 }, { "doc_id": "15848716", "title": "Bordered Riemann surfaces in C2", "abstract": "Abstract We prove that the interior of any compact complex curve with smooth boundary in C 2 admits a proper holomorphic embedding into C 2 . In particular, if D is a bordered Riemann surface whose closure admits a holomorphic embedding into C 2 , then D admits a proper holomorphic embedding into C 2 .", "corpus_id": 15848716, "score": 0 }, { "doc_id": "119613460", "title": "Embeddings of infinitely connected planar domains into C^2", "abstract": "We prove that every circled domain in the Riemann sphere admits a proper holomorphic embedding to C^2. Our methods also apply to circled domains with punctures, provided that all but finitely many of the punctures belong to the closure of the set of complementary discs.", "corpus_id": 119613460, "score": 0 }, { "doc_id": "120706258", "title": "Fixed points, Koebe uniformization and circle packings", "abstract": "A domain in the Riemann sphere \\(\\hat{\\mathbb{C}}\\) is called a circle domain if every connected component of its boundary is either a circle or a point. In 1908, P. Koebe [Ko1] posed the following conjecture, known as Koebe’s Kreisnormierungsproblem: Any plane domain is conformally homeomorphic to a circle domain in \\(\\hat{\\mathbb{C}}\\). When the domain is simply connected, this is the content of the Riemann mapping theorem.", "corpus_id": 120706258, "score": 0 }, { "doc_id": "123094831", "title": "Embedding Certain Infinitely Connected Subsets of Bordered Riemann Surfaces Properly into ℂ2", "abstract": "We prove that certain infinitely connected domains D in a bordered Riemann surface, which admits a holomorphic embedding into C2, admit a proper holomorphic embedding into C2. We also prove that certain infinitely connected open subsets D⊂ℂ admit a proper holomorphic embedding into ℂ2.", "corpus_id": 123094831, "score": 0 }, { "doc_id": "119154445", "title": "A Strong Oka Principle for Embeddings of Some Planar Domains into ℂ×ℂ∗", "abstract": "Gromov, in his seminal 1989 paper on the Oka principle, introduced the notion of an elliptic manifold and proved that every continuous map from a Stein manifold to an elliptic manifold is homotopic to a holomorphic map. We show that a much stronger Oka principle holds in the special case of maps from certain open Riemann surfaces called circular domains into ℂ×ℂ∗, namely that every continuous map is homotopic to a proper holomorphic embedding. An important ingredient is a generalization to ℂ×ℂ∗ of recent results of Wold and Forstnerič on the long-standing problem of properly embedding open Riemann surfaces into ℂ2, with an additional result on the homotopy class of the embeddings. We also give a complete solution to a question that arises naturally in Lárusson’s holomorphic homotopy theory, of the existence of acyclic embeddings of Riemann surfaces with abelian fundamental group into 2-dimensional elliptic Stein manifolds.", "corpus_id": 119154445, "score": 0 }, { "doc_id": "117865525", "title": "Embeddings of the line in the plane.", "abstract": "In their paper of this title [1], Abhyankar and Moh have shown that (up to algebraic automorphism) the only embedding of the line in the plane, in characteristic 0, is the Standard one. For the complex numbers, this is a strong sort of unknotting theorem. In this paper, using only some reasonably elementary theory of knots, I give a new proof of the theorem of Abhyankar and Moh; this proof is intrinsically topological, and does not appear merely to be a translation of their original proof using \"high-school algebra\".", "corpus_id": 117865525, "score": 0 }, { "doc_id": "117483667", "title": "The Geometry of Complex Domains", "abstract": "Preface -- 1 Preliminaries -- 2 Riemann Surfaces and Covering Spaces -- 3 The Bergman Kernel and Metric -- 4 Applications of Bergman Geometry -- 5 Lie Groups Realized as Automorphism Groups -- 6 The Significance of Large Isotropy Groups -- 7 Some Other Invariant Metrics -- 8 Automorphism Groups and Classification of Reinhardt Domains -- 9 The Scaling Method, I -- 10 The Scaling Method, II -- 11 Afterword -- Bibliography -- Index.", "corpus_id": 117483667, "score": 0 }, { "doc_id": "189829949", "title": "Approximation of biholomorphic mappings by automorphisms of Cn", "abstract": "In this paper we prove several results on approximation of biholomorphic mappings between domains in C\" (n _>-2) by holomorphic automorphisms of C\". Recall that the group of holomorphic automorphisms of C\", denoted Aut C\", consists of those holomorphic mappings ~ : C \"--, C\" that have a holomorphic inverse 4 1 : C\" --* C\". With the topology of uniform convergence on compact sets, Aut C\" is a topological group. While the group Aut C 1 of automorphisms of the complex plane consists only of the linear mappings az + b (a, b e C, a 4= 0), the group Aut C\" is very large and complicated when n > 2. Let us choose a linear coordinate system on C\" and write the coordinates as z = (z ' ,w), where Z'~-(Z1, . . . ,Zn_I)C--C n 1 and w = z ,~ C. Then AutC n contains mappings of the form", "corpus_id": 189829949, "score": 0 }, { "doc_id": "37836447", "title": "Subvarieties of ℂn with non-extendable automorphisms", "abstract": "Abstract We investigate algebraic and analytic subvarieties of ℂn with automorphisms which cannot be extended to the ambient space.", "corpus_id": 37836447, "score": 0 }, { "doc_id": "119173758", "title": "An embedding of {\\bf C} in {\\bf C}$^2$ with hyperbolic complement", "abstract": "Let $X$ be a closed, $1$-dimensional, complex subvariety of $\\CC^2$ and let $\\ol{\\BB}$ be a closed ball in $\\CC^2 - X$. Then there exists a Fatou-Bieberbach domain $\\Omega$ with $X \\subseteq \\Omega \\subseteq \\CC^2 - \\ol{\\BB}$ and a biholomorphic map $\\Phi: \\Omega \\ra \\CC^2$ such that $\\CC^2 - \\Phi(X)$ is Kobayashi hyperbolic. As corollaries, there is an embedding of the plane in $\\CC^2$ whose complement is hyperbolic, and there is a nontrivial Fatou-Bieberbach domain containing any finite collection of complex lines.", "corpus_id": 119173758, "score": 0 }, { "doc_id": "119673150", "title": "Interpolation by holomorphic automorphisms and embeddings in Cn", "abstract": "Let n > 1 and letCndenote the complex n-dimensional Euclidean space. We prove several jet-interpolation results for nowhere degenerate entire mappings F:Cn →Cnand for holomorphic automorphisms ofCnon discrete subsets ofCn.We also prove an interpolation theorem for proper holomorphic embeddings of Stein manifolds intoCn.For each closed complex submanifold (or subvariety) M ⊂Cnof complex dimension m < n we construct a domain Ω ⊂Cncontaining M and a biholomorphic map F: Ω →CnontoCnwith J F ≡ 1such that F(M) intersects the image of any nondegenerate entire map G:Cn−m →Cnat infinitely many points. If m = n − 1, we construct F as above such thatCn ∖F(M) is hyperbolic. In particular, for each m ≥ 1we construct proper holomorphic embeddings F:Cm →Cm−1such that the complementCm+1 ∖F(Cm)is hyperbolic.", "corpus_id": 119673150, "score": 0 }, { "doc_id": "120791548", "title": "Non-equivalent embeddings into complex euclidean spaces", "abstract": "We study the number of equivalence classes of proper holomorphic embeddings of a Stein space X into ℂn. In this paper we prove that if the automorphism group of X is a Lie group and there exists a proper holomorphic embedding of X into ℂn, 0 < dim X < n, then for any k ≥ 0 there exist uncountably many non-equivalent proper holomorphic embeddings Φ: X × ℂk ↪ ℂn × ℂk. For k = 0 all embeddings will be proved to satisfy the additional property of ℂn\\Φ(X) being (n - dim X)-Eisenman hyperbolic. As a corollary we conclude that there are uncountably many non-equivalent proper holomorphic embeddings of ℂk into ℂn whenever 0 < k < n.", "corpus_id": 120791548, "score": 0 }, { "doc_id": "15148483", "title": "A Fatou-bieberbach Domain in C 2 Which Is Not Runge", "abstract": "Since a paper by J.P.Rosay and W.Rudin from 1988 there has been an open question whether all Fatou-Bieberbach domains are Runge. We give an example of a Fatou-Bieberbach domain Ω in C 2 which is not Runge. The domain Ω provides (yet) a negative answer to the problem of Bremermann.", "corpus_id": 15148483, "score": 0 }, { "doc_id": "17427277", "title": "Algebraic volume density property of affine algebraic manifolds", "abstract": "We introduce the notion of algebraic volume density property for affine algebraic manifolds and prove some important basic facts about it, in particular that it implies the volume density property. The main results of the paper are producing two big classes of examples of Stein manifolds with volume density property. One class consists of certain affine modifications of ℂn equipped with a canonical volume form, the other is the class of all Linear Algebraic Groups equipped with the left invariant volume form.", "corpus_id": 17427277, "score": 0 }, { "doc_id": "119688827", "title": "Proper holomorphic discs in C^2", "abstract": "In this paper we investigate the global behavior of proper holomorphic maps f from the unit disc U={|z|<1} to C^2. The fact that U is transcendental imposes certain restrictions on the image f(U). For instance, f(U) cannot be contained in any proper complex cone in C^2 since this would force it to be algebraic. On the other hand, we show that a real cone in C^2 with axis R^2 contains the image of a proper holomorphic map f from U to C^2 if and only if the angle of the cone is larger than pi/2. We also construct maps f as above whose images avoid both coordinate axes in C^2. Equivalently, we construct a pair of positive harmonic functions u, v on U such that max{u(z),v(z)} tends to plus infinity when z tends to the boundary of U. Furthermore we show that the components f_1, f_1 of a proper holomorphic map from U to C^2, as well as polynomial and certain rational functions of f_1 and f_2, have the property that their essential range at any boundary point of U omits at most a polar set in C.", "corpus_id": 119688827, "score": 0 }, { "doc_id": "18006197", "title": "Proper discs in Stein manifolds avoiding complete pluripolar sets", "abstract": "We prove the following theorem: Let X be a Stein manifold of dimension at least 2 and Y a closed complete pluripolar subset of X. Given a point p in the complement of Y there is a proper holomorphic map f from the unit disc to X such that f(0)=p and the image of f avoids Y.", "corpus_id": 18006197, "score": 0 }, { "doc_id": "16828626", "title": "Proper holomorphic disks in the complement of varieties in \\C^2", "abstract": "For any closed analytic set X in C^2 there exists a proper holomorphic embedding of the unit disk into C^2 such that the image avoids X.", "corpus_id": 16828626, "score": 0 }, { "doc_id": "15015707", "title": "Discs in Stein manifolds", "abstract": "1. The result Let be the open unit disc in C. In the paper we prove the following THEOREM Let M be a Stein manifold, dimM 2. Given a point p 2 M and a vector X tangent to M at p there is a proper holomorphic map f: ! M such that f(0) = p and such that f 0 (0) = X for some > 0. This has been known in the special case when M is a bounded domain in C N with boundary of class C 2. It was proved in FG] by using the fact that for such domains there are bounded strictly plurisubharmonic exhaustion functions without critical points near the boundary. 2. Outline of the proof We describe the idea of the proof in the special case when M is a pseudoconvex domain in C N. Let D C N be a pseudoconvex domain and let be a strictly plurisubharmonic exhaustion function for D. The idea is to start with an analytic disc f : ! D such that f(0) = p; f 0 (0) = X for some > 0, and then to push f(); 2 b in directions that are approximately tangent to the level sets of while keeping f(0) and f 0 (0) xed, keeping f() essentially unchanged for all belonging to a xed compact subset of , and lowering (f()); 2 , only a little. We perform this inductively. If we want to get a proper map in the limit we must, at each step, increase (f()); 2 b, for a certain amount and the sum of these amounts must equal +1. However, this amount depends on the lower bound of jgradj. In particular , if a < b and if has no critical value on a; b] then there is a > 0 such that whenever a (f()) b (2 b), then, in the pushing process one can increase (f()) for at least for each 2 b. Thus, if has no critical values on (b; 1) one can go on and use the pushing process inductively to obtain a proper holomorphic map f: ! D such that f(0) = p. In this way one can prove the theorem in the special case when M is a bounded pseudoconvex domain in C N with boundary of class C 2 FG]. In the convex setting the idea of pushing boundaries of …", "corpus_id": 15015707, "score": 0 }, { "doc_id": "122702857", "title": "Immersions and embeddings in domains of holomorphy", "abstract": "Let Dx be a bounded smooth strongly pseudoconvex domain in C^ and let D2 be a domain of holomorphy in CM (2 < N, 5 < M, IN < M). There exists then a proper holomorphic immersion from Dx to D2 . Furthermore if PI(DX, D2) is the set of proper holomorphic immersions from Dx to D2 and A(DX,D2) is the set of holomorphic maps from Dx to D2 that are continuous on the boundary, then the closure of Pl(Dx , D2) in the topology of uniform convergence on compacta contains A(DX, D2). The approximating proper maps can be made tangent to any finite order of contact at a given point. The same result was obtained for proper holomorphic maps, in one codimension, when the target domain has a plurisubharmonic exhaustion function with no saddle critical points. This includes the case where the target domain is convex. Density in a weaker sense was derived in one codimension when the critical points are contained in a compact subset of the target domain. This occurs (for example) when the target domain is bounded weakly pseudoconvex with C2-smooth boundary. If the target domain is strongly pseudoconvex then the approximating proper holomorphic maps can also be made continuous on the boundary. A lesser degree of pseudoconvexity is required from the target domain when the codimension is larger than the minimal. A domain in CL is called \"Mdimensional-pseudoconvex\" (where L > M) if it has a smooth exhaustion function r such that every point w in this domain has some M-dimensional complex affine subspace going through this point for which r, restricted to this subspace, is strictly plurisubharmonic in w . In the result mentioned above the assumption that the target domain is pseudoconvex in CM (M > 2N, 5) can be substituted for the assumption that the domain is \"M-dimensionalpseudoconvex\". Similarly, the assumption that the target domain D2 is \"(N + 1 )-dimensional-pseudoconvex\" and all the critical points of some appropriate exhaustion function are \"(N+1 )-dimensional-convex\" (defined in a similar manner) yields that the closure of the set of proper holomorphic maps from Dx to D2 contains A(DX, D2). All the results are obtained with embeddings when the Euclidean dimensions are such that dimc(£>2) > 2dimc(öi) + 1 . Thus, in this case, when one of the assumptions mentioned above is fulfilled, then the closure of the set of embeddings from D\\ to D2 contains A{DX, D2).", "corpus_id": 122702857, "score": 0 }, { "doc_id": "10691259", "title": "Approximation of holomorphic mappings on strongly pseudoconvex domains", "abstract": "Abstract Let D be a relatively compact strongly pseudoconvex domain in a Stein manifold S. We prove that for every complex manifold Y the set 𝒜(D, Y) of all continuous maps → Y which are holomorphic in D is a complex Banach manifold, and every ƒ ∈ 𝒜(D, Y) can be approximated uniformly on by maps holomorphic in open neighborhoods of in S. Analogous results are obtained for maps of class 𝒜 r (D), r ∈ . We also establish the Oka property for sections of continuous or smooth fiber bundles over which are holomorphic over D and whose fiber enjoys the Convex Approximation Property (Theorem 1.7).", "corpus_id": 10691259, "score": 0 }, { "doc_id": "121755148", "title": "A Complete Bounded Complex Submanifold of C 3", "abstract": "We produce an example of a bounded complete complex submanifold of C3. This is accomplished by using the duality between H '(I) and BMO(T). The question of whether there exists a complete bounded complex submanifold of C' has been an open problem (see [3] for definitions and a discussion of this problem). We present here a method of producing such submanifolds. Suppose that f1(z) and f2(z) are two functions which are analytic and bounded in the unit disk A of C, and suppose that these two functions have the property f{ Ifl(z)I + If'(z)I da(z) = oo(1.1) for all curves F c A which terminate on aA = T. (Here a denotes Euclidean arc length.) Then z e A -) (z, f1(z), f2(z)) is an embedded complete bounded complex submanifold of C3. To construct two bounded analytic functions f1 and f2 satisfying (1.1) we use C. Fefferman's theorem [1] that every real valued function g)p E BMO(T) can be represented by gp = u + 1v, u, v E L'(T). Here 1v denotes the Hilbert transform of v. Consider the harmonic function 00 10\" qp(rei') = E -cos lOW. Then IV9gp(z)I > lOn/lOOn if z is in the annulus An = {z: 1 11 * 10-n-I < IzI < 1 -9 10-\"-'n . To see this, note that IV((l/n)rl0\" cos 10')I is of order of magnitude lO\"/n on An. The term lVnz ''? cos I 10'6) is small on An because it is bounded pointwise by 21j27 10'/j. The term", "corpus_id": 121755148, "score": 0 }, { "doc_id": "33184269", "title": "Every bordered Riemann surface is a complete proper curve in a ball", "abstract": "We prove that every bordered Riemann surface admits a complete proper holomorphic immersion into a ball of $$\\mathbb C ^2$$, and a complete proper holomorphic embedding into a ball of $$\\mathbb C ^3$$.", "corpus_id": 33184269, "score": 0 }, { "doc_id": "32285439", "title": "Complete bounded embedded complex curves in C^2", "abstract": "We prove that any convex domain of C^2 carries properly embedded complete complex curves. In particular, we exhibit the first examples of complete bounded embedded complex curves in C^2", "corpus_id": 32285439, "score": 0 }, { "doc_id": "119659561", "title": "Complete proper holomorphic embeddings of strictly pseudoconvex domains into balls", "abstract": "We construct a complete proper holomorphic embedding from any strictly pseudoconvex domain with $\\mathcal{C}^2$-boundary in $\\mathbb{C}^n$ into the unit ball of $\\mathbb{C}^N$, for $N$ large enough, thereby answering a question of Alarcon and Forstneric.", "corpus_id": 119659561, "score": 0 }, { "doc_id": "117868974", "title": "A complete complex hypersurface in the ball of C^N", "abstract": "In 1977 P.Yang asked whether there exist complete immersed complex submanifolds g : M^k --> C^N with bounded image. A positive answer is known for holomorphic curves (k=1) and partial answers are known for the case when k>1. The principal result of the present paper is a construction of a holomorphic function on the open unit ball B_N of C^N whose real part is unbounded on every path in B_N of finite length that ends on the boundary of B_N. A consequence is the existence of a complete, closed, complex hypersurface in B_N. This gives a positive answer to Yang's question in all dimensions k, N, 1\\leq k", "corpus_id": 117868974, "score": 1 }, { "doc_id": "119643597", "title": "Embedding complete holomorphic discs through discrete sets", "abstract": "Let U be the open unit disc in C and let B be the open unit ball in C^2. We prove that every discrete subset of B is contained in the range f(U) of a complete, proper holomorphic embedding f:U-->B. Here the completeness of f means that for any path p:[0,1)-->U such that |p(t)|-->1 as t-->1, the path t--> f(p(t)) from [0,1) to B has infinite length.", "corpus_id": 119643597, "score": 0 }, { "doc_id": "117134897", "title": "Holomorphic functions unbounded on curves of finite length", "abstract": "Given a pseudoconvex domain , we prove that there is a holomorphic function f on D such that the lengths of paths $$p:\\ [0,1] \\rightarrow D$$p:[0,1]→D along which $$\\mathfrak {R}f$$Rf is bounded above, with p(0) fixed, grow arbitrarily fast as $$p(1)\\rightarrow bD$$p(1)→bD. A consequence is the existence of a complete closed complex hypersurface $$ M\\subset D$$M⊂D such that the lengths of paths $$p:\\ [0,1]\\rightarrow M$$p:[0,1]→M, with p(0) fixed, grow arbitrarily fast as $$p(1)\\rightarrow bD$$p(1)→bD.", "corpus_id": 117134897, "score": 1 }, { "doc_id": "119690913", "title": "A construction of complete complex hypersurfaces in the ball with control on the topology", "abstract": "<jats:p>Given a\nclosed complex hypersurface <jats:inline-formula id=\"j_crelle-2016-0061_ineq_9999_w2aab3b7e5890b1b6b1aab1c14b1b1Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0213.png\" /><jats:tex-math>{Z\\subset\\mathbb{C}^{N+1}}</jats:tex-math></jats:alternatives></jats:inline-formula> (<jats:inline-formula id=\"j_crelle-2016-0061_ineq_9998_w2aab3b7e5890b1b6b1aab1c14b1b3Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0190.png\" /><jats:tex-math>{N\\in\\mathbb{N}}</jats:tex-math></jats:alternatives></jats:inline-formula>) and a compact subset <jats:inline-formula id=\"j_crelle-2016-0061_ineq_9997_w2aab3b7e5890b1b6b1aab1c14b1b5Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0179.png\" /><jats:tex-math>{K\\subset Z}</jats:tex-math></jats:alternatives></jats:inline-formula>, we prove the existence of a pseudoconvex Runge domain <jats:italic>D</jats:italic> in <jats:italic>Z</jats:italic> such that <jats:inline-formula id=\"j_crelle-2016-0061_ineq_9996_w2aab3b7e5890b1b6b1aab1c14b1c11Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0177.png\" /><jats:tex-math>{K\\subset D}</jats:tex-math></jats:alternatives></jats:inline-formula> and there is a complete proper holomorphic embedding from <jats:italic>D</jats:italic> into the unit ball of <jats:inline-formula id=\"j_crelle-2016-0061_ineq_9995_w2aab3b7e5890b1b6b1aab1c14b1c15Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0342.png\" /><jats:tex-math>{\\mathbb{C}^{N+1}}</jats:tex-math></jats:alternatives></jats:inline-formula>.\nFor <jats:inline-formula id=\"j_crelle-2016-0061_ineq_9994_w2aab3b7e5890b1b6b1aab1c14b1c17Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0188.png\" /><jats:tex-math>{N=1}</jats:tex-math></jats:alternatives></jats:inline-formula>, we derive the existence of complete properly embedded complex curves in the unit ball of <jats:inline-formula id=\"j_crelle-2016-0061_ineq_9993_w2aab3b7e5890b1b6b1aab1c14b1c19Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0340.png\" /><jats:tex-math>{\\mathbb{C}^{2}}</jats:tex-math></jats:alternatives></jats:inline-formula>, with arbitrarily prescribed finite topology. In particular, there exist complete proper holomorphic embeddings of the unit disc <jats:inline-formula id=\"j_crelle-2016-0061_ineq_9992_w2aab3b7e5890b1b6b1aab1c14b1c21Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0350.png\" /><jats:tex-math>{\\mathbb{D}\\subset\\mathbb{C}}</jats:tex-math></jats:alternatives></jats:inline-formula> into the unit ball of <jats:inline-formula id=\"j_crelle-2016-0061_ineq_9991_w2aab3b7e5890b1b6b1aab1c14b1c23Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0340.png\" /><jats:tex-math>{\\mathbb{C}^{2}}</jats:tex-math></jats:alternatives></jats:inline-formula>.\nThese are the first known examples of complete bounded embedded complex hypersurfaces in <jats:inline-formula id=\"j_crelle-2016-0061_ineq_9990_w2aab3b7e5890b1b6b1aab1c14b1c25Aa\"><jats:alternatives><jats:inline-graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"graphic/j_crelle-2016-0061_eq_0342.png\" /><jats:tex-math>{\\mathbb{C}^{N+1}}</jats:tex-math></jats:alternatives></jats:inline-formula> with any control on the topology.</jats:p>", "corpus_id": 119690913, "score": 0 }, { "doc_id": "119319002", "title": "Minimal surfaces in minimally convex domains", "abstract": "In this paper, we prove that every conformal minimal immersion of a compact bordered Riemann surface $M$ into a minimally convex domain $D\\subset \\mathbb{R}^3$ can be approximated, uniformly on compacts in $\\mathring M=M\\setminus bM$, by proper complete conformal minimal immersions $\\mathring M\\to D$. We also obtain a rigidity theorem for complete immersed minimal surfaces of finite total curvature contained in a minimally convex domain in $\\mathbb{R}^3$, and we characterize the minimal surface hull of a compact set $K$ in $\\mathbb{R}^n$ for any $n\\ge 3$ by sequences of conformal minimal disks whose boundaries converge to $K$ in the measure theoretic sense.", "corpus_id": 119319002, "score": 0 }, { "doc_id": "40808295", "title": "The Calabi–Yau problem, null curves, and Bryant surfaces", "abstract": "In this paper we prove that every bordered Riemann surface $$M$$M admits a complete proper null holomorphic embedding into a ball of the complex Euclidean 3-space $$\\mathbb {C}^3$$C3. The real part of such an embedding is a complete conformal minimal immersion $$M\\rightarrow \\mathbb {R}^3$$M→R3 with bounded image. For any such $$M$$M we also construct proper null holomorphic embeddings $$M\\hookrightarrow \\mathbb {C}^3$$M↪C3 with a bounded coordinate function; these give rise to properly embedded null curves $$M\\hookrightarrow SL_2(\\mathbb {C})$$M↪SL2(C) and to properly immersed Bryant surfaces $$M\\rightarrow \\mathbb {H}^3$$M→H3 in the hyperbolic 3-space. In particular, we provide the first examples of proper Bryant surfaces with finite topology and of hyperbolic conformal type. The main novelty when compared to the existing results in the literature is that we work with a fixed conformal structure on $$M$$M. This is accomplished by introducing a conceptually new method based on complex analytic techniques. One of our main tools is an approximate solution to certain Riemann-Hilbert boundary value problems for null curves in $$\\mathbb {C}^3$$C3, developed in Sect. 3.", "corpus_id": 40808295, "score": 0 }, { "doc_id": "11039894", "title": "Noncritical holomorphic functions on Stein manifolds", "abstract": "We prove that every Stein manifold X of dimension n admits [(n+1)/2] holomorphic functions with pointwise independent differentials, and this number is maximal for every n. In particular, X admits a holomorphic function without critical points; this extends a result of Gunning and Narasimhan from 1967 who constructed such functions on open Riemann surfaces. Furthermore, every surjective complex vector bundle map from the tangent bundle TX onto the trivial bundle of rank q < n=dim X is homotopic to the differential of a holomorphic submersion of X to C^q. It follows that every complex subbundle E in the tangent bundle TX with trivial quotient bundle TX/E is homotopic to the tangent bundle of a holomorphic foliation of X. If X is parallelizable, it admits a submersion to C^{n-1} and nonsingular holomorphic foliations of any dimension; the question whether such X also admits a submersion (=immersion) in C^n remains open. Our proof involves a blend of techniques (holomorphic automorphisms of Euclidean spaces, solvability of the di-bar equation with uniform estimates, Thom's jet transversality theorem, Gromov's convex integration method). A result of possible independent interest is a lemma on compositional splitting of biholomorphic mappings close to the identity (Theorem 4.1).", "corpus_id": 11039894, "score": 0 }, { "doc_id": "121744180", "title": "Boundary Behaviour of Conformal Maps", "abstract": "1. Some Basic Facts.- 2. Continuity and Prime Ends.- 3. Smoothness and Corners.- 4. Distortion.- 5. Quasidisks.- 6. Linear Measure.- 7. Smirnov and Lavrentiev Domains.- 8. Integral Means.- 9. Curve Families and Capacity.- 10. Hausdorff Measure.- 11. Local Boundary Behaviour.- References.- Author Index.", "corpus_id": 121744180, "score": 0 }, { "doc_id": "119602018", "title": "A properly embedded holomorphic disc in the ball with finite area and dense boundary", "abstract": "In this paper we construct a properly embedded holomorphic disc in the unit ball $$\\mathbb {B}^2$$B2 of $$\\mathbb {C}^2$$C2 having a surprising combination of properties: on the one hand, it has finite area and hence is the zero set of a bounded holomorphic function on $$\\mathbb {B}^2$$B2; on the other hand, its boundary curve is everywhere dense in the sphere $$b\\mathbb {B}^2$$bB2. A similar result is proved in higher dimensions. Our construction is based on an approximation result in contact geometry, also proved in the paper.", "corpus_id": 119602018, "score": 0 }, { "doc_id": "119305328", "title": "The generalized Oka-Grauert principle for 1-convex manifolds", "abstract": "This paper presents a proof of the generalized Oka-Grauert principle for 1-convex manifolds: Every continuous mapping from a 1-convex manifold X to a complex manifold Y which is already holomorphic on a neighborhood of the exceptional set is homotopic to a holomorphic one provided that either Y satisfies CAP or we are free to change the complex structure on X.", "corpus_id": 119305328, "score": 0 }, { "doc_id": "122502085", "title": "TOPOLOGICAL CHARACTERIZATION OF STEIN MANIFOLDS OF DIMENSION >2", "abstract": "In this paper I give a completed topological characterization of Stein manifolds of complex dimension >2. Another paper (see [E14]) is devoted to new topogical obstructions for the existence of a Stein complex structure on real manifolds of dimension 4. Main results of the paper have been announced in [E13].", "corpus_id": 122502085, "score": 0 }, { "doc_id": "118671586", "title": "From Stein to Weinstein and Back: Symplectic Geometry of Affine Complex Manifolds", "abstract": "A beautiful and comprehensive introduction to this important field. --Dusa McDuff, Barnard College, Columbia University This excellent book gives a detailed, clear, and wonderfully written treatment of the interplay between the world of Stein manifolds and the more topological and flexible world of Weinstein manifolds. Devoted to this subject with a long history, the book serves as a super introduction to this area and also contains the authors' new results. --Tomasz Mrowka, MIT This book is devoted to the interplay between complex and symplectic geometry in affine complex manifolds. Affine complex (a.k.a. Stein) manifolds have canonically built into them symplectic geometry which is responsible for many phenomena in complex geometry and analysis. The goal of the book is the exploration of this symplectic geometry (the road from \"Stein to Weinstein\") and its applications in the complex geometric world of Stein manifolds (the road \"back\"). This is the first book which systematically explores this connection, thus providing a new approach to the classical subject of Stein manifolds. It also contains the first detailed investigation of Weinstein manifolds, the symplectic counterparts of Stein manifolds, which play an important role in symplectic and contact topology. Assuming only a general background from differential topology, the book provides introductions to the various techniques from the theory of functions of several complex variables, symplectic geometry, $h$-principles, and Morse theory that enter the proofs of the main results. The main results of the book are original results of the authors, and several of these results appear here for the first time. The book will be beneficial for all students and mathematicians interested in geometric aspects of complex analysis, symplectic and contact topology, and the interconnections between these subjects.|This book is devoted to the interplay between complex and symplectic geometry in affine complex manifolds. Affine complex (a.k.a. Stein) manifolds have canonically built into them symplectic geometry which is responsible for many phenomena in complex geometry and analysis. The goal of the book is the exploration of this symplectic geometry (the road from \"\"Stein to Weinstein\"\") and its applications in the complex geometric world of Stein manifolds (the road \"\"back\"\"). This is the first book which systematically explores this connection, thus providing a new approach to the classical subject of Stein manifolds. It also contains the first detailed investigation of Weinstein manifolds, the symplectic counterparts of Stein manifolds, which play an important role in symplectic and contact topology. Assuming only a general background from differential topology, the book provides introductions to the various techniques from the theory of functions of several complex variables, symplectic geometry, $h$-principles, and Morse theory that enter the proofs of the main results. The main results of the book are original results of the authors, and several of these results appear here for the first time. The book will be beneficial for all students and mathematicians interested in geometric aspects of complex analysis, symplectic and contact topology, and the interconnections between these subjects.", "corpus_id": 118671586, "score": 0 } ]

{ "doc_id": "2269556", "title": "Fear of crime and the environment: systematic review of UK qualitative evidence", "abstract": "BackgroundThe fear of crime may have negative consequences for health and wellbeing. It is influenced by factors in the physical and social environment. This study aimed to review and synthesize qualitative evidence from the UK on fear of crime and the environment.MethodsEighteen databases were searched, including crime, health and social science databases. Qualitative studies conducted in the UK which presented data on fear of crime and the environment were included. Quality was assessed using Hawker et al.’s framework. Data were synthesized thematically.ResultsA total of 40 studies were included in the review. Several factors in the physical environment are perceived to impact on fear of crime, including visibility and signs of neglect. However, factors in the local social environment appear to be more important as drivers of fear of crime, including social networks and familiarity. Broader social factors appear to be of limited relevance. There is considerable evidence for limitations on physical activity as a result of fear of crime, but less for mental health impacts.ConclusionsFear of crime represents a complex set of responses to the environment. It may play a role in mediating environmental impacts on health and wellbeing.", "corpus_id": 2269556 }

[ { "doc_id": "72431282", "title": "The impacts of crime on health and health services: A literature review", "abstract": "Crime poses substantial risks to the health of victims and, consequently, generates additional demand for health services. This literature review examines the current state of knowledge and understanding of the impacts of crime on physical and psychological health; responses to the needs of victims by health workers and other professionals; and resulting costs to health services. The review concludes by identifying issues for research, policy and practice.", "corpus_id": 72431282, "score": 0 }, { "doc_id": "205083887", "title": "Crime, fear of crime, environment, and mental health and wellbeing: mapping review of theories and causal pathways.", "abstract": "This paper presents the findings from a review of the theoretical and empirical literature on the links between crime and fear of crime, the social and built environment, and health and wellbeing. A pragmatic approach was employed, with iterative stages of searching and synthesis. This produced a holistic causal framework of pathways to guide future research. The framework emphasises that crime and fear of crime may have substantial impacts on wellbeing, but the pathways are often highly indirect, mediated by environmental factors, difficult to disentangle and not always in the expected direction. The built environment, for example, may affect health via its impacts on health behaviours; via its effects on crime and fear of crime; or via the social environment. The framework also helps to identify unexpected factors which may affect intervention success, such as the risk of adverse effects from crime prevention interventions as a result of raising awareness of crime.", "corpus_id": 205083887, "score": 0 }, { "doc_id": "46300117", "title": "Association between fear of crime and mental health and physical functioning.", "abstract": "OBJECTIVES\nStudies have reported an inverse association between fear of crime and subjective mental and physical health. We investigated the direction of causality and the curtailment of physical and social activities as a possible mediating pathway.\n\n\nMETHODS\nWe analyzed data from 2002 to 2004 of the Whitehall II study, a longitudinal study of more than 10 000 London-based civil servants aged 35 to 55 years at baseline.\n\n\nRESULTS\nFear of crime was associated with poorer mental health, reduced physical functioning on objective and subjective indicators, and lower quality of life. Participants reporting greater fear were 1.93 (95% confidence interval [CI]=1.55, 2.41) times as likely to have depression as those reporting lower fear of crime and had lower mental health scores (0.9 points on the Medical Outcomes Survey Short Form 36; 95% CI=0.4, 1.3). They exercised less, saw friends less often, and participated in fewer social activities compared with the less fearful participants. Curtailed physical and social activities helped explain the link between fear of crime and health.\n\n\nCONCLUSIONS\nFear of crime may be a barrier to participation in health-promoting physical and social activities. Public health practitioners should support fear-reduction initiatives.", "corpus_id": 46300117, "score": 0 }, { "doc_id": "146132184", "title": "Fear of Crime: A Review of the Literature1", "abstract": "The literature on fear of crime has grown rapidly in the last three decades. This paper examines the reasons for this growth and attempts to put some structure on the work to date. The inadequacies of measures of fear of crime are discussed and alternative approaches suggested. Alternative explanatory theories are compared and strategies for reducing fear reviewed.", "corpus_id": 146132184, "score": 0 }, { "doc_id": "21344202", "title": "Appraising the Evidence: Reviewing Disparate Data Systematically", "abstract": "The authors describe a method of systematically reviewing research from different paradigms. They draw on the methods adapted, developed, and designed during a study concerned with the delivery of care across professional boundaries. Informed by the established method of systematic review, the authors undertook the review in distinct stages. They describe the methods developed for each stage and outline the difficulties encountered, the solutions devised, and the appraisal tools developed. Although many of the problems encountered were related to the critical assessment of qualitative research, the authors argue that the method of systematic review can be adapted for use with different data and across disciplines.", "corpus_id": 21344202, "score": 0 }, { "doc_id": "145610852", "title": "WOMEN AND THE ‘FEAR OF CRIME’Challenging the Accepted Stereotype", "abstract": "Professional empirically generated survey data about the fear of crime persistently indicate relatively small but statistically significant differences between fear rates expressed by men and women. Such differences are contrasted with objective crime victimization risk ratios; regularly magnified by amateur surveys; and have been ossified as stereotypes by the media. Subsequently, all women are believed to be fearful of crime; and all men fearless. The research reported herein encountered, paradoxically, fearful men and fearless women. A dissection of their qualitatively garnered feelings indicates, in a very provisional way, the general conditions under which crime-related fears are reduced and enhanced.", "corpus_id": 145610852, "score": 1 }, { "doc_id": "152695658", "title": "Crime and Social Change in Middle England: Questions of Order in an English Town", "abstract": "Crime and Social Change in Middle England offers a new way of looking at contemporary debates on the fear of crime. Using observation, interviews and documentary analysis it traces the reactions of citizens of one very ordinary town to events, conflicts and controversies around such topical subjects of criminological investigation as youth, public order, drugs, policing and home security in their community. In doing so it moves in place from comfortable suburbs to hard pressed inner city estates, from the affluent to the impoverished, from old people watching the town where they grew up change around them to young in-comers who are part of that change. This is a book which will give all students of crime a rare and fascinating insight into how issues at the heart of contemporary law and order politics both nationally and internationally actually play out on the ground.", "corpus_id": 152695658, "score": 1 }, { "doc_id": "140379708", "title": "Social geographies of women's fear of crime", "abstract": "Traditional approaches to mapping fear of crime are limited to describing or explaining the impact of sexual and physical violence as a reflection of gender inequality. Using empirical evidence from recent research, a social geography of women's fear is developed. Four important areas of geographical analysis are highlighted: the imposition of constraints on the use of urban space, the distinction between public and private space in perceptions of danger, the social construction of space into 'safe' and 'dangerous' places, and the social control of women's spaces. Within this framework, it is shown how women's experiences of social class, age, disability and motherhood can determine their experience of, and reactions to fear of, violent crime.", "corpus_id": 140379708, "score": 1 }, { "doc_id": "144714573", "title": "Revisiting fear and place: women's fear of attack and the built environment", "abstract": "Abstract The effort to `design out fear' through altering built environments has been popular amongst academics and planners. Success is limited, as simplistic notions of the fear of crime – its experience by individuals and its constitution as a social reality – tend to be employed. This paper examines the relationship between the built environment and women's fear of crime, based on qualitative studies in two European cities. While particular environments are often identified when women talk about the threat of attack, this reflects much broader processes operating to create fear. Fear influences our experience of places, as much as places influence our experiences of fear.", "corpus_id": 144714573, "score": 1 }, { "doc_id": "143511067", "title": "‘When, Where, if, and but’: Qualifying GIS and the Effect of Streetlighting on Crime and Fear", "abstract": "Geographical information systems (GIS) are increasingly used in England and Wales as a tool to monitor crime and aid community-safety planning. This is despite the widely known limitations of police-recorded data on crime victimisation, and concerns about the quality and specificity of available data on fear of crime. Meanwhile, improving streetlighting is a popular strategy both for improving community safety and for reducing fear of crime. In this paper we report on research carried out in Northumberland, northeast England, which aimed to identify locations most in need of new streetlighting. First, GIS crime hotspot maps and lighting coverage maps were analysed to identify potential areas to target. Qualitative rapid appraisal techniques were then used in these areas to explore local residents' perceptions and understandings of the relationships between streetlighting, victimisation, and fear of crime. The qualitative data were used to interpret the hotspot maps further, and to inform the location and type of streetlighting interventions. The research demonstrates that people's experiences of crime and fear, and their understandings of the relationships these have to streetlighting, are complex and reflective. At most, streetlighting was held to have a marginal and even then contradictory influence on the problems of crime and fear that people face. The implications are considered. We conclude that qualifying the outputs of GIS mapping was essential in this case, and has wide potential in critical policy research to promote more inclusive knowledge and more effective decisionmaking.", "corpus_id": 143511067, "score": 0 }, { "doc_id": "154288358", "title": "Women's fear of crime: A rural perspective", "abstract": "Abstract This paper examines women's experience of fear of crime in rural areas. It argues that much existing research on issues of gender, fear and safety have focused on urban areas and that as a result we know relatively little about women's experience of fear in a rural context. As well as arguing that we need to redress the balance and respond to the dearth of knowledge about rural women's fear, the paper asserts the importance of a rural perspective in understanding the relationship between fear and the social and cultural construction of place. The rural in particular provides an important site for such an understanding since, as is argued here, the notion of safety is central to constructions of rurality. The paper presents data on rural women's experience of fear and crime from research carried out in New Zealand and the UK. It draws on work undertaken in four rural communities and begins to identify the extent and nature of women's fears and how these relate to their experience of rurality. The paper shows how while popular constructions of the rural as friendly, safe and largely crime free endure, there is a recognition amongst rural women of the growing problems surrounding personal safety. It also demonstrates the importance of social constructions of the rural community in identifying the relevance of the ‘stranger’ and the marginalised ‘other’ to women's feelings of fear.", "corpus_id": 154288358, "score": 0 }, { "doc_id": "154754264", "title": "Managing crime and the fear of crime at railway stations––a case study in South Wales (UK)", "abstract": "Abstract Rail users consistently perceive their risks from crime to be significantly higher than official statistics suggest, discouraging many from using rail transport. The aims of the paper include a discussion of Crime Prevention Through Environmental Design (CPTED) and current policy initiatives for reducing crime and the fear of crime on the railways. This exploratory study focuses on adult passengers' perceptions of crime and nuisance as they relate to the management, design and maintenance of railway stations and their immediate access routes. The study innovatively utilises interactive virtual reality (VR) scenes of `representative' stations as the environmental stimulus and concludes that such an approach provides an analytical and pragmatic framework for managers of railway stations that are unlikely to receive Secure Station accreditation.", "corpus_id": 154754264, "score": 0 }, { "doc_id": "143029701", "title": "BOYS DON'T CRY Masculinities, Fear of Crime and Fearlessness", "abstract": "The gendered stereotypes of fearless male/fearful female' are not supported by the reality of complex and multiple identities and the shifting meanings of fear and fearlessness which are brought to and evolve from these identities. Referring to evidence from the author's own research, childhood and adolescence are put forward as crucial stages in identity development where one can begin to unpack the processes by which gendered meanings of fear and fearlessness become fixed'. This paper argues that the image of the fearless' male, from childhood onwards, is not a helpful one. The benefits to the male sex from taking on a fearless' persona, alongside its negative social implications, are discussed with reference to hegemonic masculinity. Class and race are put forward as significant variables in the development of hegemonic masculinity's emotionally inarticulate persona and racism is highlighted as one of the ugliest expressions of exaggerated masculinity. The above is placed and developed within the theoretical context of the hegemonic masculine biography'.", "corpus_id": 143029701, "score": 1 }, { "doc_id": "143759973", "title": "‘Old age’ and Ageism in Urban Research: The Case of Fear of Crime", "abstract": "\"A critique has recently been made of research and theory on ageing in spatial research, arguing for the development of approaches which are informed by critical theoretical perspectives. Perhaps the most significant of these is the recognition that 'old age' is culturally constructed. This paper illustrates the value of such an approach with reference to understanding of fear of crime. It is suggested that many difficulties with past research result from epistemological problems, including ageism. A number of assumptions about elderly people and crime can be contested if scrutiny is informed by humanistic, feminist and social constructionist perspectives. Drawing on in depth interviews with elderly people, some of the problems and prospects of work on old age are discussed. Age is only one dimension by which people situate themselves and are situated by others in relation to the risk of crime. Local contexts, life course experiences and other social identities are involved in the constitution of fear for each individual. While the role of ageing can be understood within a framework of power relations, its positive as well as negative impacts on reactions to crime require representation. Similar analysis could profitably be developed in other areas of urban research.\" Copyright Joint Editors and Blackwell Publishers Ltd 1997.", "corpus_id": 143759973, "score": 0 }, { "doc_id": "143349600", "title": "A safe place to grow up? Parenting, perceptions of children's safety and the rural idyll", "abstract": "Abstract This paper explores how an imagining of the countryside as an idealised place in which to grow up is constructed, mobilised and contested by rural parents in their accounts of their children's lives. It begins by considering how parents mobilise popular understandings of the rural idyll in their accounts of the opportunities for children in the village of Wheldale. It then goes on to explore how parents simultaneously challenge this imagining of the rural in their accounts of their children's safety, contradicting popular constructions of the rural as a safe, harmonious place, and contesting assumptions about the idyllic nature of rural childhood. Finally the paper considers how in order to justify their claims about the relative safety of the village as a place to grow up, in the face of their own descriptions of the dangers it may hold, parents further mobilise another ingredient of the ‘rural idyll’ — community. The paper concludes by considering the importance of recognising that places, like people, can have multiple meanings and identities.", "corpus_id": 143349600, "score": 1 }, { "doc_id": "144327142", "title": "Through children's eyes: childhood, place and the fear of crime", "abstract": "Abstract This article seeks to bring young respondents more sharply into focus by considering fear of crime ‘through children’s eyes’. By incorporating children’s perspectives it is argued that more inclusive and integrative community safety initiatives may arise. Inspired by the recent flowering of research undertaken in childhood studies by social and cultural geographers, the study seeks to make a theoretical, empirical and spatial contribution to debates in the field. Based on the findings of a large-scale school survey, the responses indicate that children have an acute place-based sensitivity to a range of highly relevant community safety issues. This includes detailed reflections concerning the place of policing, boredom, youth gangs, motorcars and drugs in their neighbourhoods. It is suggested that the inclusion of children’s accounts into geographical debates not only enriches our knowledge of childhood studies, but also adds detail and texture to our understandings of fear of crime.", "corpus_id": 144327142, "score": 0 }, { "doc_id": "146481152", "title": "Lesbian Safety Talk: Problematizing Definitions and Experiences of Violence, Sexuality and Space", "abstract": "The `Violence, Sexuality and Space' Research Project is the first major research project in Britain to explore how `safe', `public' spaces are created and sustained in response to homophobic violence. The research presented here examines lesbian safety talk and centres on lesbian focus group participants' responses to headline findings from a large-scale survey. The article illustrates the complexities involved in defining and interpreting violence and safety. It highlights the temporal and relative context of space, together with the importance of subjective, social and ideological constructions of violence and safety. The impact of sexuality on risk assessment and safety strategies is discussed alongside the influence of gender presentation, gender deviation and interpretative frameworks.", "corpus_id": 146481152, "score": 0 }, { "doc_id": "72589184", "title": "Environmental constraints on health: listening to children's views", "abstract": "Children are major users of their local environments yet they are largely excluded from discussions about transport, planning and environmental health, and may be seen only as 'problems' or 'victims'. However, if children's own accounts are studied it is clear that they are active risk-assessors and problem-solvers who develop strategies to survive hostile environments. This study involved children from four schools in broadly working-class areas of Birmingham. A semi-structured question naire was completed by a total of 492 9-11-year-old and 13-14-year-old pupils, and focus-group discussions were held with one group from each class taking part in the questionnaire. This paper reports on the focus groups, during which participants identified considerable environmental constraints on their activities. Many were not allowed to play outdoors, use local parks or cycle to school — or they did not feel comfortable doing so. Girls especially were restricted in how late they were allowed out. In the children's views, traffic danger, 'stranger danger' and social and cultural factors interact to create barriers to keeping healthy and active. An understanding of children's perceptions of risk and an incorporation of their ideas for change are central to the success of any physical activity strategy.", "corpus_id": 72589184, "score": 1 }, { "doc_id": "73146023", "title": "Inequality in access to local environments: the experiences of Asian and non-Asian girls", "abstract": "The growing emphasis on building healthy public policy draws attention to social and environmental inequalities in health, including the impact of racism and crime. This study reports on questionnaire and focus group research with a sample of 214 Year 7 and Year 9 girls (11-14 years old), of whom just under half were of Asian origin. The findings highlighted considerable differences between the attitudes and behaviour reported by Asian-origin and non-Asian girls. The problems encountered in managing hostile urban environments were seen as significantly greater by Asian-origin girls and fears about assault and harassment resulted in restricted access and a home-focused style of life. They reported restrictions on their physical activity, and some degree of frustration about their lack of freedom, which have policy implications for health promoters.", "corpus_id": 73146023, "score": 1 }, { "doc_id": "21129564", "title": "\"Nae as nice a scheme as it used to be\": lay accounts of neighbourhood incivilities and well-being.", "abstract": "This paper is based upon qualitative research conducted in a relatively deprived neighbourhood in Edinburgh, Scotland, and it explores how contextual and compositional features of place may interact to influence well-being. I present women's accounts of their experiences of neighbourhood incivilities, and I discuss their perceptions of the influence of incivilities upon their sense of well-being. I suggest that aspects of individual biographies mediate experiences of neighbourhood incivilities. Furthermore, some individuals seem to engage in \"distancing strategies\", which I suggest may be interpreted as a way of resisting the potentially harmful psycho-social influence of incivilities upon well-being.", "corpus_id": 21129564, "score": 0 }, { "doc_id": "46079516", "title": "Keeping Children Safe", "abstract": "The aim of this article is to present qualitative data from a study of mothers on a housing estate in Leeds, UK, enabling them to voice their concerns about child safety. The estate contains many environmental hazards, from traffic, ‘drugusers’, ‘strangers’ and litter. A high profile given to the vulnerability of children in public places has resulted in parents becoming ever vigilant and subjecting children to increased surveillance, in the face of a lack of environmental measures which would support their efforts to keep children safe. There are costs to parents in time and activities foregone. Moreover, the emphasis on the key role of parents in child safety and the perception of increasing hazards to children is affecting parents' psychological well-being. The article attempts to place parents' concerns within a social context which may begin to explain parental behaviour and anxieties.", "corpus_id": 46079516, "score": 0 }, { "doc_id": "143396367", "title": "Imagining the Victim of Crime", "abstract": "'...the clarity in which the wide range of relevant issues are presented throughout the book makes this must-reading for new entrants to this field and for students' - \"International Review of Victimology\". This book situates the contemporary preoccupation with criminal victimisation within the broader socio-cultural changes of the last twenty five years. In so doing it addresses not only the policy possibilities that have been generated as a consequence of those changes but also concerns itself with the ability of victimology to help make sense of this change. Written in the post 9/11 context this book considers the efficacy of theory and policy relating to questions of victimhood to accommodate the current political and cultural climate and offers a critical understanding of both.It adopts an explicitly cross-cultural position on these questions. It will be vital reading for anyone interested in the problems and possibilities posed by criminal victimisation understood in the broadest terms.", "corpus_id": 143396367, "score": 0 } ]

{ "doc_id": "11390842", "title": "Guided Self-Organization in a Dynamic Embodied System Based on Attractor Selection Mechanism", "abstract": "Guided self-organization can be regarded as a paradigm proposed to understand how to guide a self-organizing system towards desirable behaviors, while maintaining its non-deterministic dynamics with emergent features. It is, however, not a trivial problem to guide the self-organizing behavior of physically embodied systems like robots, as the behavioral dynamics are results of interactions among their controller, mechanical dynamics of the body, and the environment. This paper presents a guided self-organization approach for dynamic robots based on a coupling between the system mechanical dynamics with an internal control structure known as the attractor selection mechanism. The mechanism enables the robot to gracefully shift between random and deterministic behaviors, represented by a number of attractors, depending on internally generated stochastic perturbation and sensory input. The robot used in this paper is a simulated curved beam hopping robot: a system with a variety of mechanical dynamics which depends on its actuation frequencies. Despite the simplicity of the approach, it will be shown how the approach regulates the probability of the robot to reach a goal through the interplay among the sensory input, the level of inherent stochastic perturbation, i.e., noise, and the mechanical dynamics.", "corpus_id": 11390842 }

[ { "doc_id": "8554572", "title": "Variants of guided self-organization for robot control", "abstract": "Autonomous robots can generate exploratory behavior by self-organization of the sensorimotor loop. We show that the behavioral manifold that is covered in this way can be modified in a goal-dependent way without reducing the self-induced activity of the robot. We present three strategies for guided self-organization, namely by using external rewards, a problem-specific error function, or assumptions about the symmetries of the desired behavior. The strategies are analyzed for two different robots in a physically realistic simulation.", "corpus_id": 8554572, "score": 0 }, { "doc_id": "12917644", "title": "Evolving Spatiotemporal Coordination in a Modular Robotic System", "abstract": "In this paper we present a novel information-theoretic measure of spatiotemporal coordination in a modular robotic system, and use it as a fitness function in evolving the system This approach exemplifies a new methodology formalizing co-evolution in multi-agent adaptive systems: information-driven evolutionary design The methodology attempts to link together different aspects of information transfer involved in adaptive systems, and suggests to approximate direct task-specific fitness functions with intrinsic selection pressures In particular, the information-theoretic measure of coordination employed in this work estimates the generalized correlation entropy K2 and the generalized excess entropy E2 computed over a multivariate time series of actuators' states The simulated modular robotic system evolved according to the new measure exhibits regular locomotion and performs well in challenging terrains.", "corpus_id": 12917644, "score": 1 }, { "doc_id": "18392312", "title": "A Sensor-Based Learning Algorithm for the Self-Organization of Robot Behavior", "abstract": "Author to whom correspondence should be addressed.Received: 30 November 2008 / Accepted: 26 February 2009 / Published: 4 March 2009Abstract: Ideally, sensory information forms the only source of information to a robot. Weconsider an algorithm for the self-organization of a controller. At short time scales the con-troller is merely reactive but the parameter dynamics and the acquisition of knowledge by aninternal model lead to seemingly purposeful behavior on longer time scales. As a paradigmaticexample, we study the simulation of an underactuated snake-like robot. By interacting withthe real physical system formed by the robotic hardware and the environment, the controllerachieves a sensitive and body-specific actuation of the robot.Keywords: Self-Organization; Autonomous Robot Control; Neural Networks; Homeokine-sis.", "corpus_id": 18392312, "score": 0 }, { "doc_id": "15045220", "title": "What Is Stochastic Resonance? Definitions, Misconceptions, Debates, and Its Relevance to Biology", "abstract": "Stochastic resonance is said to be observed when increases in levels of unpredictable fluctuations—e.g., random noise—cause an increase in a metric of the quality of signal transmission or detection performance, rather than a decrease. This counterintuitive effect relies on system nonlinearities and on some parameter ranges being “suboptimal”. Stochastic resonance has been observed, quantified, and described in a plethora of physical and biological systems, including neurons. Being a topic of widespread multidisciplinary interest, the definition of stochastic resonance has evolved significantly over the last decade or so, leading to a number of debates, misunderstandings, and controversies. Perhaps the most important debate is whether the brain has evolved to utilize random noise in vivo, as part of the “neural code”. Surprisingly, this debate has been for the most part ignored by neuroscientists, despite much indirect evidence of a positive role for noise in the brain. We explore some of the reasons for this and argue why it would be more surprising if the brain did not exploit randomness provided by noise—via stochastic resonance or otherwise—than if it did. We also challenge neuroscientists and biologists, both computational and experimental, to embrace a very broad definition of stochastic resonance in terms of signal-processing “noise benefits”, and to devise experiments aimed at verifying that random variability can play a functional role in the brain, nervous system, or other areas of biology.", "corpus_id": 15045220, "score": 0 }, { "doc_id": "8560654", "title": "Stochastic Resonance:. from Climate to Biology", "abstract": "In this paper I will review some basic aspects of the mechanism of stochastic resonance. Stochastic resonance was first introduced as a possible mechanism to explain long term climatic variation. Since then, there have been many applications of stochastic resonance in physical and biological systems. I will show that in complex system, stochastic resonance can substantially change as a function of the ``system complexity''. Also, I will briefly mention how to apply stochastic resonance for the case of Brownian motors.", "corpus_id": 8560654, "score": 0 }, { "doc_id": "6710563", "title": "Stochastic resonance in biology. How noise can enhance detection of weak signals and help improve biological information processing.", "abstract": "Noise is usually thought of as the enemy of order rather than as a constructive influence. In nonlinear systems that possess some sort of threshold, random noise plays a beneficial role in enhancing the detection of weak information-carrying signals. This phenomenon, termed stochastic resonance, does find useful applications in physical, biological, and biomedical contexts. Certain biological systems may even use this effect for optimizing function and behavior.", "corpus_id": 6710563, "score": 0 }, { "doc_id": "6571216", "title": "Brownian motion, fluctuation and life", "abstract": "The measurements of dynamic behaviors of biomolecules in relation to their functions have been allowed using single molecule measurements. Thermal Brownian motion causes random step motion of motor proteins and structural fluctuation of protein molecules between multiple states. In hierarchic structure of life, the fluctuation is modulated. Random fluctuation is biased to directional motion and reactions as a result of interaction of proteins. The fluctuation of kinetic state of signaling proteins results in polarization and localization of cells. A recognition process in brain is also explained by the equation analogous to biochemical reaction at the molecular level. Thus dynamic processes originated from thermal motion may play an important role in activation processes in life.", "corpus_id": 6571216, "score": 1 }, { "doc_id": "10528022", "title": "Order in Spontaneous Behavior", "abstract": "Brains are usually described as input/output systems: they transform sensory input into motor output. However, the motor output of brains (behavior) is notoriously variable, even under identical sensory conditions. The question of whether this behavioral variability merely reflects residual deviations due to extrinsic random noise in such otherwise deterministic systems or an intrinsic, adaptive indeterminacy trait is central for the basic understanding of brain function. Instead of random noise, we find a fractal order (resembling Lévy flights) in the temporal structure of spontaneous flight maneuvers in tethered Drosophila fruit flies. Lévy-like probabilistic behavior patterns are evolutionarily conserved, suggesting a general neural mechanism underlying spontaneous behavior. Drosophila can produce these patterns endogenously, without any external cues. The fly's behavior is controlled by brain circuits which operate as a nonlinear system with unstable dynamics far from equilibrium. These findings suggest that both general models of brain function and autonomous agents ought to include biologically relevant nonlinear, endogenous behavior-initiating mechanisms if they strive to realistically simulate biological brains or out-compete other agents.", "corpus_id": 10528022, "score": 0 }, { "doc_id": "39788764", "title": "Stochastic resonance and the evolution of Daphnia foraging strategy.", "abstract": "Search strategies are currently of great interest, with reports on foraging ranging from albatrosses and spider monkeys to microzooplankton. Here, we investigate the role of noise in optimizing search strategies. We focus on the zooplankton Daphnia, which move in successive sequences consisting of a hop, a pause and a turn through an angle. Recent experiments have shown that their turning angle distributions (TADs) and underlying noise intensities are similar across species and age groups, suggesting an evolutionary origin of this internal noise. We explore this hypothesis further with a digital simulation (EVO) based solely on the three central Darwinian themes: inheritability, variability and survivability. Separate simulations utilizing stochastic resonance (SR) indicate that foraging success, and hence fitness, is maximized at an optimum TAD noise intensity, which is represented by the distribution's characteristic width, sigma. In both the EVO and SR simulations, foraging success is the criterion, and the results are the predicted characteristic widths of the TADs that maximize success. Our results are twofold: (1) the evolving characteristic widths achieve stasis after many generations; (2) as a hop length parameter is changed, variations in the evolved widths generated by EVO parallel those predicted by SR. These findings provide support for the hypotheses that (1) sigma is an evolved quantity and that (2) SR plays a role in evolution.", "corpus_id": 39788764, "score": 0 }, { "doc_id": "6989398", "title": "Lévy Walks Evolve Through Interaction Between Movement and Environmental Complexity", "abstract": "Animals’ movements may not only respond to the environment, but may also shape it, and thus affect fitness. Ecological theory predicts that animal movement is shaped by its efficiency of resource acquisition. Focusing solely on efficiency, however, ignores the fact that animal activity can affect resource availability and distribution. Here, we show that feedback between individual behavior and environmental complexity can explain movement strategies in mussels. Specifically, experiments show that mussels use a Lévy walk during the formation of spatially patterned beds, and models reveal that this Lévy movement accelerates pattern formation. The emergent patterning in mussel beds, in turn, improves individual fitness. These results suggest that Lévy walks evolved as a result of the selective advantage conferred by autonomously generated, emergent spatial patterns in mussel beds. Our results emphasize that an interaction between individual selection and habitat complexity shapes animal movement in natural systems.", "corpus_id": 6989398, "score": 0 }, { "doc_id": "16131554", "title": "From Lévy to Brownian: A Computational Model Based on Biological Fluctuation", "abstract": "Background Theoretical studies predict that Lévy walks maximizes the chance of encountering randomly distributed targets with a low density, but Brownian walks is favorable inside a patch of targets with high density. Recently, experimental data reports that some animals indeed show a Lévy and Brownian walk movement patterns when forage for foods in areas with low and high density. This paper presents a simple, Gaussian-noise utilizing computational model that can realize such behavior. Methodology/Principal Findings We extend Lévy walks model of one of the simplest creature, Escherichia coli, based on biological fluctuation framework. We build a simulation of a simple, generic animal to observe whether Lévy or Brownian walks will be performed properly depends on the target density, and investigate the emergent behavior in a commonly faced patchy environment where the density alternates. Conclusions/Significance Based on the model, animal behavior of choosing Lévy or Brownian walk movement patterns based on the target density is able to be generated, without changing the essence of the stochastic property in Escherichia coli physiological mechanism as explained by related researches. The emergent behavior and its benefits in a patchy environment are also discussed. The model provides a framework for further investigation on the role of internal noise in realizing adaptive and efficient foraging behavior.", "corpus_id": 16131554, "score": 1 }, { "doc_id": "8612065", "title": "Bacteria-inspired underactuated mobile robot based on a biological fluctuation", "abstract": "Interpretation of the living organism’s ability to utilize noise from engineering point of view may be beneficial for realizing a simple, yet adaptive, robotic system. This paper presents a bacteria-inspired mobile robot, with a 1-DOF motor and a single sensor. Even with such limitations, the underactuated mobile robot is able to navigate toward a gradient-inducing goal in a two-dimensional space by properly utilizing environmental noise that directly affects its motion. The way the robot utilizes this external noise to control its navigation behavior is interpreted based on biological fluctuation: a simple perspective commonly used to describe how living beings utilize internally generated biological noises.", "corpus_id": 8612065, "score": 1 }, { "doc_id": "33011647", "title": "'Yuragi'-Based Adaptive Mobile Robot Search With and Without Gradient Sensing: From Bacterial Chemotaxis to a Levy Walk", "abstract": "Many biologically inspired approaches have been investigated in relation to research on mobile robot(s) that can effectively locate targets that induce gradient information. Here, we concentrate on realizing an adaptive searching behavior in a mobile robot that is simple, yet effective with and without sensing the gradient information. We are interested in two searching behaviors found in biological creatures: bacterial chemotaxis (probably the simplest yet effective gradient sources searching behavior found in living creatures) and Levy walk (a specialized random walk with fractal movement trajectories that optimize random search for sparsely and randomly distributed target(s)). Our approach is to propose a unifying framework based on 'yuragi' (biological fluctuation) to implement and combine the two searching behaviors.", "corpus_id": 33011647, "score": 1 }, { "doc_id": "13363604", "title": "Self-Organization, Embodiment, and Biologically Inspired Robotics", "abstract": "Robotics researchers increasingly agree that ideas from biology and self-organization can strongly benefit the design of autonomous robots. Biological organisms have evolved to perform and survive in a world characterized by rapid changes, high uncertainty, indefinite richness, and limited availability of information. Industrial robots, in contrast, operate in highly controlled environments with no or very little uncertainty. Although many challenges remain, concepts from biologically inspired (bio-inspired) robotics will eventually enable researchers to engineer machines for the real world that possess at least some of the desirable properties of biological organisms, such as adaptivity, robustness, versatility, and agility.", "corpus_id": 13363604, "score": 0 }, { "doc_id": "17042720", "title": "The implications of embodiment for behavior and cognition: animal and robotic case studies", "abstract": "In this paper, we will argue that if we want to understand the function of the brain (or the control in the case of robots), we must understand how the brain is embedded into the physical system, and how the organism interacts with the real world. While embodiment has often been used in its trivial meaning, i.e. 'intelligence requires a body', the concept has deeper and more important implications, concerned with the relation between physical and information (neural, control) processes. A number of case studies are presented to illustrate the concept. These involve animals and robots and are concentrated around locomotion, grasping, and visual perception. A theoretical scheme that can be used to embed the diverse case studies will be presented. Finally, we will establish a link between the low-level sensory-motor processes and cognition. We will present an embodied view on categorization, and propose the concepts of 'body schema' and 'forward models' as a natural extension of the embodied approach toward first representations.", "corpus_id": 17042720, "score": 0 }, { "doc_id": "23906343", "title": "Morphological Computation and Morphological Control: Steps Toward a Formal Theory and Applications", "abstract": "Morphological computation can be loosely defined as the exploitation of the shape, material properties, and physical dynamics of a physical system to improve the efficiency of a computation. Morphological control is the application of morphological computing to a control task. In its theoretical part, this article sharpens and extends these definitions by suggesting new formalized definitions and identifying areas in which the definitions we propose are still inadequate. We go on to describe three ongoing studies, in which we are applying morphological control to problems in medicine and in chemistry. The first involves an inflatable support system for patients with impaired movement, and is based on macroscopic physics and concepts already tested in robotics. The two other case studies (self-assembly of chemical microreactors; models of induced cell repair in radio-oncology) describe processes and devices on the micrometer scale, in which the emergent dynamics of the underlying physical system (e.g., phase transitions) are dominated by stochastic processes such as diffusion.", "corpus_id": 23906343, "score": 0 }, { "doc_id": "6032830", "title": "Sensing through body dynamics", "abstract": "Abstract It has been shown that sensory morphology and sensory–motor coordination enhance the capabilities of sensing in robotic systems. The tasks of categorization and category learning, for example, can be significantly simplified by exploiting the morphological constraints, sensory–motor couplings and the interaction with the environment. This paper argues that, in the context of sensory–motor control, it is essential to consider body dynamics derived from morphological properties and the interaction with the environment in order to gain additional insight into the underlying mechanisms of sensory–motor coordination, and more generally the nature of perception. A locomotion model of a four-legged robot is used for the case studies in both simulation and real world. The locomotion model demonstrates how attractor states derived from body dynamics influence the sensory information, which can then be used for the recognition of stable behavioral patterns and of physical properties in the environment. A comprehensive analysis of behavior and sensory information leads to a deeper understanding of the underlying mechanisms by which body dynamics can be exploited for category learning of autonomous robotic systems.", "corpus_id": 6032830, "score": 0 }, { "doc_id": "12930643", "title": "An Energy-Efficient Hopping Robot Based on Free Vibration of a Curved Beam", "abstract": "This paper explores a design strategy of hopping robots, which makes use of free vibration of an elastic curved beam. In this strategy, the leg structure consists of a specifically shaped elastic curved beam and a small rotating mass that induces free vibration of the entire robot body. Although we expect to improve energy efficiency of locomotion by exploiting the mechanical dynamics, it is not trivial to take advantage of the coupled dynamics between actuation and mechanical structures for the purpose of locomotion. From this perspective, this paper explains the basic design principles through modeling, simulation, and experiments of a minimalistic hopping robot platform. More specifically, we show how to design elastic curved beams for stable hopping locomotion and the control method by using unconventional actuation. In addition, we also analyze the proposed design strategy in terms of energy efficiency and discuss how it can be applied to the other forms of legged robot locomotion.", "corpus_id": 12930643, "score": 1 }, { "doc_id": "109729337", "title": "Minimalistic Models of an Energy-Efficient Vertical-Hopping Robot", "abstract": "The use of free vibration in elastic structure can lead to energy-efficient robot locomotion, since it significantly reduces the energy expenditure if properly designed and controlled. However, it is not well understood how to harness the dynamics of free vibration for the robot locomotion, because of the complex dynamics originated in discrete events and energy dissipation during locomotion. From this perspective, the goals of this paper are to propose a design strategy of hopping robot based on elastic curved beams and actuated rotating masses and to identify the minimalistic model that can characterize the basic principle of robot locomotion. Since the robot mainly exhibits vertical hopping, three 1-D models are examined that contain different configurations of simple spring-damper-mass components. The real-world and simulation experiments show that one of the models best characterizes the robot hopping, through analyzing the basic kinematics and negative works in actuation. Based on this model, the self-stability of hopping motion under disturbances is investigated, and design and control parameters are analyzed for the energy-efficient hopping. In addition, further analyses show that this robot can achieve the energy-efficient hopping with the variation in payload, and the source of energy dissipation of the robot hopping is investigated.", "corpus_id": 109729337, "score": 1 }, { "doc_id": "6104996", "title": "Estimating contact dynamics", "abstract": "Motion and interaction with the environment are fundamentally intertwined. Few people-tracking algorithms exploit such interactions, and those that do assume that surface geometry and dynamics are given. This paper concerns the converse problem, i.e., the inference of contact and environment properties from motion. For 3D human motion, with a 12-segment articulated body model, we show how one can estimate the forces acting on the body in terms of internal forces (joint torques), gravity, and the parameters of a contact model (e.g., the geometry and dynamics of a spring-based model). This is tested on motion capture data and video-based tracking data, with walking, jogging, cartwheels, and jumping.", "corpus_id": 6104996, "score": 0 }, { "doc_id": "11597093", "title": "Learning from Observation and from Practice Using Behavioral Primitives", "abstract": "We describe a memory-based approach to learning how to select and provide sub-goals for behavioral primitives, given an existing library of primitives. We demonstrate both learning from observation and learning from practice on a marble maze task, Labyrinth.", "corpus_id": 11597093, "score": 0 }, { "doc_id": "7762753", "title": "Deriving action and behavior primitives from human motion data", "abstract": "We address the problem of creating basis behaviors for modularizing humanoid robot control and representing human activity. These behaviors, called perceptual-motor primitives, serve as a substrate for linking a system's perception of human activities and the ability to perform those activities. We present a data-driven method for deriving perceptual-motor action and behavior primitives from human motion capture data. In order to find these primitives, we employ a spatio-temporal non-linear dimension reduction technique on a set of motion segments. From this transformation, motions representing the same action can be clustered and generalized. Further dimension reduction iterations are applied to derive extended-duration behaviors.", "corpus_id": 7762753, "score": 0 }, { "doc_id": "13366009", "title": "Active sampling and decision making in Drosophila chemotaxis", "abstract": "The ability to respond to chemical stimuli is fundamental to the survival of motile organisms, but the strategies underlying odour tracking remain poorly understood. Here we show that chemotaxis in Drosophila melanogaster larvae is an active sampling process analogous to sniffing in vertebrates. Combining computer-vision algorithms with reconstructed olfactory environments, we establish that larvae orient in odour gradients through a sequential organization of stereotypical behaviours, including runs, stops, lateral head casts and directed turns. Negative gradients, integrated during runs, control the timing of turns. Positive gradients detected through high-amplitude head casts determine the direction of individual turns. By genetically manipulating the peripheral olfactory circuit, we examine how orientation adapts to losses and gains of function in olfactory input. Our findings suggest that larval chemotaxis represents an intermediate navigation strategy between the biased random walks of Escherichia Coli and the stereo-olfaction observed in rats and humans.", "corpus_id": 13366009, "score": 0 }, { "doc_id": "178516210", "title": "Motile Behavior of Bacteria", "abstract": "Escherichia coli is a single‐celled organism that lives in your gut. It is equipped with a set of rotary motors only 45 nm in diameter. Each motor drives a long, thin, helical filament that extends several cell body lengths out into the external medium. The assemblage of motor and filament is called a flagellum. The concerted motion of several flagella enables a cell to swim. A cell can move toward regions that it deems more favorable by measuring changes in the concentrations of certain chemicals in its environment (mostly nutrients), deciding whether life is getting better or worse, and then modulating the direction of rotation of its flagella. Thus, in addition to rotary engines and propellers, E. coli's standard accessories include particle counters, rate meters, and gear boxes. This microorganism is a nanotechnologist's dream. I will discuss the features that make it so, from the perspectives of several scientific disciplines: anatomy, genetics, chemistry, and physics.", "corpus_id": 178516210, "score": 0 }, { "doc_id": "7674305", "title": "The Fundamental Role of Pirouettes in Caenorhabditis elegans Chemotaxis", "abstract": "To investigate the behavioral mechanism of chemotaxis inCaenorhabditis elegans, we recorded the instantaneous position, speed, and turning rate of single worms as a function of time during chemotaxis in gradients of the attractants ammonium chloride or biotin. Analysis of turning rate showed that each worm track could be divided into periods of smooth swimming (runs) and periods of frequent turning (pirouettes). The initiation of pirouettes was correlated with the rate of change of concentration (dC/dt) but not with absolute concentration. Pirouettes were most likely to occur when a worm was heading down the gradient (dC/dt < 0) and least likely to occur when a worm was heading up the gradient (dC/dt > 0). Further analysis revealed that the average direction of movement after a pirouette was up the gradient. These observations suggest that chemotaxis is produced by a series of pirouettes that reorient the animal to the gradient. We tested this idea by imposing the correlation between pirouettes and dC/dt on a stochastic point model of worm motion. The model exhibited chemotaxis behavior in a radial gradient and also in a novel planar gradient. Thus, the pirouette model ofC. elegans chemotaxis is sufficient and general.", "corpus_id": 7674305, "score": 0 }, { "doc_id": "36821429", "title": "Behaviour of dogs during olfactory tracking.", "abstract": "The ability to detect the direction of a track is of vital importance to animals of prey and is retained in many modern breeds of dogs. To study this ability, four trained German shepherd tracking dogs, equipped with head microphones to transmit sniffing activity, were video-monitored after being brought at right angles to a track where the position of each footprint was known. Three phases could be recognized in the dogs' behaviour: (1) an initial searching phase, during which the dog tried to find the track, (2) a deciding phase, during which it tried to determine the direction of the track and (3) a tracking phase, in which it followed the track. During ten tests on 20-min-old tracks on grass, and ten tests on 3-min-old tracks on concrete, the dogs always followed the track in the correct direction (i.e. in the direction the track was leading). During the deciding phase the dogs moved at half the speed and their periods of sniffing lasted three times as long as during the other two phases. The deciding phase lasted 3-5 s, while the dogs sniffed at 2-5 footprints. The dogs' ability to determine track direction in this time must rely on accurate methods of sampling air and a remarkable sensitivity for certain substances.", "corpus_id": 36821429, "score": 0 }, { "doc_id": "37386879", "title": "Neural bases of goal-directed locomotion in vertebrates—An overview", "abstract": "The different neural control systems involved in goal-directed vertebrate locomotion are reviewed. They include not only the central pattern generator networks in the spinal cord that generate the basic locomotor synergy and the brainstem command systems for locomotion but also the control systems for steering and control of body orientation (posture) and finally the neural structures responsible for determining which motor programs should be turned on in a given instant. The role of the basal ganglia is considered in this context. The review summarizes the available information from a general vertebrate perspective, but specific examples are often derived from the lamprey, which provides the most detailed information when considering cellular and network perspectives.", "corpus_id": 37386879, "score": 0 }, { "doc_id": "10242589", "title": "Toward open-ended evolutionary robotics: evolving elementary robotic units able to self-assemble and self-reproduce", "abstract": "In this paper, we discuss the limitations of current evolutionary robotics models and we propose a new framework that might solve some of these problems and lead to an open-ended evolutionary process in hardware. More specifically, the paper describes a novel approach where the usual concepts of population, generations and fitness are made implicit in the system. Individuals co-evolve embedded in their environment. Exploiting the self-assembling capabilities of the (simulated) robots, the genotype of a successful individual can spread in the population. In this way, interesting behaviours emerge spontaneously, resulting in chasing and evading other individuals, collective obstacle avoidance and co-ordinated motion of self-assembled structures.", "corpus_id": 10242589, "score": 0 }, { "doc_id": "6652458", "title": "Reinforcement Learning in Continuous Time and Space", "abstract": "This article presents a reinforcement learning framework for continuous-time dynamical systems without a priori discretization of time, state, and action. Basedonthe Hamilton-Jacobi-Bellman (HJB) equation for infinite-horizon, discounted reward problems, we derive algorithms for estimating value functions and improving policies with the use of function approximators. The process of value function estimation is formulated as the minimization of a continuous-time form of the temporal difference (TD) error. Update methods based on backward Euler approximation and exponential eligibility traces are derived, and their correspondences with the conventional residual gradient, TD (0), and TD () algorithms are shown. For policy improvement, two methodsa continuous actor-critic method and a value-gradient-based greedy policyare formulated. As a special case of the latter, a nonlinear feedback control law using the value gradient and the model of the input gain is derived. The advantage updating, a model-free algorithm derived previously, is also formulated in the HJB-based framework. The performance of the proposed algorithms is first tested in a nonlinear control task of swinging a pendulum up with limited torque. It is shown in the simulations that (1) the task is accomplished by the continuous actor-critic method in a number of trials several times fewer than by the conventional discrete actor-critic method; (2) among the continuous policy update methods, the value-gradient-based policy with a known or learned dynamic model performs several times better than the actor-critic method; and (3) a value function update using exponential eligibility traces is more efficient and stable than that based on Euler approximation. The algorithms are then tested in a higher-dimensional task: cart-pole swing-up. This task is accomplished in several hundred trials using the value-gradient-based policy with a learned dynamic model.", "corpus_id": 6652458, "score": 0 }, { "doc_id": "1452734", "title": "Developmental robotics: a survey", "abstract": "Developmental robotics is an emerging field located at the intersection of robotics, cognitive science and developmental sciences. This paper elucidates the main reasons and key motivations behind the convergence of fields with seemingly disparate interests, and shows why developmental robotics might prove to be beneficial for all fields involved. The methodology advocated is synthetic and two-pronged: on the one hand, it employs robots to instantiate models originating from developmental sciences; on the other hand, it aims to develop better robotic systems by exploiting insights gained from studies on ontogenetic development. This paper gives a survey of the relevant research issues and points to some future research directions.", "corpus_id": 1452734, "score": 0 } ]

{ "doc_id": "697573", "title": "UNCLES: method for the identification of genes differentially consistently co-expressed in a specific subset of datasets", "abstract": "BackgroundCollective analysis of the increasingly emerging gene expression datasets are required. The recently proposed binarisation of consensus partition matrices (Bi-CoPaM) method can combine clustering results from multiple datasets to identify the subsets of genes which are consistently co-expressed in all of the provided datasets in a tuneable manner. However, results validation and parameter setting are issues that complicate the design of such methods. Moreover, although it is a common practice to test methods by application to synthetic datasets, the mathematical models used to synthesise such datasets are usually based on approximations which may not always be sufficiently representative of real datasets.ResultsHere, we propose an unsupervised method for the unification of clustering results from multiple datasets using external specifications (UNCLES). This method has the ability to identify the subsets of genes consistently co-expressed in a subset of datasets while being poorly co-expressed in another subset of datasets, and to identify the subsets of genes consistently co-expressed in all given datasets. We also propose the M-N scatter plots validation technique and adopt it to set the parameters of UNCLES, such as the number of clusters, automatically. Additionally, we propose an approach for the synthesis of gene expression datasets using real data profiles in a way which combines the ground-truth-knowledge of synthetic data and the realistic expression values of real data, and therefore overcomes the problem of faithfulness of synthetic expression data modelling. By application to those datasets, we validate UNCLES while comparing it with other conventional clustering methods, and of particular relevance, biclustering methods. We further validate UNCLES by application to a set of 14 real genome-wide yeast datasets as it produces focused clusters that conform well to known biological facts. Furthermore, in-silico-based hypotheses regarding the function of a few previously unknown genes in those focused clusters are drawn.ConclusionsThe UNCLES method, the M-N scatter plots technique, and the expression data synthesis approach will have wide application for the comprehensive analysis of genomic and other sources of multiple complex biological datasets. Moreover, the derived in-silico-based biological hypotheses represent subjects for future functional studies.", "corpus_id": 697573 }

[ { "doc_id": "24509304", "title": "Meta-analysis of microarray results: challenges, opportunities, and recommendations for standardization.", "abstract": "Microarray profiling of gene expression is a powerful tool for discovery, but the ability to manage and compare the resulting data can be problematic. Biological, experimental, and technical variations between studies of the same phenotype/phenomena create substantial differences in results. The application of conventional meta-analysis to raw microarray data is complicated by differences in the type of microarray used, gene nomenclatures, species, and analytical methods. An alternative approach to combining multiple microarray studies is to compare the published gene lists which result from the investigators' analyses of the raw data, as implemented in Lists of Lists Annotated (LOLA: www.lola.gwu.edu) and L2L (depts.washington.edu/l2l/). The present review considers both the potential value and the limitations of databasing and enabling the comparison of results from different microarray studies. Further, a major impediment to cross-study comparisons is the absence of a standard for reporting microarray study results. We propose a reporting standard: standard microarray results template (SMART), which will facilitate the integration of microarray studies.", "corpus_id": 24509304, "score": 0 }, { "doc_id": "24695222", "title": "An atlas of tissue-specific conserved coexpression for functional annotation and disease gene prediction", "abstract": "Gene coexpression relationships that are phylogenetically conserved between human and mouse have been shown to provide important clues about gene function that can be efficiently used to identify promising candidate genes for human hereditary disorders. In the past, such approaches have considered mostly generic gene expression profiles that cover multiple tissues and organs. The individual genes of multicellular organisms, however, can participate in different transcriptional programs, operating at scales as different as single-cell types, tissues, organs, body regions or the entire organism. Therefore, systematic analysis of tissue-specific coexpression could be, in principle, a very powerful strategy to dissect those functional relationships among genes that emerge only in particular tissues or organs. In this report, we show that, in fact, conserved coexpression as determined from tissue-specific and condition-specific data sets can predict many functional relationships that are not detected by analyzing heterogeneous microarray data sets. More importantly, we find that, when combined with disease networks, the simultaneous use of both generic (multi-tissue) and tissue-specific conserved coexpression allows a more efficient prediction of human disease genes than the use of generic conserved coexpression alone. Using this strategy, we were able to identify high-probability candidates for 238 orphan disease loci. We provide proof of concept that this combined use of generic and tissue-specific conserved coexpression can be very useful to prioritize the mutational candidates obtained from deep-sequencing projects, even in the case of genetic disorders as heterogeneous as XLMR.", "corpus_id": 24695222, "score": 0 }, { "doc_id": "33766143", "title": "Genome-wide coexpression dynamics: Theory and application", "abstract": "High-throughput expression profiling enables the global study of gene activities. Genes with positively correlated expression profiles are likely to encode functionally related proteins. However, all biological processes are interlocked, and each protein may play multiple cellular roles. Thus the coexpression of any two functionally related genes may depend on the constantly varying, yet often-unknown cellular state. To initiate a systematic study on this issue, a theory of coexpression dynamics is presented. This theory is used to rationalize a strategy of conducting a genome-wide search for the most critical cellular players that may affect the coexpression pattern of any two genes. In one example, using a yeast data set, our method reveals how the enzymes associated with the urea cycle are expressed to ensure proper mass flow of the involved metabolites. The correlation between ARG2 and CAR2 is found to change from positive to negative as the expression level of CPA2 increases. This delicate interplay in correlation signifies a remarkable control on the influx and efflux of ornithine and reflects well the intrinsic cellular demand for arginine. In addition to the urea cycle, our examples include SCH9 and CYR1 (both implicated in a recent longevity study), cytochrome c1 (mitochondrial electron transport), calmodulin (main calcium-binding protein), PFK1 and PFK2 (glycolysis), and two genes, ECM1 and YNL101W, the functions of which are newly revealed. The complexity in computation is eased by a new result from mathematical statistics.", "corpus_id": 33766143, "score": 1 }, { "doc_id": "3131371", "title": "A Gene-Coexpression Network for Global Discovery of Conserved Genetic Modules", "abstract": "To elucidate gene function on a global scale, we identified pairs of genes that are coexpressed over 3182 DNA microarrays from humans, flies, worms, and yeast. We found 22,163 such coexpression relationships, each of which has been conserved across evolution. This conservation implies that the coexpression of these gene pairs confers a selective advantage and therefore that these genes are functionally related. Manyof these relationships provide strong evidence for the involvement of new genes in core biological functions such as the cell cycle, secretion, and protein expression. We experimentallyconfirmed the predictions implied bysome of these links and identified cell proliferation functions for several genes. By assembling these links into a gene-coexpression network, we found several components that were animal-specific as well as interrelationships between newly evolved and ancient modules.", "corpus_id": 3131371, "score": 0 }, { "doc_id": "19412190", "title": "The budding yeast rRNA and ribosome biosynthesis (RRB) regulon contains over 200 genes", "abstract": "The ribosome biogenesis pathway constitutes one of the major metabolic obligations for a dividing yeast cell and it depends upon the activity of hundreds of gene products to produce the necessary rRNA and ribosomal protein components. Previously, we reported that a set of 65 S. cerevisiae genes that function in the rRNA biosynthesis pathway are transcriptionally co‐regulated as cells pass through a variety of physiological transitions. By analysing multiple microarray‐based transcriptional datasets, we have extended that study and now suggest that the ribosomal and rRNA biosynthesis regulon contains over 200 genes. This regulon is distinct from the set of ribosomal protein genes, and the promoters of the expanded RRB gene set are highly enriched for the PAC and RRPE motifs. Since a similar pattern of organization and gene regulation can be recognized in C. albicans, the RRB regulon appears to be a conserved, extensive, and metabolically important group of genes. Copyright © 2006 John Wiley & Sons, Ltd.", "corpus_id": 19412190, "score": 1 }, { "doc_id": "9622989", "title": "An empirical comparison of four initialization methods for the K-Means algorithm", "abstract": "In this paper, we aim to compare empirically four initialization methods for the K-Means algorithm: random, Forgy, MacQueen and Kaufman. Although this algorithm is known for its robustness, it is widely reported in the literature that its performance depends upon two key points: initial clustering and instance order. We conduct a series of experiments to draw up (in terms of mean, maximum, minimum and standard deviation) the probability distribution of the square-error values of the final clusters returned by the K-Means algorithm independently on any initial clustering and on any instance order when each of the four initialization methods is used. The results of our experiments illustrate that the random and the Kaufman initialization methods outperform the rest of the compared methods as they make the K-Means more effective and more independent on initial clustering and on instance order. In addition, we compare the convergence speed of the K-Means algorithm when using each of the four initialization methods. Our results suggest that the Kaufman initialization method induces to the K-Means algorithm a more desirable behaviour with respect to the convergence speed than the random initialization method.", "corpus_id": 9622989, "score": 1 }, { "doc_id": "5612356", "title": "Cluster analysis and display of genome-wide expression patterns.", "abstract": "A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.", "corpus_id": 5612356, "score": 1 }, { "doc_id": "371422", "title": "Gene clustering using self-organizing maps and particle swarm optimization", "abstract": "Gene clustering, the process of grouping related genes in the same cluster, is at the foundation of different genomic studies that aim at analyzing the function of genes. Microarray technologies have made it possible to measure gene expression levels for thousand of genes simultaneously. For knowledge to be extracted from the datasets generated by these technologies, the datasets have to be presented to a scientist in a meaningful way. Gene clustering methods serve this purpose. In this paper, a hybrid clustering approach that is based on self-organizing maps and particle swarm optimization is proposed. In the proposed algorithm, the rate of convergence is improved by adding a conscience factor to the self-organizing maps algorithm. The robustness of the result is measured by using a resampling technique. The algorithm is implemented on a cluster of workstations.", "corpus_id": 371422, "score": 1 }, { "doc_id": "14813790", "title": "Paradigm of Tunable Clustering Using Binarization of Consensus Partition Matrices (Bi-CoPaM) for Gene Discovery", "abstract": "Clustering analysis has a growing role in the study of co-expressed genes for gene discovery. Conventional binary and fuzzy clustering do not embrace the biological reality that some genes may be irrelevant for a problem and not be assigned to a cluster, while other genes may participate in several biological functions and should simultaneously belong to multiple clusters. Also, these algorithms cannot generate tight clusters that focus on their cores or wide clusters that overlap and contain all possibly relevant genes. In this paper, a new clustering paradigm is proposed. In this paradigm, all three eventualities of a gene being exclusively assigned to a single cluster, being assigned to multiple clusters, and being not assigned to any cluster are possible. These possibilities are realised through the primary novelty of the introduction of tunable binarization techniques. Results from multiple clustering experiments are aggregated to generate one fuzzy consensus partition matrix (CoPaM), which is then binarized to obtain the final binary partitions. This is referred to as Binarization of Consensus Partition Matrices (Bi-CoPaM). The method has been tested with a set of synthetic datasets and a set of five real yeast cell-cycle datasets. The results demonstrate its validity in generating relevant tight, wide, and complementary clusters that can meet requirements of different gene discovery studies.", "corpus_id": 14813790, "score": 1 }, { "doc_id": "15327847", "title": "Comprehensive analysis of forty yeast microarray datasets reveals a novel subset of genes (APha-RiB) consistently negatively associated with ribosome biogenesis", "abstract": "BackgroundThe scale and complexity of genomic data lend themselves to analysis using sophisticated mathematical techniques to yield information that can generate new hypotheses and so guide further experimental investigations. An ensemble clustering method has the ability to perform consensus clustering over the same set of genes from different microarray datasets by combining results from different clustering methods into a single consensus result.ResultsIn this paper we have performed comprehensive analysis of forty yeast microarray datasets. One recently described Bi-CoPaM method can analyse expressions of the same set of genes from various microarray datasets while using different clustering methods, and then combine these results into a single consensus result whose clusters’ tightness is tunable from tight, specific clusters to wide, overlapping clusters. This has been adopted in a novel way over genome-wide data from forty yeast microarray datasets to discover two clusters of genes that are consistently co-expressed over all of these datasets from different biological contexts and various experimental conditions. Most strikingly, average expression profiles of those clusters are consistently negatively correlated in all of the forty datasets while neither profile leads or lags the other.ConclusionsThe first cluster is enriched with ribosomal biogenesis genes. The biological processes of most of the genes in the second cluster are either unknown or apparently unrelated although they show high connectivity in protein-protein and genetic interaction networks. Therefore, it is possible that this mostly uncharacterised cluster and the ribosomal biogenesis cluster are transcriptionally oppositely regulated by some common machinery. Moreover, we anticipate that the genes included in this previously unknown cluster participate in generic, in contrast to specific, stress response processes. These novel findings illuminate coordinated gene expression in yeast and suggest several hypotheses for future experimental functional work. Additionally, we have demonstrated the usefulness of the Bi-CoPaM-based approach, which may be helpful for the analysis of other groups of (microarray) datasets from other species and systems for the exploration of global genetic co-expression.", "corpus_id": 15327847, "score": 0 }, { "doc_id": "20348491", "title": "A system for enhancing genome-wide coexpression dynamics study.", "abstract": "Statistical similarity analysis has been instrumental in elucidation of the voluminous microarray data. Genes with correlated expression profiles tend to be functionally associated. However, the majority of functionally associated genes turn out to be uncorrelated. One conceivable reason is that the expression of a gene can be sensitively dependent on the often-varying cellular state. The intrinsic state change has to be plastically accommodated by gene-regulatory mechanisms. To capture such dynamic coexpression between genes, a concept termed \"liquid association\" (LA) has been introduced recently. LA offers a scoring system to guide a genome-wide search for critical cellular players that may interfere with the coexpression of a pair of genes, thereby weakening their overall correlation. Although the LA method works in many cases, a direct extension to more than two genes is hindered by the \"curse of dimensionality.\" Here we introduce a strategy of finding an informative 2D projection to generalize LA for multiple genes. A web site is constructed that performs on-line LA computation for any user-specified group of genes. We apply this scoring system to study yeast protein complexes by using the Saccharomyces cerevisiae protein complexes database of the Munich Information Center for Protein Sequences. Human genes are also investigated by profiling of 60 cancer cell lines of the National Cancer Institute. In particular, our system links the expression of the Alzheimer's disease hallmark gene APP (amyloid-beta precursor protein) to the beta-site-cleaving enzymes BACE and BACE2, the gamma-site-cleaving enzymes presenilin 1 and 2, apolipoprotein E, and other Alzheimer's disease-related genes.", "corpus_id": 20348491, "score": 0 }, { "doc_id": "16095037", "title": "Differential coexpression analysis using microarray data and its application to human cancer", "abstract": "MOTIVATION\nMicroarrays have been used to identify differential expression of individual genes or cluster genes that are coexpressed over various conditions. However, alteration in coexpression relationships has not been studied. Here we introduce a model for finding differential coexpression from microarrays and test its biological validity with respect to cancer.\n\n\nRESULTS\nWe collected 10 published gene expression datasets from cancers of 13 different tissues and constructed 2 distinct coexpression networks: a tumor network and normal network. Comparison of the two networks showed that cancer affected many coexpression relationships. Functional changes such as alteration in energy metabolism, promotion of cell growth and enhanced immune activity were accompanied with coexpression changes. Coregulation of collagen genes that may control invasion and metastatic spread of tumor cells was also found. Cluster analysis in the tumor network identified groups of highly interconnected genes related to ribosomal protein synthesis, the cell cycle and antigen presentation. Metallothionein expression was also found to be clustered, which may play a role in apoptosis control in tumor cells. Our results show that this model would serve as a novel method for analyzing microarrays beyond the specific implications for cancer.", "corpus_id": 16095037, "score": 0 }, { "doc_id": "23815964", "title": "Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart", "abstract": "VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.", "corpus_id": 23815964, "score": 0 }, { "doc_id": "6321522", "title": "Biclustering of Expression Data", "abstract": "An efficient node-deletion algorithm is introduced to find submatrices in expression data that have low mean squared residue scores and it is shown to perform well in finding co-regulation patterns in yeast and human. This introduces \"biclustering\", or simultaneous clustering of both genes and conditions, to knowledge discovery from expression data. This approach overcomes some problems associated with traditional clustering methods, by allowing automatic discovery of similarity based on a subset of attributes, simultaneous clustering of genes and conditions, and overlapped grouping that provides a better representation for genes with multiple functions or regulated by many factors.", "corpus_id": 6321522, "score": 0 }, { "doc_id": "11403283", "title": "A systematic comparison and evaluation of biclustering methods for gene expression data", "abstract": "MOTIVATION\nIn recent years, there have been various efforts to overcome the limitations of standard clustering approaches for the analysis of gene expression data by grouping genes and samples simultaneously. The underlying concept, which is often referred to as biclustering, allows to identify sets of genes sharing compatible expression patterns across subsets of samples, and its usefulness has been demonstrated for different organisms and datasets. Several biclustering methods have been proposed in the literature; however, it is not clear how the different techniques compare with each other with respect to the biological relevance of the clusters as well as with other characteristics such as robustness and sensitivity to noise. Accordingly, no guidelines concerning the choice of the biclustering method are currently available.\n\n\nRESULTS\nFirst, this paper provides a methodology for comparing and validating biclustering methods that includes a simple binary reference model. Although this model captures the essential features of most biclustering approaches, it is still simple enough to exactly determine all optimal groupings; to this end, we propose a fast divide-and-conquer algorithm (Bimax). Second, we evaluate the performance of five salient biclustering algorithms together with the reference model and a hierarchical clustering method on various synthetic and real datasets for Saccharomyces cerevisiae and Arabidopsis thaliana. The comparison reveals that (1) biclustering in general has advantages over a conventional hierarchical clustering approach, (2) there are considerable performance differences between the tested methods and (3) already the simple reference model delivers relevant patterns within all considered settings.", "corpus_id": 11403283, "score": 0 }, { "doc_id": "2664253", "title": "Yeast gene CMR1/YDL156W is consistently co-expressed with genes participating in DNA-metabolic processes in a variety of stringent clustering experiments", "abstract": "The binarization of consensus partition matrices (Bi-CoPaM) method has, among its unique features, the ability to perform ensemble clustering over the same set of genes from multiple microarray datasets by using various clustering methods in order to generate tunable tight clusters. Therefore, we have used the Bi-CoPaM method to the most synchronized 500 cell-cycle-regulated yeast genes from different microarray datasets to produce four tight, specific and exclusive clusters of co-expressed genes. We found 19 genes formed the tightest of the four clusters and this included the gene CMR1/YDL156W, which was an uncharacterized gene at the time of our investigations. Two very recent proteomic and biochemical studies have independently revealed many facets of CMR1 protein, although the precise functions of the protein remain to be elucidated. Our computational results complement these biological results and add more evidence to their recent findings of CMR1 as potentially participating in many of the DNA-metabolism processes such as replication, repair and transcription. Interestingly, our results demonstrate the close co-expressions of CMR1 and the replication protein A (RPA), the cohesion complex and the DNA polymerases α, δ and ɛ, as well as suggest functional relationships between CMR1 and the respective proteins. In addition, the analysis provides further substantial evidence that the expression of the CMR1 gene could be regulated by the MBF complex. In summary, the application of a novel analytic technique in large biological datasets has provided supporting evidence for a gene of previously unknown function, further hypotheses to test, and a more general demonstration of the value of sophisticated methods to explore new large datasets now so readily generated in biological experiments.", "corpus_id": 2664253, "score": 1 }, { "doc_id": "13523816", "title": "Application of the Bi-CoPaM Method to Five Escherichia Coli Datasets Generated under Various Biological Conditions", "abstract": "The increasing amounts of high-throughput biological datasets stimulate the information engineering and machine learning research community to direct more studies towards designing and applying novel methods which are sophisticated and specialised to tackle the problems that are specific in such datasets. The recently proposed binarisation of consensus partition matrices (Bi-CoPaM) method tackles the problem of scrutinising multiple gene expression microarray datasets to identify the subsets of genes which are consistently co-expressed across them. It allows for clustering results which better reflect the biological fact that most of the genes in any cell are expected to be irrelevant to the specific context in hand, as well as the fact that many genes might participate in multiple processes. This has been achieved by clustering the given set of genes while allowing any gene to have any of the three eventualities, to be exclusively assigned to a single cluster, to be simultaneously assigned to multiple clusters, or not to be assigned to any of the clusters. In this study, we expand the scope of application of the Bi-CoPaM method by applying it, for the first time, to bacterial datasets, namely to a set of five Escherichia coli bacterial datasets generated under different biological conditions, in order to identify the subsets of genes which are consistently co-expressed, i.e. well correlated with each other. We identify two clusters with such consistent co-expression, and interestingly, they themselves are consistently negatively correlated with each other. The first cluster is enriched with genes participating in protein synthesis and DNA repair while the second is enriched with transporting genes. Consequently, we draw biological hypotheses that relate some of the genes with currently unknown biological processes to their potential processes. These hypotheses can serve as pilots for focused future gene discovery studies.", "corpus_id": 13523816, "score": 0 }, { "doc_id": "436744", "title": "Enhanced SMART framework for gene clustering using successive processing", "abstract": "In this paper, we develop an enhanced splitting merging awareness tactics (E-SMART) framework using successive processing. Instead of selecting the best clustering from the results by using clustering selection criterion in original SMART framework, we introduce a successive processing strategy into the framework to subtract clusters one by one in iterations. In doing so, the silhouette index is employed to evaluate the intermediate clusters and order them according to their index values from high to low. Then we subtract the best cluster from the original dataset and iterate the remaining dataset back to the splitting-while-merging (SWM) process to start a new iteration. The clustering and subtracting are repeated successively and terminated automatically, once no splitting happened in the SWM process. Consequently, all clusters can be obtained by iterations. We implement the framework using component-wise expectation maximization (CEM) for finite mixture models (FMM). The E-SMART-FMM implementation is tested in real NCI-60 cancer dataset. We evaluate the clustering results from the proposed algorithm, together with two existing self-splitting algorithms, using two popular validation indices other than the silhouette index. The results of both validation indices consistently demonstrate that E-SMART-FMM is superior to the existing algorithms.", "corpus_id": 436744, "score": 0 }, { "doc_id": "95931968", "title": "Selecting variables for k-means cluster analysis by using a genetic algorithm that optimises the silhouettes", "abstract": "The goal of present work is to analyse the effect of having non-informative variables (NIV) in a data set when applying cluster analysis and to propose a method computationally capable of detecting and removing these variables. The method proposed is based on the use of a genetic algorithm to select those variables important to make the presence of groups in data clear. The procedure has been implemented to be used with k-means and using the cluster silhouettes as fitness function for the genetic algorithm. \n \nThe main problem that can appear when applying the method to real data is the fact that, in general, we do not know a priori what the real cluster structure is (number and composition of the groups). \n \nThe work explores the evolution of the silhouette values computed from the clusters built by using k-means when non-informative variables are added to the original data set in both a literature data set as well as some simulated data in higher dimension. The procedure has also been applied to real data sets.", "corpus_id": 95931968, "score": 0 }, { "doc_id": "15712376", "title": "Cytoplasmic-nuclear genomic barriers in rice pollen development revealed by comparison of global gene expression profiles among five independent cytoplasmic male sterile lines.", "abstract": "Cytoplasmic male sterility (CMS) is one of the most ideal phenomena known in higher plants to describe the incompatibilities between mitochondrial-nuclear genomic interactions. To elucidate the dependency of pollen development on mitochondrial genotypes and cytoplasmic-nuclear genomic barriers, we employed five CMS isogenic lines of rice, CW-, W11-, LD-, BT- and WA-type CMS lines, that exhibit distinct pollen-defective phenotypes, and we characterized the CMS phenotypes and the nuclear gene expression patterns in conjunction with their mitochondrial genomic structures. These five CMS lines carried independent mitotypes, and W11, LD and BT mitochondrial genomes were relatively close with respect to their phylogeny. In anthers at the uninucleate microspore and bicellular pollen stages, 8,199 genes significantly changed their expression in at least one of the CMS lines. Common expression patterns were observed in BT, LD and W11 after k-means clustering. Among the genes encoding putative mitochondrial proteins, ALTERNATIVE OXIDASE 1A, a gene for the well-known mitochondrial stress marker, was included in the group ectopically up-regulated in anthers at the bicellular pollen stage of BT, LD and W11. Several other clusters were also regulated in a cytoplasm-specific manner during pollen development. These clear similarities in gene regulatory networks of BT-, LD- and W11-CMS lines indicate that the phylogenetic relationships of the mitochondrial genotypes are strongly correlated with nuclear gene expression patterns and pollen abortion phenotypes, providing evidence of the mitochondrial epistacy over the nuclear genome during pollen development.", "corpus_id": 15712376, "score": 0 }, { "doc_id": "30205867", "title": "Identification of embryonic pancreatic genes using Xenopus DNA microarrays", "abstract": "The pancreas is both an exocrine and endocrine endodermal organ involved in digestion and glucose homeostasis. During embryogenesis, the anlagen of the pancreas arise from dorsal and ventral evaginations of the foregut that later fuse to form a single organ. To better understand the molecular genetics of early pancreas development, we sought to isolate markers that are uniquely expressed in this tissue. Microarray analysis was performed comparing dissected pancreatic buds, liver buds, and the stomach region of tadpole stage Xenopus embryos. A total of 912 genes were found to be differentially expressed between these organs during early stages of organogenesis. K‐means clustering analysis predicted 120 of these genes to be specifically enriched in the pancreas. Of these, we report on the novel expression patterns of 24 genes. Our analyses implicate the involvement of previously unsuspected signaling pathways during early pancreas development. Developmental Dynamics 238:1455–1466, 2009. © 2009 Wiley‐Liss, Inc.", "corpus_id": 30205867, "score": 0 }, { "doc_id": "43724327", "title": "Regulation of megakaryocytic differentiation of K562 cells by FosB, a member of the Fos family of AP-1 transcription factors", "abstract": "Abstract.The regulation of megakaryocytic differentiation is poorly understood. Using K562 cells, which can partly recapitulate the process in response to phorbol 12-myristate 13-acetate (PMA), we performed microarray-based gene expression profiling to identify genes that play significant roles in megakaryopoiesis. Here, we describe the function of FosB, an AP-1 transcription factor. FosB is induced in PMA treated K562 cells in a sustained manner and forms an active AP-1 protein-DNA complex. Down-regulation of FosB with specific shRNAs inhibited the induction of CD41, a specific cell surface marker of megakaryocytes. We also show that activation of the PKC-MEK-ERK signaling pathway is required for induction of FosB and CD41. Finally, we cross-examined the microarray data in conjunction with gene function annotation data to identify additional target genes of FosB. We define 3 genes, INHBA, CD9, and ITGA2B as regulatory targets of FosB and show that CD9, in particular, is a direct target of FosB.", "corpus_id": 43724327, "score": 0 }, { "doc_id": "23264453", "title": "Genome-wide analysis of gene expression profiles during the kernel development of maize (Zea mays L.).", "abstract": "Maize kernel is an important source of food, feed, and industrial raw materials. The elucidation of the molecular mechanisms of maize kernel development will be helpful for the manipulation of maize improvements. A microarray with approximately 58,000 probes was used to study dynamic gene expression during kernel development from fertilization to physiological maturity. By comparing six consecutive time points, 3445 differentially expressed genes were identified. These genes were then grouped into 10 clusters showing specific expression patterns using a K-means clustering algorithm. An investigation of function and expression patterns of genes elucidate the regulation mechanism underlying the important developmental processes cell division and kernel filling. The differential expression of genes involved in plant hormone signaling pathways suggested that phytohormone might play a critical role in the kernel developmental process. Moreover, regulation of some transcription factors and protein kinases might be involved in the whole developmental process.", "corpus_id": 23264453, "score": 0 }, { "doc_id": "16771648", "title": "Finding large average submatrices in high dimensional data", "abstract": "The search for sample-variable associations is an important problem in the exploratory analysis of high dimensional data. Biclustering methods search for sample-variable associations in the form of distinguished submatrices of the data matrix. (The rows and columns of a submatrix need not be contiguous.) In this paper we propose and evaluate a statistically motivated biclustering procedure (LAS) that finds large average submatrices within a given real-valued data matrix. The procedure operates in an iterative-residual fashion, and is driven by a Bonferroni-based significance score that effectively trades off between submatrix size and average value. We examine the performance and potential utility of LAS, and compare it with a number of existing methods, through an extensive three-part validation study using two gene expression datasets. The validation study examines quantitative properties of biclusters, biological and clinical assessments using auxiliary information, and classification of disease subtypes using bicluster membership. In addition, we carry out a simulation study to assess the effectiveness and noise sensitivity of the LAS search procedure. These results suggest that LAS is an effective exploratory tool for the discovery of biologically relevant structures in high dimensional data. Software is available at this https URL", "corpus_id": 16771648, "score": 0 }, { "doc_id": "15590424", "title": "A random-periods model for expression of cell-cycle genes.", "abstract": "We propose a nonlinear regression model for quantitatively analyzing periodic gene expression in studies of experimentally synchronized cells. Our model accounts for the observed attenuation in cycle amplitude by a simple and biologically plausible mechanism. We represent the expression level for each gene as an average across a large number of cells. For a given cell-cycle gene, we model its expression in each cell in the culture as following the same sinusoidal function except that the period, which in any individual cell must be the same for all cell-cycle genes, varies randomly across cells. We model these random periods by using a lognormal distribution. The variability in period causes the measured amplitude of the cyclic expression trajectory to attenuate over time as cells fall increasingly out of synchrony. Gene-specific parameters include initial amplitude and phase angle. Applying the model to data from Whitfield et al. [Whitfield, M. L., Sherlock, G., Saldanha, A. J., Murray, J, I., Ball, C. A., et al. (2002) Mol. Biol. Cell 13, 1977-2000], we fit the trajectories of 18 well characterized phase-marker genes and find that the fit does not suffer when a common lognormal distribution is assumed for all 18 genes compared with a separate distribution for each. We then use the model to identify 337 periodically expressed transcripts, including the 18 phase-marker genes. The model permits estimation of and hypothesis testing about biologically meaningful parameters that characterize cycling genes.", "corpus_id": 15590424, "score": 0 }, { "doc_id": "377350", "title": "Principal component analysis for clustering gene expression data", "abstract": "MOTIVATION\nThere is a great need to develop analytical methodology to analyze and to exploit the information contained in gene expression data. Because of the large number of genes and the complexity of biological networks, clustering is a useful exploratory technique for analysis of gene expression data. Other classical techniques, such as principal component analysis (PCA), have also been applied to analyze gene expression data. Using different data analysis techniques and different clustering algorithms to analyze the same data set can lead to very different conclusions. Our goal is to study the effectiveness of principal components (PCs) in capturing cluster structure. Specifically, using both real and synthetic gene expression data sets, we compared the quality of clusters obtained from the original data to the quality of clusters obtained after projecting onto subsets of the principal component axes.\n\n\nRESULTS\nOur empirical study showed that clustering with the PCs instead of the original variables does not necessarily improve, and often degrades, cluster quality. In particular, the first few PCs (which contain most of the variation in the data) do not necessarily capture most of the cluster structure. We also showed that clustering with PCs has different impact on different algorithms and different similarity metrics. Overall, we would not recommend PCA before clustering except in special circumstances.", "corpus_id": 377350, "score": 0 }, { "doc_id": "29173982", "title": "Gene expression microarray data analysis demystified.", "abstract": "The increasing use of gene expression microarrays, and depositing of the resulting data into public repositories, means that more investigators are interested in using the technology either directly or through meta analysis of the publicly available data. The tools available for data analysis have generally been developed for use by experts in the field, making them difficult to use by the general research community. For those interested in entering the field, especially those without a background in statistics, it is difficult to understand why experimental results can be so variable. The purpose of this review is to go through the workflow of a typical microarray experiment, to show that decisions made at each step, from choice of platform through statistical analysis methods to biological interpretation, are all sources of this variability.", "corpus_id": 29173982, "score": 0 }, { "doc_id": "4643842", "title": "A Survey of Clustering Ensemble Algorithms", "abstract": "Cluster ensemble has proved to be a good alternative when facing cluster analysis problems. It consists of generating a set of clusterings from the same dataset and combining them into a final clustering. The goal of this combination process is to improve the quality of individual data clusterings. Due to the increasing appearance of new methods, their promising results and the great number of applications, we consider that it is necessary to make a critical analysis of the existing techniques and future projections. This paper presents an overview of clustering ensemble methods that can be very useful for the community of clustering practitioners. The characteristics of several methods are discussed, which may help in the selection of the most appropriate one to solve a problem at hand. We also present a taxonomy of these techniques and illustrate some important applications.", "corpus_id": 4643842, "score": 0 }, { "doc_id": "5704362", "title": "Spectral biclustering of microarray data: coclustering genes and conditions.", "abstract": "Global analyses of RNA expression levels are useful for classifying genes and overall phenotypes. Often these classification problems are linked, and one wants to find \"marker genes\" that are differentially expressed in particular sets of \"conditions.\" We have developed a method that simultaneously clusters genes and conditions, finding distinctive \"checkerboard\" patterns in matrices of gene expression data, if they exist. In a cancer context, these checkerboards correspond to genes that are markedly up- or downregulated in patients with particular types of tumors. Our method, spectral biclustering, is based on the observation that checkerboard structures in matrices of expression data can be found in eigenvectors corresponding to characteristic expression patterns across genes or conditions. In addition, these eigenvectors can be readily identified by commonly used linear algebra approaches, in particular the singular value decomposition (SVD), coupled with closely integrated normalization steps. We present a number of variants of the approach, depending on whether the normalization over genes and conditions is done independently or in a coupled fashion. We then apply spectral biclustering to a selection of publicly available cancer expression data sets, and examine the degree to which the approach is able to identify checkerboard structures. Furthermore, we compare the performance of our biclustering methods against a number of reasonable benchmarks (e.g., direct application of SVD or normalized cuts to raw data).", "corpus_id": 5704362, "score": 0 }, { "doc_id": "3193955", "title": "An Improved Biclustering Method for Analyzing Gene Expression Profiles", "abstract": "Microarrays are one of the latest breakthroughs in experimental molecular biology, which provide a powerful tool by which the expression patterns of thousands of genes can be monitored simultaneously and are already producing huge amount of valuable data. The concept of bicluster was introduced by Cheng and Church1 to capture the coherence of a subset of genes and a subset of conditions. A set of heuristic algorithms were also designed to either find one bicluster or a set of biclusters, which consist of iterations of masking null values and discovered biclusters, coarse and fine node deletion, node addition, and the inclusion of inverted data. These heuristics inevitably suffer from some serious drawback. The masking of null values and discovered biclusters with random numbers may result in the phenomenon of random interference which in turn impacts the discovery of high quality biclusters. To address this issue and to further accelerate the biclustering process, we generalize the model of bicluster to incorporate null values and propose a probabilistic algorithm (FLOC) that can discover a set of k possibly overlapping biclusters simultaneously. Furthermore, this algorithm can easily be extended to support additional features that suit different requirements at virtually little cost. Experimental study on the yeast gene expression data2 shows that the FLOC algorithm can offer substantial improvements over the previously proposed algorithm.", "corpus_id": 3193955, "score": 0 }, { "doc_id": "10011119", "title": "Extracting Conserved Gene Expression Motifs from Gene Expression Data", "abstract": "We propose a representation for gene expression data called conserved gene expression motifs or XMOTIFs. A gene's expression level is conserved across a set of samples if the gene is expressed with the same abundance in all the samples. A conserved gene expression motif is a subset of genes that is simultaneously conserved across a subset of samples. We present a computational technique to discover large conserved gene motifs that cover all the samples and classes in the data. When applied to published data sets representing different cancers or disease outcomes, our algorithm constructs XMOTIFS that distinguish between the various classes.", "corpus_id": 10011119, "score": 0 }, { "doc_id": "11847258", "title": "Co-clustering documents and words using bipartite spectral graph partitioning", "abstract": "Both document clustering and word clustering are well studied problems. Most existing algorithms cluster documents and words separately but not simultaneously. In this paper we present the novel idea of modeling the document collection as a bipartite graph between documents and words, using which the simultaneous clustering problem can be posed as a bipartite graph partitioning problem. To solve the partitioning problem, we use a new spectral co-clustering algorithm that uses the second left and right singular vectors of an appropriately scaled word-document matrix to yield good bipartitionings. The spectral algorithm enjoys some optimality properties; it can be shown that the singular vectors solve a real relaxation to the NP-complete graph bipartitioning problem. We present experimental results to verify that the resulting co-clustering algorithm works well in practice.", "corpus_id": 11847258, "score": 0 }, { "doc_id": "5839507", "title": "Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization.", "abstract": "We sought to create a comprehensive catalog of yeast genes whose transcript levels vary periodically within the cell cycle. To this end, we used DNA microarrays and samples from yeast cultures synchronized by three independent methods: alpha factor arrest, elutriation, and arrest of a cdc15 temperature-sensitive mutant. Using periodicity and correlation algorithms, we identified 800 genes that meet an objective minimum criterion for cell cycle regulation. In separate experiments, designed to examine the effects of inducing either the G1 cyclin Cln3p or the B-type cyclin Clb2p, we found that the mRNA levels of more than half of these 800 genes respond to one or both of these cyclins. Furthermore, we analyzed our set of cell cycle-regulated genes for known and new promoter elements and show that several known elements (or variations thereof) contain information predictive of cell cycle regulation. A full description and complete data sets are available at http://cellcycle-www.stanford.edu", "corpus_id": 5839507, "score": 0 }, { "doc_id": "24107017", "title": "A genome-wide transcriptional analysis of the mitotic cell cycle.", "abstract": "Progression through the eukaryotic cell cycle is known to be both regulated and accompanied by periodic fluctuation in the expression levels of numerous genes. We report here the genome-wide characterization of mRNA transcript levels during the cell cycle of the budding yeast S. cerevisiae. Cell cycle-dependent periodicity was found for 416 of the 6220 monitored transcripts. More than 25% of the 416 genes were found directly adjacent to other genes in the genome that displayed induction in the same cell cycle phase, suggesting a mechanism for local chromosomal organization in global mRNA regulation. More than 60% of the characterized genes that displayed mRNA fluctuation have already been implicated in cell cycle period-specific biological roles. Because more than 20% of human proteins display significant homology to yeast proteins, these results also link a range of human genes to cell cycle period-specific biological functions.", "corpus_id": 24107017, "score": 0 }, { "doc_id": "2958291", "title": "The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle.", "abstract": "Transcription patterns shift dramatically as cells transit from one phase of the cell cycle to another. To better define this transcriptional circuitry, we collected new microarray data across the cell cycle of budding yeast. The combined analysis of these data with three other cell cycle data sets identifies hundreds of new highly periodic transcripts and provides a weighted average peak time for each transcript. Using these data and phylogenetic comparisons of promoter sequences, we have identified a late S-phase-specific promoter element. This element is the binding site for the forkhead protein Hcm1, which is required for its cell cycle-specific activity. Among the cell cycle-regulated genes that contain conserved Hcm1-binding sites, there is a significant enrichment of genes involved in chromosome segregation, spindle dynamics, and budding. This may explain why Hcm1 mutants show 10-fold elevated rates of chromosome loss and require the spindle checkpoint for viability. Hcm1 also induces the M-phase-specific transcription factors FKH1, FKH2, and NDD1, and two cell cycle-specific transcriptional repressors, WHI5 and YHP1. As such, Hcm1 fills a significant gap in our understanding of the transcriptional circuitry that underlies the cell cycle.", "corpus_id": 2958291, "score": 0 }, { "doc_id": "205213307", "title": "Global control of cell-cycle transcription by coupled CDK and network oscillators", "abstract": "A significant fraction of the Saccharomyces cerevisiae genome is transcribed periodically during the cell division cycle, indicating that properly timed gene expression is important for regulating cell-cycle events. Genomic analyses of the localization and expression dynamics of transcription factors suggest that a network of sequentially expressed transcription factors could control the temporal programme of transcription during the cell cycle. However, directed studies interrogating small numbers of genes indicate that their periodic transcription is governed by the activity of cyclin-dependent kinases (CDKs). To determine the extent to which the global cell-cycle transcription programme is controlled by cyclin–CDK complexes, we examined genome-wide transcription dynamics in budding yeast mutant cells that do not express S-phase and mitotic cyclins. Here we show that a significant fraction of periodic genes are aberrantly expressed in the cyclin mutant. Although cells lacking cyclins are blocked at the G1/S border, nearly 70% of periodic genes continued to be expressed periodically and on schedule. Our findings reveal that although CDKs have a function in the regulation of cell-cycle transcription, they are not solely responsible for establishing the global periodic transcription programme. We propose that periodic transcription is an emergent property of a transcription factor network that can function as a cell-cycle oscillator independently of, and in tandem with, the CDK oscillator.", "corpus_id": 205213307, "score": 0 }, { "doc_id": "680949", "title": "The transcriptional program of sporulation in budding yeast.", "abstract": "Diploid cells of budding yeast produce haploid cells through the developmental program of sporulation, which consists of meiosis and spore morphogenesis. DNA microarrays containing nearly every yeast gene were used to assay changes in gene expression during sporulation. At least seven distinct temporal patterns of induction were observed. The transcription factor Ndt80 appeared to be important for induction of a large group of genes at the end of meiotic prophase. Consensus sequences known or proposed to be responsible for temporal regulation could be identified solely from analysis of sequences of coordinately expressed genes. The temporal expression pattern provided clues to potential functions of hundreds of previously uncharacterized genes, some of which have vertebrate homologs that may function during gametogenesis.", "corpus_id": 680949, "score": 0 }, { "doc_id": "17686011", "title": "Genomic expression responses to DNA-damaging agents and the regulatory role of the yeast ATR homolog Mec1p.", "abstract": "Eukaryotic cells respond to DNA damage by arresting the cell cycle and modulating gene expression to ensure efficient DNA repair. The human ATR kinase and its homolog in yeast, MEC1, play central roles in transducing the damage signal. To characterize the role of the Mec1 pathway in modulating the cellular response to DNA damage, we used DNA microarrays to observe genomic expression in Saccharomyces cerevisiae responding to two different DNA-damaging agents. We compared the genome-wide expression patterns of wild-type cells and mutants defective in Mec1 signaling, including mec1, dun1, and crt1 mutants, under normal growth conditions and in response to the methylating-agent methylmethane sulfonate (MMS) and ionizing radiation. Here, we present a comparative analysis of wild-type and mutant cells responding to these DNA-damaging agents, and identify specific features of the gene expression responses that are dependent on the Mec1 pathway. Among the hundreds of genes whose expression was affected by Mec1p, one set of genes appears to represent an MEC1-dependent expression signature of DNA damage. Other aspects of the genomic responses were independent of Mec1p, and likely independent of DNA damage, suggesting the pleiotropic effects of MMS and ionizing radiation. The complete data set as well as supplemental materials is available at http://www-genome.stanford.edu/mec1.", "corpus_id": 17686011, "score": 0 }, { "doc_id": "2596007", "title": "How yeast re-programmes its transcriptional profile in response to different nutrient impulses", "abstract": "BackgroundA microorganism is able to adapt to changes in its physicochemical or nutritional environment and this is crucial for its survival. The yeast, Saccharomyces cerevisiae, has developed mechanisms to respond to such environmental changes in a rapid and effective manner; such responses may demand a widespread re-programming of gene activity. The dynamics of the re-organization of the cellular activities of S. cerevisiae in response to the sudden and transient removal of either carbon or nitrogen limitation has been studied by following both the short- and long-term changes in yeast's transcriptomic profiles.ResultsThe study, which spans timescales from seconds to hours, has revealed the hierarchy of metabolic and genetic regulatory switches that allow yeast to adapt to, and recover from, a pulse of a previously limiting nutrient. At the transcriptome level, a glucose impulse evoked significant changes in the expression of genes concerned with glycolysis, carboxylic acid metabolism, oxidative phosphorylation, and nucleic acid and sulphur metabolism. In ammonium-limited cultures, an ammonium impulse resulted in the significant changes in the expression of genes involved in nitrogen metabolism and ion transport. Although both perturbations evoked significant changes in the expression of genes involved in the machinery and process of protein synthesis, the transcriptomic response was delayed and less complex in the case of an ammonium impulse. Analysis of the regulatory events by two different system-level, network-based approaches provided further information about dynamic organization of yeast cells as a response to a nutritional change.ConclusionsThe study provided important information on the temporal organization of transcriptomic organization and underlying regulatory events as a response to both carbon and nitrogen impulse. It has also revealed the importance of a long-term dynamic analysis of the response to the relaxation of a nutritional limitation to understand the molecular basis of the cells' dynamic behaviour.", "corpus_id": 2596007, "score": 0 }, { "doc_id": "41766468", "title": "Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes.", "abstract": "Translation regulation is a critical means by which cells control growth, division, and apoptosis. To gain further insight into translation and related processes, we performed multifaceted mass spectrometry-based proteomic screens of yeast ribosomal complexes and discovered an association of 77 uncharacterized yeast proteins with ribosomes. Immunoblotting revealed an EDTA-dependent cosedimentation with ribosomes in sucrose gradients for 11 candidate translation-machinery-associated (TMA) proteins. Tandem affinity purification linked one candidate, LSM12, to the RNA processing proteins PBP1 and PBP4. A second candidate, TMA46, interacted with RBG1, a GTPase that interacts with ribosomes. By adapting translation assays to high-throughput screening methods, we showed that null yeast strains harboring deletions for several of the TMA genes had alterations in protein synthesis rates (TMA7 and TMA19), susceptibility to drugs that inhibit translation (TMA7), translation fidelity (TMA20), and polyribosome profiles (TMA7, TMA19, and TMA20). TMA20 has significant sequence homology with the oncogene MCT-1. Expression of human MCT-1 in the Deltatma20 yeast mutant complemented translation-related defects, strongly implying that MCT-1 functions in translation-related processes. Together these findings implicate the TMA proteins and, potentially, their human homologs, in translation related processes.", "corpus_id": 41766468, "score": 0 }, { "doc_id": "2047843", "title": "Identification of a novel methyltransferase, Bmt2, responsible for the N-1-methyl-adenosine base modification of 25S rRNA in Saccharomyces cerevisiae", "abstract": "The 25S rRNA of yeast contains several base modifications in the functionally important regions. The enzymes responsible for most of these base modifications remained unknown. Recently, we identified Rrp8 as a methyltransferase involved in m1A645 modification of 25S rRNA. Here, we discovered a previously uncharacterized gene YBR141C to be responsible for second m1A2142 modification of helix 65 of 25S rRNA. The gene was identified by reversed phase–HPLC screening of all deletion mutants of putative RNA methyltransferase and was confirmed by gene complementation and phenotypic characterization. Because of the function of its encoded protein, YBR141C was named BMT2 (base methyltransferase of 25S RNA). Helix 65 belongs to domain IV, which accounts for most of the intersubunit surface of the large subunit. The 3D structure prediction of Bmt2 supported it to be an Ado Met methyltransferase belonging to Rossmann fold superfamily. In addition, we demonstrated that the substitution of G180R in the S-adenosyl-l-methionine–binding motif drastically reduces the catalytic function of the protein in vivo. Furthermore, we analysed the significance of m1A2142 modification in ribosome synthesis and translation. Intriguingly, the loss of m1A2142 modification confers anisomycin and peroxide sensitivity to the cells. Our results underline the importance of RNA modifications in cellular physiology.", "corpus_id": 2047843, "score": 0 }, { "doc_id": "11725765", "title": "90S pre-ribosomes include the 35S pre-rRNA, the U3 snoRNP, and 40S subunit processing factors but predominantly lack 60S synthesis factors.", "abstract": "We report the characterization of early pre-ribosomal particles. Twelve TAP-tagged components each showed nucleolar localization, sedimented at approximately 90S on sucrose gradients, and coprecipitated both the 35S pre-rRNA and the U3 snoRNA. Thirty-five non-ribosomal proteins were coprecipitated, including proteins associated with U3 (Nop56p, Nop58p, Sof1p, Rrp9, Dhr1p, Imp3p, Imp4p, and Mpp10p) and other factors required for 18S rRNA synthesis (Nop14p, Bms1p, and Krr1p). Mutations in components of the 90S pre-ribosomes impaired 40S subunit assembly and export. Strikingly, few components of recently characterized pre-60S ribosomes were identified in the 90S pre-ribosomes. We conclude that the 40S synthesis machinery predominately associates with the 35S pre-rRNA factors, whereas factors required for 60S subunit synthesis largely bind later, showing an unexpected dichotomy in binding.", "corpus_id": 11725765, "score": 0 }, { "doc_id": "4421200", "title": "Transcriptional regulatory code of a eukaryotic genome", "abstract": "DNA-binding transcriptional regulators interpret the genome's regulatory code by binding to specific sequences to induce or repress gene expression. Comparative genomics has recently been used to identify potential cis-regulatory sequences within the yeast genome on the basis of phylogenetic conservation, but this information alone does not reveal if or when transcriptional regulators occupy these binding sites. We have constructed an initial map of yeast's transcriptional regulatory code by identifying the sequence elements that are bound by regulators under various conditions and that are conserved among Saccharomyces species. The organization of regulatory elements in promoters and the environment-dependent use of these elements by regulators are discussed. We find that environment-specific use of regulatory elements predicts mechanistic models for the function of a large population of yeast's transcriptional regulators.", "corpus_id": 4421200, "score": 0 }, { "doc_id": "14228237", "title": "Sch9 regulates ribosome biogenesis via Stb3, Dot6 and Tod6 and the histone deacetylase complex RPD3L", "abstract": "TORC1 is a conserved multisubunit kinase complex that regulates many aspects of eukaryotic growth including the biosynthesis of ribosomes. The TOR protein kinase resident in TORC1 is responsive to environmental cues and is potently inhibited by the natural product rapamycin. Recent characterization of the rapamycin‐sensitive phosphoproteome in yeast has yielded insights into how TORC1 regulates growth. Here, we show that Sch9, an AGC family kinase and direct substrate of TORC1, promotes ribosome biogenesis (Ribi) and ribosomal protein (RP) gene expression via direct inhibitory phosphorylation of the transcriptional repressors Stb3, Dot6 and Tod6. Deletion of STB3, DOT6 and TOD6 partially bypasses the growth and cell size defects of an sch9 strain and reveals interdependent regulation of both Ribi and RP gene expression, and other aspects of Ribi. Dephosphorylation of Stb3, Dot6 and Tod6 enables recruitment of the RPD3L histone deacetylase complex to repress Ribi/RP gene promoters. Taken together with previous studies, these results suggest that Sch9 is a master regulator of ribosome biogenesis through the control of Ribi, RP, ribosomal RNA and tRNA gene transcription.", "corpus_id": 14228237, "score": 0 }, { "doc_id": "13787960", "title": "Cell-cycle control of gene expression in budding and fission yeast.", "abstract": "Cell-cycle control of transcription seems to be a universal feature of proliferating cells, although relatively little is known about its biological significance and conservation between organisms. The two distantly related yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe have provided valuable complementary insight into the regulation of periodic transcription as a function of the cell cycle. More recently, genome-wide studies of proliferating cells have identified hundreds of periodically expressed genes and underlying mechanisms of transcriptional control. This review discusses the regulation of three major transcriptional waves, which roughly coincide with three main cell-cycle transitions (initiation of DNA replication, entry into mitosis, and exit from mitosis). I also compare and contrast the transcriptional regulatory networks between the two yeasts and discuss the evolutionary conservation and possible roles for cell cycle-regulated transcription.", "corpus_id": 13787960, "score": 0 } ]

{ "doc_id": "59358151", "title": "Ju n 20 15 Mechanical properties of branched actin filaments", "abstract": "Cells moving on a 2dimensional substrate generate motion by polymerizing actin filament networks inside a flat membrane protrusion. New filaments are generated by branching off existing ones, giving rise to branched network structures. We investigate the force-extension relation of branched filaments, grafted on an elastic structure at one end and pushing with the free ends against the leading edge cell membrane. Single filaments are modeled as worm-like chains, whose thermal bending fluctuations are restricted by the leading edge cell membrane, resulting in an effective force. Branching can increase the stiffness considerably; however the effect depends on branch point position and filament orientation, being most pronounced for intermediate tilt angles and intermediate branch point positions. We describe filament networks without cross-linkers to focus on the effect of branching. We use randomly positioned branch points, as generated in the process of treadmilling, and orientation distributions as measured in lamellipodia. These networks reproduce both the weak and strong force response of lamellipodia as measured in force-velocity experiments. We compare properties of branched and unbranched networks. The ratio of the network average of the force per branched filament to the average force per unbranched filament depends on the orientation distribution of the filaments. The ratio exhibits compression dependence and may go up to about 4.5 in networks with a narrow orientation distribution. With orientation distributions measured in lamellipodia, it is about 2 and essentially independent from network compression, graft elasticity and filament persistence length. PACS numbers: 00.00, 20.00, 42.10", "corpus_id": 59358151 }

[ { "doc_id": "45496707", "title": "Cell migration in tumors.", "abstract": "Invasion of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. This requires chemotactic migration of cancer cells, steered by protrusive activity of the cell membrane and its attachment to the extracellular matrix. Recent advances in intravital imaging and the development of an in vivo invasion assay have provided new insights into how cancer cell migration is regulated by elements of the local microenvironment, including the extracellular matrix architecture and other cell types found in primary tumors. These results, combined with new findings from in vitro studies, have led to new insights into the molecular mechanisms of cell protrusive activity and chemotactic migration during invasion and metastasis.", "corpus_id": 45496707, "score": 0 }, { "doc_id": "11315500", "title": "Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis", "abstract": "Macrophages within the tumor microenvironment facilitate angiogenesis and extracellular-matrix breakdown and remodeling and promote tumor cell motility. Recent studies reveal that direct communication between macrophages and tumor cells leads to invasion and egress of tumor cells into the blood vessels (intravasation). Thus, macrophages are at the center of the invasion microenvironment and are an important drug target for cancer therapy.", "corpus_id": 11315500, "score": 0 }, { "doc_id": "2708171", "title": "Analysis of the Actin–Myosin II System in Fish Epidermal Keratocytes: Mechanism of Cell Body Translocation", "abstract": "While the protrusive event of cell locomotion is thought to be driven by actin polymerization, the mechanism of forward translocation of the cell body is unclear. To elucidate the mechanism of cell body translocation, we analyzed the supramolecular organization of the actin–myosin II system and the dynamics of myosin II in fish epidermal keratocytes. In lamellipodia, long actin filaments formed dense networks with numerous free ends in a brushlike manner near the leading edge. Shorter actin filaments often formed T junctions with longer filaments in the brushlike area, suggesting that new filaments could be nucleated at sides of preexisting filaments or linked to them immediately after nucleation. The polarity of actin filaments was almost uniform, with barbed ends forward throughout most of the lamellipodia but mixed in arc-shaped filament bundles at the lamellipodial/cell body boundary. Myosin II formed discrete clusters of bipolar minifilaments in lamellipodia that increased in size and density towards the cell body boundary and colocalized with actin in boundary bundles. Time-lapse observation demonstrated that myosin clusters appeared in the lamellipodia and remained stationary with respect to the substratum in locomoting cells, but they exhibited retrograde flow in cells tethered in epithelioid colonies. Consequently, both in locomoting and stationary cells, myosin clusters approached the cell body boundary, where they became compressed and aligned, resulting in the formation of boundary bundles. In locomoting cells, the compression was associated with forward displacement of myosin features. These data are not consistent with either sarcomeric or polarized transport mechanisms of cell body translocation. We propose that the forward translocation of the cell body and retrograde flow in the lamellipodia are both driven by contraction of an actin–myosin network in the lamellipodial/cell body transition zone.", "corpus_id": 2708171, "score": 0 }, { "doc_id": "4429016", "title": "The cytoskeleton, cellular motility and the reductionist agenda", "abstract": "Eukaryotic cells depend on cytoskeletal polymers and molecular motors to establish their asymmetrical shapes, to transport intracellular constituents and to drive their motility. Cell biologists are using diverse experimental approaches to understand the molecular basis of cellular movements and to explain why defects in the component proteins cause disease. Much of the molecular machinery for motility evolved in early eukaryotes, so a limited set of general principles can explain the motility of most cells.", "corpus_id": 4429016, "score": 0 }, { "doc_id": "11890493", "title": "Dynamic Cross-linking by α-Actinin Determines the Mechanical Properties of Actin Filament Networks*", "abstract": "We used smooth muscle α-actinin to evaluate the contribution of cross-linker dynamics to the mechanical properties of actin filament networks. Recombinant actin-binding domain (residues 2–269) binds actin filaments with a K d of 1 μm at 25 °C, 20 times stronger than actin-binding domain produced by thermolysin digestion of native α-actinin (residues 25–257). Between 8 and 25 °C the rate constants for recombinant actin-binding domain to bind to (0.8–2.7 μm −1 s−1) and dissociate from (0.2–2.4 s−1) actin filaments depend on temperature. At 8 °C actin filaments cross-linked with α-actinin are stiff and nearly solid, whereas at 25 °C the mechanical properties approach those of actin filaments alone. In these experiments, high actin concentrations kept most of the α-actinin bound to actin and temperature varied a single parameter, cross-linker dynamics, because the mechanical properties of pure actin filaments (a viscoelastic gel) or biotinylated actin filaments cross-linked irreversibly by avidin (a stiff viscoelastic solid) depend little on temperature. These results show that the rate of exchange of dynamic cross-links between actin filaments is an important determinant of the mechanical properties of the networks.", "corpus_id": 11890493, "score": 0 }, { "doc_id": "14574318", "title": "Force generation by actin polymerization II: the elastic ratchet and tethered filaments.", "abstract": "The motion of many intracellular pathogens is driven by the polymerization of actin filaments. The propulsive force developed by the polymerization process is thought to arise from the thermal motions of the polymerizing filament tips. Recent experiments suggest that the nucleation of actin filaments involves a phase when the filaments are attached to the pathogen surface by a protein complex. Here we extend the \"elastic ratchet model\" of Mogilner and Oster to incorporate these new findings. We apply this \"tethered ratchet\" model to derive the force-velocity relation for Listeria and discuss relations of our theoretical predictions to experimental measurements. We also discuss \"symmetry breaking\" dynamics observed in ActA-coated bead experiments, and the implications of the model for lamellipodial protrusion in migrating cells.", "corpus_id": 14574318, "score": 0 }, { "doc_id": "1135416", "title": "Elastic Behavior of Cross-Linked and Bundled Actin Networks", "abstract": "Networks of cross-linked and bundled actin filaments are ubiquitous in the cellular cytoskeleton, but their elasticity remains poorly understood. We show that these networks exhibit exceptional elastic behavior that reflects the mechanical properties of individual filaments. There are two distinct regimes of elasticity, one reflectingbendingof single filaments and a second reflectingstretchingof entropic fluctuations of filament length. The mechanical stiffness can vary by several decades with small changes in cross-link concentration, and can increase markedly upon application of external stress. We parameterize the full range of behavior in a state diagram and elucidate its origin with a robust model.", "corpus_id": 1135416, "score": 0 }, { "doc_id": "5970246", "title": "Weak force stalls protrusion at the leading edge of the lamellipodium.", "abstract": "Protrusion, the first step of cell migration, is driven by actin polymerization coupled to adhesion at the cell's leading edge. Polymerization and adhesive forces have been estimated, but the net protrusion force has not been measured accurately. We arrest the leading edge of a moving fish keratocyte with a hydrodynamic load generated by a fluid flow from a micropipette. The flow arrests protrusion locally as the cell approaches the pipette, causing an arc-shaped indentation and upward folding of the leading edge. The effect of the flow is reversible upon pipette removal and dependent on the flow direction, suggesting that it is a direct effect of the external force rather than a regulated cellular response. Modeling of the fluid flow gives a surprisingly low value for the arresting force of just a few piconewtons per micrometer. Enhanced phase contrast, fluorescence, and interference reflection microscopy suggest that the flow does not abolish actin polymerization and does not disrupt the adhesions formed before the arrest but rather interferes with weak nascent adhesions at the very front of the cell. We conclude that a weak external force is sufficient to reorient the growing actin network at the leading edge and to stall the protrusion.", "corpus_id": 5970246, "score": 0 }, { "doc_id": "1352477", "title": "Direct measurement of the lamellipodial protrusive force in a migrating cell", "abstract": "There has been a great deal of interest in the mechanism of lamellipodial protrusion (Pollard, T., and G. Borisy. 2003. Cell. 112:453–465). However, one of this mechanism's endpoints, the force of protrusion, has never been directly measured. We place an atomic force microscopy cantilever in the path of a migrating keratocyte. The deflection of the cantilever, which occurs over a period of ∼10 s, provides a direct measure of the force exerted by the lamellipodial leading edge. Stall forces are consistent with ∼100 polymerizing actin filaments per micrometer of the leading edge, each working as an elastic Brownian ratchet and generating a force of several piconewtons. However, the force-velocity curves obtained from this measurement, in which velocity drops sharply under very small loads, is not sensitive to low loading forces, and finally stalls rapidly at large loads, are not consistent with current theoretical models for the actin polymerization force. Rather, the curves indicate that the protrusive force generation is a complex multiphase process involving actin and adhesion dynamics.", "corpus_id": 1352477, "score": 1 }, { "doc_id": "356682", "title": "Keratocyte lamellipodial protrusion is characterized by a concave force-velocity relation.", "abstract": "We report on the characterization of actin driven lamellipodial protrusion forces and velocities in keratocytes. A vertically mounted glass fiber acted as a flexible barrier positioned in front of migrating keratocytes with parallel phase contrast microscopy. A laser beam was coupled into the fiber and allowed detecting the position of the fiber by a segmented photodiode. Calibration of the fiber was carried out with the thermal oscillation method. Deflection and force signals were measured during lamellipodial protrusion. Velocity was constant during initial contact whereas loading force increased until finally the cell was stalled at higher forces. Stall forces were on the order of 2.9 ± 0.6 nN, which corresponds to a stall pressure of 2.7 ± 1.6 nN/μm(2). Assuming a density of actin filaments of 240 filaments per μm, we can estimate a stall force per actin filament of 1.7 ± 0.8 pN. To check for adaption of the cell against an external force, we let the cell push toward the glass fiber several times. On the timescale of the experiment (∼1 min), however, the cell did not adapt to previous loading events.", "corpus_id": 356682, "score": 1 }, { "doc_id": "35540610", "title": "Actin filament elasticity and retrograde flow shape the force-velocity relation of motile cells.", "abstract": "Cells migrate through a crowded environment during processes such as metastasis or wound healing, and must generate and withstand substantial forces. The cellular motility responses to environmental forces are represented by their force-velocity relation, which has been measured for fish keratocytes but remains unexplained. Even pN opposing forces slow down lamellipodium motion by three orders of magnitude. At larger opposing forces, the retrograde flow of the actin network accelerates until it compensates for polymerization, and cell motion stalls. Subsequently, the lamellipodium adapts to the stalled state. We present a mechanism quantitatively explaining the cell's force-velocity relation and its changes upon application of drugs that hinder actin polymerization or actomyosin-based contractility. Elastic properties of filaments, close to the lamellipodium leading edge, and retrograde flow shape the force-velocity relation. To our knowledge, our results shed new light on how these migratory responses are regulated, and on the mechanics and structure of the lamellipodium.", "corpus_id": 35540610, "score": 1 }, { "doc_id": "30881414", "title": "Comparison of Filamin A-induced Cross-linking and Arp2/3 Complex-mediated Branching on the Mechanics of Actin Filaments* 210", "abstract": "We compared the effects of human filamin A (FLNa) and the activated human Arp2/3 complex on mechanical properties of actin filaments. As little as 1 FLNa to 800 polymerizing actin monomers induces a sharp concentration-dependent increase in the apparent viscosity of 24 μm actin, a parameter classically defined as a gel point. The activated Arp2/3 complex, at concentrations up to 1:25 actins had no detectable actin gelation activity, even in the presence of phalloidin, to stabilize actin filaments against debranching. Increasing the activated Arp2/3 complex to actin ratio raises the FLNa concentration required to induce actin gelation, an effect ascribable to Arp2/3-mediated actin nucleation resulting in actin filament length diminution. Time lapse video microscopy of microparticles attached to actin filaments or photoactivation of fluorescence revealed actin filament immobilization by FLNa in contrast to diffusion of Arp2/3-branched actin filaments. The experimental results support theories predicting that polymer branching absent cross-linking does not lead to polymer gelation and are consistent with the observation that cells deficient in actin filament cross-linking activity have unstable surfaces. They suggest complementary roles for actin branching and cross-linking in cellular actin mechanics in vivo.", "corpus_id": 30881414, "score": 0 }, { "doc_id": "15410403", "title": "Arp2/3 Complex and Actin Depolymerizing Factor/Cofilin in Dendritic Organization and Treadmilling of Actin Filament Array in Lamellipodia", "abstract": "The leading edge (∼1 μm) of lamellipodia in Xenopus laevis keratocytes and fibroblasts was shown to have an extensively branched organization of actin filaments, which we term the dendritic brush. Pointed ends of individual filaments were located at Y-junctions, where the Arp2/3 complex was also localized, suggesting a role of the Arp2/3 complex in branch formation. Differential depolymerization experiments suggested that the Arp2/3 complex also provided protection of pointed ends from depolymerization. Actin depolymerizing factor (ADF)/cofilin was excluded from the distal 0.4 μm of the lamellipodial network of keratocytes and in fibroblasts it was located within the depolymerization-resistant zone. These results suggest that ADF/cofilin, per se, is not sufficient for actin brush depolymerization and a regulatory step is required. Our evidence supports a dendritic nucleation model (Mullins, R.D., J.A. Heuser, and T.D. Pollard. 1998. Proc. Natl. Acad. Sci. USA. 95:6181–6186) for lamellipodial protrusion, which involves treadmilling of a branched actin array instead of treadmilling of individual filaments. In this model, Arp2/3 complex and ADF/cofilin have antagonistic activities. Arp2/3 complex is responsible for integration of nascent actin filaments into the actin network at the cell front and stabilizing pointed ends from depolymerization, while ADF/cofilin promotes filament disassembly at the rear of the brush, presumably by pointed end depolymerization after dissociation of the Arp2/3 complex.", "corpus_id": 15410403, "score": 1 }, { "doc_id": "14541283", "title": "Self-polarization and directional motility of cytoplasm", "abstract": "BACKGROUND\nDirectional cell motility implies the presence of a steering mechanism and a functional asymmetry between the front and rear of the cell. How this functional asymmetry arises and is maintained during cell locomotion is, however, unclear. Lamellar fragments of fish epidermal keratocytes, which lack nuclei, microtubules and most organelles, present a simplified, perhaps minimal, system for analyzing this problem because they consist of little other than the motile machinery enclosed by a membrane and yet can move with remarkable speed and persistence.\n\n\nRESULTS\nWe have produced two types of cellular fragments: discoid stationary fragments and polarized fragments undergoing locomotion. The organization and dynamics of the actin-myosin II system were isotropic in stationary fragments and anisotropic in the moving fragments. To investigate whether the creation of asymmetry could result in locomotion, a transient mechanical stimulus was applied to stationary fragments. The stimulus induced localized contraction and the formation of an actin-myosin II bundle at one edge of the fragment. Remarkably, stimulated fragments started to undergo locomotion and the locomotion and associated anisotropic organization of the actin-myosin II system were sustained after withdrawal of the stimulus.\n\n\nCONCLUSIONS\nWe propose a model in which lamellar cytoplasm is considered a dynamically bistable system capable of existing in a non-polarized or polarized state and interconvertible by mechanical stimulus. The model explains how the anisotropic organization of the lamellum is maintained in the process of locomotion. Polarized locomotion is sustained through a positive-feedback loop intrinsic to the actin-myosin II machinery: anisotropic organization of the machinery drives translocation, which then reinforces the asymmetry of the machinery, favoring further translocation.", "corpus_id": 14541283, "score": 0 }, { "doc_id": "33572560", "title": "Tracking retrograde flow in keratocytes: news from the front.", "abstract": "Actin assembly at the leading edge of the cell is believed to drive protrusion, whereas membrane resistance and contractile forces result in retrograde flow of the assembled actin network away from the edge. Thus, cell motion and shape changes are expected to depend on the balance of actin assembly and retrograde flow. This idea, however, has been undermined by the reported absence of flow in one of the most spectacular models of cell locomotion, fish epidermal keratocytes. Here, we use enhanced phase contrast and fluorescent speckle microscopy and particle tracking to analyze the motion of the actin network in keratocyte lamellipodia. We have detected retrograde flow throughout the lamellipodium at velocities of 1-3 microm/min and analyzed its organization and relation to the cell motion during both unobstructed, persistent migration and events of cell collision. Freely moving cells exhibited a graded flow velocity increasing toward the sides of the lamellipodium. In colliding cells, the velocity decreased markedly at the site of collision, with striking alteration of flow in other lamellipodium regions. Our findings support the universality of the flow phenomenon and indicate that the maintenance of keratocyte shape during locomotion depends on the regulation of both retrograde flow and actin polymerization.", "corpus_id": 33572560, "score": 0 }, { "doc_id": "2624306", "title": "Mechanism of shape determination in motile cells", "abstract": "The shape of motile cells is determined by many dynamic processes spanning several orders of magnitude in space and time, from local polymerization of actin monomers at subsecond timescales to global, cell-scale geometry that may persist for hours. Understanding the mechanism of shape determination in cells has proved to be extremely challenging due to the numerous components involved and the complexity of their interactions. Here we harness the natural phenotypic variability in a large population of motile epithelial keratocytes from fish (Hypsophrys nicaraguensis) to reveal mechanisms of shape determination. We find that the cells inhabit a low-dimensional, highly correlated spectrum of possible functional states. We further show that a model of actin network treadmilling in an inextensible membrane bag can quantitatively recapitulate this spectrum and predict both cell shape and speed. Our model provides a simple biochemical and biophysical basis for the observed morphology and behaviour of motile cells.", "corpus_id": 2624306, "score": 0 }, { "doc_id": "32474588", "title": "Leading-edge-gel coupling in lamellipodium motion.", "abstract": "We present a model for actin-based motility that combines the dynamics of the semiflexible region at the leading edge of the lamellipodium with actomyosin gel properties in the bulk described by the theory of active polar gels. We calculate the velocity of the lamellipodium determined by the interaction of the gel and adhesion with forces in the semiflexible region. The stationary concave force-velocity relation of the model reproduces experimental results. We suggest that it is determined by retrograde flow at small forces and gel formation and retrograde flow at large ones. The variety of dynamic regimes of the semiflexible region reproducing experimentally observed morphodynamics is conserved when we couple the leading edge to the gel.", "corpus_id": 32474588, "score": 0 }, { "doc_id": "5692330", "title": "Actin-myosin viscoelastic flow in the keratocyte lamellipod.", "abstract": "The lamellipod, the locomotory region of migratory cells, is shaped by the balance of protrusion and contraction. The latter is the result of myosin-generated centripetal flow of the viscoelastic actin network. Recently, quantitative flow data was obtained, yet there is no detailed theory explaining the flow in a realistic geometry. We introduce models of viscoelastic actin mechanics and myosin transport and solve the model equations numerically for the flat, fan-shaped lamellipodial domain of keratocytes. The solutions demonstrate that in the rapidly crawling cell, myosin concentrates at the rear boundary and pulls the actin network inward, so the centripetal actin flow is very slow at the front, and faster at the rear and at the sides. The computed flow and respective traction forces compare well with the experimental data. We also calculate the graded protrusion at the cell boundary necessary to maintain the cell shape and make a number of other testable predictions. We discuss model implications for the cell shape, speed, and bi-stability.", "corpus_id": 5692330, "score": 0 }, { "doc_id": "36979045", "title": "Modeling of protrusion phenotypes driven by the actin-membrane interaction.", "abstract": "We propose a mathematical model for simulating the leading-edge dynamics of a migrating cell from the interplay among elastic properties, architecture of the actin cytoskeleton, and the mechanics of the membrane. Our approach is based on the description of the length and attachment dynamics of actin filaments in the lamellipodium network. It is used to determine the total force exerted on the membrane at each position along the leading edge and at each time step. The model reproduces the marked state switches in protrusion morphodynamics found experimentally between epithelial cells in control conditions and cells expressing constitutively active Rac, a signaling molecule involved in the regulation of lamellipodium network assembly. The model also suggests a mechanistic explanation of experimental distortions in protrusion morphodynamics induced by deregulation of Arp2/3 and cofilin activity.", "corpus_id": 36979045, "score": 0 }, { "doc_id": "5554986", "title": "An Adhesion-Dependent Switch between Mechanisms That Determine Motile Cell Shape", "abstract": "Keratocytes are fast-moving cells in which adhesion dynamics are tightly coupled to the actin polymerization motor that drives migration, resulting in highly coordinated cell movement. We have found that modifying the adhesive properties of the underlying substrate has a dramatic effect on keratocyte morphology. Cells crawling at intermediate adhesion strengths resembled stereotypical keratocytes, characterized by a broad, fan-shaped lamellipodium, clearly defined leading and trailing edges, and persistent rates of protrusion and retraction. Cells at low adhesion strength were small and round with highly variable protrusion and retraction rates, and cells at high adhesion strength were large and asymmetrical and, strikingly, exhibited traveling waves of protrusion. To elucidate the mechanisms by which adhesion strength determines cell behavior, we examined the organization of adhesions, myosin II, and the actin network in keratocytes migrating on substrates with different adhesion strengths. On the whole, our results are consistent with a quantitative physical model in which keratocyte shape and migratory behavior emerge from the self-organization of actin, adhesions, and myosin, and quantitative changes in either adhesion strength or myosin contraction can switch keratocytes among qualitatively distinct migration regimes.", "corpus_id": 5554986, "score": 0 }, { "doc_id": "23693014", "title": "Coupling actin flow, adhesion, and morphology in a computational cell motility model", "abstract": "Cell migration is a pervasive process in many biology systems and involves protrusive forces generated by actin polymerization, myosin dependent contractile forces, and force transmission between the cell and the substrate through adhesion sites. Here we develop a computational model for cell motion that uses the phase-field method to solve for the moving boundary with physical membrane properties. It includes a reaction-diffusion model for the actin-myosin machinery and discrete adhesion sites which can be in a “gripping” or “slipping” mode and integrates the adhesion dynamics with the dynamics of the actin filaments, modeled as a viscous network. To test this model, we apply it to fish keratocytes, fast moving cells that maintain their morphology, and show that we are able to reproduce recent experimental results on actin flow and stress patterns. Furthermore, we explore the phase diagram of cell motility by varying myosin II activity and adhesion strength. Our model suggests that the pattern of the actin flow inside the cell, the cell velocity, and the cell morphology are determined by the integration of actin polymerization, myosin contraction, adhesion forces, and membrane forces.", "corpus_id": 23693014, "score": 0 }, { "doc_id": "120859445", "title": "Polymerization, bending, tension: What happens at the leading edge of motile cells?", "abstract": "The forces experienced by filaments in actin based propulsion in reconstituted systems and cell motility, the mechanical properties of the lamellipodium of motile cells due to filament branching and cross-linking, the free filament contour length between branch points, the mechanisms of the force-velocity relation and velocity oscillations are all topics of ongoing debate. Here, we review results with a modelling concept considering the F-actin network as weakly cross-linked in a region with dynamic depth close to the propelled obstacle and gel-like further back. It offers quantitative explanations for steady motion and oscillation mechanisms in reconstituted systems and motile cells, and the force-velocity relation of fish keratocytes.", "corpus_id": 120859445, "score": 0 }, { "doc_id": "14297392", "title": "Entropic forces generated by grafted semiflexible polymers.", "abstract": "The entropic force exerted by the Brownian fluctuations of a grafted semiflexible polymer upon a rigid smooth wall are calculated both analytically and by Monte Carlo simulations. Such forces are thought to play an important role for several cellular phenomena, in particular, the physics of actin-polymerization-driven cell motility and movement of bacteria like Listeria. In the stiff limit, where the persistence length of the polymer is larger than its contour length, we find that the entropic force shows scaling behavior. We identify the characteristic length scales and the explicit form of the scaling functions. In certain asymptotic regimes, we give simple analytical expressions which describe the full results to a very high numerical accuracy. Depending on the constraints imposed on the transverse fluctuations of the filament, there are characteristic differences in the functional form of the entropic forces. In a two-dimensional geometry, the entropic force exhibits a marked peak.", "corpus_id": 14297392, "score": 0 }, { "doc_id": "8326264", "title": "Differentially oriented populations of actin filaments generated in lamellipodia collaborate in pushing and pausing at the cell front", "abstract": "Eukaryotic cells advance in phases of protrusion, pause and withdrawal. Protrusion occurs in lamellipodia, which are composed of diagonal networks of actin filaments, and withdrawal terminates with the formation of actin bundles parallel to the cell edge. Using correlated live-cell imaging and electron microscopy, we have shown that actin filaments in protruding lamellipodia subtend angles from 15–90° to the front, and that transitions from protrusion to pause are associated with a proportional increase in filaments oriented more parallel to the cell edge. Microspike bundles of actin filaments also showed a wide angular distribution and correspondingly variable bilateral polymerization rates along the cell front. We propose that the angular shift of filaments in lamellipodia serves in adapting to slower protrusion rates while maintaining the filament densities required for structural support; further, we suggest that single filaments and microspike bundles contribute to the construction of the lamella behind and to the formation of the cell edge when protrusion ceases. Our findings provide an explanation for the variable turnover dynamics of actin filaments in lamellipodia observed by fluorescence speckle microscopy and are inconsistent with a current model of lamellipodia structure that features actin filaments branching at 70° in a dendritic array.", "corpus_id": 8326264, "score": 1 }, { "doc_id": "15413444", "title": "Electron tomography reveals unbranched networks of actin filaments in lamellipodia", "abstract": "Eukaryotic cells can initiate movement using the forces exerted by polymerizing actin filaments to extend lamellipodial and filopodial protrusions. In the current model, actin filaments in lamellipodia are organized in a branched, dendritic network. We applied electron tomography to vitreously frozen 'live' cells, fixed cells and cytoskeletons, embedded in vitreous ice or in deep-negative stain. In lamellipodia from four cell types, including rapidly migrating fish keratocytes, we found that actin filaments are almost exclusively unbranched. The vast majority of apparent filament junctions proved to be overlapping filaments, rather than branched end-to-side junctions. Analysis of the tomograms revealed that actin filaments terminate at the membrane interface within a zone several hundred nanometres wide at the lamellipodium front, and yielded the first direct measurements of filament densities. Actin filament pairs were also identified as lamellipodium components and bundle precursors. These data provide a new structural basis for understanding actin-driven protrusion during cell migration.", "corpus_id": 15413444, "score": 0 }, { "doc_id": "26781304", "title": "Reply: Visualizing branched actin filaments in lamellipodia by electron tomography", "abstract": "colleagues have questioned the dendritic nucleation model in a recent paper1. In their study, they challenge key evidence supporting the dendritic nucleation model; namely, visualization of branched actin filaments in lamellipodia by platinum-replica electron microscopy4,5. Urban et al. argue1 that the branched configuration of the actin filaments in these samples are an artefact of critical-point drying, a part of the sample preparation. To prove their hypothesis that the actin filaments in lamellipodia are long and unbranched, they analysed the structure of lamellipodia by cryo-electron microscopy, and did not detect branched actin filaments in lamellipodia1. Because the data from platinum-replica electron microscopy that demonstrate branched actin filaments in lamellipodia have been reported primarily by our group, and because we have received multiple requests from the scientific community to comment on the results of Urban et al., we would like to share our opinion with a broader audience through this commentary. Several points, including comparison of potential artefacts produced by the two electron microscopy techniques and evaluation of evidence for and against the dendritic nucleation model, have already been addressed6,7. However, one critical point has not been discussed; namely, the fundamental consistency between our results and those of Urban et al. in spite of the different interpretations. We have carefully analysed the primary data provided as Supplementary Information by Urban et al. Based on this analysis, we argue that a subset of their results provides strong supporting evidence for the dendritic nucleation model by showing branched actin filaments in lamellipodia. We have found that Supplementary Movie S6, showing an electron tomogram of the lamellipodium in a 3T3 cell, is of particularly good quality to illustrate this point. Several examples of branched actin filaments from this movie are shown in Fig. 1a as a montage of z planes. In these examples, one of two actin filaments never re-emerges on the other side of the second filament in adjacent movie frames, despite the fact that both filaments are in the same z plane in at least one frame of the series. These features demonstrate that the end of the former filament makes a contact with the side of the latter filament, but does not cross it, which is the definition of a branch. In the zoomed region of the movie that shows a cell area of ~0.53 μm2, we have found a total of 147 branches (Fig. 1b), which is in contrast to the authors’ statement that “branches at the sides of actin filaments were extremely rare”. Branched actin filaments can be also found in other Supplementary movies, but fewer branches can be clearly detected in these movies owing to their insufficient quality and selection of regions corresponding to filopodia or filopodial precursors, which contain long unbranched filaments. Remarkably, all branches identified in our analysis invariably contained a blob at the branch point that probably corresponds to the Arp2/3 complex. Furthermore, the angle between branched filaments was 70 ± 7 degrees (n = 57), consistent with the conventional angle of ~70° produced by the Arp2/3 complex in vitro8. The actin filament branches found in data from the Urban et al. paper are virtually indistinguishable by appearance from those obtained by Hanein using cryo-electron microscopy of actin branches reconstituted in vitro from the Arp2/3 complex and actin, and could even be fitted into the three-dimensional branch model developed in these studies9. In conclusion, existence of branched actin filaments in lamellipodia is supported by two different electron microscopy techniques that probably counterbalance their potential artefacts. We are not sure why Urban et al. failed to detect branches, but this is definitely an issue of seeing or not seeing, rather than a problem with the techniques. Thus, in our opinion there should be no controversy regarding the structural organization of actin filaments in lamellipodia, and the dendritic nucleation model can serve as a conceptual framework for subsequent studies in the field.", "corpus_id": 26781304, "score": 0 }, { "doc_id": "13479541", "title": "Orientational order of the lamellipodial actin network as demonstrated in living motile cells.", "abstract": "Lamellipodia of crawling cells represent both the motor for cell advance and the primary building site for the actin cytoskeleton. The organization of actin in the lamellipodium reflects actin dynamics and is of critical importance for the mechanism of cell motility. In previous structural studies, the lamellipodial actin network was analyzed primarily by electron microscopy (EM). An understanding of lamellipodial organization would benefit significantly if the EM data were complemented and put into a kinetic context by establishing correspondence with structural features observable at the light microscopic level in living cells. Here, we use an enhanced phase contrast microscopy technique to visualize an apparent long-range diagonal actin meshwork in the advancing lamellipodia of living cells. Visualization of this meshwork permitted a correlative light and electron microscopic approach that validated the underlying organization of lamellipodia. The linear features in the light microscopic meshwork corresponded to regions of greater actin filament density. Orientation of features was analyzed quantitatively and compared with the orientation of actin filaments at the EM level. We infer that the light microscopic meshwork reflects the orientational order of actin filaments which, in turn, is related to their branching angle.", "corpus_id": 13479541, "score": 0 }, { "doc_id": "10073353", "title": "Reconstructing the orientation distribution of actin filaments in the lamellipodium of migrating keratocytes from electron microscopy tomography data", "abstract": "Migration of motile cells on flat substrates is usually driven by the polymerization of a flat actin filament network. Theoretical models have made different predictions regarding the distribution of the filament orientation in the lamellipodium with respect to the direction of motion. Here we show how one can automatically reconstruct the orientation distribution of actin filaments in the lamellipodium of migrating keratocytes from electron microscopy tomography data. We use two different image analysis methods, an algorithm which explicitly extracts an abstract network representation and an analysis of the gray scale information based on the structure tensor. We show that the two approaches give similar results, both for simulated data and for electron microscopy tomography data from migrating keratocytes. For the lamellipodium at the leading edge of fast moving cells, we find an orientation distribution that is peaked at +35/−35 degrees. For the lamellipodium at the leading edge of slow moving cells as well as for the lamellipodium at the flanks of fast moving cells, one broad peak around 0 degree dominates the distribution. © 2012 International Society for Advancement of Cytometry", "corpus_id": 10073353, "score": 0 }, { "doc_id": "8966260", "title": "Simulation of cell motility that reproduces the force–velocity relationship", "abstract": "Many cells crawl by extending an actin-rich pseudopod. We have devised a simulation that describes how the polymerization kinetics of a branched actin filament network, coupled with excluded volume effects, powers the motility of crawling cells such as amoebae and fish keratocytes. Our stochastic simulation is based on the key fundamental properties of actin polymerization, namely growth, shrinkage, capping, branching, and nucleation, and also includes contributions from the creation and breaking of adhesive contacts with the substrate together with excluded volume effects related to filament packing. When reasonable values for appropriate constants were employed, this simulation generated a force–velocity relationship that resembled closely that observed experimentally. Our simulations indicated that excluded volume effects associated with actin filament branching lead to a decreased packing efficiency and resultant swelling of the cytoskeleton gel that contributes substantially to lamellipod protrusion.", "corpus_id": 8966260, "score": 0 }, { "doc_id": "8621546", "title": "A role for actin arcs in the leading-edge advance of migrating cells", "abstract": "Epithelial cell migration requires coordination of two actin modules at the leading edge: one in the lamellipodium and one in the lamella. How the two modules connect mechanistically to regulate directed edge motion is not understood. Using live-cell imaging and photoactivation approaches, we demonstrate that the actin network of the lamellipodium evolves spatio-temporally into the lamella. This occurs during the retraction phase of edge motion, when myosin II redistributes to the lamellipodial actin and condenses it into an actin arc parallel to the edge. The new actin arc moves rearward, slowing down at focal adhesions in the lamella. We propose that net edge extension occurs by nascent focal adhesions advancing the site at which new actin arcs slow down and form the base of the next protrusion event. The actin arc thereby serves as a structural element underlying the temporal and spatial connection between the lamellipodium and the lamella during directed cell motion.", "corpus_id": 8621546, "score": 0 }, { "doc_id": "17569578", "title": "Actin branching in the initiation and maintenance of lamellipodia", "abstract": "Using correlated live-cell imaging and electron tomography we found that actin branch junctions in protruding and treadmilling lamellipodia are not concentrated at the front as previously supposed, but link actin filament subsets in which there is a continuum of distances from a junction to the filament plus ends, for up to at least 1 μm. When branch sites were observed closely spaced on the same filament their separation was commonly a multiple of the actin helical repeat of 36 nm. Image averaging of branch junctions in the tomograms yielded a model for the in vivo branch at 2.9 nm resolution, which was comparable with that derived for the in vitro actin–Arp2/3 complex. Lamellipodium initiation was monitored in an intracellular wound-healing model and was found to involve branching from the sides of actin filaments oriented parallel to the plasmalemma. Many filament plus ends, presumably capped, terminated behind the lamellipodium tip and localized on the dorsal and ventral surfaces of the actin network. These findings reveal how branching events initiate and maintain a network of actin filaments of variable length, and provide the first structural model of the branch junction in vivo. A possible role of filament capping in generating the lamellipodium leaflet is discussed and a mathematical model of protrusion is also presented.", "corpus_id": 17569578, "score": 0 }, { "doc_id": "7912526", "title": "Branching Microtubule Nucleation in Xenopus Egg Extracts Mediated by Augmin and TPX2", "abstract": "The microtubules that comprise mitotic spindles in animal cells are nucleated at centrosomes and by spindle assembly factors that are activated in the vicinity of chromatin. Indirect evidence has suggested that microtubules also might be nucleated from pre-existing microtubules throughout the spindle, but this process has not been observed directly. Here, we demonstrate microtubule nucleation from the sides of existing microtubules in meiotic Xenopus egg extracts. Daughter microtubules grow at a low branch angle and with the same polarity as mother filaments. Branching microtubule nucleation requires γ-tubulin and augmin and is stimulated by factors previously implicated in chromatin-stimulated nucleation, guanosine triphosphate(GTP)-bound Ran and its effector, TPX2. Because of the rapid amplification of microtubule numbers and the preservation of microtubule polarity, microtubule-dependent microtubule nucleation is well suited for spindle assembly and maintenance.", "corpus_id": 7912526, "score": 0 }, { "doc_id": "22288371", "title": "Flexural rigidity of microtubules and actin filaments measured from thermal fluctuations in shape", "abstract": "Microtubules are long, proteinaceous filaments that perform structural functions in eukaryotic cells by defining cellular shape and serving as tracks for intracellular motor proteins. We report the first accurate measurements of the flexural rigidity of microtubules. By analyzing the thermally driven fluctuations in their shape, we estimated the mean flexural rigidity of taxol-stabilized microtubules to be 2.2 x 10(-23) Nm2 (with 6.4% uncertainty) for seven unlabeled microtubules and 2.1 x 10(-23) Nm2 (with 4.7% uncertainty) for eight rhodamine-labeled microtubules. These values are similar to earlier, less precise estimates of microtubule bending stiffness obtained by modeling flagellar motion. A similar analysis on seven rhodamine-phalloidin- labeled actin filaments gave a flexural rigidity of 7.3 x 10(-26) Nm2 (with 6% uncertainty), consistent with previously reported results. The flexural rigidity of these microtubules corresponds to a persistence length of 5,200 microns showing that a microtubule is rigid over cellular dimensions. By contrast, the persistence length of an actin filament is only approximately 17.7 microns, perhaps explaining why actin filaments within cells are usually cross-linked into bundles. The greater flexural rigidity of a microtubule compared to an actin filament mainly derives from the former's larger cross-section. If tubulin were homogeneous and isotropic, then the microtubule's Young's modulus would be approximately 1.2 GPa, similar to Plexiglas and rigid plastics. Microtubules are expected to be almost inextensible: the compliance of cells is due primarily to filament bending or sliding between filaments rather than the stretching of the filaments themselves.", "corpus_id": 22288371, "score": 0 }, { "doc_id": "24943364", "title": "The interaction of Arp2/3 complex with actin: nucleation, high affinity pointed end capping, and formation of branching networks of filaments.", "abstract": "The Arp2/3 complex is a stable assembly of seven protein subunits including two actin-related proteins (Arp2 and Arp3) and five novel proteins. Previous work showed that this complex binds to the sides of actin filaments and is concentrated at the leading edges of motile cells. Here, we show that Arp2/3 complex purified from Acanthamoeba caps the pointed ends of actin filaments with high affinity. Arp2/3 complex inhibits both monomer addition and dissociation at the pointed ends of actin filaments with apparent nanomolar affinity and increases the critical concentration for polymerization at the pointed end from 0.6 to 1.0 microM. The high affinity of Arp2/3 complex for pointed ends and its abundance in amoebae suggest that in vivo all actin filament pointed ends are capped by Arp2/3 complex. Arp2/3 complex also nucleates formation of actin filaments that elongate only from their barbed ends. From kinetic analysis, the nucleation mechanism appears to involve stabilization of polymerization intermediates (probably actin dimers). In electron micrographs of quick-frozen, deep-etched samples, we see Arp2/3 bound to sides and pointed ends of actin filaments and examples of Arp2/3 complex attaching pointed ends of filaments to sides of other filaments. In these cases, the angle of attachment is a remarkably constant 70 +/- 7 degrees. From these in vitro biochemical properties, we propose a model for how Arp2/3 complex controls the assembly of a branching network of actin filaments at the leading edge of motile cells.", "corpus_id": 24943364, "score": 0 }, { "doc_id": "37171690", "title": "Visualizing branched actin filaments in lamellipodia by electron tomography", "abstract": "To the editor: Urban et al.1 recently challenged the dendritic nucleation model of lamellipodia protrusion based on their inability to detect branched actin filaments in lamellipodia by electron tomography. We have carefully analysed the primary data that was provided as Supplementary Information by Urban et al., and report that there are numerous branches that have been overlooked by the authors. Lamellipodia are thin veil-like protrusions of the cell edge that have important roles in cell migration. Their advance is driven by the polymerization of actin filaments. The exact mechanisms of lamellipodia protrusion are still debated, owing in part to controversy regarding the structural organization of the actin filaments in lamellipodia. Initial structural data obtained by Small et al.2 using negative-staining electron microscopy suggested that lamellipodia contained a network of long diagonally oriented actin filaments. Based on this structure, the authors proposed a treadmilling model of lamellipodia protrusion stating that actin filaments continuously elongate at their distal barbed (plus) ends, thus pushing the membrane, and continuously depolymerize from the proximal pointed (minus) ends, thus maintaining actin turnover. A large body of structural, biochemical, kinetic and functional data accumulated over the subsequent three decades has led to a revised model of lamellipodia protrusion, termed the dendritic nucleation model3. A key additional point of this model is that the actin filaments in lamellipodia are constantly nucleated by the Arp2/3 complex as branches on pre-existing filaments. However, despite the compelling evidence, Small and", "corpus_id": 37171690, "score": 0 }, { "doc_id": "2848293", "title": "Antagonism between Ena/VASP Proteins and Actin Filament Capping Regulates Fibroblast Motility", "abstract": "Cell motility requires lamellipodial protrusion, a process driven by actin polymerization. Ena/VASP proteins accumulate in protruding lamellipodia and promote the rapid actin-driven motility of the pathogen Listeria. In contrast, Ena/VASP negatively regulate cell translocation. To resolve this paradox, we analyzed the function of Ena/VASP during lamellipodial protrusion. Ena/VASP-deficient lamellipodia protruded slower but more persistently, consistent with their increased cell translocation rates. Actin networks in Ena/VASP-deficient lamellipodia contained shorter, more highly branched filaments compared to controls. Lamellipodia with excess Ena/VASP contained longer, less branched filaments. In vitro, Ena/VASP promoted actin filament elongation by interacting with barbed ends, shielding them from capping protein. We conclude that Ena/VASP regulates cell motility by controlling the geometry of actin filament networks within lamellipodia.", "corpus_id": 2848293, "score": 0 }, { "doc_id": "8433529", "title": "Tracer studies on f-actin fluctuations.", "abstract": "We present a study on the fluctuations of semiflexible actin filaments using fluorescence videomicroscopy, focusing on the end-to-end fluctuations of single filaments. In order to specifically measure the position of the polymer's ends, we developed a novel noninvasive method that consists of annealing short end tags to the filaments. This allows us to probe polymer fluctuations to a very high accuracy. We compared the distribution of the end-to-end distance with recent theoretical results, and found excellent agreement. We also studied the dynamics of the mean-square end-to-end distance deltaR2(t) and orientation of the ends, deltaTheta(2)(t), finding power laws t(3/4) and t(1/4), respectively. Scaling behavior for deltaR2(t) is observed over several decades in relaxation time in agreement with theoretical results.", "corpus_id": 8433529, "score": 0 }, { "doc_id": "36746951", "title": "Flexibility of actin filaments derived from thermal fluctuations. Effect of bound nucleotide, phalloidin, and muscle regulatory proteins", "abstract": "Single actin filaments undergoing brownian movement in two dimensions were observed at 20 degrees C in fluorescence optical video microscopy. The persistence length (Lp) was derived from the analysis of either the cosine correlation function or the average transverse fluctuations of a series of recorded shapes of filaments assembled from rhodamine-action. Phalloidin-stabilized filaments had a persistence length of 18 +/- 1 micron, in agreement with recent observations. In the absence of phalloidin, rhodamine-labeled filaments could be observed under a variety of solution conditions once diluted in free unlabeled G-actin at the appropriate critical concentration. Such nonstabilized F-ADP- actin filaments had the same Lp of 9 +/- 0.5 microns, whether they had been assembled from ATP-G-actin or from ADP-G-actin, and independently of the tightly bound divalent metal ion. In the presence of BeF3-, which mimics the gamma-phosphate of ATP, F-ADP-BeF3-actin was appreciably more rigid, with Lp = 13.5 microns. Hence, newly formed F- ADP-Pi-actin filaments are more rigid than “old” F-ADP-actin filaments, a fact which has implications in actin-based motility processes. In the presence of skeletal tropomyosin and troponin, filaments were rigid (Lp = 20 +/- 1 micron) in the off state (-Ca2+), and flexible (Lp = 12 microns) in the on state (+Ca2+), consistent with the steric blocking model. In agreement with x-ray diffraction data, no appreciable difference was recorded between the off and on states using smooth muscle tropomyosin and caldesmon (Lp = 20 +/- 1 micron). In conclusion, this method allows accurate measurement of small (< or = 15%) changes in mechanical properties of actin filaments in correlation with their biological functions.", "corpus_id": 36746951, "score": 0 }, { "doc_id": "206202384", "title": "Cofilin increases the bending flexibility of actin filaments: implications for severing and cell mechanics.", "abstract": "We determined the flexural (bending) rigidities of actin and cofilactin filaments from a cosine correlation function analysis of their thermally driven, two-dimensional fluctuations in shape. The persistence length of actin filaments is 9.8 microm, corresponding to a flexural rigidity of 0.040 pN microm(2). Cofilin binding lowers the persistence length approximately 5-fold to a value of 2.2 microm and the filament flexural rigidity to 0.0091 pN microm(2). That cofilin-decorated filaments are more flexible than native filaments despite an increased mass indicates that cofilin binding weakens and redistributes stabilizing subunit interactions of filaments. We favor a mechanism in which the increased flexibility of cofilin-decorated filaments results from the linked dissociation of filament-stabilizing ions and reorganization of actin subdomain 2 and as a consequence promotes severing due to a mechanical asymmetry. Knowledge of the effects of cofilin on actin filament bending mechanics, together with our previous analysis of torsional stiffness, provide a quantitative measure of the mechanical changes in actin filaments associated with cofilin binding, and suggest that the overall mechanical and force-producing properties of cells can be modulated by cofilin activity.", "corpus_id": 206202384, "score": 0 }, { "doc_id": "16078744", "title": "Actin filament remodeling by actin depolymerization factor/cofilin", "abstract": "We investigate, using molecular dynamics, how the severing protein, actin depolymerization factor (ADF)/cofilin, modulates the structure, conformational dynamics, and mechanical properties of actin filaments. The actin and cofilactin filament bending stiffness and corresponding persistence lengths obtained from all-atom simulations are comparable to values obtained from analysis of thermal fluctuations in filament shape. Filament flexibility is strongly affected by the nucleotide-linked conformation of the actin subdomain 2 DNase-I binding loop and the filament radial mass density distribution. ADF/cofilin binding between subdomains 1 and 3 of a filament subunit triggers reorganization of subdomain 2 of the neighboring subunit such that the DNase-I binding loop (DB-loop) moves radially away from the filament. Repositioning of the neighboring subunit DB-loop significantly weakens subunit interactions along the long-pitch helix and lowers the filament bending rigidity. Lateral filament contacts between the hydrophobic loop and neighboring short-pitch helix monomers in native filaments are also compromised with cofilin binding. These works provide a molecular interpretation of biochemical solution studies documenting the disruption of filament subunit interactions and also reveal the molecular basis of actin filament allostery and its linkage to ADF/cofilin binding.", "corpus_id": 16078744, "score": 0 } ]

{ "doc_id": "6530408", "title": "Global Non-rigid Alignment of Surface Sequences", "abstract": "This paper presents a general approach based on the shape similarity tree for non-sequential alignment across databases of multiple unstructured mesh sequences from non-rigid surface capture. The optimal shape similarity tree for non-rigid alignment is defined as the minimum spanning tree in shape similarity space. Non-sequential alignment based on the shape similarity tree minimises the total non-rigid deformation required to register all frames in a database into a consistent mesh structure with surfaces in correspondence. This allows alignment across multiple sequences of different motions, reduces drift in sequential alignment and is robust to rapid non-rigid motion. Evaluation is performed on three benchmark databases of 3D mesh sequences with a variety of complex human and cloth motion. Comparison with sequential alignment demonstrates reduced errors due to drift and improved robustness to large non-rigid deformation, together with global alignment across multiple sequences which is not possible with previous sequential approaches.", "corpus_id": 6530408 }

[ { "doc_id": "10591691", "title": "Performance capture from sparse multi-view video", "abstract": "This paper proposes a new marker-less approach to capturing human performances from multi-view video. Our algorithm can jointly reconstruct spatio-temporally coherent geometry, motion and textural surface appearance of actors that perform complex and rapid moves. Furthermore, since our algorithm is purely meshbased and makes as few as possible prior assumptions about the type of subject being tracked, it can even capture performances of people wearing wide apparel, such as a dancer wearing a skirt. To serve this purpose our method efficiently and effectively combines the power of surface- and volume-based shape deformation techniques with a new mesh-based analysis-through-synthesis framework. This framework extracts motion constraints from video and makes the laser-scan of the tracked subject mimic the recorded performance. Also small-scale time-varying shape detail is recovered by applying model-guided multi-view stereo to refine the model surface. Our method delivers captured performance data at high level of detail, is highly versatile, and is applicable to many complex types of scenes that could not be handled by alternative marker-based or marker-free recording techniques.", "corpus_id": 10591691, "score": 1 }, { "doc_id": "14152672", "title": "Model-based multiple view reconstruction of people", "abstract": "This paper presents a framework to reconstruct a scene captured in multiple camera views based on a prior model of the scene geometry. The framework is applied to the capture of animated models of people. A multiple camera studio is used to simultaneously capture a moving person from multiple viewpoints. A humanoid computer graphics model is animated to match the pose at each time frame. Constrained optimisation is then used to recover the multiple view correspondence from silhouette, stereo and feature cues, updating the geometry and appearance of the model. The key contribution of this paper is a model-based computer vision framework for the reconstruction of shape and appearance from multiple views. This is compared to current model-free approaches for multiple view scene capture. The technique demonstrates improved scene reconstruction in the presence of visual ambiguities and provides the means to capture a dynamic scene with a consistent model that is instrumented with an animation structure to edit the scene dynamics or to synthesise new content.", "corpus_id": 14152672, "score": 0 }, { "doc_id": "230280", "title": "Articulated mesh animation from multi-view silhouettes", "abstract": "Details in mesh animations are difficult to generate but they have great impact on visual quality. In this work, we demonstrate a practical software system for capturing such details from multi-view video recordings. Given a stream of synchronized video images that record a human performance from multiple viewpoints and an articulated template of the performer, our system captures the motion of both the skeleton and the shape. The output mesh animation is enhanced with the details observed in the image silhouettes. For example, a performance in casual loose-fitting clothes will generate mesh animations with flowing garment motions. We accomplish this with a fast pose tracking method followed by nonrigid deformation of the template to fit the silhouettes. The entire process takes less than sixteen seconds per frame and requires no markers or texture cues. Captured meshes are in full correspondence making them readily usable for editing operations including texturing, deformation transfer, and deformation model learning.", "corpus_id": 230280, "score": 0 }, { "doc_id": "7825085", "title": "Calculus of Nonrigid Surfaces for Geometry and Texture Manipulation", "abstract": "The experience of motion sickness in a virtual environment may be measured through pre and postexperiment self-reported questionnaires such as the simulator sickness questionnaire (SSQ). Although research provides converging evidence that users of virtual environments can experience motion sickness, there have been no controlled studies to determine to what extent the user's subjective response is a demand characteristic resulting from pre and posttest measures. In this study, subjects were given either SSQ's both pre and postvirtual environment immersion, or only postimmersion. This technique tested for contrast effects due to demand characteristics in which administration of the questionnaire itself suggested to the participant that the virtual environment may produce motion sickness. Results indicate that reports of motion sickness after immersion in a virtual environment are much greater when both pre and postquestionnaires are given than when only a posttest questionnaire is used. The implications for assessments of motion sickness in virtual environments are discussed", "corpus_id": 7825085, "score": 0 }, { "doc_id": "11894275", "title": "Probabilistic Deformable Surface Tracking from Multiple Videos", "abstract": "In this paper, we address the problem of tracking the temporal evolution of arbitrary shapes observed in multi-camera setups. This is motivated by the ever growing number of applications that require consistent shape information along temporal sequences. The approach we propose considers a temporal sequence of independently reconstructed surfaces and iteratively deforms a reference mesh to fit these observations. To effectively cope with outlying and missing geometry, we introduce a novel probabilistic mesh deformation framework. Using generic local rigidity priors and accounting for the uncertainty in the data acquisition process, this framework effectively handles missing data, relatively large reconstruction artefacts and multiple objects. Extensive experiments demonstrate the effectiveness and robustness of the method on various 4D datasets.", "corpus_id": 11894275, "score": 1 }, { "doc_id": "1012491", "title": "Correspondence labelling for wide-timeframe free-form surface matching", "abstract": "This paper addresses the problem of estimating dense correspondence between arbitrary frames from captured sequences of shape and appearance for surfaces undergoing free-form deformation. Previous techniques require either a prior model, limiting the range of surface deformations, or frame-to-frame surface tracking which suffers from stabilisation problems over complete motion sequences and does not provide correspondence between sequences. The primary contribution of this paper is the introduction of a system for wide-timeframe surface matching without the requirement for a prior model or tracking. Deformation- invariant surface matching is formulated as a locally isometric mapping at a discrete set of surface points. A set of feature descriptors are presented that are invariant to isometric deformations and a novel MAP-MRF framework is presented to label sparse-to-dense surface correspondence, preserving the relative distribution of surface features while allowing for changes in surface topology. Performance is evaluated on challenging data from a moving person with loose clothing. Ground-truth feature correspondences are manually marked and the recall-accuracy characteristic is quantified in matching. Results demonstrate an improved performance compared to non-rigid point-pattern matching using robust matching and graph-matching using relaxation labelling, with successful matching achieved across wide variations in human body pose and surface topology.", "corpus_id": 1012491, "score": 0 }, { "doc_id": "15804775", "title": "Animation cartography—intrinsic reconstruction of shape and motion", "abstract": "In this article, we consider the problem of animation reconstruction, that is, the reconstruction of shape and motion of a deformable object from dynamic 3D scanner data, without using user-provided template models. Unlike previous work that addressed this problem, we do not rely on locally convergent optimization but present a system that can handle fast motion, temporally disrupted input, and can correctly match objects that disappear for extended time periods in acquisition holes due to occlusion. Our approach is motivated by cartography: We first estimate a few landmark correspondences, which are extended to a dense matching and then used to reconstruct geometry and motion. We propose a number of algorithmic building blocks: a scheme for tracking landmarks in temporally coherent and incoherent data, an algorithm for robust estimation of dense correspondences under topological noise, and the integration of local matching techniques to refine the result. We describe and evaluate the individual components and propose a complete animation reconstruction pipeline based on these ideas. We evaluate our method on a number of standard benchmark datasets and show that we can obtain correct reconstructions in situations where other techniques fail completely or require additional user guidance such as a template model.", "corpus_id": 15804775, "score": 0 }, { "doc_id": "16004660", "title": "Dynamic surface matching by geodesic mapping for 3D animation transfer", "abstract": "This paper presents a novel approach that achieves complete matching of 3D dynamic surfaces. Surfaces are captured from multi-view video data and represented by sequences of 3D manifold meshes in motion (3D videos). We propose to perform dense surface matching between 3D video frames using geodesic diffeomorphisms. Our algorithm uses a coarse-to-fine strategy to derive a robust correspondence map, then a probabilistic formulation is coupled with a voting scheme in order to obtain local unicity of matching candidates and a smooth mapping. The significant advantage of the proposed technique compared to existing approaches is that it does not rely on a color-based feature extraction process. Hence, our method does not lose accuracy in poorly textured regions and is not bounded to be used on video sequences of a unique subject. Therefore our complete surface mapping can be applied to: (1) texture transfer between surface models extracted from different sequences, (2) dense motion flow estimation in 3D video, and (3) motion transfer from a 3D video to an unanimated 3D model. Experiments are performed on challenging publicly available real-world datasets and show compelling results.", "corpus_id": 16004660, "score": 0 }, { "doc_id": "5793282", "title": "Dense non-rigid surface registration using high-order graph matching", "abstract": "In this paper, we propose a high-order graph matching formulation to address non-rigid surface matching. The singleton terms capture the geometric and appearance similarities (e.g., curvature and texture) while the high-order terms model the intrinsic embedding energy. The novelty of this paper includes: 1) casting 3D surface registration into a graph matching problem that combines both geometric and appearance similarities and intrinsic embedding information, 2) the first implementation of high-order graph matching algorithm that solves a non-convex optimization problem, and 3) an efficient two-stage optimization approach to constrain the search space for dense surface registration. Our method is validated through a series of experiments demonstrating its accuracy and efficiency, notably in challenging cases of large and/or non-isometric deformations, or meshes that are partially occluded.", "corpus_id": 5793282, "score": 0 }, { "doc_id": "5712534", "title": "Human motion synthesis from 3D video", "abstract": "Multiple view 3D video reconstruction of actor performance captures a level-of-detail for body and clothing movement which is time-consuming to produce using existing animation tools. In this paper we present a framework for concatenative synthesis from multiple 3D video sequences according to user constraints on movement, position and timing. Multiple 3D video sequences of an actor performing different movements are automatically constructed into a surface motion graph which represents the possible transitions with similar shape and motion between sequences without unnatural movement artifacts. Shape similarity over an adaptive temporal window is used to identify transitions between 3D video sequences. Novel 3D video sequences are synthesized by finding the optimal path in the surface motion graph between user specified key-frames for control of movement, location and timing. The optimal path which satisfies the user constraints whilst minimizing the total transition cost between 3D video sequences is found using integer linear programming. Results demonstrate that this framework allows flexible production of novel 3D video sequences which preserve the detailed dynamics of the captured movement for an actress with loose clothing and long hair without visible artifacts.", "corpus_id": 5712534, "score": 0 }, { "doc_id": "78045", "title": "Global temporal registration of multiple non-rigid surface sequences", "abstract": "In this paper we consider the problem of aligning multiple non-rigid surface mesh sequences into a single temporally consistent representation of the shape and motion. A global alignment graph structure is introduced which uses shape similarity to identify frames for inter-sequence registration. Graph optimisation is performed to minimise the total non-rigid deformation required to register the input sequences into a common structure. The resulting global alignment ensures that all input sequences are resampled with a common mesh structure which preserves the shape and temporal correspondence. Results demonstrate temporally consistent representation of several public databases of mesh sequences for multiple people performing a variety of motions with loose clothing and hair.", "corpus_id": 78045, "score": 0 }, { "doc_id": "17752367", "title": "Hierarchical Shape Matching for Temporally Consistent 3D Video", "abstract": "In this paper we present a novel approach for temporal alignment of reconstructed mesh sequences with non-rigid surfaces to obtain a consistent representation. We propose a hierarchical scheme for non-sequential matching of frames across the sequence using shape similarity. This gives a tree structure which represents the optimal path for alignment of each frame in the sequence to minimize the change in shape. Non-rigid alignment is performed by recursively traversing the tree to align all frames. Non-sequential alignment reduces problems of drift or tracking failure which occur in previous sequential frame-to-frame techniques. Comparative evaluation on challenging 3D video sequences demonstrates that the proposed approach produces a temporally coherent representation with reduced error in shape and correspondence.", "corpus_id": 17752367, "score": 0 }, { "doc_id": "6412862", "title": "Shape Similarity for 3D Video Sequences of People", "abstract": "This paper presents a performance evaluation of shape similarity metrics for 3D video sequences of people with unknown temporal correspondence. Performance of similarity measures is compared by evaluating Receiver Operator Characteristics for classification against ground-truth for a comprehensive database of synthetic 3D video sequences comprising animations of fourteen people performing twenty-eight motions. Static shape similarity metrics shape distribution, spin image, shape histogram and spherical harmonics are evaluated using optimal parameter settings for each approach. Shape histograms with volume sampling are found to consistently give the best performance for different people and motions. Static shape similarity is extended over time to eliminate the temporal ambiguity. Time-filtering of the static shape similarity together with two novel shape-flow descriptors are evaluated against temporal ground-truth. This evaluation demonstrates that shape-flow with a multi-frame alignment of motion sequences achieves the best performance, is stable for different people and motions, and overcome the ambiguity in static shape similarity. Time-filtering of the static shape histogram similarity measure with a fixed window size achieves marginally lower performance for linear motions with the same computational cost as static shape descriptors. Performance of the temporal shape descriptors is validated for real 3D video sequence of nine actors performing a variety of movements. Time-filtered shape histograms are shown to reliably identify frames from 3D video sequences with similar shape and motion for people with loose clothing and complex motion.", "corpus_id": 6412862, "score": 1 }, { "doc_id": "1846045", "title": "Free-form mesh tracking: A patch-based approach", "abstract": "In this paper, we consider the problem of tracking nonrigid surfaces and propose a generic data-driven mesh deformation framework. In contrast to methods using strong prior models, this framework assumes little on the observed surface and hence easily generalizes to most free-form surfaces while effectively handling large deformations. To this aim, the reference surface is divided into elementary surface cells or patches. This strategy ensures robustness by providing natural integration domains over the surface for noisy data, while enabling to express simple patch-level rigidity constraints. In addition, we associate to this scheme a robust numerical optimization that solves for physically plausible surface deformations given arbitrary constraints. In order to demonstrate the versatility of the proposed framework, we conducted experiments on open and closed surfaces, with possibly non-connected components, that undergo large deformations and fast motions. We also performed quantitative and qualitative evaluations in multicameras and monocular environments, and with different types of data including 2D correspondences and 3D point clouds.", "corpus_id": 1846045, "score": 1 }, { "doc_id": "1241772", "title": "Three-dimensional scene flow", "abstract": "Just as optical flow is the two-dimensional motion of points in an image, scene flow is the three-dimensional motion of points in the world. The fundamental difficulty with optical flow is that only the normal flow can be computed directly from the image measurements, without some form of smoothing or regularization. In this paper, we begin by showing that the same fundamental limitation applies to scene flow; however, many cameras are used to image the scene. There are then two choices when computing scene flow: 1) perform the regularization in the images or 2) perform the regularization on the surface of the object in the scene. In this paper, we choose to compute scene flow using regularization in the images. We describe three algorithms, the first two for computing scene flow from optical flows and the third for constraining scene structure from the inconsistencies in multiple optical flows.", "corpus_id": 1241772, "score": 0 }, { "doc_id": "9881027", "title": "Efficient reconstruction of nonrigid shape and motion from real-time 3D scanner data", "abstract": "We present a new technique for reconstructing a single shape and its nonrigid motion from 3D scanning data. Our algorithm takes a set of time-varying unstructured sample points that capture partial views of a deforming object as input and reconstructs a single shape and a deformation field that fit the data. This representation yields dense correspondences for the whole sequence, as well as a completed 3D shape in every frame. In addition, the algorithm automatically removes spatial and temporal noise artifacts and outliers from the raw input data. Unlike previous methods, the algorithm does not require any shape template but computes a fitting shape automatically from the input data. Our reconstruction framework is based upon a novel topology-aware adaptive subspace deformation technique that allows handling long sequences with complex geometry efficiently. The algorithm accesses data in multiple sequential passes, so that long sequences can be streamed from hard disk, not being limited by main memory. We apply the technique to several benchmark datasets, significantly increasing the complexity of the data that can be handled efficiently in comparison to previous work.", "corpus_id": 9881027, "score": 0 }, { "doc_id": "1807351", "title": "Surface Deformation Models for Nonrigid 3D Shape Recovery", "abstract": "Three-dimensional detection and shape recovery of a nonrigid surface from video sequences require deformation models to effectively take advantage of potentially noisy image data. Here, we introduce an approach to creating such models for deformable 3D surfaces. We exploit the fact that the shape of an inextensible triangulated mesh can be parameterized in terms of a small subset of the angles between its facets. We use this set of angles to create a representative set of potential shapes, which we feed to a simple dimensionality reduction technique to produce low-dimensional 3D deformation models. We show that these models can be used to accurately model a wide range of deforming 3D surfaces from video sequences acquired under realistic conditions.", "corpus_id": 1807351, "score": 0 }, { "doc_id": "17687873", "title": "Video-based reconstruction of animatable human characters", "abstract": "We present a new performance capture approach that incorporates a physically-based cloth model to reconstruct a rigged fully-animatable virtual double of a real person in loose apparel from multi-view video recordings. Our algorithm only requires a minimum of manual interaction. Without the use of optical markers in the scene, our algorithm first reconstructs skeleton motion and detailed time-varying surface geometry of a real person from a reference video sequence. These captured reference performance data are then analyzed to automatically identify non-rigidly deforming pieces of apparel on the animated geometry. For each piece of apparel, parameters of a physically-based real-time cloth simulation model are estimated, and surface geometry of occluded body regions is approximated. The reconstructed character model comprises a skeleton-based representation for the actual body parts and a physically-based simulation model for the apparel. In contrast to previous performance capture methods, we can now also create new real-time animations of actors captured in general apparel.", "corpus_id": 17687873, "score": 0 }, { "doc_id": "7121544", "title": "Semantic deformation transfer", "abstract": "Transferring existing mesh deformation from one character to another is a simple way to accelerate the laborious process of mesh animation. In many cases, it is useful to preserve the semantic characteristics of the motion instead of its literal deformation. For example, when applying the walking motion of a human to a flamingo, the knees should bend in the opposite direction. Semantic deformation transfer accomplishes this task with a shape space that enables interpolation and projection with standard linear algebra. Given several example mesh pairs, semantic deformation transfer infers a correspondence between the shape spaces of the two characters. This enables automatic transfer of new poses and animations.", "corpus_id": 7121544, "score": 0 }, { "doc_id": "1864608", "title": "Multi-View Scene Capture by Surfel Sampling: From Video Streams to Non-Rigid 3D Motion, Shape and Reflectance", "abstract": "In this paper we study the problem of recovering the 3D shape, reflectance, and non-rigid motion properties of a dynamic 3D scene. Because these properties are completely unknown and because the scene's shape and motion may be non-smooth, our approach uses multiple views to build a piecewise-continuous geometric and radiometric representation of the scene's trace in space-time. A basic primitive of this representation is the dynamic surfel, which (1) encodes the instantaneous local shape, reflectance, and motion of a small and bounded region in the scene, and (2) enables accurate prediction of the region's dynamic appearance under known illumination conditions. We show that complete surfel-based reconstructions can be created by repeatedly applying an algorithm called Surfel Sampling that combines sampling and parameter estimation to fit a single surfel to a small, bounded region of space-time. Experimental results with the Phong reflectancemodel and complex real scenes (clothing, shiny objects, skin) illustrate our method's ability to explain pixels and pixel variations in terms of their underlying causes—shape, reflectance, motion, illumination, and visibility.", "corpus_id": 1864608, "score": 0 }, { "doc_id": "14766157", "title": "Multi-View Stereo Reconstruction and Scene Flow Estimation with a Global Image-Based Matching Score", "abstract": "We present a new variational method for multi-view stereovision and non-rigid three-dimensional motion estimation from multiple video sequences. Our method minimizes the prediction error of the shape and motion estimates. Both problems then translate into a generic image registration task. The latter is entrusted to a global measure of image similarity, chosen depending on imaging conditions and scene properties. Rather than integrating a matching measure computed independently at each surface point, our approach computes a global image-based matching score between the input images and the predicted images. The matching process fully handles projective distortion and partial occlusions. Neighborhood as well as global intensity information can be exploited to improve the robustness to appearance changes due to non-Lambertian materials and illumination changes, without any approximation of shape, motion or visibility. Moreover, our approach results in a simpler, more flexible, and more efficient implementation than in existing methods. The computation time on large datasets does not exceed thirty minutes on a standard workstation. Finally, our method is compliant with a hardware implementation with graphics processor units. Our stereovision algorithm yields very good results on a variety of datasets including specularities and translucency. We have successfully tested our motion estimation algorithm on a very challenging multi-view video sequence of a non-rigid scene.", "corpus_id": 14766157, "score": 0 }, { "doc_id": "62136533", "title": "Cloth Motion Capture", "abstract": "Recent years have seen an increased interest in motion capture systems. Current systems, however, are limitedto only a few degrees of freedom, so that effectively only the motion of linked rigid bodies can be acquired. Wepresent a system for the capture of deformable surfaces, most notably moving cloth, including both geometry andparameterisation. We recover geometry using stereo correspondence, and use the Scale Invariant Feature Transform(SIFT) to identify an arbitrary pattern printed on the cloth, even in the presence of fast motion. We describea novel seed‐and‐grow approach to adapt the SIFT algorithm to deformable geometry. Finally, we interpolatefeature points to parameterise the complete geometry.", "corpus_id": 62136533, "score": 0 }, { "doc_id": "15839656", "title": "Garment motion capture using color-coded patterns", "abstract": "We present a new image-based algorithm for surface reconstruction of moving garment from multiple calibrated video cameras. Using a color-coded cloth texture, we reliably match circular features between different camera views. As surface model we use an a priori known triangle mesh. By identifying the mesh vertices with texture elements we obtain a coherent parameterization of the surface over time without further processing. Missing data points resulting from self-shadowing are plausibly interpolated by minimizing a thin-plate functional. The deforming geometry can be used for different graphics applications, e.g. for realistic retexturing. We show results for real garments demonstrating the accuracy of the recovered flexible shape.", "corpus_id": 15839656, "score": 0 }, { "doc_id": "34227392", "title": "Capturing and animating occluded cloth", "abstract": "We capture the shape of moving cloth using a custom set of color markers printed on the surface of the cloth. The output is a sequence of triangle meshes with static connectivity and with detail at the scale of individual markers in both smooth and folded regions. We compute markers' coordinates in space using correspondence across multiple synchronized video cameras. Correspondence is determined from color information in small neighborhoods and refined using a novel strain pruning process. Final correspondence does not require neighborhood information. We use a novel data driven hole-filling technique to fill occluded regions. Our results include several challenging examples: a wrinkled shirt sleeve, a dancing pair of pants, and a rag tossed onto a cup. Finally, we demonstrate that cloth capture is reusable by animating a pair of pants using human motion capture data.", "corpus_id": 34227392, "score": 0 }, { "doc_id": "52873123", "title": "Markerless garment capture", "abstract": "A lot of research has recently focused on the problem of capturing the geometry and motion of garments. Such work usually relies on special markers printed on the fabric to establish temporally coherent correspondences between points on the garment's surface at different times. Unfortunately, this approach is tedious and prevents the capture of off-the-shelf clothing made from interesting fabrics. In this paper, we describe a marker-free approach to capturing garment motion that avoids these downsides. We establish temporally coherent parameterizations between incomplete geometries that we extract at each timestep with a multiview stereo algorithm. We then fill holes in the geometry using a template. This approach, for the first time, allows us to capture the geometry and motion of unpatterned, off-the-shelf garments made from a range of different fabrics.", "corpus_id": 52873123, "score": 0 }, { "doc_id": "62202179", "title": "Dense 3D motion capture for human faces", "abstract": "This paper proposes a novel approach to motion capture from multiple, synchronized video streams, specifically aimed at recording dense and accurate models of the structure and motion of highly deformable surfaces such as skin, that stretches, shrinks, and shears in the midst of normal facial expressions. Solving this problem is a key step toward effective performance capture for the entertainment industry, but progress so far has been hampered by the lack of appropriate local motion and smoothness models. The main technical contribution of this paper is a novel approach to regularization adapted to nonrigid tangential deformations. Concretely, we estimate the nonrigid deformation parameters at each vertex of a surface mesh, smooth them over a local neighborhood for robustness, and use them to regularize the tangential motion estimation. To demonstrate the power of the proposed approach, we have integrated it into our previous work for markerless motion capture [9], and compared the performances of the original and new algorithms on three extremely challenging face datasets that include highly nonrigid skin deformations, wrinkles, and quickly changing expressions. Additional experiments with a dataset featuring fast-moving cloth with complex and evolving fold structures demonstrate that the adaptability of the proposed regularization scheme to nonrigid tangential motion does not hamper its robustness, since it successfully recovers the shape and motion of the cloth without overfitting it despite the absence of stretch or shear in this case.", "corpus_id": 62202179, "score": 0 }, { "doc_id": "7122579", "title": "Spherical matching for temporal correspondence of non-rigid surfaces", "abstract": "This paper introduces spherical matching to estimate dense temporal correspondence of non-rigid surfaces with genus-zero topology. The spherical domain gives a consistent 1D parameterization of non-rigid surfaces for matching. Non-rigid 3D surface correspondence is formulated as the recovery of a bijective mapping between two surfaces in the 2D domain. Formulating matching as a 2D bijection guarantees a continuous one-to-one surface correspondence without overfolding. This overcomes limitations of direct estimation of non-rigid surface correspondence in the 3D domain. A multiple resolution coarse-to-fine algorithm is introduced to robustly estimate the dense correspondence which minimizes the disparity in shape and appearance between two surfaces. Spherical matching is applied to derive the temporal correspondence between non-rigid surfaces reconstructed at successive frames from multiple view video sequences of people. Dense surface correspondence is recovered across complete motion sequences for both textured and uniform regions, without the requirement for a prior model of human shape or kinematics structure for tracking", "corpus_id": 7122579, "score": 0 }, { "doc_id": "53235192", "title": "Spacetime faces: high resolution capture for modeling and animation", "abstract": "We present an end-to-end system that goes from video sequences to high resolution, editable, dynamically controllable face models. The capture system employs synchronized video cameras and structured light projectors to record videos of a moving face from multiple viewpoints. A novel spacetime stereo algorithm is introduced to compute depth maps accurately and overcome over-fitting deficiencies in prior work. A new template fitting and tracking procedure fills in missing data and yields point correspondence across the entire sequence without using markers. We demonstrate a data-driven, interactive method for inverse kinematics that draws on the large set of fitted templates and allows for posing new expressions by dragging surface points directly. Finally, we describe new tools that model the dynamics in the input sequence to enable new animations, created via key-framing or texture-synthesis techniques.", "corpus_id": 53235192, "score": 0 }, { "doc_id": "123679568", "title": "Differential Representations for Mesh Processing", "abstract": "Surface representation and processing is one of the key topics in computer graphics and geometric modeling, since it greatly affects the range of possible applications. In this paper we will present recent advances in geometry processing that are related to the Laplacian processing framework and differential representations. This framework is based on linear operators defined on polygonal meshes, and furnishes a variety of processing applications, such as shape approximation and compact representation, mesh editing, watermarking and morphing. The core of the framework is the definition of differential coordinates and new bases for efficient mesh geometry representation, based on the mesh Laplacian operator.", "corpus_id": 123679568, "score": 0 }, { "doc_id": "2572455", "title": "A performance evaluation of local descriptors", "abstract": "In this paper, we compare the performance of descriptors computed for local interest regions, as, for example, extracted by the Harris-Affine detector [Mikolajczyk, K and Schmid, C, 2004]. Many different descriptors have been proposed in the literature. It is unclear which descriptors are more appropriate and how their performance depends on the interest region detector. The descriptors should be distinctive and at the same time robust to changes in viewing conditions as well as to errors of the detector. Our evaluation uses as criterion recall with respect to precision and is carried out for different image transformations. We compare shape context [Belongie, S, et al., April 2002], steerable filters [Freeman, W and Adelson, E, Setp. 1991], PCA-SIFT [Ke, Y and Sukthankar, R, 2004], differential invariants [Koenderink, J and van Doorn, A, 1987], spin images [Lazebnik, S, et al., 2003], SIFT [Lowe, D. G., 1999], complex filters [Schaffalitzky, F and Zisserman, A, 2002], moment invariants [Van Gool, L, et al., 1996], and cross-correlation for different types of interest regions. We also propose an extension of the SIFT descriptor and show that it outperforms the original method. Furthermore, we observe that the ranking of the descriptors is mostly independent of the interest region detector and that the SIFT-based descriptors perform best. Moments and steerable filters show the best performance among the low dimensional descriptors.", "corpus_id": 2572455, "score": 0 }, { "doc_id": "2955880", "title": "Deformation invariant image matching", "abstract": "We propose a novel framework to build descriptors of local intensity that are invariant to general deformations. In this framework, an image is embedded as a 2D surface in 3D space, with intensity weighted relative to distance in x-y. We show that as this weight increases, geodesic distances on the embedded surface are less affected by image deformations. In the limit, distances are deformation invariant. We use geodesic sampling to get neighborhood samples for interest points, and then use a geodesic-intensity histogram (GIH) as a deformation invariant local descriptor. In addition to its invariance, the new descriptor automatically finds its support region. This means it can safely gather information from a large neighborhood to improve discriminability. Furthermore, we propose a matching method for this descriptor that is invariant to affine lighting changes. We have tested this new descriptor on interest point matching for two data sets, one with synthetic deformation and lighting change, and another with real non-affine deformations. Our method shows promising matching results compared to several other approaches", "corpus_id": 2955880, "score": 0 }, { "doc_id": "129468", "title": "Shape matching and object recognition using shape contexts", "abstract": "This paper presents my work on computing shape models that are computationally fast and invariant basic transformations like translation, scaling and rotation. In this paper, I propose shape detection using a feature called shape context. Shape context describes all boundary points of a shape with respect to any single boundary point. Thus it is descriptive of the shape of the object. Object recognition can be achieved by matching this feature with a priori knowledge of the shape context of the boundary points of the object. Experimental results are promising on handwritten digits, trademark images.", "corpus_id": 129468, "score": 0 }, { "doc_id": "10641470", "title": "Three-dimensional shape searching : state-ofthe-art review and future trends", "abstract": "Three-dimensional shape searching is a problem of current interest in several different fields. Most techniques have been developed for a particular domain and reduce a shape into a simpler shape representation. The techniques developed for a particular domain will also find applications in other domains. We classify and compare various 3D shape searching techniques based on their shape representations. A brief description of each technique is provided followed by a detailed survey of the state-of-the-art. The paper concludes by identifying gaps in current shape search techniques and identifies directions for future research. q 2004 Elsevier Ltd. All rights reserved.", "corpus_id": 10641470, "score": 0 }, { "doc_id": "1742840", "title": "Pose-Oblivious Shape Signature", "abstract": "A 3D shape signature is a compact representation for some essence of a shape. Shape signatures are commonly utilized as a fast indexing mechanism for shape retrieval. Effective shape signatures capture some global geometric properties which are scale, translation, and rotation invariant. In this paper, we introduce an effective shape signature which is also pose-oblivious. This means that the signature is also insensitive to transformations which change the pose of a 3D shape such as skeletal articulations. Although some topology-based matching methods can be considered pose-oblivious as well, our new signature retains the simplicity and speed of signature indexing. Moreover, contrary to topology-based methods, the new signature is also insensitive to the topology change of the shape, allowing us to match similar shapes with different genus. Our shape signature is a 2D histogram which is a combination of the distribution of two scalar functions defined on the boundary surface of the 3D shape. The first is a definition of a novel function called the local-diameter function. This function measures the diameter of the 3D shape in the neighborhood of each vertex. The histogram of this function is an informative measure of the shape which is insensitive to pose changes. The second is the centricity function that measures the average geodesic distance from one vertex to all other vertices on the mesh. We evaluate and compare a number of methods for measuring the similarity between two signatures, and demonstrate the effectiveness of our pose-oblivious shape signature within a 3D search engine application for different databases containing hundreds of models", "corpus_id": 1742840, "score": 0 }, { "doc_id": "377286", "title": "Curvature maps for local shape comparison", "abstract": "The ability to identify similarities between shapes is important for applications such as medical diagnosis, object registration and alignment, and shape retrieval. In this paper we present a method, the curvature map that uses surface curvature properties in a region around a point to create a unique signature for that point. These signatures can then be compared to determine the similarity of one point to another. To gather curvature information around a point we explore two techniques, rings (which use the local topology of the mesh) and geodesic fans (which trace geodesies along the mesh from the point). We explore a variety of comparison functions and provide experimental evidence for which ones provide the best discriminatory power. We show that curvature maps are both more robust and provide better discrimination than simply comparing the curvature at individual points.", "corpus_id": 377286, "score": 0 }, { "doc_id": "8711585", "title": "On Bending Invariant Signatures for Surfaces", "abstract": "Isometric surfaces share the same geometric structure, also known as the \"first fundamental form.\" For example, all possible bendings of a given surface that includes all length preserving deformations without tearing or stretching the surface are considered to be isometric. We present a method to construct a bending invariant signature for such surfaces. This invariant representation is an embedding of the geometric structure of the surface in a small dimensional Euclidean space in which geodesic distances are approximated by Euclidean ones. The bending invariant representation is constructed by first measuring the intergeodesic distances between uniformly distributed points on the surface. Next, a multidimensional scaling technique is applied to extract coordinates in a finite dimensional Euclidean space in which geodesic distances are replaced by Euclidean ones. Applying this transform to various surfaces with similar geodesic structures (first fundamental form) maps them into similar signature surfaces. We thereby translate the problem of matching nonrigid objects in various postures into a simpler problem of matching rigid objects. As an example, we show a simple surface classification method that uses our bending invariant signatures.", "corpus_id": 8711585, "score": 0 }, { "doc_id": "4096688", "title": "Non-sequential structure from motion", "abstract": "Prior work on multi-view structure from motion is dominated by sequential approaches starting from a single two-view reconstruction, then adding new images one by one. In contrast, we propose a non-sequential methodology based on rotational consistency and robust estimation using convex optimization. The resulting system is more robust with respect to (i) unreliable two-view estimations caused by short baselines, (ii) repetitive scenes with locally consistent structures that are not consistent with the global geometry and (iii) loop closing as errors are not propagated in a sequential manner. Both theoretical justifications and experimental comparisons are given to support these claims.1", "corpus_id": 4096688, "score": 0 }, { "doc_id": "42298366", "title": "Samantha: Towards Automatic Image-Based Model Acquisition", "abstract": "In this paper we describe SAMANTHA, a Structure and Motion pipeline from images which is both more robust and computationally cheaper than current competing approaches. Pictures are organized into a hierarchical tree which has single images as leaves and partial reconstructions as internal nodes. The method proceeds bottom up until it reaches the root node, corresponding to the final result. This framework is one order of magnitude faster than sequential approaches, inherently parallel, less sensitive to the error accumulation causing drift and truly uncalibrated, not needing EXIF metadata to be present in pictures. We have verified the quality of our reconstructions both qualitatively producing compelling point clouds and quantitatively, comparing them with laser scans serving as ground truth. We also show how to automatically extract a meaningful collection of planar patches obtaining a compact, stable representation of scenes.", "corpus_id": 42298366, "score": 0 }, { "doc_id": "21457291", "title": "High-quality passive facial performance capture using anchor frames", "abstract": "We present a new technique for passive and markerless facial performance capture based on anchor frames. Our method starts with high resolution per-frame geometry acquisition using state-of-the-art stereo reconstruction, and proceeds to establish a single triangle mesh that is propagated through the entire performance. Leveraging the fact that facial performances often contain repetitive subsequences, we identify anchor frames as those which contain similar facial expressions to a manually chosen reference expression. Anchor frames are automatically computed over one or even multiple performances. We introduce a robust image-space tracking method that computes pixel matches directly from the reference frame to all anchor frames, and thereby to the remaining frames in the sequence via sequential matching. This allows us to propagate one reconstructed frame to an entire sequence in parallel, in contrast to previous sequential methods. Our anchored reconstruction approach also limits tracker drift and robustly handles occlusions and motion blur. The parallel tracking and mesh propagation offer low computation times. Our technique will even automatically match anchor frames across different sequences captured on different occasions, propagating a single mesh to all performances.", "corpus_id": 21457291, "score": 1 }, { "doc_id": "120649066", "title": "Shortest connection networks and some generalizations", "abstract": "The basic problem considered is that of interconnecting a given set of terminals with a shortest possible network of direct links. Simple and practical procedures are given for solving this problem both graphically and computationally. It develops that these procedures also provide solutions for a much broader class of problems, containing other examples of practical interest.", "corpus_id": 120649066, "score": 0 }, { "doc_id": "120068278", "title": "On the shortest spanning subtree of a graph and the traveling salesman problem", "abstract": "7. A. Kurosh, Ringtheoretische Probleme die mit dem Burnsideschen Problem uber periodische Gruppen in Zussammenhang stehen, Bull. Acad. Sei. URSS, Ser. Math. vol. 5 (1941) pp. 233-240. 8. J. Levitzki, On the radical of a general ring, Bull. Amer. Math. Soc. vol. 49 (1943) pp. 462^66. 9. -, On three problems concerning nil rings, Bull. Amer. Math. Soc. vol. 49 (1943) pp. 913-919. 10. -, On the structure of algebraic algebras and related rings, Trans. Amer. Math. Soc. vol. 74 (1953) pp. 384-409.", "corpus_id": 120068278, "score": 0 }, { "doc_id": "207261", "title": "On Linear Variational Surface Deformation Methods", "abstract": "This survey reviews the recent advances in linear variational mesh deformation techniques. These methods were developed for editing detailed high-resolution meshes like those produced by scanning real-world objects. The challenge of manipulating such complex surfaces is threefold: The deformation technique has to be sufficiently fast, robust, intuitive, and easy to control to be useful for interactive applications. An intuitive and, thus, predictable deformation tool should provide physically plausible and aesthetically pleasing surface deformations, which, in particular, requires its geometric details to be preserved. The methods that we survey generally formulate surface deformation as a global variational optimization problem that addresses the differential properties of the edited surface. Efficiency and robustness are achieved by linearizing the underlying objective functional such that the global optimization amounts to solving a sparse linear system of equations. We review the different deformation energies and detail preservation techniques that were proposed in recent years, together with the various techniques to rectify the linearization artifacts. Our goal is to provide the reader with a systematic classification and comparative description of the different techniques, revealing the strengths and weaknesses of each approach in common editing scenarios.", "corpus_id": 207261, "score": 0 }, { "doc_id": "40659497", "title": "Deformation transfer for triangle meshes", "abstract": "Deformation transfer applies the deformation exhibited by a source triangle mesh onto a different target triangle mesh. Our approach is general and does not require the source and target to share the same number of vertices or triangles, or to have identical connectivity. The user builds a correspondence map between the triangles of the source and those of the target by specifying a small set of vertex markers. Deformation transfer computes the set of transformations induced by the deformation of the source mesh, maps the transformations through the correspondence from the source to the target, and solves an optimization problem to consistently apply the transformations to the target shape. The resulting system of linear equations can be factored once, after which transferring a new deformation to the target mesh requires only a backsubstitution step. Global properties such as foot placement can be achieved by constraining vertex positions. We demonstrate our method by retargeting full body key poses, applying scanned facial deformations onto a digital character, and remapping rigid and non-rigid animation sequences from one mesh onto another.", "corpus_id": 40659497, "score": 0 } ]

{ "doc_id": "52140620", "title": "Numerical Simulation of Fracking in Shale Rocks: Current State and Future Approaches", "abstract": "Extracting gas from shale rocks is one of the current engineering challenges but offers the prospect of cheap gas. Part of the development of an effective engineering solution for shale gas extraction in the future will be the availability of reliable and efficient methods of modelling the development of a fracture system, and the use of these models to guide operators in locating, drilling and pressurising wells. Numerous research papers have been dedicated to this problem, but the information is still incomplete, since a number of simplifications have been adopted such as the assumption of shale as an isotropic material. Recent works on shale characterisation have proved this assumption to be wrong. The anisotropy of shale depends significantly on the scale at which the problem is tackled (nano, micro or macroscale), suggesting that a multiscale model would be appropriate. Moreover, propagation of hydraulic fractures in such a complex medium can be difficult to model with current numerical discretisation methods. The crack propagation may not be unique, and crack branching can occur during the fracture extension. A number of natural fractures could exist in a shale deposit, so we are dealing with several cracks propagating at once over a considerable range of length scales. For all these reasons, the modelling of the fracking problem deserves considerable attention. The objective of this work is to present an overview of the hydraulic fracture of shale, introducing the most recent investigations concerning the anisotropy of shale rocks, then presenting some of the possible numerical methods that could be used to model the real fracking problem.", "corpus_id": 52140620 }

[ { "doc_id": "129957381", "title": "An approach for assessing engineering risk from shale gas wells in the United States", "abstract": "In response to a series of “energy crises” in the 1970s, the United States government began investigating the potential of unconventional, domestic sources of energy to offset imported oil. Hydraulic fracturing applied to vertical tight sand and coal bed methane wells achieved some degree of success during a period of high energy prices in the early 1980s, but shale gas remained largely untapped until the late 1990s with the application of directional drilling, a mature technology adapted from deepwater offshore platforms that allowed horizontal wells to penetrate kilometers of organic-rich shale, and staged hydraulic fracturing, which created high permeability flowpaths from the horizontal wells into a much greater volume of the target formations than previous completion methods. \n \nThese new engineering techniques opened up vast unconventional natural gas and oil reserves, but also raised concerns about potential environmental impacts. These include short-term and long-term impacts to air and water quality from rig operations, potential migration of gas, fluids and chemicals through the ground, and effects on small watersheds and landscapes from roads, pads and other surface structures. \n \nEngineering risk assessment commonly uses integrated assessment models (IAMs), which define sources of risk from features, events and processes. The risk from each system element is assessed using high-fidelity models. Output from these is simplified into reduced-order models, so that a large, integrated site performance assessment can be run using the IAM. The technique has been applied to engineered systems in geologic settings for sequestering carbon dioxide, and it is also applicable to shale gas, albeit with some modifications of the various system elements. \n \nPreliminary findings indicate that shale gas well drilling and hydraulic fracturing techniques are generally safe when properly applied. Incident reports recorded by state environmental agencies suggest that human error resulting from the disregard of prescribed practices is the greatest cause of environmental incidents. This can only be addressed through education, regulations and enforcement.", "corpus_id": 129957381, "score": 0 }, { "doc_id": "54694458", "title": "Oil and gas wells and their integrity : implications for shale and unconventional resource exploitation", "abstract": "Data from around the world (Australia, Austria, Bahrain, Brazil, Canada, the Netherlands, Poland, the UK and the USA) show that more than four million onshore hydrocarbon wells have been drilled globally. Here we assess all the reliable datasets (25) on well barrier and integrity failure in the published literature and online. These datasets include production, injection, idle and abandoned wells, both onshore and offshore, exploiting both conventional and unconventional reservoirs. The datasets vary considerably in terms of the number of wells examined, their age and their designs. Therefore the percentage of wells that have had some form of well barrier or integrity failure is highly variable (1.9%–75%). Of the 8030 wells targeting the Marcellus shale inspected in Pennsylvania between 2005 and 2013, 6.3% of these have been reported to the authorities for infringements related to well barrier or integrity failure. In a separate study of 3533 Pennsylvanian wells monitored between 2008 and 2011, there were 85 examples of cement or casing failures, 4 blowouts and 2 examples of gas venting. In the UK, 2152 hydrocarbon wells were drilled onshore between 1902 and 2013 mainly targeting conventional reservoirs. UK regulations, like those of other jurisdictions, include reclamation of the well site after well abandonment. As such, there is no visible evidence of 65.2% of these well sites on the land surface today and monitoring is not carried out. The ownership of up to 53% of wells in the UK is unclear; we estimate that between 50 and 100 are orphaned. Of 143 active UK wells that were producing at the end of 2000, one has evidence of a well integrity failure.", "corpus_id": 54694458, "score": 0 }, { "doc_id": "67847487", "title": "Reservoir modeling of shale formations", "abstract": "Abstract Economic production from shale has been intimately tied to hydraulic fracturing since the first signs of success in Barnet Shale in the late 90s. The introduction of horizontal wells and multi-stage hydraulic fracturing was met by a huge move by operators toward developing shale formations that were mainly ignored in the past. Today using pad drilling, multiple horizontal wells share surface facilities and infrastructure, a development that minimizes the industry's environmental footprint. To understand production from shale reservoirs one must understand the network of natural fractures in the shale and the role of hydraulically induced fractures and their interaction. Hydraulic fracturing has been around and been studied by engineers for decades. Analytical, numerical and data-driven models have been built to explain their behavior and contribution to flow. Contribution of natural fracture networks to storage and flow in carbonate (and some sandstone) reservoirs had led to the development of techniques to study and model them. Since they are the predominant source of porosity and permeability in shale, more attention has been focused on their characteristics in the recent years. Studies of methane production from coal seams in the mid 80s provided insights on sorption as a storage mechanism and desorption and diffusion as a transport phenomenon in reservoirs that came to be known as CBM (Coalbed Methane). Today, production from shale is mainly modeled based on lessons learned in the past several decades where all the above techniques are integrated to create the modern shale reservoir models. The coupling of hydraulic fractures and natural fracture networks and their integration and interaction with the shale matrix remains the major challenge in reservoir simulation and modeling of shale formations. This article reviews the methods used by scientists and engineers in recent years to understand the complexities associated with production from shale. This will shed light on the commonly held belief amongst some of the best minds in reservoir engineering (those that have been intimately involved in modeling production from shale) that there is much to be learned about this complex resource and that our best days in understanding and modeling how oil and gas are produced from shale are still ahead of us.", "corpus_id": 67847487, "score": 0 }, { "doc_id": "201733856", "title": "Clay mineral diagenesis in sedimentary basins — a key to the prediction of rock properties. Examples from the North Sea Basin", "abstract": "Abstract Dissolution of feldspar and mica and precipitation of kaolinite require a through flow of meteoric water to remove cations such as Na+ and K+ and silica. Compaction driven pore-water flow is in most cases too slow to be significant in terms of transport of solids. The very low solubility of Al suggests that precipitation of new authigenic clay minerals requires unstable Al-bearing precursor minerals. Chlorite may form diagenetically from smectite and from kaolinite when a source of Fe and Mg is present. In the North Sea Basin, the main phase of illite precipitation reducing the quality of Jurassic reservoirs occurs at depths close to 4 km (130-140°C) but the amount of illite depends on the presence of both kaolinite and K-feldspar. Clay mineral reactions in shales and sandstones are very important factors determining mechanical and chemical compaction and are thus critical for realistic basin modelling.", "corpus_id": 201733856, "score": 0 }, { "doc_id": "129739071", "title": "Principal aspects of compaction and fluid flow in mudstones", "abstract": "Abstract Compaction and fluid flow in sedimentary basins are usually modelled as mechanical compaction assuming that the main driving force is the effective stress. However, in the deeper part of sedimentary basins (> 2–3 km, 70–100°C), compaction also involves dissolution and precipitation of minerals, and these processes are strongly controlled by temperature and to a lesser extent by variations in effective stress. The total pore-water flux is relatively independent of the permeability and pressure gradients because it is controlled by the rate of compaction. The main effect of permeability variations is the focusing of the compaction-driven flow. Fluids are also released by petroleum generation and dehydration of clay minerals; both these processes are also essentially temperature dependent. If the minimum permeability in one sedimentary layer (seal) falls below a critical value and there is little lateral drainage, the pressure will build up to fracture pressure. Pore pressures and fluid flow cannot be calculated from the matrix permeability of the rock when fracture pressures are reached, because much of the flow occurs along the generated fractures. The permeability produced by fracturing is a dynamic variable adjusting itself to the flux; it is not a rock property like the intergranular permeability. The intergranular permeability of shale samples before fracturing is also difficult to measure reliably in the laboratory as a result of unloading. This makes pressure prediction using one-dimensional pressure modelling uncertain. The prediction of permeability distributions in three dimensions is much more difficult.", "corpus_id": 129739071, "score": 0 }, { "doc_id": "140592967", "title": "Definition and practical application of mudstone porosity–effective stress relationships", "abstract": "The relationship developed in soil mechanics between void ratio and vertical effective stress is a simple but practical way of describing the one-dimensional, mechanical compaction of fine-grained, clastic mudstones. The compression coefficients (e100 and ß) that define this relationship are strongly influenced by grain size, which can be simply described by the sediment's clay content. In this paper, data both from the soil mechanics literature and from geological samples from the North Sea and Gulf of Mexico are used to construct the relationship between clay content and compression coefficients. The two datasets yield different values for the coefficients, but the authors believe that the coefficients derived from the large geological database should be used to describe geological compaction. Regression of the geological data generates the following relationships between clay content and compression coefficients: \\batchmode \\documentclass[fleqn,10pt,legalpaper]{article} \\usepackage{amssymb} \\usepackage{amsfonts} \\usepackage{amsmath} \\pagestyle{empty} \\begin{document} \\[e_{100}{\\,}={\\,}0.3024{\\,}+{\\,}1.6867clay{\\,}+{\\,}1.9505clay^{2}\\] \\end{document} \\batchmode \\documentclass[fleqn,10pt,legalpaper]{article} \\usepackage{amssymb} \\usepackage{amsfonts} \\usepackage{amsmath} \\pagestyle{empty} \\begin{document} \\[{\\beta}{\\,}={\\,}0.0407{\\,}+{\\,}0.2479clay{\\,}+{\\,}0.3684clay^{2}\\] \\end{document} There is excellent agreement between true porosities and porosities calculated using the standard soil mechanics compaction equation with these coefficients. This indicates that the mechanical compaction of natural mudstones to 40 MPa can be adequately described using the soil mechanics approach. Practical application of the work is a two-stage process which first involves the evaluation of clay content and, thus, compression coefficients directly from wireline log data. These data can then be used to (a) help define effective stress–porosity inputs for basin models and (b) estimate mudstone pore pressures. Examples of pore pressure estimates are shown from west Africa, the North Sea and the Gulf of Mexico.", "corpus_id": 140592967, "score": 0 }, { "doc_id": "129044817", "title": "Mechanism of burial metamorphism of argillaceous sediment: 1. Mineralogical and chemical evidence", "abstract": "A detailed mineralogical and chemical investigation has been made of shale cuttings from a well (Case Western Reserve University Gulf Coast 6) in Oligocene-Miocene sediment of the Gulf Coast of the United States. The 10-µm fractions from the 1,250- to 5,500-m stratigraphic interval were analyzed by x-ray diffraction. Major mineralogic changes with depth take place over the interval 2,000 to 3,700 m, after which no significant changes are detectable. The most abundant mineral, illite/smectite, undergoes a conversion from less than 20 percent to about 80 percent illite layers over this interval, after which the proportion of illite layers remains constant. Over the same interval, calcite decreases from about 20 percent of the rock to almost zero, disappearing from progressively larger size fractions with increasing depth; potassium feldspar (but not albite) decreases to zero; and chlorite appears to increase in amount. Variations in the bulk chemical composition of the shale with depth show only minor changes, except for a marked decrease in CaO concomitant with the decrease in calcite. By contrast, the <0.1-µm fraction (virtually pure illite/smectite) shows a large increase in K2O and Al2O3 and a decrease in SiO2 The atomic proportions closely approximate the reaction smectite + Al+3 + K+ = illite + Si+4. The potassium and aluminum appear to be derived from the decomposition of potassium feldspar (and mica?), and the excess silicon probably forms quartz. We interpret all the major mineralogical and chemical changes as the response of the shale to burial metamorphism and conclude that the shale acted as a closed system for all components except H2O, CaO, Na2O, and CO2. Compositional changes in the shale as a function of metamorphic grade closely parallel compositional changes in shale as a function of geologic age.", "corpus_id": 129044817, "score": 0 }, { "doc_id": "130565896", "title": "NATURE OF MIXED-LAYER CLAYS AND MECHANISMS OF THEIR FORMATION AND ALTERATION", "abstract": "▪ Abstract Mixed-layer clay minerals are intermediate products of reactions involving pure end-member clays. They come from natural environments ranging from surface to low-grade metamorphic and hydrothermal conditions. Most often mixed layering is essentially two component, but more complicated interstratifications have also been documented. Variable tendency to form regular 1:1 interstratifications has been observed and explanations of this phenomenon have been proposed. Mixed-layer clays are either di- or trioctahedral; di/trioctahedral interstratifications are rare. Most mixed-layer clays contain smectite or vermiculte as a swelling component. Exceptions are all trioctahedral: serpentine/chlorite in low-temperature environments, and mica/chlorite and talc/chlorite at high temperatures. Solid state transformation and dissolution/crystallization are the two mechanisms responsible for the formation of different mixed-layer clays. In general, the weathering reactions that produce mixed layering are revers...", "corpus_id": 130565896, "score": 0 }, { "doc_id": "44222734", "title": "Diagenetic reorientation of phyllosilicate minerals in Paleogene mudstones of the Podhale Basin, southern Poland", "abstract": "We used high-resolution X-ray texture goniometry to quantify changes in the mm-scale orientation of phyllosilicate minerals in a suite of Paleogene mudstones from the Podhale Basin in southern Poland. The sample set covers an estimated range of burial depths between 2.4 and 7.0 km, corresponding to a temperature range of 60–160°C. Although mechanical compaction has reduced porosities to ∼10% in the shallowest samples, the phyllosilicate fabric is only modestly aligned. Coarser-grained (>10 µm) detrital chlorite and mica appear to be more strongly aligned with (001) parallel to bedding, suggesting their deposition as single grains rather than as isotropic flocs or aggregates. From 2.4 to 4.6 km, R0 illite-smectite with 40–50% illite layers changes to R1 illite-smectite with 70–80%) illite layers. At the same time kaolinite is lost and diagenetic chlorite is formed. The mineralogical changes are accompanied by a strong increase in the alignment of illite-smectite, chlorite, and detrital illite, parallel to bedding and normal to the presumed principal effective stress. We propose that the development of a more aligned I-S fabric results from the dissolution of smectite and the growth of illite with (001) normal to the maximum effective stress. Water released by illitization may act as a lubricant for the rotation of all platy minerals into nanoporosity transiently formed by the illitization reaction. At greater depths and temperatures, further illitization is inhibited through the exhaustion of K-feldspar. After the cessation of illitization, a further 2.4 km of burial only results in a small increase in phyllosilicate alignment. At such small values for porosity and pore size, increasing stress does not substantially reorient phyllosilicates in the absence of mineralogical change.", "corpus_id": 44222734, "score": 0 }, { "doc_id": "41539159", "title": "Fabric anisotropy induced by primary depositional variations in the silt: clay ratio in two fine-grained slope fan complexes: Texas Gulf Coast and northern North Sea", "abstract": "article i nfo High-resolution X-ray texture goniometry (HRXTG) has been used to quantify the alignment (anisotropy) of phyllosilicate minerals in a series of diagenetically altered mudstone samples from the deep subsurface of the Texas Gulf Coast and the northern North Sea. The sampled formations have undergone a simple burial history with no overprint of tectonic deformation that may have influenced the phyllosilicate orientation. Observations have been made in two constrained temperature windows 148-150 °C (North Sea data) and 169-210 °C (Texas Gulf Coast) wherein less than 20% smectite remains in the mixed layer phase illite- smectite. Quantitative X-ray powder diffraction (XRPD) shows quartz (which is dominantly detrital) and phyllosilicate content having an inverse relationship. Quantified illite-smectite fabric intensity (phyllosi- licate alignments) ranges from low alignment values of 2.42 m.r.d. (multiples of a random distribution) to high alignment values 6.75 m.r.d. and chlorite+kaolinite ranges from 1.80 to 6.46 m.r.d. We propose that the broad range of phyllosilicate fabric intensity observed reflects the range of quartz/phyllosilicate ratios that are the imprint of depositional setting, bedform truncation, and initial grain size. Detrital quartz acts to disrupt fabric intensity by being non-platy, producing areas sheltered from effective stress ('pressure shadows'), and acting as a matrix support. There is no evidence that bioturbation is a significant control on phyllosilicate alignment in these quartz/phyllosilicate mixtures. These findings have important implications for the role of grain-scale alignment on seismic anisotropy in mudstone systems. Fabric intensity in post- diagenetic samples can be predicted from (1) quartz content and (2) total clay content where:", "corpus_id": 41539159, "score": 0 }, { "doc_id": "129674363", "title": "Preferred Orientation of Phyllosilicates in Gulf Coast Mudstones and Relation to the Smectite-Illite Transition", "abstract": "Development of preferred orientations of illite-smectite (I-S) has been studied using X-ray diffraction (XRD) texture goniometry to produce pole figures for clay minerals of a suite of 16 mudstone samples from a core from the Gulf Coast. Samples represent a compaction-loading environment in which the smectite-to-illite (S-I) transition occurs. In five shallow, pre-transition samples, there is no significant preferred orientation for smectite-rich I-S. Development of preferred orientation of I-S, although weak, was first detected at depths slightly less than that of the S-I transition. The degree of preferred orientation, which is always bedding-parallel, increases rather abruptly, but continuously, over a narrow interval corresponding to the onset of the S-I transition, then continues to strengthen only slightly with increasing depth. The degree of post-transition preferred orientation is also dependent on lithology, where the preferred orientation is less well-defined for quartz-rich samples.Previously obtained transmission electron microscope (TEM) data define textures consistent with the change in orientation over many crystallites. The smectite in pre-transition rocks consists largely of anastomosing, “wavy” layers with variable orientation and whose mean orientation is parallel to bedding, but which deviate continuously from that orientation. This results in broad, poorly defined peaks in pole figures. Post-transition illite, by contrast, consists of thin, straight packets, with most individual crystallites being parallel or nearly parallel to bedding. This results in pole figures with sharply defined maxima. By analogy with development of slaty cleavage in response to tectonic stress during metamorphism, the S-I transition is marked by dissolution of smectite and neocrystallization of illite or I-S locally within the continuous “megacrystals” of smectite. The transition is inferred to have some component of mechanical rotation of coherent illite crystals within a pliant matrix of smectite. The data suggest that change in orientation and coalescence of clay packets plays an important role in the formation of the hydraulic seal required for overpressure generation.", "corpus_id": 129674363, "score": 0 }, { "doc_id": "129710049", "title": "Clay mineral diagenesis and quartz cementation in mudstones: The effects of smectite to illite reaction on rock properties", "abstract": "Abstract The Late Cretaceous to Early Tertiary sequence of the Voring and More Basins from the Norwegian Sea has been examined with respect to mineralogy based on 319 cutting samples from five wells. A clear relationship between mineralogy and well log data is demonstrated. A significant change with respect to velocity, porosity and density occurs within the depth interval corresponding to 80–90 °C. At shallow depths/temperatures (", "corpus_id": 129710049, "score": 0 }, { "doc_id": "129617633", "title": "Quartz cementation in Late Cretaceous mudstones, northern North Sea: Changes in rock properties due to dissolution of smectite and precipitation of micro-quartz crystals", "abstract": "Abstract Late Cretaceous mudstones from two wells located in the northern North Sea and the Norwegian Sea have been examined with respect to quartz cement. Two different types of quartz cement (Type 1 and Type 2) have been identified using SEM/EDS/CL-analysis of drill-bit cuttings at depths 2370–2670 m (80–85 °C). Type 1 appears as relatively large aggregates (30–100 μm) of depth/temperature related crypto- or microcrystalline to macrocrystalline irregular quartz cement formed by local re-crystallization of biogenic silica. The CL-responses of Type 1 quartz cement give a clear indication of an authigenic origin. Type 2 quartz cement represents relatively high amounts of extremely fine-grained micro-sized (1–3 μm) crystals embedded as discrete, short chains or small clusters/nests within the illitized clay matrix. The CL-responses of micro-quartz crystals indicate an authigenic origin. The micro-quartz is most probably sourced from silica released during the smectite to illite dissolution–precipitation reaction. The petrographic evidence indicates that most of the silica released by the smectite to illite reaction has not been exported out of the mudstones. The silica released produce a subtle inter-connected micro-quartz network interlocked with aggregates of micro-quartz and authigenic clay crystals. This micro-quartz cementation process causes a significant and sharp change in the mudstone stiffness at the onset of the chemical compaction regime. This is indicated by an abrupt increase in well log velocity (Vp) and change in seismic facies close to 2500 m (80/85 °C).", "corpus_id": 129617633, "score": 0 }, { "doc_id": "140688470", "title": "An evaluation of temperature scales for silica diagenesis in diatomaceous sequences including a new approach based on the Miocene Monterey Formation, California", "abstract": "Geologic relations indicate that silica phases transformed in the Monterey Formation in two zones that persist over a narrow depth/temperature range and do not stratigraphically overlap. The wide and overlapping range of reported temperatures of these transformations is mainly a result of the many uncertainties inherent in the different methods used to estimate temperature and does not indicate that phases transform throughout these ranges. Our approach to a reliable temperature scale for silica diagenesis combines as empirical zonation of silica phases with temperature calibration from a sequence at maximum temperature and depth of burial.", "corpus_id": 140688470, "score": 0 }, { "doc_id": "128547516", "title": "Silica diagenesis; II, General mechanisms", "abstract": "ABSTRACT Amorphous silica phases (opal-A) precipitate in nature due to the formation of dense colloids in supersaturated alkaline aqueous solutions with low relative concentrations of other ions. Opal-A dissolves and yields solutions of still relatively high silica content. In pore waters containing abundant cations, open framework polymers form which flocculate to yield opal-CT. Opal-CT becomes increasingly ordered, primarily due to preferential growth of cristobalite relative to tridymite and crystal size increase. Opal-CT dissolves to yield pore waters of low silica concentration, which allows slow growth of quartz crystals from monomeric solution. The quartz crystals then slowly increase in size and crystallinity. Carbonates appear to enhance opal-CT formation, possibly due to the activity of positively charged hydroxyl complexes. Hence, polymerization in relatively pure systems is involved in opal-A formation and polymerization in impure systems is involved in opal-CT formation, and slow growth from monomeric (low silica concentration) solutions is involved in precipitation of quartz in sedimentary realms.", "corpus_id": 128547516, "score": 0 }, { "doc_id": "131079770", "title": "Pressure solution during diagenesis", "abstract": "Pressure solution is a durable problem in geology. It has engendered continuing arguments on its mechanism, thermodynamic basis, and geo­ logical significance. Recently, it has drawn renewed attention both for its important role in the diagenesis of sedimentary rocks and for its relation to rock deformation. Pressure solution is defined as a process by which grains dissolve at intergranular or intercrystalline contacts. This process is presumably related to the higher solubility under nonhydrostatic stress at the contacts than at free grain surfaces. The process often, although not always, is accompanied by reprecipitation at adjacent free grain surfaces. Nevertheless, it is not justifiable to treat pressure solution as a recrys­ tallization process. Two common types of pressure solution are recognized: intergranular pressure solution and stylolitization. The former, occurring at individual grain contacts, was first described by Sorby (1863) based on experiments and theoretical predictions by Thompson ( l862a,b). The latter produces \"a surface or contact that is marked by an irregular and interlocking penetration of the two sidcs, and is supposedly formcd diagenctically by differential vertical movement under pressure, accompanied by solution\" (Bates & Jackson 1980). Here we use the term stylolite for a surface that involves an aggregate of grains (the \"aggregate stylolite\" of Park & Schot 1968), originating exclusively by dissolution under nonhydrostatic stress.", "corpus_id": 131079770, "score": 0 }, { "doc_id": "130510686", "title": "From Oil-Prone Source Rock to Gas-Producing Shale Reservoir - Geologic and Petrophysical Characterization of Unconventional Shale Gas Reservoirs", "abstract": "Many currently producing shale-gas reservoirs are overmature oil-prone source rocks. Through burial and heating these reservoirs evolve from organic-matter-rich mud deposited in marine, lacustrine, or swamp environments. Key characterization parameters are: total organic carbon (TOC), maturity level (vitrinite reflectance), mineralogy, thickness, and organic matter type. Hydrogento-carbon (HI) and oxygen-to-carbon (OI) ratios are used to classify organic matter that ranges from oil-prone algal and herbaceous to gas-prone woody/coaly material. Although organic-matter-rich intervals can be hundreds of meters thick, vertical variability in TOC is high ( 50% of the total porosity, and these pores may be hydrocarbon wet, at least during most of the thermal maturation process. A full understanding of the relation of porosity and gas content will result in development of optimized processes for hydrocarbon recovery in shale-gas reservoirs.", "corpus_id": 130510686, "score": 0 }, { "doc_id": "130641048", "title": "Unconventional shale-gas systems: The Mississippian Barnett Shale of north-central Texas as one model for thermogenic shale-gas assessment", "abstract": "Shale-gas resource plays can be distinguished by gas type and system characteristics. The Newark East gas field, located in the Fort Worth Basin, Texas, is defined by thermogenic gas production from low-porosity and low-permeability Barnett Shale. The Barnett Shale gas system, a self-contained source-reservoir system, has generated large amounts of gas in the key productive areas because of various characteristics and processes, including (1) excellent original organic richness and generation potential; (2) primary and secondary cracking of kerogen and retained oil, respectively; (3) retention of oil for cracking to gas by adsorption; (4) porosity resulting from organic matter decomposition; and (5) brittle mineralogical composition. The calculated total gas in place (GIP) based on estimated ultimate recovery that is based on production profiles and operator estimates is about 204 bcf/section (5.78 × 10 9 m 3 /1.73 × 10 4 m 3 ). We estimate that the Barnett Shale has a total generation potential of about 609 bbl of oil equivalent/ac-ft or the equivalent of 3657 mcf/ac-ft (84.0 m 3 /m 3 ). Assuming a thickness of 350 ft (107 m) and only sufficient hydrogen for partial cracking of retained oil to gas, a total generation potential of 820 bcf/section is estimated. Of this potential, approximately 60% was expelled, and the balance was retained for secondary cracking of oil to gas, if sufficient thermal maturity was reached. Gas storage capacity of the Barnett Shale at typical reservoir pressure, volume, and temperature conditions and 6% porosity shows a maximum storage capacity of 540 mcf/ac-ft or 159 scf/ton.", "corpus_id": 130641048, "score": 0 }, { "doc_id": "129783556", "title": "Some pragmatic perspectives in source rock geochemistry", "abstract": "Abstract Conceptual advances in petroleum source rock geochemistry made during the last decade are reviewed and some problem areas in analytical geochemistry are outlined. Areas of discussion include views of source rocks based on assessment of hydrocarbon expulsion, kinetic models of kerogen maturation/vitrinite reflectance evolution and a discussion of the data dilemma facing modern source rock geochemistry. The increased application of petroleum geochemistry to the quantitative solution of geological problems is stressed.", "corpus_id": 129783556, "score": 0 }, { "doc_id": "129176136", "title": "Simple kinetic models of petroleum formation. Part III : Modelling an open system", "abstract": "Abstract The movement of petroleum from organic-rich source beds to potential carrier beds is the net result of two processes: expulsion—the release of generated petroleum from kerogen within the source bed; and primary migration — flow of a petroleum phase through the inorganic void networks of the source bed and all other intervening fine-grained rocks. Expulsion is by far the more important process within the source bed. Orgas , a simple zero-dimensional model of the source rock as an open system, explicitly models expulsion, concurrent with oil and gas generation and oi-lgas cracking, as a storage/threshold problem. Oil and gas are retained (adsorbed/absorbed) within kerogen until their concentrations exceed the respective sorptive capacity of the residual organic carbon (0.1 and 0.02 g g CK −1 ). The initial hydrogen index (Hl 0 ) controls the important balance between potential sorbate (petroleum) and sorbant (residual carbon). Using simple geochemical measurements, the initial organic carbon is divided into initial oil, inert kerogen and oil- and gas-generative (reactive) kerogen components. reactive kerogens are assigned to one of five global kinetic organofacies with pre-determined kinetic parameter sets governing separately rates of oil and gas generation. Kinetic parameters governing the rates of oil cracking within the source rock are predicted from Hl 0 . The two most important determinants of source rock behaviour are organofacies and Hl 0 . At a reference constant heating rate of 2°C Ma −1 , the projected oil expulsion threshold for typical organofacies members increases in the order A-DE (100, 110, 120, 135°C); F typically expels no oil. An order of magnitude increase (decrease) in heating rate increases (decreases) these thresholds by ca. 15°C. Typical cumulative gas mass fractions in their ultimate expulsion products are (A–F): 0.25, 0.3, 0.25, 0.65 and 1.0 g g −1 . A value of 200 mg HC g C −1 is an approximate minimum Hl 0 prerequisite for oil expulsion, irrespective of absolute petroleum potential (P 0 ). As a family, coals vary dramatically in their expulsion behaviour as their Hl 0 ranges both above and velow this value. Primary migration is efficient: for expulsive source rocks, movement within the source bed is limited only at low P 0 . A source rocks total genetic potential (P 0 , thickness) becomes important during migration outside the source bed: it potentially restricts the primary migration distance and the excess of petroleum available for secondary migration and entrapment. We evaluate primary migration approximately using a small migration loss factor (no more than about 10% saturation of porosity or 1 mg g −1 ), coupled with an understanding of fluid potential gradients which determine migration direction within the stratigraphic architecture. Ultimately, kerogen degradation and oil to gas cracking in the source rock are the rate-limiting processes in petroleum accumulation.", "corpus_id": 129176136, "score": 0 }, { "doc_id": "98444079", "title": "Changes in Type II Kerogen Density as a Function of Maturity: Evidence from the Kimmeridge Clay Formation", "abstract": "Kerogens were purified from 26 samples of the Kimmeridge Clay Formation over the full range of maturities pertinent to petroleum generation. Most samples comprised >90% amorphous organic matter (AOM). Prior to and during the early phase of petroleum generation, kerogen densities range between 1.18 and 1.25 g cm-3. During peak and late stage petroleum generation, densities increase to ∼1.35 g cm-3 as hydrogen indices decrease from ∼350 to 50 mg HC/g C. The data are qualitatively consistent with the loss of alkyl carbon from kerogen to petroleum and the increased aromatization of remaining carbon. The density increase observed for AOM contrasts with the data for vitrinite, which exhibits a decrease in density at maturity levels relevant to petroleum generation. The contrasting behavior of AOM and vitrinite is thought to reflect the differing structural composition of the two kerogen types, most obviously the greater initial aromaticity of vitrinite.", "corpus_id": 98444079, "score": 0 }, { "doc_id": "99373077", "title": "Mechanical properties of organic matter in shales mapped at the nanometer scale", "abstract": "Abstract The mechanical properties of organic matter strongly affect the way shales deform and fracture. However, the way organic matter responds to mechanical stresses is poorly understood, representing a critical obstacle to assessing oil and gas production in shale formations. Little is known about the mechanical properties of organic matter in fine grained rocks primarily because it often occupies tiny nanometer-scale voids between the mineral grains which cannot be accessed using standard mechanical testing techniques. Here, we use a new atomic force microscopy technique (PeakForce QNM™) to map the mechanical properties of organic and inorganic components at the nanometer scale. We find that the method is able to distinguish between different phases such as pyrite, quartz, clays, and organic matter. Moreover, within the organic component Young's modulus values ranged from 0 to 25 GPa; in 3 different samples – all of which come from thermally mature Type II/III source rocks in the dry gas window – a modal value of 15–16 GPa was measured, with additional peaks measured at ≤10 GPa. In addition, the maps suggest that some porous organic macerals possess a soft core surrounded by a harder outer shell 50–100 nm thick. Thus, our results demonstrate that the method represents a powerful new petrographic tool with which to characterize the mechanical properties of organic-rich sedimentary rocks.", "corpus_id": 99373077, "score": 0 }, { "doc_id": "129315747", "title": "Mudstone diversity: Origin and implications for source, seal, and reservoir properties in petroleum systems", "abstract": "Mudstone is the most abundant sedimentary rock and variously acts as sources, seals, and shale gas reservoirs in petroleum systems. Many important physicochemical properties of mudstones are strongly influenced by the mineralogy and size of deposited grains, and by diagenetic changes (precompaction and postcompaction); these are commonly predictable. The diverse composition of mudstones reflects input and hydrodynamic segregation of detrital materials to basins, primary production within basins, and diagenetic processes (both precipitation and dissolution) in the sediment. High-magnification observations both in modern and ancient sediments demonstrate that mudstones are texturally and mineralogically heterogeneous; this variability is not always readily apparent. Although some mud is indeed deposited by suspension settling out of low-energy buoyant plumes, textural analyses reveal that it is commonly dispersed by a combination of waves, gravity-driven processes, and unidirectional currents driven variously by storms and tides. Such dispersal mechanisms mean that muddy successions are typically organized into packages that can be interpreted using sequence stratigraphy. Early bioturbation homogenizes mud, whereas early chemical diagenesis can result in highly cemented zones developing, especially at stratal surfaces. The nature of deeper burial diagenesis, which involves compaction, mineral dissolution, recrystallization, mineral reorientation and lithification, and petroleum generation, is preconditioned by depositional and early diagenetic characteristics of the mud. Although the petrophysical properties of homogeneous mudstones are reasonably well known, the quantitative implications of heterogeneity for petroleum expulsion, retention, petroleum migration, seal capacity, acoustic anisotropy, and identification of shale gas reservoir sweet spots are essentially unexplored. Future work should seek to redress this position.", "corpus_id": 129315747, "score": 0 }, { "doc_id": "129215209", "title": "Parasequence types in shelfal mudstone strata—Quantitative observations of lithofacies and stacking patterns, and conceptual link to modern depositional regimes", "abstract": "Mudstone strata have a vast variety of physical, biogenic, and chemical attributes at the lamina to bed scale (approximately millimeters to decimeters thick). Our observations of more than 7 km of Paleozoic to Cenozoic mudstones revealed ordered patterns in this variety, i.e., recurrent associations of lithofacies, bedding style, sedimentary structures, and stratal architecture at bedset to parasequence scales (approximately decimeters to meters thick). We quantified characteristics of each association and their stacking patterns in vertical succession and linked them to sets of depositional processes. Most shelf mudstone strata appear to have accumulated in one of three facies association successions (FASs) that can be related to depositional regimes through characteristic modes of sediment transport and accumulation, as well as variations in benthic-energy and oxygen levels. We interpret these three FASs as records of mud accumulation on different portions of continental shelves that were dominated by storm waves, river floods, or tidal currents. Each FAS records a distinct parasequence type. This approach can help fully integrate insights from oceanographic studies into more robust interpretations of the rock record and rock-property maps.", "corpus_id": 129215209, "score": 0 }, { "doc_id": "54041012", "title": "Lenticular Shale Fabrics Resulting from Intermittent Erosion of Water-Rich Muds—Interpreting the Rock Record in the Light of Recent Flume Experiments", "abstract": "Lenticular lamination is a fabric that is known from shales of all ages, but its origin and paleoenvironmental significance is poorly understood. We have successfully reproduced this fabric in flume experiments. Beds of water-rich mud were eroded in a flume and yielded sub-millimeter to centimeter-size fragments that can be transported in bedload for distances of ten kilometers or more. Upon redeposition and compaction, these deposits have the same textural qualities as lenticular laminated shales from the rock record. Although accumulation of fecal pellets or abundant burrow tubes in a shale may produce comparable fabrics upon compaction, these can be distinguished from erosion-produced lenticular lamination via petrographic criteria. Lenticular lamination in shales that is due to deposition of water-rich mud fragments most likely records intermittent erosion and transport of surficial muds by currents.", "corpus_id": 54041012, "score": 0 }, { "doc_id": "128973505", "title": "Small-scale (<5.0 m) vertical heterogeneity in mudstones: implications for high-resolution stratigraphy in siliciclastic mudstone successions", "abstract": "48 mudstone samples, from the Peterborough Member, Oxford Clay Formation, have been analysed to determine the small-scale vertical and lateral lithofacies variability in this succession. The samples were collected every 0.15 m from Saxon and King's Dyke brickpits (Whittlesey, Peterborough, UK) over a short vertical interval (15 m). The sampled interval spans the obductum to the grossouvrei Subzones of the Callovian (Upper Jurassic). Lithofacies present were described using combined field logging, optical and backscattered electron optical techniques. The succession predominantly comprises silt-rich mudstones, with subordinate clay-rich mudstones, shell-beds and shell-pavements. The individual units are variously composed of detrital clay, quartz, pyrite, calcite with minor apatite, kaolinite and glauconite. In some units millimetre-scale upward-fining couplets are present; elsewhere, the original bedding structures have been destroyed by bioturbation. Comparison of successive thin sections reveals that upward-coarsening is present on a metre-scale and that shell-enriched units are located close to the tops of these upward-shoaling units. Comparison of samples collected laterally on a 0.01–1.0 m scale from the same level (3.0 m below the top of Bed 14) indicates that there is lateral lithofacies variability. The small-scale (0.001 m) couplets are interpreted to be beds deposited by waning flow currents. Significant breaks between these depositional events allowed a dysaerobic infauna to colonize the sediment. The metre-scale upward-coarsening intervals which are capped by shell-enriched units are interpreted to be parasequences. The observed small-scale lateral lithofacies variability is interpreted to be a product of small, but significant vertical miscorrelation errors rather that systematic lateral facies changes. These data suggest that producing reliable, bed-scale lateral correlations over distances of more than 1 km in this, and successions like it, will be very difficult.", "corpus_id": 128973505, "score": 0 }, { "doc_id": "136830611", "title": "The nano-mechanical morphology of shale", "abstract": "Abstract Shale, the sealing formations in most hydrocarbon reservoirs, is made of highly compacted clay particles of sub-micrometer size, nanometric porosity and different mineralogy. In this paper, we propose and validate a technique to identify the nano-mechanical morphology of such a nanocomposite material. In particular, by means of a massive nanoindentation campaign at two different scales on a large range of shale materials, we show that the highly compacted plate- or sheet-like clay particles have a distinct nano-mechanical morphology with no privileged orientation of the particle-to-particle contact surface, as evidenced by a mechanical percolation threshold of η 0  ⩾ 0.5. Furthermore, the nanoindentation results provide strong evidence that the nano-mechanical elementary building block of shales is transversely isotropic in stiffness, and isotropic and frictionless in strength. These observations lead to a sphere-like mechanical morphology for visibly plate- or sheet-like clay particles. The contact forces between the sphere-like particles activate the intrinsicly anisotropic elastic properties within the clay particles and the cohesive bonds between the clay particles. The mechanical stiffness and strength properties of porous clay scale with the clay packing density toward a unique set of shale-invariant material properties. The determination of mechanical microstructure and invariant material properties are of great importance for the development of predictive microporomechanical models of the stiffness and strength properties of shale. The approach presented here also applies to other chemically and mechanically complex materials exhibiting nanogranular behavior.", "corpus_id": 136830611, "score": 0 }, { "doc_id": "129398791", "title": "The effect of the nanogranular nature of shale on their poroelastic behavior", "abstract": "Natural composite materials are highly heterogeneous porous materials, with porosities that manifest themselves at scales much below the macroscale of engineering applications. A typical example is shale, the transverse isotropic sealing formation of most hydrocarbon bearing reservoirs. By means of a closed loop approach of microporomechanics modeling, calibration and validation of elastic properties at multiple length scales of shale, we show that the nanogranular nature of this highly heterogeneous material translates into a unique poroelastic signature. The self-consistent scaling of the porous clay stiffness with the clay packing density minimizes the anisotropy of the Biot pore pressure coefficients; whereas the intrinsic anisotropy of the elementary particle translates into a pronounced anisotropy of the Skempton coefficients. This new microporoelasticity model depends only on two shale-specific material parameters which neatly summarize clay mineralogy and bulk density, and which makes the model most appealing for quantitative geomechanics, geophysics and exploitation engineering applications.", "corpus_id": 129398791, "score": 0 }, { "doc_id": "131165807", "title": "The nanogranular acoustic signature of shale", "abstract": "A multiscale, micromechanics model has been developed for the prediction of anisotropic acoustic properties of shale. The model is based on the recently identified nanogranular mechanical response of shale through indentation experiments. It recognizes the dominant role of the anisotropic elastic properties of compacted clay in the anisotropic elasticity of shale at different length scales compared to contributions of shape and orientation of particles. Following a thorough validation at multiple length scales using mineral elasticity data, nanoindentation experiment results, and ultrasonic pulse velocity tests, the model predictions compare adequately with measurements on kerogen-free and kerogen-rich shales and shaley sandstones. The acoustic signature of shale thus is found to be controlled by two volumetric parameters that synthesize the porosity and mineralogy information: the clay-packing density and the silt inclusion volume fraction. Through a series of dimensionless isoparametric plots, the micromechanics model predicts trends of increasing elastic anisotropy with increasing clay-packing density (or decreasing porosity), which correspond to the intrinsic mechanical response of unfractured shale, and quantifies the stiffness reduction induced by the presence of kerogen.", "corpus_id": 131165807, "score": 0 }, { "doc_id": "122153912", "title": "The effect of particle shape and grain‐scale properties of shale: A micromechanics approach", "abstract": "Traditional approaches for modeling the anisotropic elasticity response of the highly heterogeneous clay fabric in shale have mainly resorted to geometric factors such as definitions of particles shapes and orientations. However, predictive models based on these approaches have been mostly validated using macroscopic elasticity data. The recent implementation of instrumented indentation aimed at probing nano-scale mechanical behaviors has provided a new context for characterizing and modeling the anisotropy of the porous clay in shale. Nanoindentation experimental data revealed the significant contribution of the intrinsic anisotropy of the solid clay to the measured elastic response. In this investigation, we evaluate both the effects of geometric factors and of the intrinsic anisotropic elasticity of the solid clay phase on the observed anisotropy of shale at multiple length scales through the development of a comprehensive theoretical micromechanics approach. It was found that among various combinations of these sources of anisotropy, the elastic response of the clay fabric represented as a granular ensemble of aligned effective clay particles with spherical morphology and anisotropic elasticity compares satisfactorily to nanoindentation and ultrasonic pulse velocity measurements at nano- and macroscopic length scales, respectively. Other combinations of sources of anisotropy could yield comparable predictions, particularly at macroscopic scales, at the expense of requiring additional experimental data to characterize the morphology and orientations of particles. Copyright © 2009 John Wiley & Sons, Ltd.", "corpus_id": 122153912, "score": 0 }, { "doc_id": "128482605", "title": "The nanogranular nature of shale", "abstract": "Despite their ubiquitous presence as sealing formations in hydrocarbon bearing reservoirs affecting many fields of exploitation, the source of anisotropy of this earth material is still an enigma that has deceived many decoding attempts from experimental and theoretical sides. Sedimentary rocks, such as shales, are made of highly compacted clay particles of sub-micrometer size, nanometric porosity and different mineralogy. In this paper, we present, for the first time, results from a new experimental technique that allows one to rationally assess the elasticity content of the highly heterogeneous clay fabric of shales from nano- and microindentation. Based on the statistical analysis of massive nanoindentation tests, we find (1) that the in-situ elasticity content of the clayfabric at a scale of a few hundred to thousands nanometers is almost an order of magnitude smaller than reported clay stiffness values of clay minerals, and (2) that the elasticity and the anisotropy scale linearly with the clay packing density beyond a percolation threshold of roughly 50%. Furthermore, we show that the elasticity content sensed by nano- and microindentation tests is equal to the one that is sensed by (small strain) velocity measurements. From those observations, we conclude that shales are nanogranular composite materials, whose mechanical properties are governed by particle-to-particle contact and by characteristic packing densities, and that the much stiffer mineral properties play a secondary role.", "corpus_id": 128482605, "score": 1 }, { "doc_id": "18905735", "title": "Statistical indentation techniques for hydrated nanocomposites: concrete, bone, and shale", "abstract": "Concrete, bone and shale have one thing in common: their load-bearing mineral phase is a hydrated nanocomposite. Yet the link between material genesis, microstructure, and mechanical performance for these materials is still an enigma that has deceived many decoding attempts. In this article, we advance statistical indentation analysis techniques that make it possible to assess, in situ, the nanomechanical properties, packing density distributions, and morphology of hydrated nanocomposites. These techniques are applied to identify intrinsic and structural sources of anisotropy of hydrated nanoparticles: calcium–silicate–hydrate (C–S–H), apatite, and clay. It is shown that C–S–H and apatite, the binding phase in, respectively, cement-based materials and bone, are intrinsically isotropic; this is most probably due to a random precipitation and growth process of particles in calcium oversaturated pore solutions, which can also explain the nonnegligible internanoparticle friction. In contrast, the load-bearing clay phase in shale, the sealing formation of most hydrocarbon reservoirs, is found to be intrinsically anisotropic and frictionless. This is indicative of a ‘smooth’ deposition and compaction history, which, in contrast to mineral growth in confined spaces, minimizes nanoparticle interlocking. In all cases, the nanomechanical behavior is governed by packing density distributions of elementary particles delimitating macroscopic diversity.", "corpus_id": 18905735, "score": 0 }, { "doc_id": "22329205", "title": "Producing Gas from Its Source", "abstract": "For help in preparation of this article, thanks to Barbara Anderson, Ridgefield, Connecticut, USA; Walter Arias, Rio de Janeiro, Brazil; Keith Greaves, Salt Lake City, Utah; Valerie Jochen, College Station, Texas; Barbara Marin and Mark Puckett, Houston, Texas; Camron Miller, Oklahoma City, Oklahoma; and Jeron Williamson, Pittsburgh, Pennsylvania. AIT (Array Induction Imager Tool), ClearFRAC, ECLIPSE, ECS (Elemental Capture Spectroscopy sonde), ELANPlus, FiberFRAC, FMI (Fullbore Formation MicroImager), geoVISION, Platform Express and SpectroLith are marks of Schlumberger. Shale, the most abundant of sedimentary rocks, is finally getting its due. Shale has", "corpus_id": 22329205, "score": 0 }, { "doc_id": "110046409", "title": "Regulating hydraulic fracturing in shale gas plays: The case of Texas", "abstract": "The ability to economically produce natural gas from unconventional shale gas reservoirs has been made possible recently through the application of horizontal drilling and hydraulic fracturing. This new technique has radically changed the energy future of the United States. The U.S. has shifted from a waning producer of natural gas to a growing producer. The Energy Information Administration forecasts that by 2035 nearly half of U.S. natural gas will come from shale gas. Texas is a major player in these developments. Of the eight states and coastal areas that account for the bulk of U.S. gas, Texas has the largest proved reserves. Texas' Barnett Shale already produces six percent of the continental U.S.' gas and exploration of Texas' other shale gas regions is just beginning. Shale gas production is highly controversial, in part because of environmental concerns. Some U.S. states have put hydraulic fracturing moratoriums in place because of fear of drinking water contamination. The federal government has gotten involved and some states, like Texas, have accused it of overreaching. The contention over shale gas drilling in the U.S. may be a bellwether for other parts of the world that are now moving forward with their own shale gas production.", "corpus_id": 110046409, "score": 0 }, { "doc_id": "130215687", "title": "Natural fractures in some US shales and their importance for gas production", "abstract": "Abstract Shale gas reservoirs are commonly produced using hydraulic fracture treatments. Microseismic monitoring of hydraulically induced fracture growth shows that hydraulic fractures sometimes propagate away from the present-day maximum horizontal stress direction. One likely cause is that natural opening-mode fractures, which are present in most mudrocks, act as weak planes that reactivate during hydraulic fracturing. Knowledge of the geometry and intensity of the natural fracture system and the likelihood of reactivation is therefore necessary for effective hydraulic fracture treatment design. Changing effective stress and concomitant diagenetic evolution of the host-rock controls fracture initiation and key fracture attributes such as intensity, spatial distribution, openness and strength. Thus, a linked structural-diagenesis approach is needed to predict the fracture types likely to be present, their key attributes and an assessment of whether they will impact hydraulic fracture treatments significantly. Steep (>75°), narrow ( 100, indicating that the fractures are clustered. These fractures, especially where present in clusters, are likely to divert hydraulic fracture strands. Early, sealed, compacted fractures, fractures associated with deformation around concretions and sealed, bedding-parallel fractures also occur in many mudrocks but are unlikely to impact hydraulic fracture treatments significantly because they are not widely developed. There is no evidence of natural open microfractures in the samples studied.", "corpus_id": 130215687, "score": 0 }, { "doc_id": "15178633", "title": "Natural fractures in the Barnett Shale and their importance for hydraulic fracture treatments", "abstract": "Gas production from the Barnett Shale relies on hydraulic fracture stimulation. Natural opening-mode fractures reactivate during stimulation and enhance efficiency by widening the treatment zone. Knowledge of both the present-day maximum horizontal stress, which controls the direction of hydraulic fracture propagation, and the geometry of the natural fracture system, which we discuss here, is therefore necessary for effective hydraulic fracture treatment design. We characterized natural fractures in four Barnett Shale cores in terms of orientation, size, and sealing properties. We measured a mechanical rock property, the subcritical crack index, which governs fracture pattern development. Natural fractures are common, narrow (0.05 mm; 0.002 in.), sealed with calcite, and present in en echelon arrays. Individual fractures have high length/width aspect ratios (1000:1). They are steep (75), and the dominant trend is west-northwest. Other sets trend north-south. The narrow fractures are sealed and cannot contribute to reservoir storage or enhance permeability, but the population may follow a power-law size distribution where the largest fractures are open. The subcritical crack index for the Barnett Shale is high, indicating fracture clustering, and we suggest that large open fractures exist in clusters spaced several hundred feet apart. These fracture clusters may enhance permeability locally, but they may be problematic for hydraulic fracture treatments. The smaller sealed fractures act as planes of weakness and reactivate during hydraulic fracture treatments. Because the maximum horizontal stress trends northeast-southwest and is nearly normal to the dominant natural fractures, reactivation widens the treatment zone along multiple strands.", "corpus_id": 15178633, "score": 0 }, { "doc_id": "110080815", "title": "Computer simulation of hydraulic fractures", "abstract": "We provide a brief historical background of the development of hydraulic fracturing models for use in the petroleum and other industries. We discuss scaling laws and the propagation regimes that control the growth of hydraulic fractures from the laboratory to the field scale. We introduce the mathematical equations and boundary conditions that govern the hydraulic fracturing process, and discuss numerical implementation issues including: tracking of the fracture footprint, the control of the growth of the hydraulic fracture as a function of time, coupling of the equations, and time-stepping schemes. We demonstrate the complexity of hydraulic fracturing by means of an application example based on real data. Finally, we highlight some key areas of research that need to be addressed in order to improve current models.", "corpus_id": 110080815, "score": 0 }, { "doc_id": "119705535", "title": "Plane strain propagation of a hydraulic fracture in a permeable rock", "abstract": "This paper describes the solution of the plane strain problem of a hydraulic fracture propagating in a permeable, linear elastic medium. The fracture propagation is driven by injection of an incompressible Newtonian fluid at a constant rate. The fracture opening and the fluid pressure are related through an elastic singular integral equation, and the flow of fluid within the fracture is modeled using lubrication theory. The leak-off or infiltration of fracturing fluid into the surrounding medium is treated as a one-dimensional diffusion process. The solution of this problem is restricted to cases where the toughness of the medium and the lag between the fluid front and the fracture tip are both zero. These particular conditions are taken to correspond to limiting cases where the energy rate dissipated in fracturing the medium is negligible compared to viscous dissipation (zero toughness) and the far-field stress perpendicular to the fracture is large (zero lag). The problem is solved numerically, using an explicit time-marching algorithm. A description of the near-tip asymptotic behavior, which is of fundamental importance for the successful convergence of the algorithm, is also included. We obtain the semi-analytic asymptotic solutions corresponding to small and large time, and compare them with the numerical solution, in order to delineate the limits of the propagation regimes.", "corpus_id": 119705535, "score": 0 }, { "doc_id": "129029777", "title": "Propagation Regimes of Fluid-Driven Fractures in Impermeable Rocks", "abstract": "This paper reviews recent results of a research program aimed at developing a theoretical framework to understand and predict the different modes of propagation of a fluid-driven fracture. The research effort involves constructing detailed solutions of the crack tip region, developing global models of hydraulic fractures for plane strain and radial geometry, and identifying the parameters controlling the fracture growth. The paper focuses on the propagation of hydraulic fractures in impermeable rocks. The controlling parameters are identified from scaling laws that recognize the existence of two dissipative processes: fracturing of the rock (toughness) and dissipation in the fracturing fluid (viscosity). It is shown that the two limit solutions (corresponding to zero toughness and zero viscosity) are characterized by a power law dependence on time and that the transition between these two asymptotic solutions depends on a single number, which can be chosen to be either a dimensionless toughness or a dimen...", "corpus_id": 129029777, "score": 0 }, { "doc_id": "135671765", "title": "An approximate solution for toughness-dominated near-surface hydraulic fractures", "abstract": "Asymptotic solutions for fracture opening, volume and specific surface energy for small and large fracture radii are presented from the literature. By comparison to numerical simulation of static circular fractures subject to constant and uniform internal pressures, it is found that a good approximation for fracture opening, for intermediate fracture radii, is obtained from a power mean (with exponent 1/2) of the small and large fracture radii limiting cases. The power mean equation for fracture opening is used to derive corresponding equations for fracture volume, specific surface energy and mode I and II stress intensities. These are then combined to form an approximate solution to describe the propagation of circular toughness-dominated near-surface hydraulic fractures, suitable for small, large and intermediate fracture radii. The approximate solution is shown to closely approximate results from equivalent numerical simulation.", "corpus_id": 135671765, "score": 0 }, { "doc_id": "120855958", "title": "Hydraulic Fracture Propagation with 3-D Leak-off", "abstract": "Hydraulic fracture models typically couple a fracture elasticity model with a geological reservoir model to forecast the rate of fluid leak-off from the propagating fracture. The most commonly used leak-off model is that originally specified by Carter, which involves the assumption that the fracture is embedded within an infinite homogenous porous medium where flow only occurs perpendicular to the fracture plane. The objectives of this paper are: (1) to show that assuming one-dimensional leak-off can lead to erroneous conclusions, (2) to present a robust numerical methodology for simulating three-dimensional leak-off from propagating hydraulic fractures, and (3) to present and compare a new analytical method based on assuming three-dimensional flow of an incompressible fluid through an incompressible porous formation from a circular planar fracture. Provided the fluid and formation compressibility can be ignored within the reservoir flow model, the three-dimensional leak-off from a circular planar fracture can be written in closed-form as a function, which depends linearly on fracture pressure and radial extent. This simple expression for leak-off can be easily coupled to a range of circular fracture elasticity models. As a comparison example, the Carter model, our new function and a three-dimensional numerical model of the full problem are coupled to the PK-radial fracture model. Comparison with the numerical model shows that our new function overestimates fracture growth during intermediate times but accurately predicts both the early and late-time asymptotic behavior. In contrast, the Carter model fails to replicate both the early and late-time asymptotic behavior. Our new function additionally improves on the Carter model by not requiring the evaluation of convolution integrals and allowing easy evaluation of both the spatial leakage flux distribution across the fracture face and the three-dimensional pressure distribution within the porous formation.", "corpus_id": 120855958, "score": 1 }, { "doc_id": "120061176", "title": "An implicit level set method for modeling hydraulically driven fractures", "abstract": "We describe a novel implicit level set algorithm to locate the free boundary for a propagating hydraulic fracture. A number of characteristics of the governing equations for hydraulic fractures and their coupling present considerable challenges for numerical modeling, namely: the degenerate lubrication equation; the hypersingular elastic integral equation; the indeterminate form of the velocity of the unknown fracture front, which precludes the implementation of established front evolution strategies that require an explicit velocity field; and the computationally prohibitive cost of resolving all the length scales. An implicit algorithm is also necessary for the efficient solution of the stiff evolution equations that involve fully populated matrices associated with the coupled non-local elasticity and degenerate lubrication equations. The implicit level set algorithm that we propose exploits the local tip asymptotic behavior, applicable at the computational length scale, in order to locate the free boundary. Local inversion of this tip asymptotic relation yields the boundary values for the Eikonal equation, whose solution gives the fracture front location as well as the front velocity field. The efficacy of the algorithm is tested by comparing the level set solution to analytic solutions for hydraulic fractures propagating in a number of distinct regimes. The level set algorithm is shown to resolve the free boundary problem with first order accuracy. Further it captures the field variables, such as the fracture width, with the first order accuracy that is consistent with the piecewise constant discretization that is used.", "corpus_id": 120061176, "score": 0 }, { "doc_id": "121648594", "title": "Propagation of a hydraulic fracture parallel to a free surface", "abstract": "This paper analyses the plane strain problem of a fracture, driven by injection of an incompressible viscous Newtonian fluid, which propagates parallel to the free surface of an elastic half-plane. The problem is governed by a hyper-singular integral equation, which relates crack opening to net pressure according to elasticity, and by the lubrication equations which describe the laminar fluid flow inside the fracture. The challenge in solving this problem results from the changing nature of the elasticity operator with growth of the fracture, and from the existence of a lag zone of a priori unknown length between the crack tip and the fluid front. Scaling of the governing equations indicates that the evolution problem depends in general on two numbers, one which can be interpreted as a dimensionless toughness and the other as a dimensionless confining stress. The numerical method adopted to solve this non-linear evolution problem combines the displacement discontinuity method and a finite difference scheme on a fixed grid, together with a technique to track both crack and fluid fronts. It is shown that the solution evolves in time between two asymptotic similarity solutions. The small time asymptotic solution corresponding to the solution of a hydraulic fracture in an infinite medium under zero confining stress, and the large time to a solution where the aperture of the fracture is similar to the transverse deflection of a beam clamped at both ends and subjected to a uniformly distributed load. It is shown that the size of the lag decreases (to eventually vanish) with increasing toughness and compressive confining stress. Copyright © 2005 John Wiley & Sons, Ltd.", "corpus_id": 121648594, "score": 0 }, { "doc_id": "120785096", "title": "A review on phase-field models of brittle fracture and a new fast hybrid formulation", "abstract": "In this contribution we address the issue of efficient finite element treatment for phase-field modeling of brittle fracture. We start by providing an overview of the existing quasi-static and dynamic phase-field fracture formulations from the physics and the mechanics communities. Within the formulations stemming from Griffith’s theory, we focus on quasi-static models featuring a tension-compression split, which prevent cracking in compression and interpenetration of the crack faces upon closure, and on the staggered algorithmic implementation due to its proved robustness. In this paper, we establish an appropriate stopping criterion for the staggered scheme. Moreover, we propose and test the so-called hybrid formulation, which leads within a staggered implementation to an incrementally linear problem. This enables a significant reduction of computational cost—about one order of magnitude—with respect to the available (non-linear) models. The conceptual and structural similarities of the hybrid formulation to gradient-enhanced continuum damage mechanics are outlined as well. Several benchmark problems are solved, including one with own experimental verification.", "corpus_id": 120785096, "score": 0 }, { "doc_id": "135488217", "title": "Cohesive modeling of transverse cracking in laminates under in-plane loading with a single layer of elements per ply", "abstract": "Abstract This study aims to bridge the gap between classical understanding of transverse cracking in cross-ply laminates and recent computational methods for the modeling of progressive laminate failure. Specifically, the study investigates under what conditions a finite element model with cohesive X-FEM cracks can reproduce the in situ effect for the ply strength. It is shown that it is possible to do so with a single element across the thickness of the ply, provided that the interface stiffness is properly selected. The optimal value for this interface stiffness is derived with an analytical shear lag model. It is also shown that, when the appropriate statistical variation of properties has been applied, models with a single element through the thickness of a ply can predict the density of transverse matrix cracks.", "corpus_id": 135488217, "score": 0 }, { "doc_id": "97253887", "title": "Dynamic fracture propagation in hydraulic re-fracturing", "abstract": "Re-fracturing is important for stimulating low-permeability reservoirs, for the effective production duration after the initial fracturing is short and needs to be stimulated again. However, the fracture configuration caused by re-fracturing affects the re-stimulated production greatly. Based on fracture mechanics and hydraulic fracturing theory, a model for dynamic path of fracture propagation during re-fracturing is proposed, and computation shows that stress difference and initiation angle contribute to changes in fracture propagation path. The new fracture changes its direction gradually, until to the direction of the maximum horizontal stress. Horizontal stress difference has great obvious influence on fracture dynamic reorientation, the larger the horizontal stress difference is, the shorter the distance of reoriented fracture away from the maximum horizontal stress will be. The predicted paths are in good accordance with those from the surface micro-seismic monitoring and tri-axial large-scale experiments. The model and conclusions are significant to further understanding of re-fracturing process.", "corpus_id": 97253887, "score": 0 }, { "doc_id": "135624399", "title": "Dynamic Fracture Mechanics", "abstract": "Preface List of symbols 1. Background and overview 2. Basic elastodynamic solutions for a stationary crack 3. Further results for a stationary crack 4. Asymptotic fields near a moving crack tip 5. Energy concepts in dynamic fracture 6. Elastic crack growth at constant speed 7. Elastic crack growth at nonuniform speed 8. Plasticity and rate effects during crack growth Bibliography Index.", "corpus_id": 135624399, "score": 1 }, { "doc_id": "136665651", "title": "Dynamic crack tip fields and dynamic crack propagation characteristics of anisotropic material", "abstract": "Abstract Based on mechanics of anisotropic material, the dynamic crack propagation problem of I/II mixed mode crack in an infinite anisotropic body is investigated. Expressions of dynamic stress intensity factors for modes I and II crack are obtained. Components of dynamic stress and dynamic displacements around the crack tip are derived. The strain energy density theory is used to predict the dynamic crack extension angle. The critical strain energy density is determined by the strength parameters of anisotropic materials. The obtained dynamic crack tip fields are unified and applicable to the analysis of the crack tip fields of anisotropic material, orthotropic material and isotropic material under dynamic or static load. The obtained results show Crack propagation characteristics are represented by the mechanical properties of anisotropic material, i.e., crack propagation velocity M and fiber direction α. In particular, the fiber direction α and the crack propagation velocity M give greater influence on the variations of the stress fields and displacement fields. Fracture angle is found to depend not only on the crack propagation but also on the anisotropic character of the material.", "corpus_id": 136665651, "score": 0 }, { "doc_id": "136013319", "title": "Mixed mode crack propagation in homogeneous anisotropic solids", "abstract": "Abstract The maximum circumferential tensile stress theory, originally developed for isotropic solids, is extended to an anisotropic one. A two parameter fracture toughness characterization is assumed, and a simplifying relationship among them postulated. The criteria is reformulated in terms of the maximization of the ratio of the maximum circumferential tensile stress (a function of the two stress intensity factors K I and K II ) over the material critical tensile strength (which has a polar variation in terms of two fracture toughnesses). It is found that material anisotropy can strongly deviate the angle of crack extension from the one predicted by current isotropic models.", "corpus_id": 136013319, "score": 0 }, { "doc_id": "135929682", "title": "Strain Energy Release Rate for a Crack Under Combined Mode I and Mode II", "abstract": "Abstract : The energy release rate for a crack subjected simultaneously to mode I and mode II conditions is computed. The energy was computed by path-independent integrals, using the elastic solution of a deflected crack, having a main branch and a propagation branch. The elasticity solution was obtained from the functional integral equations by the process of iterations. This process leads to a point-wise exact solution in the limit as the propagation branch goes to zero. Using the Griffith-Irwin criterion, incipient paths of propagation of such a crack were obtained from the maximum value of the energy release rate. An experiment, which gives a pure mode II condition at the tip of the crack, was devised. The results were in excellent agreement with the theory. The energy release rate, in parametric form, can be used for any crack subjected to mode I and mode II loading conditions. (Author, modified-PL)", "corpus_id": 135929682, "score": 0 }, { "doc_id": "121225607", "title": "The Partition of Unity Method", "abstract": "A new finite element method is presented that features the ability to include in the finite element space knowledge about the partial differential equation being solved. This new method can therefore be more efficient than the usual finite element methods. An additional feature of the partition-of-unity method is that finite element spaces of any desired regularity can be constructed very easily. This paper includes a convergence proof of this method and illustrates its efficiency by an application to the Helmholtz equation for high wave numbers. The basic estimates for a posteriori error estimation for this new method are also proved. © 1997 by John Wiley & Sons, Ltd.", "corpus_id": 121225607, "score": 0 }, { "doc_id": "120454330", "title": "THREE-DIMENSIONAL CRACK GROWTH SIMULATION USING BEM", "abstract": "Abstract In this paper an application of dual boundary element method to the analysis of three-dimensional mixed-mode crack growth is presented. The crack growth processes are simulated numerically with an incremental crack-extension analysis based on the minimum strain energy density criterion and a fatigue crack growth law. For each crack extension, the size of the increment (crack growth) and direction of crack growth is evaluated along the crack front. The dual boundary element analysis is applied to perform a single-region analysis and the stress intensity factors are evaluated using a displacement-based method. The crack extension is modelled with the introduction of new boundary elements, removing the requirement of interior remeshing, an intrinsic feature of the dual boundary element method. Results of analysis are presented for several geometries, including planar and non-planar crack growth.", "corpus_id": 120454330, "score": 0 }, { "doc_id": "120200957", "title": "Time-harmonic BEM for 2-D piezoelectricity applied to eigenvalue problems", "abstract": "Abstract We will derive the fundamental generalized displacement solution, using the Radon transform, and present the direct formulation of the time-harmonic boundary element method (BEM) for the two-dimensional general piezoelectric solids. The fundamental solution consists of the static singular and the dynamics regular parts; the former, evaluated analytically, is the fundamental solution for the static problem and the latter is given by a line integral along the unit circle. The static BEM is a component of the time-harmonic BEM, which is formulated following the physical interpretation of Somigliana’s identity in terms of the fundamental generalized line force and dislocation solutions obtained through the Stroh–Lekhnitskii (SL) formalism. The time-harmonic BEM is obtained by adding the boundary integrals for the dynamic regular part which, from the original double integral representation over the boundary element and the unit circle, are reduced to simple line integrals along the unit circle. The BEM will be applied to the determination of the eigen frequencies of piezoelectric resonators. The eigenvalue problem deals with full non-symmetric complex-valued matrices whose components depend non-linearly on the frequency. A comparative study will be made of non-linear eigenvalue solvers: QZ algorithm and the implicitly restarted Arnoldi method (IRAM). The FEM results whose accuracy is well established serve as the basis of the comparison. It is found that the IRAM is faster and has more control over the solution procedure than the QZ algorithm. The use of the time-harmonic fundamental solution provides a clean boundary only formulation of the BEM and, when applied to the eigenvalue problems with IRAM, provides eigen frequencies accurate enough to be used for industrial applications. It supersedes the dual reciprocity BEM and challenges to replace the FEM designed for the eigenvalue problems for piezoelectricity.", "corpus_id": 120200957, "score": 0 }, { "doc_id": "136812422", "title": "An experimental investigation into dynamic fracture: III. On steady-state crack propagation and crack branching", "abstract": "This is the third in a series of four papers in which problems of dynamic crack propagation are examined experimentally in large, thin sheets of Homalite-100 such that crack growth in an unbounded plate is simulated. In the first paper crack initiation resulting from stress wave loading to the crack tip as well as crack arrest were reported. It was found that for increasing rates of loading in the microsecond range the stress intensity required for initiation rises markedly. Crack arrest occurs abruptly without any deceleration phase at a stress intensity lower than that which causes initiation under quasi-static loading.In the second paper we analyze the occurrence of micro cracks at the front of the running main crack which control the rate of crack growth. The micro cracks are recorded by real time photography. By the same means it is shown that these micro cracks grow and turn away smoothly from the direction of the main crack in the process of branching.In the present paper we report results on crack propagation and branching. It is found that crack propagation occurs at a constant velocity although the stress intensity factor changes markedly. Furthermore, the velocity is determined by the stress wave induced intensity factor at initiation. The terminal velocity in Homalite-100 was found to be about half the Rayleigh wave speed (0.45 Cr). These observations are analyzed in terms of a microcrack model alluded to in the second paper of this series. A mechanism for crack branching is proposed which considers branching to be a natural evolution from a “cloud” of microcracks that accompany and lead the main crack. These results are believed to apply to quasi-brittle materials other than Homalite-100 and the reasons for this belief are discussed briefly in the first paper of this series.In the final paper of the series the effect of stress waves impinging on the tip of a rapidly moving crack is examined. Waves affect the velocity and the direction of propagation as well as the process of crack branching.", "corpus_id": 136812422, "score": 0 }, { "doc_id": "137186535", "title": "An experimental investigation into dynamic fracture: II. Microstructural aspects", "abstract": "This is the second of a series of four papers in which problems of dynamic crack propagation are examined experimentally in large, thin sheets of Homalite 100 simulating crack growth in an unbounded plate. In the first paper crack initiation resulting from stress wave loading to the crack tip and crack arrest were investigated. It was found that for increasing rates of loading in the micro second range, the stress intensity required for initiation rises markedly. Crack arrest occurs abruptly without any deceleration phase at a stress intensity below that value which causes initiation under quasi-static loading.In this paper we investigate the microscopic processes that control the process of dynamic fracture. Through post-mortem examination of the fracture surfaces it is established that microcracks are nucleated and grown ahead of a propagating crack. A measure of the size of the fracture process zone in which these microcracks are activated is obtained. Real time high speed photomicrography is used to capture the evolution of crack growth and crack branching. Under conditions of low stress intensity the crack front exhibits “thumbnail” curvature similar to the crack front profiles associated with quasi-static fracture processes. At increasing stress intensity the crack front straightens out and is identifiable as a front of multiple microfractures.The third contribution establishes the hitherto unreported occurrence that cracks can propagate rapidly with constant velocity even though the stress intensity factor varies considerably during this propagation. This velocity is determined by the initial stress wave loading on the crack tip and is changed, within limits, only by stress pulses of sufficient magnitude and brevity of rise time.The final paper in the series deals with the effect of stress waves on the behavior of running cracks, in particular with the influence of stress waves on the branching phenomenon. Also, crack curving under transient stress waves is examined. These results are believed to apply to brittle materials other than Homalite 100 and the reasons for this belief are discussed briefly in the first paper of this series.RésuméLe présent mémoire est le deuxième d'une série de quatre, consacrés à l'examen des problèmes de propagation dynamique d'une fissure par voie expérimentale dans des feuillards minces d'Homalite 100 destinés à simuler la croissance d'une fissure dans une tôle non limitée. Dans le premier mémoire, l'amorçage de la fissure qui résulte d'une sollicitation par contrainte ondulée à l'extrémité de cette fissure, ainsi que les problèmes d'arrét de fissure ont été étudiés. On a trouvé que, lorsque la vitesse de mise en charge s'accélère dans la gamme de la microseconde, l'intensité de contrainte requise pour l'amor¢age s'accroit de manière significative. L'arrêt de fissure se produit brutalement sans la moindre phase de décélération à une intensité de contrainte inférieure à la valeur qui provoque l'amor¢age sous des sollicitations quasi-statique.Dans le présent mémoire, on examine le processus microscopique qui régit la rupture dynamique. Grâce à l'examen post-mortem des surfaces de rupture, on établit que des micro-fissures sont créées et croissent en avant d'une fissure en cours de propagation. On obtient une mesure de la taille de la zone concernée par le processus de rupture dans laquelle ces micro-fissures se trouvent activées. L'utilisation est faite de la photo-micrographie à haute vitesse et à temps réel en vue de capter l'évolution de croissance de la fissure ainsi que son arborescence. Sous des conditions de faible intensité de contrainte, le front de fissuration fait état d'une courbure en ongle similaire au profil de front de fissure associé avec un processus de rupture quasi-statique. Lorsque s'accroit l'intensité de contrainte, le front de fissure tend à devenir droit et est identifiable à un front de micro-ruptures multiples.La troisième contribution de cette série rapporte le phénomène jusqu'ici non publié selon lequel des fissures peuvent se propager rapidement avec une vitesse constante même si le facteur d'intensité de contrainte évolve considérablement au course de cette propagation. Cette vitesse est déterminée par la charge ondulante initiale à l'extrémité de la fissure et ne se modifie, du moins dans certaines limites, que par des pulsations de contrainte d'une amplitude suffisante et d'une soudaineté d'apparition.Le dernier des documents de cette série est relatif à l'effet des ondes de contrainte sur le comportement de fissure en cours de propagation en particulier en tenant compte de l'influence des ondes de contraintes sur le phénomène d'arborescence. On examine également la courbure que peut prendre une fissure sous l'effet d'ondes de contrainte transitoire. On pense que ces résultats s'appliquent a des materiaux fragiles autres que l'Homalite 100 et l'on discute brièvement dans le premier document de cette série les raisons de cet avis.", "corpus_id": 137186535, "score": 0 }, { "doc_id": "15339485", "title": "Instability in dynamic fracture.", "abstract": "Cracks in brittle materials have terminal velocities far below theoretical predictions. To address this problem we have investigated the propagation of cracks in a brittle plastic (polymethylmethacrylate). Velocity measurements with resolution an order of magnitude better than past experiments reveal the existence of a critical velocity at which the velocity begins to oscillate, the mean acceleration drops sharply, and a pattern is formed on the fracture surface. Thus the dynamics of cracks may be governed by a dynamical instability.", "corpus_id": 15339485, "score": 0 }, { "doc_id": "14925870", "title": "Theory of dynamic crack branching in brittle materials", "abstract": "The problem of dynamic symmetric branching of a tensile crack propagating in a brittle material is studied within Linear Elastic Fracture Mechanics theory. The Griffith energy criterion and the principle of local symmetry provide necessary conditions for the onset of dynamic branching instability and for the subsequent paths of the branches. The theory predicts a critical velocity for branching and a well defined shape described by a branching angle and a curvature of the side branches. The model rests on a scenario of crack branching based on reasonable assumptions and on exact dynamic results for the anti-plane branching problem. Our results reproduce within a simplified 2D continuum mechanics approach the main experimental features of the branching instability of fast cracks in brittle materials.", "corpus_id": 14925870, "score": 0 }, { "doc_id": "118408475", "title": "THE MATHEMATICAL THEORY OF EQUILIBRIUM CRACKS IN BRITTLE FRACTURE", "abstract": "Publisher Summary In recent years, the interest in the problem of brittle fracture and, in particular, in the theory of cracks has grown appreciably in connection with various technical applications. Numerous investigations have been carried out, enlarging in essential points the classical concepts of cracks and methods of analysis. The qualitative features of the problems of cracks, associated with their peculiar nonlinearity as revealed in these investigations, makes the theory of cracks stand out distinctly from the whole range of problems in terms of the theory of elasticity. The chapter presents a unified view of the way basic problems in the theory of equilibrium cracks are formulated and discusses the results obtained thereby. The object of the theory of equilibrium cracks is the study of the equilibrium of solids in the presence of cracks. However, there exists a fundamental distinction between these two problems, The form of a cavity undergoes only slight changes even under a considerable variation in the load acting on a body, while the cracks whose surface also constitutes a part of the body boundary can expand even with small increase of the load to which the body is subjected.", "corpus_id": 118408475, "score": 0 }, { "doc_id": "136484892", "title": "Yielding of steel sheets containing slits", "abstract": "Abstract Y ielding at the end of a slit in a sheet is investigated, and a relation is obtained between extent of plastic yielding and external load applied. To verify this relation, panels containing internal and edge slits were loaded in tension and lengths of plastic zones were measured.", "corpus_id": 136484892, "score": 0 }, { "doc_id": "137604476", "title": "The cohesive zone model: advantages, limitations and challenges", "abstract": "Abstract This paper reviews the cohesive process zone model, a general model which can deal with the nonlinear zone ahead of the crack tip––due to plasticity or microcracking––present in many materials. Furthermore, the cohesive zone model is able to adequately predict the behaviour of uncracked structures, including those with blunt notches, and not only the response of bodies with cracks––a usual drawback of most fracture models. The cohesive zone model, originally applied to concrete and cementitious composites, can be used with success for other materials. More powerful computer programs and better knowledge of material properties may widen its potential field of application. In this paper, the cohesive zone model is shown to provide good predictions for concrete and for different notched samples of a glassy polymer (PMMA) and some steels. The paper is structured in two main sections: First, the cohesive model is reviewed and emphasis is on determination of the softening function, an essential ingredient of the cohesive model, by inverse analysis procedures. The second section is devoted to some examples of the predictive capability of the cohesive zone model when applied to different materials; concrete, PMMA and steel.", "corpus_id": 137604476, "score": 0 }, { "doc_id": "136823072", "title": "Extended Finite Element Method: for Fracture Analysis of Structures", "abstract": "Dedication. Preface . Nomenclature . Chapter 1 Introduction. 1.1 ANALYSIS OF STRUCTURES. 1.2 ANALYSIS OF DISCONTINUITIES. 1.3 FRACTURE MECHANICS. 1.4 CRACK MODELLING. 1.4.1 Local and non-local models. 1.4.2 Smeared crack model. 1.4.3 Discrete inter-element crack. 1.4.4 Discrete cracked element. 1.4.5 Singular elements. 1.4.6 Enriched elements. 1.5 ALTERNATIVE TECHNIQUES. 1.6 A REVIEW OF XFEM APPLICATIONS. 1.6.1 General aspects of XFEM. 1.6.2 Localisation and fracture. 1.6.3 Composites. 1.6.4 Contact. 1.6.5 Dynamics. 1.6.6 Large deformation/shells. 1.6.7 Multiscale. 1.6.8 Multiphase/solidification. 1.7 SCOPE OF THE BOOK. Chapter 2 Fracture Mechanics, a Review. 2.1 INTRODUCTION. 2.2 BASICS OF ELASTICITY. 2.2.1 Stress-strain relations. 2.2.2 Airy stress function. 2.2.3 Complex stress functions. 2.3 BASICS OF LEFM. 2.3.1 Fracture mechanics. 2.3.2 Circular hole. 2.3.3 Elliptical hole. 2.3.4 Westergaard analysis of a sharp crack. 2.4 STRESS INTENSITY FACTOR, K . 2.4.1 Definition of the stress intensity factor. 2.4.2 Examples of stress intensity factors for LEFM. 2.4.3 Griffith theories of strength and energy. 2.4.4 Brittle material. 2.4.5 Quasi-brittle material. 2.4.6 Crack stability. 2.4.7 Fixed grip versus fixed load. 2.4.8 Mixed mode crack propagation. 2.5 SOLUTION PROCEDURES FOR K AND G . 2.5.1 Displacement extrapolation/correlation method. 2.5.2 Mode I energy release rate. 2.5.3 Mode I stiffness derivative/virtual crack model. 2.5.4 Two virtual crack extensions for mixed mode cases. 2.5.5 Single virtual crack extension based on displacement decomposition. 2.5.6 Quarter point singular elements. 2.6 ELASTOPLASTIC FRACTURE MECHANICS (EPFM). 2.6.1 Plastic zone. 2.6.2 Crack tip opening displacements (CTOD). 2.6.3 J integral. 2.6.4 Plastic crack tip fields. 2.6.5 Generalisation of J . 2.7 NUMERICAL METHODS BASED ON THE J INTEGRAL. 2.7.1 Nodal solution. 2.7.2 General finite element solution. 2.7.3 Equivalent domain integral (EDI) method. 2.7.4 Interaction integral method. Chapter 3 Extended Finite Element Method for Isotropic Problems. 3.1 INTRODUCTION. 3.2 A REVIEW OF XFEM DEVELOPMENT. 3.3 BASICS OF FEM. 3.3.1 Isoparametric finite elements, a short review. 3.3.2 Finite element solutions for fracture mechanics. 3.4 PARTITION OF UNITY. 3.5 ENRICHMENT. 3.5.1 Intrinsic enrichment. 3.5.2 Extrinsic enrichment. 3.5.3 Partition of unity finite element method. 3.5.4 Generalised finite element method. 3.5.5 Extended finite element method. 3.5.6 Hp-clouds enrichment. 3.5.7 Generalisation of the PU enrichment. 3.5.8 Transition from standard to enriched approximation. 3.6 ISOTROPIC XFEM. 3.6.1 Basic XFEM approximation. 3.6.2 Signed distance function. 3.6.3 Modelling strong discontinuous fields. 3.6.4 Modelling weak discontinuous fields. 3.6.5 Plastic enrichment. 3.6.6 Selection of nodes for discontinuity enrichment. 3.6.7 Modelling the crack. 3.7 DISCRETIZATION AND INTEGRATION. 3.7.1 Governing equation. 3.7.2 XFEM discretization. 3.7.3 Element partitioning and numerical integration. 3.7.4 Crack intersection. 3.8 TRACKING MOVING BOUNDARIES. 3.8.1 Level set method. 3.8.2 Fast marching method. 3.8.3 Ordered upwind method. 3.9 NUMERICAL SIMULATIONS. 3.9.1 A tensile plate with a central crack. 3.9.2 Double edge cracks. 3.9.3 Double internal collinear cracks. 3.9.4 A central crack in an infinite plate. 3.9.5 An edge crack in a finite plate. Chapter 4 XFEM for Orthotropic Problems. 4.1 INTRODUCTION. 4.2 ANISOTROPIC ELASTICITY. 4.2.1 Elasticity solution. 4.2.2 Anisotropic stress functions. 4.2.3 Orthotropic mixed mode problems. 4.2.4 Energy release rate and stress intensity factor for anisotropic. materials. 4.2.5 Anisotropic singular elements. 4.3 ANALYTICAL SOLUTIONS FOR NEAR CRACK TIP. 4.3.1 Near crack tip displacement field (class I). 4.3.2 Near crack tip displacement field (class II). 4.3.3 Unified near crack tip displacement field (both classes). 4.4 ANISOTROPIC XFEM. 4.4.1 Governing equation. 4.4.2 XFEM discretization. 4.4.3 SIF calculations. 4.5 NUMERICAL SIMULATIONS. 4.5.1 Plate with a crack parallel to material axis of orthotropy. 4.5.2 Edge crack with several orientations of the axes of orthotropy. 4.5.3 Single edge notched tensile specimen with crack inclination. 4.5.4 Central slanted crack. 4.5.5 An inclined centre crack in a disk subjected to point loads. 4.5.6 A crack between orthotropic and isotropic materials subjected to. tensile tractions. Chapter 5 XFEM for Cohesive Cracks. 5.1 INTRODUCTION. 5.2 COHESIVE CRACKS. 5.2.1 Cohesive crack models. 5.2.2 Numerical models for cohesive cracks. 5.2.3 Crack propagation criteria. 5.2.4 Snap-back behaviour. 5.2.5 Griffith criterion for cohesive crack. 5.2.6 Cohesive crack model. 5.3 XFEM FOR COHESIVE CRACKS. 5.3.1 Enrichment functions. 5.3.2 Governing equations. 5.3.3 XFEM discretization. 5.4 NUMERICAL SIMULATIONS. 5.4.1 Mixed mode bending beam. 5.4.2 Four point bending beam. 5.4.3 Double cantilever beam. Chapter 6 New Frontiers. 6.1 INTRODUCTION. 6.2 INTERFACE CRACKS. 6.2.1 Elasticity solution for isotropic bimaterial interface. 6.2.2 Stability of interface cracks. 6.2.3 XFEM approximation for interface cracks. 6.3 CONTACT. 6.3.1 Numerical models for a contact problem. 6.3.2 XFEM modelling of a contact problem. 6.4 DYNAMIC FRACTURE. 6.4.1 Dynamic crack propagation by XFEM. 6.4.2 Dynamic LEFM. 6.4.3 Dynamic orthotropic LEFM. 6.4.4 Basic formulation of dynamic XFEM. 6.4.5 XFEM discretization. 6.4.6 Time integration. 6.4.7 Time finite element method. 6.4.8 Time extended finite element method. 6.5 MULTISCALE XFEM. 6.5.1 Basic formulation. 6.5.2 The zoom technique. 6.5.3 Homogenisation based techniques. 6.5.4 XFEM discretization. 6.6 MULTIPHASE XFEM. 6.6.1 Basic formulation. 6.6.2 XFEM approximation. 6.6.3 Two-phase fluid flow. 6.6.4 XFEM approximation. Chapter 7 XFEM Flow. 7.1 INTRODUCTION. 7.2 AVAILABLE OPEN-SOURCE XFEM. 7.3. FINITE ELEMENT ANALYSIS. 7.3.1 Defining the model. 7.3.2 Creating the finite element mesh. 7.3.3 Linear elastic analysis. 7.3.4 Large deformation. 7.3.5 Nonlinear (elastoplastic) analysis. 7.3.6 Material constitutive matrix. 7.4 XFEM. 7.4.1 Front tracking. 7.4.2 Enrichment detection. 7.4.3 Enrichment functions. 7.4.4 Ramp (transition) functions. 7.4.5 Evaluation of the B matrix. 7.5 NUMERICAL INTEGRATION. 7.5.1 Sub-quads. 7.5.2 Sub-triangles. 7.6 SOLVER. 7.6.1 XFEM degrees of freedom. 7.6.2 Time integration. 7.6.3 Simultaneous equations solver. 7.6.4 Crack length control. 7.7 POST-PROCESSING. 7.7.1 Stress intensity factor. 7.7.2 Crack growth. 7.7.3 Other applications. 7.8 CONFIGURATION UPDATE. References . Index", "corpus_id": 136823072, "score": 1 }, { "doc_id": "137666036", "title": "Asymptotic analysis of a cohesive crack: 1. Theoretical background", "abstract": "A method to analyze the evolution of a cohesive crack, particularly appropriate for asymptotic analysis, is presented. Detailed descriptions of the zeroth order and first order asymptotic approaches are given and from these results the far field equivalent elastic crack theorem is derived. An analytically soluble example, the Griffith crack, and a simple model, the Dugdale model, are used to exemplify the results.", "corpus_id": 137666036, "score": 0 }, { "doc_id": "4901392", "title": "Effect of in-plane deformation on the cohesive failure of heterogeneous adhesives", "abstract": "The effect of in-plane deformations on the failure response of heterogeneous adhesives with a second phase of spherical elastic particles is investigated numerically using a 3D cohesive framework. The methodology includes a new interface-enriched generalized finite element scheme for the solution of structural problems with weak discontinuities, allowing for the efficient and accurate prediction of the stress and displacement fields in the adhesive based on finite element meshes that do not conform to the heterogeneities. A rate-dependent isotropic failure model is adopted to capture the failure in the matrix, while the stiff inclusions are assumed to be linearly elastic. Cohesive failure envelopes resulting from the micro-to-macro analysis are extracted for a wide variety of failure mode conditions. A study of 1611the impact of in-plane tensile and shear strains on the macroscopic failure response under tensile (mode I) loading is also presented.", "corpus_id": 4901392, "score": 0 }, { "doc_id": "137123096", "title": "Simulation of fracture in heterogeneous elastic materials with cohesive zone models", "abstract": "In brittle composite materials, failure mechanisms like debonding of the matrix-fiber interface or fiber breakage can result in crack deflection and hence in the improvement of the damage tolerance. More generally it is known that high values of fracture energy dissipation lead to toughening of the material. Our aim is to investigate the influence of material parameters and geometrical aspects of fibers on the fracture energy as well as the crack growth for given load scenarios. Concerning simulations of crack growth the cohesive element method in combination with the Discontinuous Galerkin method provides a framework to model the fracture considering strength, stiffness and failure energy in an integrated manner. Cohesive parameters are directly determined by DFT supercell calculations. We perform studies with prescribed crack paths as well as free crack path simulations. In both cases computational results reveal that fracture energy depends on both the material parameters but also the geometry of the fibers. In particular it is shown that the dissipated energy can be increased by appropriate choices of cohesive parameters of the interface and geometrical aspects of the fiber. In conclusion, our results can help to guide the manufacturing process of materials with a high fracture toughness.", "corpus_id": 137123096, "score": 0 }, { "doc_id": "121759385", "title": "A boundary cohesive grain element formulation for modelling intergranular microfracture in polycrystalline brittle materials", "abstract": "In this paper, a cohesive grain boundary integral formulation is proposed, for simulating intergranular microfracture evolution in polycrystalline brittle materials. Artificially generated polycrystalline microstructures are discretized using the proposed anisotropic boundary element method, considering the random location, morphology and material orientation of each grain. Each grain is assumed as a single crystal with general elastic orthotropic mechanical behaviour. Crack initiation and propagation along the grain boundaries interfaces are modelled using a linear cohesive law, considering mixed mode failure conditions. Furthermore, a non-linear frictional contact analysis is performed over cracked grain interfaces to encounter cases where crack surfaces come into contact, slide or separate. The effect of randomly located pre-existing flaws on the overall behaviour and microcracking evolution of a polycrystalline material is also investigated for different Weibull moduli. The stochastic effects of each grain morphology-orientation, internal friction and randomly distributed pre-existing flaws, under different loading conditions, are studied probabilistically by simulating various randomly generated microstructures. Copyright © 2006 John Wiley & Sons, Ltd.", "corpus_id": 121759385, "score": 0 }, { "doc_id": "137986719", "title": "A nonlinear cohesive model for mixed-mode delamination of composite laminates", "abstract": "Abstract An anisotropic nonlinear cohesive model based on continuum damage mechanics is proposed to predict the mixed-mode delamination initiation and growth of composite laminates numerically. A damaged exponential traction–displacement jump relationship is proposed for the cohesive model and an exponential damage evolution law on the evolvement of displacement jump is proposed to describe the irreversible delamination crack propagation. The implementation of cohesive model uses zero-thickness cohesive element and middle-plane isoparametric interpolation technique. The mesh size effect is solved by regulating the delamination fracture toughness by the cohesive length, and the numerical convergence problem for the snap instability is addressed by viscous regularization. Four representative delamination cases of composite laminates are used to validate the proposed cohesive model: (a) double cantilever beam (mode-I), (b) end notch flexure (mode-II), (c) mixed-mode bending fracture, and (d) fixed ratio mixed mode. The effects of the cohesive strengths and mesh sizes on the global load–displacement response for four cases are studied. In addition, the numerical results using proposed cohesive model are also compared with the results obtained by the virtual crack closure technique and other existing cohesive models. The proposed cohesive model is demonstrated to predict the mixed-mode delamination response of composite laminates accurately and effectively.", "corpus_id": 137986719, "score": 0 }, { "doc_id": "136847044", "title": "A Stochastic XFEM Model to Study Delamination in PPS/Glass UD Composites: Effect of Uncertain Fracture Properties", "abstract": "A nonlinear extended finite element (XFEM) modeling framework under a stochastic cohesive zone is presented for realistic prediction of delamination in polyphenylene sulfide (PPS)/glass composites in mode I of fracture. The cohesive zone model adopts damage evolution of the material based on a bilinear traction-separation law, the critical energy release rate and the J-integral method to formulate the delamination interface under stochastic fracture properties. To demonstrate the application of the approach, numerical predictions are compared to experimental data using Double Cantilever Beam (DCB) tests. In particular, it is shown how the XFEM model can be used to capture test non-repeatability due to uncertain fracture properties, which is often the case during the characterization of composites using standard fracture tests.", "corpus_id": 136847044, "score": 0 }, { "doc_id": "122070401", "title": "Cohesive-zone-model formulation and implementation using the symmetric Galerkin boundary element method for homogeneous solids", "abstract": "A new symmetric boundary integral formulation for cohesive cracks growing in the interior of homogeneous linear elastic isotropic media with a known crack path is developed and implemented in a numerical code. A crack path can be known due to some symmetry implications or the presence of a weak or bonded surface between two solids. The use of a two-dimensional exponential cohesive law and of a special technique for its inclusion in the symmetric Galerkin boundary element method allows us to develop a simple and efficient formulation and implementation of a cohesive zone model. This formulation is dependent on only one variable in the cohesive zone (relative displacement). The corresponding constitutive cohesive equations present a softening branch which induces to the problem a potential instability. The development and implementation of a suitable solution algorithm capable of following the growth of the cohesive zone and subsequent crack growth becomes an important issue. An arc-length control combined with a Newton–Raphson algorithm for iterative solution of nonlinear equations is developed. The boundary element method is very attractive for modeling cohesive crack problems as all nonlinearities are located along the boundaries (including the crack boundaries) of linear elastic domains. A Galerkin approximation scheme, applied to a suitable symmetric integral formulation, ensures an easy treatment of cracks in homogeneous media and excellent convergence behavior of the numerical solution. Numerical results for the wedge split and mixed-mode flexure tests are presented.", "corpus_id": 122070401, "score": 0 }, { "doc_id": "135628116", "title": "Instability during cohesive zone growth", "abstract": "Tensile microcracking of quasi-brittle materials is studied by means of micromechanics, based on (i) an elasto-damaging cohesive zone model accounting for cohesive softening and (ii) a dilute distribution of non-interacting microcracks of uniform orientation and size. Considering virgin microcracks (initially without cohesive zones), macroscopic tensile load increase results in growth of cohesive zones ahead of stationary (non-propagating) cracks and, subsequently, in crack propagation which, notably, will be encountered before the cohesive zones are fully developed i.e. onset of instable cohesive zone growth will be encountered at a load level (i) at which tractions are still transmitted across the inner edges of the cohesive zones and (ii) at which the separation at the inner edges of the cohesive zones is smaller than its critical value. Focusing on onset of instable cohesive zone growth, the chosen approach allows for accessing quantities characterizing the stability limit (e.g., the intensity of the macroscopic loading and the opening at the inner edges of the cohesive zones), without raising the need for non-linear Finite Element analyses. It is shown that the tensile macrostrength of materials containing virgin microcracks is larger than the one related to cracks with already initially fully developed cohesive zones, and related strength differences are quantified for a wide class of cohesive softening behavior. The proposed model is validated by comparing model predictions with an exact solution (available for the special case of constant cohesive tractions) and with results from reliable Finite Element analyses. The paper will be of interest for engineers involved in testing and/or in modeling of quasi-brittle media including cementitious materials and rock.", "corpus_id": 135628116, "score": 0 }, { "doc_id": "137362783", "title": "Simulation of interlaminar damage in mixed-mode bending tests using large deformation self-adaptive cohesive zones", "abstract": "Cohesive zone models are common tools for the simulation of delamination since two decades. However, application of these models in a quasi-static finite element framework requires a sufficiently fine discretization to resolve a quasi-brittle process zone. As an alternative to mesh refinement, an adaptive approximation of the growing delamination was obtained in earlier work by enriching the elements in the fracture process zone. Discretization-induced numerical instabilities are thereby avoided and a standard Newton–Raphson iterative scheme remains applicable. This enriched 2D cohesive zone model is here extended to a large deformation self-adaptive finite element framework, which makes it suitable for general engineering applications where geometrical and material non-linearities are expected. Based on recent experimental results from miniaturized mixed-mode bending tests, an irreversible mixed-mode traction–separation law is considered for the simulation of delamination over a wide range of mode mixities. The developed model is used for the simulation of mixed-mode bending tests on bi-material interfaces and the response is compared to the experimental results. Numerical simulations using coarse discretizations in a quasi-static finite element framework show the effectiveness of the self-adaptive cohesive zone model.", "corpus_id": 137362783, "score": 0 }, { "doc_id": "136609796", "title": "Fracture in quasi-brittle materials: a review of continuum damage-based approaches", "abstract": "Abstract Starting from the early ideas on smeared-crack modelling of quasi-brittle materials (concrete, rock) as pioneered in the late 1960s various refinements are discussed such as the shear retention factor, the tension-stiffening concept and the tension-softening concept. Next, smeared-crack models are put in the unified context of damage mechanics together with the multiple-smeared crack approach and the (closely) related microplane damage models. The concept of fracture energy is introduced for tensile and compressive loadings and is also elaborated for reinforced concrete. A concise summary is given of recent finite element concepts for cohesive-zone models (fracture energy models).", "corpus_id": 136609796, "score": 0 }, { "doc_id": "137309935", "title": "Cohesive models for quasistatic cracking in inelastic solids", "abstract": "In has been shown that slow stable cracking process can be sustained by strain-softening materials such as cementitious composites, e.g., rock, concrete, mortars, ceramics and others. A mathematical model is proposed based on the theory of quasi-static crack extension governed by Wnuk's criterion of final stretch (equivalent to the CTOA condition). Requirement of self-similarity of the crack opening profile, maintained during the quasistatic growth phase, leads to a differential equation defining the material resistance to sustained crack extension, as a function of crack growth increment, material properties such as tearing modulus, strain-softening parameter, and the size of the process zone.The equations derived on the basis of the step-like distribution of the restraining stress which operates within a structured end zone associated with a moving crack, are compared against the Wnuk-Rice-Sorensen equation to ran R-curve in an ideal elasto-plastic material, and with the more recent results of Wnuk and Hunsacharoonroj [1] pertaining to strain-hardening materials which obey the Ramberg-Osgood power law.Present results suggest that the nature of constitutive equations substantially influence composite fracture resistance as measured by the R-curve. Ability to absorb energy and the ensuing resistance to crack growth can be significantly enhanced when the mechanisms of energy dissipation within the matrix are properly understood. This work establishes a “bridge” between the continuum mechanics and micromechanics of deformation and meture processes by providing a relation between material fracture toughness and its constitutive equations supplemented by certain microstructural characteristics.", "corpus_id": 137309935, "score": 0 }, { "doc_id": "137147147", "title": "Determination of quasibrittle fracture law for cohesive crack models", "abstract": "Abstract A basic and necessary ingredient of cohesive crack models, so widely used for numerical quasibrittle fracture simulations, is the softening function which characterizes the property of concrete-like materials. In this paper, a simple procedure to determine the softening parameters for such functions is proposed. In addition to knowledge of the tensile strength—typically obtainable within about 20% from a cylinder splitting strength (Brazilian) test—the only other requirement is knowledge of the load-displacement curve, as would be obtained from a standard three-point bending test. The method is particularly suitable for materials, such as fiber reinforced concrete, which exhibit a long tail in their load-displacement response. Although suitable for identifying both nonlinear and piece-wise linear relations, we illustrate applications of the scheme using a bilinear law.", "corpus_id": 137147147, "score": 0 }, { "doc_id": "121293715", "title": "Modelling large crack propagation: from gradient damage to cohesive zone models", "abstract": "Continuum Damage Mechanics and cohesive zone models are both prone to model large crack propagation inside quasi-brittle materials. Comparing the advantages of the formulations, the latter could be advantageously applied in cases where the crack path is known a priori while the former implicitly encompasses crack path prediction but requires more complex computations involving nonlocal interactions. In order to assess the acceptability of such a hierarchy for industrial studies, it is necessary that the predictions coincide quantitatively. Starting from a gradient damage model in a one-dimensional context, a cohesive law is derived as the asymptotic response of the damage model for vanishing nonlocal length scale. The cohesive law is hence independent of the nonlocal length scale, which is consistent with the fact that it ignores details characteristic of the “best-estimate” damage approach. Besides, the existence of such a limit ensures that the damage model is not much sensitive to a small nonlocal length scale, which then appears rather as a numerical regularisation parameter. A numerical comparison between the damage model and its asymptotic cohesive law is then carried out for large bi-dimensional crack propagation. The computed responses remain close to each other although some small discrepancies arise probably related to the damage spread resulting from the stress distribution in the vicinity of the crack tip: the hierarchy strategy is thus validated.", "corpus_id": 121293715, "score": 0 }, { "doc_id": "123316095", "title": "Cohesive zone size of microcracks in brittle materials", "abstract": "Abstract Consideration of cohesive microcracks in continuum micromechanics is a challenging task since a lot of applications (such as, e.g., estimation of the stiffness of a microcracked solid) require a priori knowledge of the size of the cohesive zone. The latter, however, can be determined analytically only for the special case of Barenblatt–Dugdale cracks, i.e. for cracks with spatially constant cohesive tractions. Herein, we deal with the general case of spatially non-constant cohesive tractions: Generalizing the Barenblatt–Dugdale approach, we consider that each crack is surrounded by a plane annular cohesive zone characterized by a constitutive softening law (introduced as a power law) relating the vector of cohesive tractions to the displacement discontinuity. The size of this cohesive zone is then estimated using the theorem of minimum potential energy, based on a class of kinematically admissible displacement fields.", "corpus_id": 123316095, "score": 0 }, { "doc_id": "135948204", "title": "A simple J-integral governed bilinear constitutive relation for simulating fracture propagation in quasi-brittle material", "abstract": "The present paper develops a bilinear constitutive relation for material at fracture tip based on the cohesive zone model and the J-integral theory. In this bilinear constitutive relation, the stress linearly decreases rather than suddenly drops down to zero at the post-peak stage. The slope of stress degradation is related to the critical J-integral of material and the element size. By this bilinear constitutive relation, the tensile and mixed fracture propagation can be well simulated for the strain energy release rate can be preserved with element size decreasing. The simulation results are almost free of the element size sensitivity. The present model and its implementation are very simple. For the elements at fracture tip, the derived bilinear constitutive relation is adopted while for the rest elements, the ideal elastic-brittle model is adopted. For the fracture propagation is represented by the deterioration of stiffness through constitutive relation, no separate fracture criterion is needed, which makes the evaluation of the fracture propagation by separate fracture criterion and the mesh modification after each load step unnecessary. The simulation examples of tensile and mixed fracture suggest that the present method is valid and highly efficient.", "corpus_id": 135948204, "score": 0 }, { "doc_id": "136678831", "title": "Experimental and numerical study of the dependency of interface fracture in concrete–rock specimens on mode mixity", "abstract": "Abstract The interface between the concrete and the rock is usually considered the weakest link in concrete structures built on rock foundations. The fracture behaviour at the concrete–rock interface is influenced by many factors e.g. the material properties of the individual constituents, the fracture process zone at the interface and the mode mixity ratio. This paper investigates the dependency of the fracture behaviour of concrete–rock interfaces on the mode mixity ratio using experimental and numerical methods. The experimental program involves four-point-shearing of concrete–rock composite beams. It is designed to test a wide range of mode mixity ratio. Using linear elastic fracture mechanics theory, the fracture toughness and the fracture energy are first quantified in terms of the mode mixity ratio. The scaled boundary finite element method, which is known for its accuracy in modelling fracture, is used to compute the fracture toughness and fracture energy. Next, the crack propagation process of the concrete–rock composite beam is modelled using nonlinear fracture mechanics theory. The scaled boundary finite element method is coupled with interface elements to model the fracture process zone, which is a characteristic of fracture in quasi-brittle materials such as concrete and rock. A revised scaled boundary finite element method formulation using generalized coordinates is used to model the cohesive tractions. The cohesive crack at the interface is assumed to propagate when either the Mode 1 or the Mode 2 stress intensity factors change sign. A simple remeshing algorithm is used to propagate the crack at the interface. The numerical simulations are validated by the experimental measurements. The simulated crack propagation processes are described in terms of the mode mixity ratio.", "corpus_id": 136678831, "score": 0 }, { "doc_id": "129022450", "title": "Linear Elastic and Cohesive Fracture Analysis to Model Hydraulic Fracture in Brittle and Ductile Rocks", "abstract": "Hydraulic fracturing technology is being widely used within the oil and gas industry for both waste injection and unconventional gas production wells. It is essential to predict the behavior of hydraulic fractures accurately based on understanding the fundamental mechanism(s). The prevailing approach for hydraulic fracture modeling continues to rely on computational methods based on Linear Elastic Fracture Mechanics (LEFM). Generally, these methods give reasonable predictions for hard rock hydraulic fracture processes, but still have inherent limitations, especially when fluid injection is performed in soft rock/sand or other non-conventional formations. These methods typically give very conservative predictions on fracture geometry and inaccurate estimation of required fracture pressure. One of the reasons the LEFM-based methods fail to give accurate predictions for these materials is that the fracture process zone ahead of the crack tip and softening effect should not be neglected in ductile rock fracture analysis. A 3D pore pressure cohesive zone model has been developed and applied to predict hydraulic fracturing under fluid injection. The cohesive zone method is a numerical tool developed to model crack initiation and growth in quasi-brittle materials considering the material softening effect. The pore pressure cohesive zone model has been applied to investigate the hydraulic fracture with different rock properties. The hydraulic fracture predictions of a three-layer water injection case have been compared using the pore pressure cohesive zone model with revised parameters, LEFM-based pseudo 3D model, a Perkins-Kern–Nordgren (PKN) model, and an analytical solution. Based on the size of the fracture process zone and its effect on crack extension in ductile rock, the fundamental mechanical difference of LEFM and cohesive fracture mechanics-based methods is discussed. An effective fracture toughness method has been proposed to consider the fracture process zone effect on the ductile rock fracture.", "corpus_id": 129022450, "score": 0 }, { "doc_id": "134890834", "title": "The Effective Fracture Toughness in Hydraulic Fracturing", "abstract": "This paper examines the effective fracture toughness approach which is used in hydraulic fracturing in order to explain the high net-pressures that are often observed in field operations. The effective fracture toughness is calculated using a fully deterministic elasto-plastic hydraulic fracturing model. Rock is modelled by Mohr–Coulomb flow theory of plasticity for cohesive-frictional dilatant material. Fluid flow is modelled by lubrication theory. A cohesive crack model which takes into account the softening behaviour of rocks is employed as the propagation criterion. The fully coupled model is solved numerically by the finite element method and the effective fracture toughness is calculated using the path independent J-integral. The results show that plastic yielding near the tip of a propagating fracture provides an effective shielding, resulting in an increase in the rock effective fracture toughness by more than an order of magnitude. It is demonstrated that an elastic model based on the concept of effective fracture toughness matches the results of plasticity quite well. The effective fracture toughness increases with formation yielding, which is influenced by the deviator of the in-situ stresses, the rock strength, the elastic modulus and the pumping parameters. Tables of effective fracture toughness for a representative set of physical parameters are presented.", "corpus_id": 134890834, "score": 0 }, { "doc_id": "122297595", "title": "Multiple scale analysis of heterogeneous elastic structures using homogenization theory and voronoi cell finite element method", "abstract": "Abstract This paper deals with the development of a multiple scale finite element method by combining the asymptotic homogenization theory with Voronoi cell (VCFEM) for microstructural modeling. The Voronoi cell finite element model originates from Dirichlet tessellation of a representative material element or a base cell in the microstructure. Homogenized material coefficients for a global displacement finite element model are generated by VCFEM analysis using periodic boundary conditions on the base cell. Following the macroscopic analysis, the local VCFEM analysis is implemented to depict the true evolution of microstructural stresses and strains. Various numerical examples are executed for validating the effectiveness of VCFEM macro-micro modeling of elastic materials. The effect of size, shape, orientation and distribution of heterogeneities on the local and global response are examined.", "corpus_id": 122297595, "score": 0 }, { "doc_id": "135941954", "title": "Multiscale modeling of cohesive geomaterials with a polycrystalline approach", "abstract": "The main objective of this paper is to investigate the macroscopic elastic-plastic behaviors of a class of cohesive geomaterials with the aid of classical polycrystalline schemes. Specific local constitutive equations are proposed to describe the typical features of geomaterials. The local yield criterion for crystallographic sliding systems takes into account the pressure sensitivity and a non-associated plastic potential is introduced to properly describe the plastic dilatancy. Consequently, the concentration law is also modified in order to establish the relationship between the macroscopic stress tensor and the local stress tensor in each mineral grain. Computational aspects associated with the numerical implementation of polycrystalline model are revisited and discussed. The proposed model is applied to a typical polycrystalline rock, granite. After the identification of material parameters, its validity is verified through comparisons between model's predictions and experimental data on both conventional and true triaxial compression tests.", "corpus_id": 135941954, "score": 0 }, { "doc_id": "122550488", "title": "The determination of the elastic field of an ellipsoidal inclusion, and related problems", "abstract": "It is supposed that a region within an isotropic elastic solid undergoes a spontaneous change of form which, if the surrounding material were absent, would be some prescribed homogeneous deformation. Because of the presence of the surrounding material stresses will be present both inside and outside the region. The resulting elastic field may be found very simply with the help of a sequence of imaginary cutting, straining and welding operations. In particular, if the region is an ellipsoid the strain inside it is uniform and may be expressed in terms of tabulated elliptic integrals. In this case a further problem may be solved. An ellipsoidal region in an infinite medium has elastic constants different from those of the rest of the material; how does the presence of this inhomogeneity disturb an applied stress-field uniform at large distances? It is shown that to answer several questions of physical or engineering interest it is necessary to know only the relatively simple elastic field inside the ellipsoid.", "corpus_id": 122550488, "score": 0 }, { "doc_id": "119853168", "title": "The elastic field outside an ellipsoidal inclusion", "abstract": "The results of an earlier paper are extended. The elastic field outside an inclusion or inhomogeneity is treated in greater detail. For a general inclusion the harmonic potential of a certain surface distribution may be used in place of the biharmonic potential used previously. The elastic field outside an ellipsoidal inclusion or inhomogeneity may be expressed entirely in terms of the harmonic potential of a solid ellipsoid. The solution gives incidentally the velocity field about an ellipsoid which is deforming homogeneously in a viscous fluid. An expression given previously for the strain energy of an ellipsoidal region which has undergone a shear transformation is generalized to the case where the region has elastic constants different from those of its surroundings. The Appendix outlines a general method of calculating biharmonic potentials.", "corpus_id": 119853168, "score": 0 }, { "doc_id": "137618543", "title": "THEORETICAL PREDICTION OF PLASTIC STRAINS OF POLYCRYSTALS", "abstract": "Abstract : Plastic strain is considered a consequence of slipping on some of the 12 slip systems of facecentered-cubic single crystals. The polycrystal is assumed to be macroscopically homogeneous and initially isotropic -- that is, the crystal orientations, sizes, shapes and locations are random and uncorrelated. The rotations of the grains during deformation are neglected, and the average plastic strain in grains of a given orientation is calculated on the basis of the assumption that the grains under consideration are spherical and elastically isotropic. (Author)", "corpus_id": 137618543, "score": 0 }, { "doc_id": "16582710", "title": "A multiscale cohesive zone model and simulations of fractures", "abstract": "In this work, a novel multiscale cohesive zone model is proposed, in which the bulk material is modeled as a local quasi-continuum medium that obeys the Cauchy–Born rule while the cohesive force and displacement relations inside the cohesive zone are governed by a coarse grained depletion potential. The interface depletion potential is constructed based on the Derjaguin approximation of nonlocal colloidal interactions. By doing so, the interface constitutive descriptions are made genetically consistent with the bulk constitutive relations that are enriched from underneath atomistic structure. The method provides an effective means to describe properties of material inhomogeneities such as grain boundaries, bi-material interfaces, slip lines, and inclusions, etc. We have developed and implemented the proposed multiscale cohesive zone model in a cohesive finite element weak Galerkin formulation, and we have applied it to simulate dynamic fracture problems in solids. The numerical simulation results have shown that the method has successfully captured the phenomenon of spall fracture during simulations of impacts and penetrations.", "corpus_id": 16582710, "score": 0 }, { "doc_id": "986700", "title": "The Quasicontinuum Method: Overview, applications and current directions", "abstract": "The Quasicontinuum (QC) Method, originally conceived and developed by Tadmor, Ortiz and Phillips [1] in 1996, has since seen a great deal of development and application by a number of researchers. The idea of the method is a relatively simple one. With the goal of modeling an atomistic system without explicitly treating every atom in the problem, the QC provides a framework whereby degrees of freedom are judiciously eliminated and force/energy calculations are expedited. This is combined with adaptive model refinement to ensure that full atomistic detail is retained in regions of the problem where it is required while continuum assumptions reduce the computational demand elsewhere. This article provides a review of the method, from its original motivations and formulation to recent improvements and developments. A summary of the important mechanics of materials results that have been obtained using the QC approach is presented. Finally, several related modeling techniques from the literature are briefly discussed. As an accompaniment to this paper, a website designed to serve as a clearinghouse for information on the QC method has been established at www.qcmethod.com. The site includes information on QC research, links to researchers, downloadable QC code and documentation.", "corpus_id": 986700, "score": 0 }, { "doc_id": "12449683", "title": "Flow and transport in unsaturated fractured rock: effects of multiscale heterogeneity of hydrogeologic properties.", "abstract": "The heterogeneity of hydrogeologic properties at different scales may have different effects on flow and transport processes in a subsurface system. A model for the unsaturated zone of Yucca Mountain, Nevada, is developed to represent complex heterogeneity at two different scales: (1) layer scale corresponding to geologic layering and (2) local scale. The layer-scale hydrogeologic properties are obtained using inverse modeling, based on the available measurements collected from the Yucca Mountain site. Calibration results show a significant lateral and vertical variability in matrix and fracture properties. Hydrogeologic property distributions in a two-dimensional, vertical cross-section of the site are generated by combining the average layer-scale matrix and fracture properties with local-scale perturbations generated using a stochastic simulation method. The unsaturated water flow and conservative (nonsorbing) tracer transport through the cross-section are simulated for different sets of matrix and fracture property fields. Comparison of simulation results indicates that the local-scale heterogeneity of matrix and fracture properties has a considerable effect on unsaturated flow processes, leading to fast flow paths in fractures and the matrix. These paths shorten the travel time of a conservative tracer from the source (repository) horizon in the unsaturated zone to the water table for small fractions of total released tracer mass. As a result, the local-scale heterogeneity also has a noticeable effect on global tracer transport processes, characterized by an average breakthrough curve at the water table, especially at the early arrival time of tracer mass. However, the effect is not significant at the later time after 20% tracer mass reaches the water table. The simulation results also verify that matrix diffusion plays an important role in overall solute transport processes in the unsaturated zone at Yucca Mountain.", "corpus_id": 12449683, "score": 0 }, { "doc_id": "120883701", "title": "Multiscale, Multiphysics Network Modeling of Shale Matrix Gas Flows", "abstract": "We present a pore network model to determine the permeability of shale gas matrix. Contrary to the conventional reservoirs, where permeability is only a function of topology and morphology of the pores, the permeability in shale depends on pressure as well. In addition to traditional viscous flow of Hagen–Poiseuille or Darcy type, we included slip flow and Knudsen diffusion in our network model to simulate gas flow in shale systems that contain pores on both micrometer and nanometer scales. This is the first network model in 3D that combines pores with nanometer and micrometer sizes with different flow physics mechanisms on both scales. Our results showed that estimated apparent permeability is significantly higher when the additional physical phenomena are considered, especially at lower pressures and in networks where nanopores dominate. We performed sensitivity analyses on three different network models with equal porosity; constant cross-section model (CCM), enlarged cross-section model (ECM) and shrunk length model (SLM). For the porous systems with variable pore sizes, the apparent permeability is highly dependent on the fraction of nanopores and the pores’ connectivity. The overall permeability in each model decreased as the fraction of nanopores increased.", "corpus_id": 120883701, "score": 0 }, { "doc_id": "122664756", "title": "A multiscale modeling of damage and time-dependent behavior of cohesive rocks", "abstract": "The present paper deals with a micromechanical approach to modeling the time-dependent mechanical behavior of a class of cohesive geomaterials. The considered material is Callovo-Oxfordian argillite, which is mainly composed of three constituents: an elastoviscoplastic clay matrix, elastic quartz minerals, and elastic damaged calcite grains. The macroscopic constitutive law is obtained by adapting the incremental method proposed by Hill (J. Mech. Phys. Solids 1965; 13:89-101). Its unified formulation allows a description of not only the time-dependent behavior of the argillite but also its elastoplastic damage response. The developed model is first validated by comparison with finite element solutions and then it is applied to the prediction of argillites' macroscopic responses in connection with their mineralogical compositions. The validity of the model is checked through comparisons between the model's predictions and experimental data.", "corpus_id": 122664756, "score": 0 }, { "doc_id": "129516290", "title": "A two-scale poromechanical model for cohesive rocks", "abstract": "This paper presents a computational homogenization approach in the framework of poromechanics. A fully coupled hydromechanics problem is formulated at the macroscopic scale. The constitutive equations are replaced by results of numerical computations on a Representative Elementary Volume in order to obtain the overall stress of the mixture as well as its transmissivity properties. At the microscale, the material is assumed to be composed of an assembly of hyperelastic grains connected by cohesive interfaces. These interfaces are also channels of a network where the fluid can percolate. The fluid acts on the boundaries of the grains and influences the behavior of the cohesive interfaces. Conversely, the opening of the interfaces induces changes in the transmissivity properties of the corresponding channels. This yields a fully coupled hydromechanical problem at the microscopic scale. The finite element method is considered for the numerical solutions at both scales, the present approach extending the purely mechanical FE2 scheme to the coupled hydromechanical framework. The local macroscopic behavior resulting from the homogenization scheme is illustrated on different numerical tests. The results clearly show the coupling between damage and fluid permeability in the overall response, as a consequence of the small-scale interaction between the action of the percolating fluid, the deformation of the solid skeleton, and the failure of the cohesive interfaces.", "corpus_id": 129516290, "score": 0 }, { "doc_id": "137228965", "title": "A multi-scale rate dependent crack model for quasi-brittle heterogeneous materials", "abstract": "A multi-scale numerical approach for modeling cracking in heterogeneous quasi-brittle materials under dynamic loading is presented. In the model, a discontinuous crack model is used at macro-scale to simulate fracture and a gradient-enhanced damage model has been used at meso-scale to simulate diffuse damage. The traction-separation law for the cohesive zone model at macro-scale is obtained from the meso-scale through the discontinuous computational homogenization method. An implicit time integration is used to solve the dynamic problem at the macro-scale while the meso-scale model is solved as a quasi-static problem. The effect of crack opening rate on the macro cohesive law is taken into account by relating the material properties of the meso-scale model to the macro crack opening rate. The objectivity of the model response with respect to the representative volume element size is demonstrated for wave propagation problems. The model is verified by comparison with a direct numerical simulation.", "corpus_id": 137228965, "score": 0 }, { "doc_id": "122202754", "title": "Boundary element methods for potential problems", "abstract": "Abstract The boundary element formulation of potential problems is presented using weighted residual techniques. The paper emphasizes the simplicity of the boundary methods and the way in which they can be applied in engineering. The advantage of using this method in preference to finite elements is discussed in the applications.", "corpus_id": 122202754, "score": 0 }, { "doc_id": "119457767", "title": "Rapid solution of integral equations of classical potential theory", "abstract": "An algorithm is described for rapid solution of classical boundary value problems (Dirichlet an Neumann) for the Laplace equation based on iteratively solving integral equations of potential theory. CPU time requirements for previously published algorithms of this type are proportional to n2, where n is the number of nodes in the discretization of the boundary of the region. The CPU time requirements for the algorithm of the present paper are proportional to n, making it considerably more practical for large scale problems.", "corpus_id": 119457767, "score": 0 }, { "doc_id": "54218692", "title": "Traction boundary elements for cracks in anisotropic solids", "abstract": "A general mixed boundary element approach based on displacement and traction integral equations for anisotropic media is presented. Integration of the singular and hypersingular kernels along general quadratic line elements is carried out by analytical transformation of the integrals into regular ones, which are numerically evaluated, plus simple singular integrals with known analytical solution. This is achieved by the simple election of an integration variable, which is consistent with that of the anisotropic fundamental solution. The generality of the method allows for the use of curved elements and discontinuous quarter-point elements to represent Fracture Mechanics problems. Stress Intensity Factors are accurately computed from the crack opening displacement at the nodes of the quarter-point element. Several examples, including curved crack geometries and different material properties are presented. q 2003 Elsevier Ltd. All rights reserved.", "corpus_id": 54218692, "score": 0 }, { "doc_id": "119898837", "title": "Crack propagation by element-free Galerkin methods", "abstract": "Abstract Element free Galerkin methods (EFG) are gridless methods for solving partial differential equations which employ moving least square interpolants for the trial and test functions. EFG methods require only nodes and a description of the external and internal boundaries and interfaces of the model; no element connectivity is needed. The implementation of EFG to arbitrary crack growth in static problems such as fatigue is described. Numerical examples show that accurate stress intensity factors can be obtained by this method without any enrichment of the displacement field by a near crack tip singularity and that crack growth can be easily modeled since it requires almost no remeshing.", "corpus_id": 119898837, "score": 0 }, { "doc_id": "120151602", "title": "Fracture of magnetoelectroelastic composite materials using boundary element method (BEM)", "abstract": "Abstract The behavior of cracked linear magnetoelectroelastic solids is analysed by means of the dual Boundary Element Method (BEM) approach. Media possessing fully coupled piezoelectric, piezomagnetic and magnetoelectric effects are considered. An explicit 2-D Green’s function in terms of the extended Stroh formalism for magnetoelectroelastic full-plane under static loading is implemented. Hypersingular integrals arising in the traction boundary integral equations are computed through a regularization technique. Evaluation of fracture parameters directly from computed nodal values is discussed. The stress intensity factors (SIF), the electric displacement intensity factor (EDIF), the magnetic induction intensity factor (MIIF) as well as the mechanical strain energy release rate (MSERR) are evaluated for different crack configurations in both finite and infinite solids subjected to in-plane combined magnetic–electric–mechanical loading conditions. The accuracy of the boundary element solution is confirmed by comparison with selected analytical solutions in the literature. The new results that can be of interest in the design and maintenance of novel magnetoelectroelastic devices are also discussed.", "corpus_id": 120151602, "score": 0 }, { "doc_id": "10110167", "title": "Recent Advances and Emerging Applications of the Boundary Element Method", "abstract": "Sponsored by the U.S. National Science Foundation, a workshop on the boundary element method (BEM) was held on the campus of the University of Akron during September 1–3, 2010 (NSF, 2010, “Workshop on the Emerging Applications and Future Directions of the Boundary Element Method,” University of Akron, Ohio, September 1–3). This paper was prepared after this workshop by the organizers and participants based on the presentations and discussions at the workshop. The paper aims to review the major research achievements in the last decade, the current status, and the future directions of the BEM in the next decade. The review starts with a brief introduction to the BEM. Then, new developments in Green's functions, symmetric Galerkin formulations, boundary meshfree methods, and variationally based BEM formulations are reviewed. Next, fast solution methods for efficiently solving the BEM systems of equations, namely, the fast multipole method, the pre-corrected fast Fourier transformation method, and the adaptive cross approximation method are presented. Emerging applications of the BEM in solving microelectromechanical systems, composites, functionally graded materials, fracture mechanics, acoustic, elastic and electromagnetic waves, time-domain problems, and coupled methods are reviewed. Finally, future directions of the BEM as envisioned by the authors for the next five to ten years are discussed. This paper is intended for students, researchers, and engineers who are new in BEM research and wish to have an overview of the field. Technical details of the BEM and related approaches discussed in the review can be found in the Reference section with more than 400 papers cited in this review.", "corpus_id": 10110167, "score": 0 }, { "doc_id": "121628885", "title": "Analysis of anisotropic Kirchhoff plates using a novel hypersingular BEM", "abstract": "In this article a hypersingular boundary element method (BEM) for bending of thin anisotropic plates is presented. A new complex variable fundamental solution is implemented in the algorithm. For spatial discretization a collocation method with discontinuous quadratic elements is adopted. The domain integrals arising from the transversely applied load are transformed analytically into boundary integrals by means of the radial integration technique. The considered numerical examples prove that the novel BEM formulation presented in this study is much more efficient than previous formulations developed for the analysis of this kind of problems.", "corpus_id": 121628885, "score": 0 }, { "doc_id": "120144539", "title": "Dual reciprocity boundary element method in Laplace domain applied to anisotropic dynamic crack problems", "abstract": "In this paper the dual reciprocity boundary element method in the Laplace domain for anisotropic dynamic fracture mechanic problems is presented. Crack problems are analyzed using the subregion technique. The dynamic stress intensity factors are computed using traction singular quarter-point elements positioned at the tip of the crack. Numerical inversion from the Laplace domain to the time domain is achieved by the Durbin method. Numerical examples of dynamic stress intensity factor evaluation are considered for symmetric and non-symmetric problems. The influence of the number of Laplace parameters and internal points in the solution is investigated.", "corpus_id": 120144539, "score": 0 }, { "doc_id": "55424433", "title": "Two-dimensional time-harmonic BEM for cracked anisotropic solids", "abstract": "A mixed time-harmonic boundary element procedure for the analysis of two-dimensional dynamic problems in cracked solids of general anisotropy is presented. To the author's knowledge, no previous BE approach for time-harmonic two-dimensional crack problems in anisotropic solids exists. In the present work, the fundamental solution is split into the static singular part plus dynamic regular terms. Hypersingular integrals associated to the singular part in the traction boundary integral equation are transformed, by means of a simple change of variable, into regular ones plus very simple singular integrals with known analytical solution. Subsequently, only regular (frequency dependent) terms have to be added to the regularized static fundamental solution in order to solve the dynamic problem. The generality of this procedure permits the use of general straight or curved quadratic boundary elements. In particular, discontinuous quarter-point elements are used to represent the crack-tip behavior. Stress intensity factors are accurately computed from the nodal crack opening displacements at discontinuous quarter-point elements. The efficiency and robustness of the present time-harmonic BEM are verified numerically by several test examples. Results are also obtained for more complex configurations, not previously studied in the literature. They include curved crack geometry.", "corpus_id": 55424433, "score": 0 }, { "doc_id": "122142142", "title": "A comparative study of three BEM for transient dynamic crack analysis of 2-D anisotropic solids", "abstract": "Three different boundary element methods (BEM) for transient dynamic crack analysis in two-dimensional (2-D), homogeneous, anisotropic and linear elastic solids are presented. Hypersingular traction boundary integral equations (BIEs) in frequency- domain, Laplace-domain and time-domain with the corresponding elastodynamic fundamental solutions are applied for this purpose. In the frequency-domain and the Laplace-domain BEM, numerical solutions are first obtained in the transformed domain for discrete frequency or Laplace-transform parameters. Time-dependent results are subsequently obtained by means of the inverse Fourier-transform and the inverse Laplace-transform algorithm of Stehfest. In the time-domain BEM, the quadrature formula of Lubich is adopted to approximate the arising convolution integrals in the time-domain BIEs. Hypersingular integrals involved in the traction BIEs are computed through a regularization process that converts the hypersingular integrals to regular integrals, which can be computed numerically, and singular integrals which can be integrated analytically. Numerical results for the dynamic stress intensity factors are presented and discussed for a finite crack in an infinite domain subjected to an impact crack-face loading.", "corpus_id": 122142142, "score": 0 }, { "doc_id": "96453252", "title": "Analysis of cracked magnetoelectroelastic composites under time-harmonic loading", "abstract": "This paper presents a numerical model for the analysis of cracked magnetoelectroelastic materials subjected to in-plane mechanical, electric and magnetic dynamic time-harmonic loading. A traction boundary integral equation formulation is applied to solve the problem in combination with recently obtained time-harmonic Green’s functions (Rojas-Diaz et al., 2008). The hypersingular boundary integral equations appearing in the formulation are first regularized via a simple change of variables that permits to isolate the singularities. Relevant fracture parameters, namely stress intensity factors, electric displacement intensity factor and magnetic induction intensity factor are directly evaluated as functions of the computed nodal opening displacements and the electric and magnetic potentials jumps across the crack faces. The method is checked by comparing numerical results against existing solutions for piezoelectric solids. Finally, numerical results for scattering of plane waves in a magnetoelectroelastic material by different crack configurations are presented for the first time. The obtained results are analyzed to evaluate the dependence of the fracture parameters on the coupled magnetoelectromechanical load, the crack geometry and the characteristics of the incident wave motion.", "corpus_id": 96453252, "score": 0 }, { "doc_id": "55284358", "title": "Hypersingular BEM for dynamic fracture in 2-D piezoelectric solids", "abstract": "Fracture behavior of piezoelectric solids under time-harmonic loading is numerically analyzed in this paper. A 2-D boundary element method (BEM) based on both displacement and traction boundary integral equations is presented. The time-harmonic Green’s functions for the infinite plane are split into singular plus regular terms, the singular ones coinciding with the static Green’s functions. In this manner the singular and hypersingular integrals arising in the formulation may be treated by the same simple regularization procedure proposed by the authors for static piezoelectricity. Quarter-point elements are used for the direct evaluation of stress and electric displacement intensity factors from nodal values. Several numerical examples for the scattering of waves by different crack configurations including branched and curved cracks and crack interaction problems are given to demonstrate the performance of the proposed method. 2006 Elsevier B.V. All rights reserved.", "corpus_id": 55284358, "score": 0 }, { "doc_id": "121074949", "title": "A hypersingular time‐domain BEM for 2D dynamic crack analysis in anisotropic solids", "abstract": "A hypersingular time-domain boundary element method (BEM) for transient elastodynamic crack analysis in two-dimensional (2D), homogeneous, anisotropic, and linear elastic solids is presented in this paper. Stationary cracks in both infinite and finite anisotropic solids under impact loading are investigated. On the external boundary of the cracked solid the classical displacement boundary integral equations (BIEs) are used, while the hypersingular traction BIEs are applied to the crack-faces. The temporal discretization is performed by a collocation method, while a Galerkin method is implemented for the spatial discretization. Both temporal and spatial integrations are carried out analytically. Special analytical techniques are developed to directly compute strongly singular and hypersingular integrals. Only the line integrals over an unit circle arising in the elastodynamic fundamental solutions need to be computed numerically by standard Gaussian quadrature. An explicit time-stepping scheme is obtained to compute the unknown boundary data including the crack-opening-displacements (CODs). Special crack-tip elements are adopted to ensure a direct and an accurate computation of the elastodynamic stress intensity factors from the CODs. Several numerical examples are given to show the accuracy and the efficiency of the present hypersingular time-domain BEM. Copyright © 2008 John Wiley & Sons, Ltd.", "corpus_id": 121074949, "score": 0 }, { "doc_id": "55448788", "title": "A 2D hypersingular time-domain traction BEM for transient elastodynamic crack analysis", "abstract": "A two-dimensional (2D) hypersingular time-domain traction BEM for transient elastodynamic crack analysis is presented in this paper. Time-domain traction boundary integral equations (BIEs) are applied for this purpose, to both crack-faces and external boundaries of the cracked solid. A numerical solution procedure is developed for solving the hypersingular time-domain traction BIEs. A time-stepping scheme in conjunction with a collocation method is applied. The time-stepping scheme uses a linear temporal shape-function which makes an analytical time-integration of the convolution integrals possible. As spatial shape-functions, two different shape-functions are adopted: a square-root crack-tip shape-function for elements adjacent to crack-tips and a constant shape-function for elements away from crack-tips. In this manner, the local behavior of the crack-opening-displacements (CODs) at crack-tips is correctly approximated by the square-root crack-tip shape-function. This allows us to accurately compute the dynamic stress intensity factors from the CODs. Suitable methods for evaluating the hypersingular and the strongly singular integrals are presented. Numerical examples for unbounded and bounded solids with cracks are given to show the efficiency and the accuracy of the time-domain BEM for transient elastodynamic crack analysis.", "corpus_id": 55448788, "score": 0 }, { "doc_id": "122730272", "title": "CRACK TIP FINITE ELEMENTS ARE UNNECESSARY", "abstract": "It is shown that a singularity occurs in isoparametric finite elements if the mid-side nodes are moved sufficiently from their normal position. By choosing the mid-side node positions on standard isoparametric elements so that the singularity occurs exactly at the corner of an element it is possible to obtain quite accurate solutions to the problem of determining the stress intensity at the tip of a crack. The solutions compare favourably with those obtained using some types of special crack tip elements, but are not as accurate as those given by a crack tip element based on the hybrid principle. However, the hybrid elements are more difficult to use.", "corpus_id": 122730272, "score": 0 }, { "doc_id": "119719301", "title": "Hypersingular quarter‐point boundary elements for crack problems", "abstract": "The present paper deals with the study and effective implementation for Stress Intensity Factor computation of a mixed boundary element approach based on the standard displacement integral equation and the hypersingular traction integral equation. Expressions for the evaluation of the hypersingular integrals along general curved quadratic line elements are presented. The integration is carried out by transformation of the hypersingular integrals into regular integrals, which are evaluated by standard quadratures, and simple singular integrals, which are integrated analytically. The generality of the method allows for the modelling of curved cracks and the use of straight line quarter-point elements. The Stress Intensity Factors can be computed very accurately from the Crack Opening Displacement at collocation points extremely close to the crack tip. Several examples with different crack geometries are analyzed. The computed results show that the proposed approach for Stress Intensity Factors evaluation is simple, produces very accurate solutions and has little dependence on the size of the elements near the crack tip.", "corpus_id": 119719301, "score": 0 }, { "doc_id": "15831109", "title": "A path-independent integral and the approximate analysis of strain", "abstract": "Abstract : An integral is exhibited which has the same value for all paths surrounding a class of notches in two-dimensional deformation fields of linear or non-linear elastic materials. The integral may be evaluated almost by inspection for a few notch configurations. Also, for materials of the elastic- plastic type (treated through a deformation rather than incremental formulation) , with a linear response to small stresses followed by non-linear yielding, the integral may be evaluated in terms of Irwin's stress intensity factor when yielding occurs on a scale small in comparison to notch size. On the other hand, the integral may be expressed in terms of the concentrated deformation field in the vicinity of the notch tip. This implies that some information on strain concentrations is obtainable without recourse to detailed non-linear analyses. Such an approach is exploited here. Applications are made to: Approximate estimates of strain concentrations at smooth ended notch tips in elastic and elastic-plastic materials, A general solution for crack tip separation in the Barenblatt-Dugdale crack model, leading to a proof of the identity of the Griffith theory and Barenblatt cohesive theory for elastic brittle fracture and to the inclusion of strain hardening behavior in the Dugdale model for plane stress yielding, and An approximate perfectly plastic plane strain analysis, based on the slip line theory, of contained plastic deformation at a crack tip and of crack blunting.", "corpus_id": 15831109, "score": 0 }, { "doc_id": "128900549", "title": "Fracture Mechanics Analysis of Cracked Discs of Anisotropic Rock Using the Boundary Element Method", "abstract": "This paper is the second of a series of two papers dealing with the determination of the deformability, tensile strength and fracturing of anisotropic rocks by diametral compression (Brazilian test) of discs of rock. It is shown how a new formulation of the Boundary Element Method (BEM), proposed recently by the authors, can be used to determine the stress intensity factors (SIFs) and the fracture toughness of anisotropic rocks from the results of diametral compression tests on initially cracked discs. Crack initiation angles and propagation paths can also be predicted using a numerical procedure based on the BEM and maximum tensile stress criterion. Numerical examples of calculation of mixed mode SIFs are presented for both isotropic and anisotropic media. The calculated SIFs for the special isotropic case are found to be in good agreement with those reported by previous authors. Diametral loading tests were conducted on Cracked Straight Through Brazilian Disc (CSTBD) specimens of a shale in order to evaluate its fracture toughness, the angle of crack initiation and the path of crack propagation. It was found that the numerical simulations of crack initiation and propagation in the CSTBD specimens of the shale were in good agreement with the experimental observations.", "corpus_id": 128900549, "score": 0 }, { "doc_id": "137605485", "title": "Determination of Fracture Toughness of Anisotropic Rocks by Boundary Element Method", "abstract": "SummaryThis paper presents a systematic procedure for determining fracture toughness of an anisotropic marble using the diametral compression test (Brazilian test) with a central crack on the discs. Additionally, a novel formulation to increase the accuracy in Stress Intensity Factor (SIF) calculations using Boundary Element Method (BEM) is applied to determine the stress intensity factors and the fracture toughness of anisotropic rocks under mixed-mode loading. The numerical results show that the SIFs for both isotropic and anisotropic problems are in good agreement with those reported by previous authors. The marble with clear white-black foliation from Hualien (in eastern Taiwan), was selected for the Brazilian tests. Diametral loading was conducted on the Cracked Straight Through Brazilian Disc (CSTBD) specimens to evaluate their fracture toughness. In addition, a new fracture criterion was developed to predict pure mode I, pure mode II or mixed mode (I–II) fracture toughness of the anisotropic marble. The new fracture criterion is based on the examination of mode I, mode II and mixed mode (I–II) fracture toughness for different crack angles and anisotropic orientation.", "corpus_id": 137605485, "score": 0 }, { "doc_id": "59131202", "title": "Modeling crack propagation path of anisotropic rocks using boundary element method", "abstract": "In a cracked material, the stress intensity factors (SIFs) at the crack tips, which govern the crack propagation and are associated with the strength of the material, are strongly affected by the crack inclination angle and the orientation with respect to the principal direction of anisotropy. In this paper, a formulation of the boundary element method (BEM), based on the relative displacements of the crack tip, is used to determine the mixed-mode SIFs of isotropic and anisotropic rocks. Numerical examples of the application of the formulation for different crack inclination angles, crack lengths, and degree of material anisotropy are presented. Furthermore, the BEM formulation combined with the maximum circumferential stress criterion is adopted to predict the crack initiation angles and simulate the crack propagation paths. The propagation path in cracked straight through Brazilian disc specimen is numerically predicted and the results of numerical and experimental data compared with the actual laboratory observations. Good agreement is found between the two approaches. The proposed BEM formulation is therefore suitable to simulate the process of crack propagation. Copyright © 2008 John Wiley & Sons, Ltd.", "corpus_id": 59131202, "score": 0 }, { "doc_id": "121286583", "title": "Dual boundary element incremental analysis of crack propagation", "abstract": "Abstract This paper describes an application of the dual boundary element method to the analysis of mixed-mode crack growth in linear elastic fracture mechanics. Crack-growth processes are simulated with an incremental crack-extension analysis based on the maximum principal stress criterion which is expressed in terms of the stress intensity factors. For each increment of the crack extension, the dual boundary element method is applied to perform a single-region stress analysis of the cracked structure and the J-integral technique is used to compute the stress intensity factors. When the crack extension is modelled with new boundary elements, remeshing is not required because of the single-region analysis, an intrinsic feature of the dual boundary element method. Results of this incremental crack-extension analysis are presented for several geometries. The analysis of fatigue crack-growth is introduced as a post-processing procedure on the crack-extension results and an example is presented.", "corpus_id": 121286583, "score": 0 }, { "doc_id": "135912462", "title": "Cohesive crack growth modelling based on an alternative nonlinear BEM formulation", "abstract": "Abstract Fracture mechanics and crack propagation problems have been widely studied by the scientific community in recent years, because crack growth phenomenon can explain the failure of structures. In order to model accurately the structural behaviour of complex engineering structures numerical techniques are required. In this regard, the boundary element method (BEM) has been widely used to solve complex engineering problems, especially those where its mesh dimension reduction includes advantages on the modelling. This paper addresses the analysis of crack propagation in quasi-brittle materials using an alternative BEM formulation. In this type of problem, the damaged zone ahead the crack tip is modelled based on the fictitious crack model. Therefore, the residual resistance of the damaged zone is represented by cohesive stresses, which tends to close the crack faces. The alternative BEM formulation proposed aims at modelling the cohesive stresses using the domain term of the direct integral representation. This term is degenerated, in order to be non null only at the fictitious crack path. As a result of the domain term manipulation, appears a dipole of stresses, which will govern the cohesive stresses. It leads a nonlinear formulation, where the cohesive stresses are determined according the crack opening displacement. Linear, bi-linear and exponential cohesive laws are used to model the residual resistance of the cohesive zone. The results achieved by the proposed formulation are compared with experimental and numerical ones available in literature, in order to validate and prove its robustness and accuracy.", "corpus_id": 135912462, "score": 0 }, { "doc_id": "55403033", "title": "A single-domain dual-boundary-element formulation incorporating a cohesive zone model for elastostatic cracks", "abstract": "A cracked elastostatic structure is artificially divided into subdomains of simpler topology such that the well-developed classic dual integral equations can be applied appropriately to each domain. Applying the continuity and equilibrium conditions along artificial boundaries and properties of the integral kernels a single-domain dual-boundary-integral equation formulation is derived for a cracked elastic structure. A cohesive zone model is used to model the crack tip processes and is coupled with the single-domain dual-boundary-integral equation formulation; the resulting nonlinear equations are solved using the iterative method of successive-over-relaxation. The constitutive law used for a crack includes three parts: a law relating cohesive force to crack displacement difference when a crack is opening, a characterization of tangential interaction between crack surfaces when the crack surfaces are in contact, and a maximum principal stress criterion of crack advance. Incorporation of local unloading effect of the cohesive zone material has enabled a simulation of fracture with initial damage, partial development of the failure process zone at structural instability and multiple crack interaction. Some of the features of the method are demonstrated by considering three examples. The first problem is a single-edge-cracked specimen that exhibits a snap-back instability. The second example is the development of wing cracks from an angled crack under compression. The last example demonstrates the capability to consider mixed-mode crack growth and interaction of cracks. Thus, the problem of crack growth has been reduced to the determination of the cohesive model for the fracture process.", "corpus_id": 55403033, "score": 0 }, { "doc_id": "137003029", "title": "Crack growth analysis in concrete using boundary element method", "abstract": "Abstract In this paper, the dual boundary element method is extended to include the non-linear behaviour of cracking in concrete. The fictitious crack model is used to simulate the pure mode I and mixed mode crack propagation in concrete. The fictitious crack in the fracture zone in front of the real crack tip is replaced by the closing forces acting on both crack surfaces. When the force at the fictitious crack tip exceeds the maximum tensile strength of the concrete, the crack will propagate perpendicular to the maximum principal stress. The numerical simulation is controlled through the crack length as a monotonic increasing function during the fracture process. Three-point bending and four-point shear specimens are used to check the numerical results for mode I and mixed mode, respectively. Under the crack length controlled scheme, the snapback instability is observed in the mixed mode problem.", "corpus_id": 137003029, "score": 0 }, { "doc_id": "123397572", "title": "Boundary element analysis of the pullout behaviour of an anchor bolt embedded in concrete", "abstract": "A boundary element formulation for the analysis of pullout behaviour of an anchor bolt embedded in concrete is presented. The pullout analysis involves modelling two different bodies (i.e. anchor head and concrete) which are in contact over a certain region. The fracture of concrete is represented by the fictitious crack model (FCM) in which the fracture zone is replaced by applying closing forces on both crack surface. The FCM in conjunction with the boundary element method (BEM) allows the simulation of crack growth in concrete in a straight forward manner without remeshing. The crack path need not be known in advance as it is calculated during the iteration process. The numerical results obtained are compared with the round-robin analysis of pullout test proposed by RILEM TC 90-FMA.", "corpus_id": 123397572, "score": 0 }, { "doc_id": "123535361", "title": "Crack Growth Analysis in Reinforced Concrete Using BEM", "abstract": "A boundary-element formulation for modeling the nonlinear behavior of reinforced concrete is presented. The influence of reinforcements on the concrete is considered as a distribution of forces over the region of attachment. The solution for the attachment forces is obtained from the condition that the deformations of the concrete and the reinforcement under the action of the external loading are compatible. The yielding of reinforcement is considered when the total force at any section of the reinforcement is greater than the yielding force and is assumed to be broken when the strain reaches the maximum strain. The fracture of concrete is simulated using the fictitious crack model in which the fracture zone is replaced by closing forces acting on both crack surfaces. In using the boundary-element method to simulate cracks, the crack path is not known in advance because it can be calculated during the iteration process, and then the need of remeshing becomes obsolete. The numerical results obtained are compared to the finite-element method analysis and experimental results.", "corpus_id": 123535361, "score": 0 }, { "doc_id": "137257477", "title": "Fracture mechanics analysis of cracking in plain and reinforced concrete using the boundary element method", "abstract": "Boundary element formulations for modelling the nonlinear behaviour of concrete are reviewed. The analysis based on the dual boundary element method (BEM) to represent the cracks in concrete is presented. The fictitious crack is adopted to represent the fracture process zone in concrete. The influence of reinforcements on the concrete is considered as a distribution of forces over the region of attachment. The yielding of reinforcement is considered when the total force at any section of the reinforcement is greater than the yielding force and is assumed to be broken when the strain reaches the maximum strain. In using the BEM to simulate cracks, the crack path need not be known in advance since it can be calculated during the iteration process and as such remeshing becomes obsolete. The numerical results obtained are compared to the FEM analysis.", "corpus_id": 137257477, "score": 0 }, { "doc_id": "18390597", "title": "GMRES: a generalized minimal residual algorithm for solving nonsymmetric linear systems", "abstract": "We present an iterative method for solving linear systems, which has the property of minimizing at every step the norm of the residual vector over a Krylov subspace. The algorithm is derived from t...", "corpus_id": 18390597, "score": 0 }, { "doc_id": "123063832", "title": "A fast multipole boundary integral equation method for crack problems in 3D", "abstract": "This paper discusses a three-dimensional fast multipole boundary integral equation method for crack problems for Laplace's equation. The proposed implementation uses collocation and piecewise constant shape functions to discretise the hypersingular boundary integral equation for crack problems. The resulting numerical equation is solved with GMRES (generalised minimum residual method) in connection with FMM (fast multipole method). It is found that the obtained code is faster than a conventional one when the number of unknowns is greater than about 1300.", "corpus_id": 123063832, "score": 0 }, { "doc_id": "120373507", "title": "Application of fast multipole Galerkin boundary integral equation method to elastostatic crack problems in 3D", "abstract": "Fast multipole method (FMM) has been developed as a technique to reduce the computational cost and memory requirements in solving large-scale problems. This paper discusses an application of FMM to three-dimensional boundary integral equation method for elastostatic crack problems. The boundary integral equation for many crack problems is discretized with FMM and Galerkin's method. The resulting algebraic equation is solved with generalized minimum residual method (GMRES). The numerical results show that FMM is more efficient than conventional methods when the number of unknowns is more than about 1200 and, therefore, can be useful in large-scale analyses of fracture mechanics. Copyright © 2001 John Wiley & Sons, Ltd.", "corpus_id": 120373507, "score": 0 }, { "doc_id": "1044734", "title": "GPU-accelerated indirect boundary element method for voxel model analyses with fast multipole method", "abstract": "Abstract An indirect boundary element method (BEM) that uses the fast multipole method (FMM) was accelerated using graphics processing units (GPUs) to reduce the time required to calculate a three-dimensional electrostatic field. The BEM is designed to handle cubic voxel models and is specialized to consider square voxel walls as boundary surface elements. The FMM handles the interactions among the surface charge elements and directly outputs surface integrals of the fields over each individual element. The CPU code was originally developed for field analysis in human voxel models derived from anatomical images. FMM processes are programmed using the NVIDIA Compute Unified Device Architecture (CUDA) with double-precision floating-point arithmetic on the basis of a shared pseudocode template. The electric field induced by DC-current application between two electrodes is calculated for two models with 499,629 (model 1) and 1,458,813 (model 2) surface elements. The calculation times were measured with a four-GPU configuration (two NVIDIA GTX295 cards) with four CPU cores (an Intel Core i7-975 processor). The times required by a linear system solver are 31 s and 186 s for models 1 and 2, respectively. The speed-up ratios of the FMM range from 5.9 to 8.2 for model 1 and from 5.0 to 5.6 for model 2. The calculation speed for element-interaction in this BEM analysis was comparable to that of particle-interaction using FMM on a GPU.", "corpus_id": 1044734, "score": 0 }, { "doc_id": "60969845", "title": "An adaptive dual-information FMBEM for 3D elasticity and its GPU implementation", "abstract": "Abstract Combined the boundary element method (BEM) with the fast multipole method (FMM), the fast multipole BEM (FMBEM) is proposed to solve large scale problems. A key issue the FMBEM has to address is the element integrals, which usually consumes much time when the FMM for N -body problems is directly used. In order to accelerate element integrals, we present an adaptive FMBEM with a particular dual-information tree structure which contains both node and element information, and use it for 3D elasticity in this paper. In our adaptive FMBEM, the Multipole Expansions (ME), Moment-to-Local (M2L) translation, Local Expansions (LE), and the Near Field Direct Computation (NFDC) are level independent so that they are suitable for parallel computing. The examples show that the time of ME and NFDC in our FMBEM is almost 1/3 and 1/2 compared with that in a node-based FMBEM which deals with FMBEM in a particle interaction mode. We develop two GPU parallel strategies to accelerate the processes of ME, M2L and NFDC and implement them on a NVIDIA GTX 285 GPU, and the speedups to an Intel Core2 Q9550 CPU using 4 cores can reach 10.7 for ME, 16.2 for M2L, and 3.6 for NFDC.", "corpus_id": 60969845, "score": 0 }, { "doc_id": "118010911", "title": "Fast Multipole Boundary Element Method: Theory and Applications in Engineering", "abstract": "1. Introduction 2. Conventional BEM for potential problems 3. Fast multipole BEM for potential problems 4. Elastostatic problems 5. Stokes flow problems 6. Acoustic wave problems.", "corpus_id": 118010911, "score": 0 }, { "doc_id": "121961774", "title": "Improved implementation and robustness study of the X-FEM for stress analysis around cracks", "abstract": "Numerical crack propagation schemes were augmented in an elegant manner by the X-FEM method. The use of special tip enrichment functions, as well as a discontinuous function along the sides of the crack allows one to do a complete crack analysis virtually without modifying the underlying mesh, which is of industrial interest, especially when a numerical model for crack propagation is desired. This paper improves the implementation of the X-FEM method for stress analysis around cracks in three ways. First, the enrichment strategy is revisited. The conventional approach uses a 'topological' enrichment (only the elements touching the front are enriched). We suggest a 'geometrical' enrichment in which a given domain size is enriched. The improvements obtained with this enrichment are discussed. Second, the conditioning of the X-FEM both for topological and geometrical enrichments is studied. A preconditioner is introduced so that 'off the shelf' iterative solver packages can be used and perform as well on X-FEM matrices as on standard FEM matrices. The preconditioner uses a local (nodal) Cholesky based decomposition. Third, the numerical integration scheme to build the X-FEM stiffness matrix is dramatically improved for tip enrichment functions by the use of an ad hoc integration scheme. A 2D benchmark problem is designed to show the improvements and the robustness.", "corpus_id": 121961774, "score": 0 }, { "doc_id": "16426779", "title": "Solving a large dense linear system by adaptive cross approximation", "abstract": "An efficient algorithm for the direct solution of a linear system associated with the discretization of boundary integral equations (in two dimensions) is described without having to compute the complete matrix of the linear system. This algorithm is based on the unitary-weight representation, for which a new construction based on adaptive cross approximation is proposed. This low rank approximation uses only a small part of the entries to construct the adaptive cross representation, and therefore the linear system can be solved efficiently.", "corpus_id": 16426779, "score": 0 }, { "doc_id": "122135814", "title": "Numerical analysis of multi-crack large-scale plane problems with adaptive cross approximation and hierarchical matrices", "abstract": "The problem of interaction of large number of cracks in a plate is considered by the method of singular integral equations (SIE). The corresponding system of SIE is solved by using Gauss–Chebyshev quadratures, which results in a large system of linear algebraic equations. The solution of the latter employs the adaptive cross approximation (ACA) technique that has not previously been applied for studying multi-crack large-scale plane problems. Therefore, several benchmarks problems with large number of cracks modelling periodical arrangements have been tested to investigate performance of the method; these include arrays of collinear cracks, parallel cracks, and double network of parallel cracks. Comparisons with analytical and numerical periodical solutions available for the mentioned cases reveal high accuracy and fast performance of the method. It is also applied for studying effective characteristics of bodies with up to 20,000 cracks and for accurate modelling of interaction of a macrocrack with thousands of microcracks.", "corpus_id": 122135814, "score": 0 }, { "doc_id": "119615110", "title": "A fast hierarchical dual boundary element method for three-dimensional elastodynamic crack problems", "abstract": "In this work a fast solver for large-scale three-dimensional elastodynamic crack problems is presented, implemented, and tested. The dual boundary element method in the Laplace transform domain is used for the accurate dynamic analysis of cracked bodies. The fast solution procedure is based on the use of hierarchical matrices for the representation of the collocation matrix for each computed value of the Laplace parameter. An ACA (adaptive cross approximation) algorithm is used for the population of the low rank blocks and its performance at varying Laplace parameters is investigated. A preconditioned GMRES is used for the solution of the resulting algebraic system of equations. The preconditioners are built exploiting the hierarchical arithmetic and taking full advantage of the hierarchical format. An original strategy, based on the computation of some local preconditioners only, is presented and tested to further speed up the overall analysis. The reported numerical results demonstrate the effectiveness of the technique for both uncracked and cracked solids and show significant reductions in terms of both memory storage and computational time.", "corpus_id": 119615110, "score": 0 }, { "doc_id": "120492982", "title": "Adaptive cross-approximation applied to the solution of system of equations and post-processing for 3D elastostatic problems using the boundary element method", "abstract": "We present the hierarchical matrix (H-matrix) technique combined with the adaptive cross-approximation (ACA) applied to a three-dimensional (3D) elastostatic problem using the boundary element method (BEM). This is used in structural geology and geomechanics for the evaluation of the deformation and perturbed stress field associated with surfaces of displacement discontinuity. Such optimization significantly reduces (i) the time and memory needed for the resolution of the system of equations, but more importantly (ii) the time needed for the post-processing at observation points where the deformation and the perturbed stress field are evaluated. Specifically, it is shown that the H-matrix structure used with the ACA, clearly captures the kernel smoothness during the post-processing stage according to the field point positions, and optimizes the computation accordingly. Combined with the parallelization on multi-core processors, this technique allows intensive computations to be done on personal desktop and laptop computers. Numerical simulations are presented, showing the advantages of such optimizations compared to the standard method.", "corpus_id": 120492982, "score": 0 }, { "doc_id": "73661313", "title": "Investigation of 3D crack propagation problems via fast BEM formulations", "abstract": "AbstactThe simulation of 3D fatigue crack growth is investigated and in combination with suitable experiments it is aimed to identify a reliable crack growth criterion. To perform the crack growth simulation as effectively as possible the boundary element method (BEM) in terms of the 3D Dual BEM is utilized. The relevant boundary integral equations are evaluated in the framework of a collocation procedure. To compress the system matrix and to speed-up the solution procedure the adaptive cross approximation (ACA) method is applied. It is an algebraic technique acting purely on the system matrix itself. The efficiency of this procedure with respect to crack problems will be shown on both a standard fracture specimen and an industrial application.", "corpus_id": 73661313, "score": 0 }, { "doc_id": "122684866", "title": "Developing new enrichment functions for crack simulation in orthotropic media by the extended finite element method", "abstract": "New enrichment functions are proposed for crack modelling in orthotropic media using the extended finite element method (XFEM). In this method, Heaviside and near-tip functions are utilized in the framework of the partition of unity method for modelling discontinuities in the classical finite element method. In this procedure, by using meshless based ideas, elements containing a crack are not required to conform to crack edges. Therefore, mesh generation is directly performed ignoring the existence of any crack while the method remains capable of extending the crack without any remeshing requirement. Furthermore, the type of elements around the crack-tip remains the same as other parts of the finite element model and the number of nodes and consequently degrees of freedom are reduced considerably in comparison to the classical finite element method. Mixed-mode stress intensity factors (SIFs) are evaluated to determine the fracture properties of domain and to compare the proposed approach with other available methods. In this paper, the interaction integral (M-integral) is adopted, which is considered as one of the most accurate numerical methods for calculating stress intensity factors.", "corpus_id": 122684866, "score": 0 }, { "doc_id": "123078802", "title": "ENRICHED ELEMENT-FREE GALERKIN METHODS FOR CRACK TIP FIELDS", "abstract": "SUMMARY The Element-Free Galerkin (EFG) method is a meshless method for solving partial di⁄erential equations which uses only a set of nodal points and a CAD-like description of the body to formulate the discrete model. It has been used extensively for fracture problems and has yielded good results when adequate refinement is used near the crack tip, but stresses tend to be oscillatatory near the crack tip unless substantial refinement is used. An enriched EFG formulation for fracture problems is proposed. Two methods are used: (1) adding the asymptotic fields to the trial function and (2) augmenting the basis by the asymptotic fields. A local mapping of the enriched fields for curved cracks is also described. Results show that both methods greatly reduce stress oscillations and allow the calculation of accurate stress intensity factors with far fewer degrees of freedom. ( 1997 by John Wiley & Sons, Ltd.", "corpus_id": 123078802, "score": 0 }, { "doc_id": "137186889", "title": "Fracture analysis for orthotropic cracked plates", "abstract": "The present investigation is intended to study the elastostatic fracture response of an orthotropic cracked plate subjected at infinity to a biaxial uniform load. The effects of orthotropy and load biaxiality on the near crack tip elastic fields is pointed out. Considering the non-singular terms, the angle of incipient crack propagation and the fracture loci are obtained. For this purposes the strain energy density theory and the maximum circumferential stress theory are considered and extended to orthotropic materials. A numerical analysis is performed for a wide range of orthotropic material properties and applied loads.", "corpus_id": 137186889, "score": 0 }, { "doc_id": "122379125", "title": "On the construction of blending elements for local partition of unity enriched finite elements", "abstract": "For computational efficiency, partition of unity enrichments are preferably localized to the sub-domains where they are needed. It is shown that an appropriate construction of the elements in the blending area, the regionwhere the enriched elements blend to unenriched elements, is often crucial for good performance of local partition of unity enrichments. An enhanced strain formulation is developed which leads to good performance; the optimal rate of convergence is achieved. For polynomial enrichments, it is shown that a proper choice of the finite element shape functions and partition of unity shape functions also improves the accuracy and convergence. The methods are illustrated by several examples. The examples deal primarily with the signed distance function enrichment for treating discontinuous derivatives inside an element, but other enrichments are also considered. Results show that both methods provide optimal rates of convergence.", "corpus_id": 122379125, "score": 0 }, { "doc_id": "123646956", "title": "A corrected XFEM approximation without problems in blending elements", "abstract": "The extended finite element method (XFEM) enables local enrichments of approximation spaces. Standard finite elements are used in the major part of the domain and enriched elements are employed where special solution properties such as discontinuities and singularities shall be captured. In elements that blend the enriched areas with the rest of the domain problems arise in general. These blending elements often require a special treatment in order to avoid a decrease in the overall convergence rate. A modification of the XFEM approximation is proposed in this work. The enrichment functions are modified such that they are zero in the standard elements, unchanged in the elements with all their nodes being enriched, and varying continuously in the blending elements. All nodes in the blending elements are enriched. The modified enrichment function can be reproduced exactly everywhere in the domain and no problems arise in the blending elements. The corrected XFEM is applied to problems in linear elasticity and optimal convergence rates are achieved. Copyright © 2007 John Wiley & Sons, Ltd.", "corpus_id": 123646956, "score": 0 }, { "doc_id": "136702352", "title": "eXtended Finite Element Method for fracture characterization of adhesive joints in pure mode I", "abstract": "Abstract Adhesive-bonding for the unions in structures is gaining momentum over welding, riveting and fastening. It is vital for the design of bonded structures the availability of reliable damage models to predict their fracture behaviour. Cohesive Zone Models (CZM’s) have been extensively used in the past, taking advantage of traction-separation laws between stresses and relative displacements to simulate crack growth along predefined paths. The eXtended Finite Element Method (XFEM) is a recent improvement of the Finite Element Method (FEM) that relies on damage laws based on the bulk strength of materials for damage initiation and strain for the assessment of failure, rather than the tipping tractions and tensile/shear relative displacements used for the CZM’s. Compared to the FEM, XFEM excels in allowing discontinuities to grow within bulk solids along an arbitrary path. This work aims to assess the viability of the XFEM to predict the fracture behaviour of a thin layer of adhesive between stiff and compliant adherends. To build the XFEM damage laws, the fracture toughness in pure mode I (GIc) and tensile cohesive strength (\n\t\t\t\t σ n 0 ) of the two adhesives were initially determined by Double-Cantilever Beam (DCB) and bulk tensile tests, respectively. Particular emphasis was given to GIc, as this is the most influent parameter for the numerical predictions. The numerical simulations of the DCB tests with the proposed laws matched accurately the experimental load–displacement (P–δ) curves, which validated the analysis procedure. The accuracy of the data reduction methods for calculation of GIc was checked by comparison of the input values in the simulations with the results of GIc calculations, with good results.", "corpus_id": 136702352, "score": 0 }, { "doc_id": "121460248", "title": "X-FEM a good candidate for energy conservation in simulation of brittle dynamic crack propagation", "abstract": "Abstract This paper is devoted to the simulation of dynamic brittle crack propagation in an isotropic medium. It focuses on cases where the crack deviates from a straight-line trajectory and goes through stop-and-restart stages. Our argument is that standard methods such as element deletion or remeshing, although easy to use and implement, are not robust tools for this type of simulation essentially because they do not enable one to assess local energy conservation. Standard cohesive zone models behave much better when the crack’s path is known in advance, but are difficult to use when the crack’s path is unknown. The simplest method which consists in placing the cohesive segments along the sides of the finite elements leads to crack trajectories which are mesh-sensitive. The adaptive cohesive element formulation, which adds new cohesive elements when the crack propagates, is shown to have the proper energy conservation properties during remeshing. We show that the X-FEM is a good candidate for the simulation of complex dynamic crack propagation. A two-dimensional version of the proposed X-FEM approach is validated against dynamic experiments on a brittle isotropic plate.", "corpus_id": 121460248, "score": 0 }, { "doc_id": "136889042", "title": "Extended finite element method for cohesive crack growth", "abstract": "The extended finite element method allows one to model displacement discontinuities which do not conform to interelement surfaces. This method is applied to modeling growth of arbitrary cohesive cracks. The growth of the cohesive zone is governed by requiring the stress intensity factors at the tip of the cohesive zone to vanish. This energetic approach avoids the evaluation of stresses at the mathematical tip of the crack. The effectiveness of the proposed approach is demonstrated by simulations of cohesive crack growth in concrete.", "corpus_id": 136889042, "score": 0 }, { "doc_id": "10781649", "title": "New anisotropic crack-tip enrichment functions for the extended finite element method", "abstract": "In this paper, the extended finite element method (X-FEM) is implemented to analyze fracture mechanics problems in elastic materials that exhibit general anisotropy. In the X-FEM, crack modeling is addressed by adding discontinuous enrichment functions to the standard FE polynomial approximation within the framework of partition of unity. In particular, the crack interior is represented by the Heaviside function, whereas the crack-tip is modeled by the so-called crack-tip enrichment functions. These functions have previously been obtained in the literature for isotropic, orthotropic, piezoelectric and magnetoelectroelastic materials. In the present work, the crack-tip functions are determined by means of the Stroh’s formalism for fully anisotropic materials, thus providing a new set of enrichment functions in a concise and compact form. The proposed formulation is validated by comparing the obtained results with other analytical and numerical solutions. Convergence rates for both topological and geometrical enrichments are presented. Performance of the newly derived enrichment functions is studied, and comparisons are made to the well-known classical crack-tip functions for isotropic materials.", "corpus_id": 10781649, "score": 1 }, { "doc_id": "123663997", "title": "Cohesive and non-cohesive fracture by higher-order enrichment of XFEM", "abstract": "SUMMARY \nA comprehensive study is performed on the use of higher-order terms of the crack tip asymptotic fields as enriching functions for the eXtended FEM (XFEM) for both cohesive and traction-free cracks. For traction-free cracks, the Williams asymptotic field is used to obtain highly accurate stress intensity factors (SIFs), directly from the enriched degrees of freedom without any post-processing. The low accuracy of the results of the original research on this subject by Liu et al. [Int. J. Numer. Meth. Engng., 2004; 59:1103–1118] is remedied here by appropriate modifications of the enrichment scheme. The modifications are simple and can be easily included into an XFEM computer code. For cohesive cracks, the relevant asymptotic field is used, and two widely used criteria including the SIFs criterion and the stress criterion are examined for the crack growth simulation. Both linear and nonlinear cohesive laws are used. For the stress criterion, averaging is avoided due to the highly accurate crack tip approximation because of the higher-order enrichment. Then, a modified stress criterion is proposed, which is shown to be applicable to a wider class of problems. Several numerical examples, including straight and curved cracks, stationary and growing cracks, single and multiple cracks, and traction-free and cohesive cracks, are studied to investigate in detail the robustness and efficiency of the proposed enrichment scheme. Copyright © 2012 John Wiley & Sons, Ltd.", "corpus_id": 123663997, "score": 0 }, { "doc_id": "54020585", "title": "Two-Dimensional Mode I Crack Propagation in Saturated Ionized Porous Media Using Partition of Unity Finite Elements", "abstract": "Shales, clays, hydrogels, and tissues swell and shrink under changing osmotic conditions, which may lead to failure. The relationship between the presence of cracks and fluid flow has had little attention. The relationship between failure and osmotic conditions has had even less attention. The aim of this research is to study the effect of osmotic conditions on propagating discontinuities under different types of loads for saturated ionized porous media using the finite element method (FEM). Discontinuous functions are introduced in the shape functions of the FEM by partition of unity method, independently of the underlying mesh. Damage ahead of the crack-tip is introduced by a cohesive zone model. Tensile loading of a crack in an osmoelastic medium results in opening of the crack and high pressure gradients between the crack and the formation. The fluid flow in the crack is approximated by Couette flow. Results show that failure behavior depends highly on the load, permeability, (osmotic) prestress and the stiffness of the material. In some cases it is seen that when the crack propagation initiates, fluid is attracted to the crack-tip from the crack rather than from the surrounding medium causing the crack to close. The results show reasonable mesh-independent crack propagation for materials with a high stiffness. Stepwise crack propagation through the medium is seen due to consolidation, i.e., crack propagation alternates with pauses in which the fluid redistributes. This physical phenomenon challenges the numerical scheme. Furthermore, propagation is shown to depend on the osmotic prestressing of the medium. This mechanism may explain the tears observed in intervertebral disks as degeneration progresses.", "corpus_id": 54020585, "score": 0 }, { "doc_id": "123110366", "title": "A continuous-discontinuous approach to simulate physical degradation processes in porous media", "abstract": "A macroscopic framework for the simulation of physical degradation processes in quasi-brittle porous materials is proposed. The framework employs the partition of unity (PU) concept and introduces a cohesive zone model, capturing the entire failure process starting from the growth and coalescence of micro-defects until the formation of macro-cracks. The framework incorporates the interaction between the failure process and the heat and mass transfer in the porous medium. As an example, physical degradation of an outside render is studied. The analysis illustrates that both material and interface failure can be investigated with this formulation. Depending on the boundary conditions, either one dominant crack or a network of small cracks is formed. Copyright © 2010 John Wiley & Sons, Ltd.", "corpus_id": 123110366, "score": 0 }, { "doc_id": "137365435", "title": "Recent efforts toward modeling interactions of matrix cracks and delaminations: an integrated XFEM-CE approach", "abstract": "This paper presents a novel integrated approach using the extended finite element method (XFEM) and cohesive elements (CEs) for modeling three-dimensional (3D) delaminations, matrix cracks, and their interactions in progressive failure of composite laminates. In the proposed XFEM-CE approach, the matrix cracks are explicitly modeled by the XFEM through nodal enrichment and element partition, and the inter-ply delaminations are modeled by cohesive elements through traction–separation law. An XFEM-based cohesive element enrichment scheme is developed in order to properly model the interactions between the delaminations and matrix cracks. It is critical to enrich the cohesive elements at the local juncture where cracks meet, in order to obtain the correct crack path interactions. Examples are presented for failure analysis of double-cantilever-beam and end-notch-flexure laminates with different layups. The results show strong explicit matrix crack–delamination interactions in these laminates. This work presents another significant development of a computational platform for realistic modeling of progressive damage in composites.", "corpus_id": 137365435, "score": 0 }, { "doc_id": "122528836", "title": "New crack‐tip elements for XFEM and applications to cohesive cracks", "abstract": "An extended finite element method scheme for a static cohesive crack is developed with a new formulation for elements containing crack tips. This method can treat arbitrary cracks independent of the mesh and crack growth without remeshing. All cracked elements are enriched by the sign function so that no blending of the local partition of unity is required. This method is able to treat the entire crack with only one type of enrichment function, including the elements containing the crack tip. This scheme is applied to linear 3-node triangular elements and quadratic 6-node triangular elements. To ensure smooth crack closing of the cohesive crack, the stress projection normal to the crack tip is imposed to be equal to the material strength. The equilibrium equation and the traction condition are solved by the Newton–Raphson method to obtain the nodal displacements and the external load simultaneously. The results obtained by the new extended finite element method are compared to reference solutions and show excellent agreement. Copyright © 2003 John Wiley & Sons, Ltd.", "corpus_id": 122528836, "score": 0 }, { "doc_id": "119384516", "title": "An XFEM/Spectral element method for dynamic crack propagation", "abstract": "A high-order extended finite element method based on the spectral element method for the simulation of dynamic fracture is developed. The partition of unity for the discontinuous displacement is constructed by employing p order spectral element. This method shows great advantages in the simulations of moving crack and mixed mode crack. The numerical oscillations are effectively suppressed and the accuracy of computed stress intensity factors and crack path are improved markedly. Furthermore the simulation results show that p-refinement is more effective in improving the stress contour near the crack tip than h-refinement. The well known form of the explicit central difference method is used and the critical time step for this method is investigated. We find that by using lumped mass matrix the critical time step Δtc for this high-order extended finite element is almost independent of the crack position.", "corpus_id": 119384516, "score": 0 }, { "doc_id": "135491928", "title": "Time dependent crack tip enrichment for dynamic crack propagation", "abstract": "We study several enrichment strategies for dynamic crack propagation in the context of the extended finite element method and the effect of different directional criteria on the crack path. A new enrichment method with a time dependent enrichment function is proposed. In contrast to previous approaches, it entails only one crack tip enrichment function. Results for stress intensity factors and crack paths for different enrichments and direction criteria are given.", "corpus_id": 135491928, "score": 0 }, { "doc_id": "136567736", "title": "Dynamic analysis of fixed cracks in composites by the extended finite element method", "abstract": "Abstract This paper is dedicated to simulation of dynamic analysis of fixed cracks in orthotropic media using an extended finite element method. This work is in fact an extension to dynamic problems of the recently developed orthotropic extended finite element method for fracture analysis of composites. In this method, the Heaviside and near-tip enrichment functions are used in the framework of the partition of unity for modeling crack discontinuity and crack-tip singularities within the classical finite element method. In this procedure, elements that include a crack are not required to conform to crack edges. Therefore, mesh generation can be performed without any need to comply to crack edges and the method is capable of modeling the crack propagation without any remeshing. To determine the fracture properties, mixed-mode dynamic stress intensity factors (DSIFs) are evaluated by means of domain separation integral (J′-integral) method. Results of the proposed method are compared with other available analytical and computational results.", "corpus_id": 136567736, "score": 0 }, { "doc_id": "56151440", "title": "Fracture analysis of composites by time independent moving-crack orthotropic XFEM", "abstract": "Abstract Time-independent orthotropic enrichment functions are introduced for dynamic propagation analysis of moving cracks in composites by the extended finite element method (XFEM). The proposed enrichment functions are derived from the analytical solutions for a moving/propagating crack in orthotropic media, and can be considered as a new extension to the available XFEM techniques for dynamic analysis of stationary and moving cracks in orthotropic materials. They are included within the framework of partition of unity and XFEM to enhance the accuracy of basic FEM solution near a moving crack tip in orthotropic media. The method allows for analysis of the whole crack propagation pattern on an unaltered finite element mesh, which is independently defined from the existence of any predefined crack or its propagation path. A combination of dynamic crack initiation toughness and crack orientation along the maximum circumferential stress is used to design a relatively simple and efficient formulation. Dynamic stress intensity factors (DSIFs) are evaluated by means of the domain separation integral method and the dynamic energy release rate. The time dependent XFEM equations are constructed by discretizing the standard weak formulation of the governing elastodynamics equation. They are solved by the unconditionally stable Newmark time integration scheme. A number of benchmark and test problems are simulated and the results are compared with the available reference results to illustrate the accuracy and efficiency of the proposed scheme.", "corpus_id": 56151440, "score": 0 }, { "doc_id": "14314726", "title": "An XFEM method for modeling geometrically elaborate crack propagation in brittle materials", "abstract": "We present a method for simulating quasistatic crack propagation in 2-D which combines the extended finite element method (XFEM) with a general algorithm for cutting triangulated domains, and introduce a simple yet general and flexible quadrature rule based on the same geometric algorithm. The combination of these methods gives several advantages. First, the cutting algorithm provides a flexible and systematic way of determining material connectivity, which is required by the XFEM enrichment functions. Also, our integration scheme is straightforward to implement and accurate, without requiring a triangulation that incorporates the new crack edges or the addition of new degrees of freedom to the system. The use of this cutting algorithm and integration rule allows for geometrically complicated domains and complex crack patterns. Copyright © 2011 John Wiley & Sons, Ltd.", "corpus_id": 14314726, "score": 0 }, { "doc_id": "122246511", "title": "Energy-based modeling of cohesive and cohesionless cracks via X-FEM", "abstract": "Numerical analyses of structures made of brittle materials such as glass or quasi-brittle materials such as concrete or ceramics require robust models for the opening and propagation of cracks which adequately represent the discontinuous character of the fracture process and consider adequately cohesive forces acting within the fracture process zone. The extended finite element method (X-FEM) is capable to model cracks as propagating discontinuities within the structure independent of the finite element discretization. Nevertheless, the analysis of crack propagation using discrete crack models crucially depends on the crack growth criterion. In this paper, a global energy-based method is proposed for the determination of the crack propagation length as well as for the crack propagation direction. The method is formulated within an X-FEM-based analysis model leading to a variational formulation in terms of displacements, crack lengths and crack angles. Both cohesive and cohesionless cracks are considered. The constitutive model for cohesive cracks considers the transfer of residual stresses parallel as well as orthogonal to the crack faces. For the representation of the displacement field in the vicinity of the tip of cohesive cracks, enriched approximations which do not lead to a singularity of the stresses at the crack tip are proposed in the paper. After linearization, the proposed energy-based finite element crack propagation model results in a coupled system of equations analogous to a multifield problem. The model is verified by means of comparisons with crack growth analyses based on linear elastic fracture mechanics using the maximum circumferential stress criterion for the determination of the crack propagation direction. Furthermore, two examples, characterized by Mode I and Mixed-Mode fracture, respectively, are used to study the performance of the developed energy-based crack propagation model.", "corpus_id": 122246511, "score": 0 }, { "doc_id": "137357537", "title": "A continuous–discontinuous approach to simulate fracture processes in quasi-brittle materials", "abstract": "A macroscopic framework for the simulation of failure processes in quasi-brittle materials is proposed. The framework employs the partition of unity (PU) concept and introduces a new cohesive zone model, capturing the transition between the initial continuum state and the final discrete state. The model is generic in a sense that it allows extension of most continuum models to a discontinuous framework in an efficient and robust way, thereby adding the effect of macro-crack formation by the growth and coalescence of micro-defects. Both material failure and interface failure can be studied with this formulation.", "corpus_id": 137357537, "score": 0 }, { "doc_id": "49487204", "title": "A partition of unity enriched dual boundary element method for accurate computations in fracture mechanics", "abstract": "We introduce a novel enriched Boundary Element Method (BEM) and Dual Boundary Element Method (DBEM) approach for accurate evaluation of Stress Intensity Factors (SIFs) in crack problems. The formulation makes use of the Partition of Unity Method (PUM) such that functions obtained from a priori knowledge of the solution space can be incorporated in the element formulation. An enrichment strategy is described, in which boundary integral equations formed at additional collocation points are used to provide auxiliary equations in order to accommodate the extra introduced unknowns. In addition, an efficient numerical quadrature method is outlined for the evaluation of strongly singular and hypersingular enriched boundary integrals. Finally, results are shown for mixed mode crack problems; these illustrate that the introduction of PUM enrichment provides for an improvement in accuracy of approximately one order of magnitude in comparison to the conventional unenriched DBEM.", "corpus_id": 49487204, "score": 0 }, { "doc_id": "122633218", "title": "Element‐free Galerkin methods", "abstract": "An element-free Galerkin method which is applicable to arbitrary shapes but requires only nodal data is applied to elasticity and heat conduction problems. In this method, moving least-squares interpolants are used to construct the trial and test functions for the variational principle (weak form); the dependent variable and its gradient are continuous in the entire domain. In contrast to an earlier formulation by Nayroles and coworkers, certain key differences are introduced in the implementation to increase its accuracy. The numerical examples in this paper show that with these modifications, the method does not exhibit any volumetric locking, the rate of convergence can exceed that of finite elements significantly and a high resolution of localized steep gradients can be achieved. The moving least-squares interpolants and the choices of the weight function are also discussed in this paper.", "corpus_id": 122633218, "score": 0 }, { "doc_id": "3688083", "title": "A new Meshless Local Petrov-Galerkin (MLPG) approach in computational mechanics", "abstract": "Abstract A local symmetric weak form (LSWF) for linear potential problems is developed, and a truly meshless method, based on the LSWF and the moving least squares approximation, is presented for solving potential problems with high accuracy. The essential boundary conditions in the present formulation are imposed by a penalty method. The present method does not need a “finite element mesh”, either for purposes of interpolation of the solution variables, or for the integration of the “energy”. All integrals can be easily evaluated over regularly shaped domains (in general, spheres in three-dimensional problems) and their boundaries. No post-smoothing technique is required for computing the derivatives of the unknown variable, since the original solution, using the moving least squares approximation, is already smooth enough. Several numerical examples are presented in the paper. In the example problems dealing with Laplace & Poisson's equations, high rates of convergence with mesh refinement for the Sobolev norms ||·||0 and ||·||1 have been found, and the values of the unknown variable and its derivatives are quite accurate. In essence, the present meshless method based on the LSWF is found to be a simple, efficient, and attractive method with a great potential in engineering applications.", "corpus_id": 3688083, "score": 0 }, { "doc_id": "53985594", "title": "Imposing essential boundary conditions in mesh-free methods", "abstract": "Imposing essential boundary conditions is a key issue in mesh-free methods. The mesh-free interpolation does not verify the Kronecker delta property and, therefore, the imposition of prescribed values is not as straightforward as for the finite element method. The aim of this paper is to present a general overview on the existing techniques to enforce essential boundary conditions in Galerkin based mesh-free methods. Special attention is paid to the mesh-free coupling with finite elements for the imposition of prescribed values and to methods based on a modification of the Galerkin weak form. Particular examples are used to analyze and compare their performance in different situations.", "corpus_id": 53985594, "score": 0 }, { "doc_id": "15303123", "title": "Meshless methods: An overview and recent developments", "abstract": "Abstract Meshless approximations based on moving least-squares, kernels, and partitions of unity are examined. It is shown that the three methods are in most cases identical except for the important fact that partitions of unity enable p-adaptivity to be achieved. Methods for constructing discontinuous approximations and approximations with discontinuous derivatives are also described. Next, several issues in implementation are reviewed: discretization (collocation and Galerkin), quadrature in Galerkin and fast ways of constructing consistent moving least-square approximations. The paper concludes with some sample calculations.", "corpus_id": 15303123, "score": 0 }, { "doc_id": "67762778", "title": "Classification and Overview of Meshfree Methods", "abstract": "This paper gives an overview over Meshfree Methods. Starting point is an extended and modified classification of Meshfree Methods due to three aspects: The construction of a partition of unity, the choice of an approximation either with or without using an extrinsic basis and the choice of test functions, resulting into a collocation, Bubnov-Galerkin or Petrov-Galerkin Meshfree Method. Most of the relevant Meshfree Methods are described taking into account their different origins and viewpoints as well as their advantages and disadvantages. Typical problems arising in meshfree methods like integration, treatment of essential boundary conditions, coupling with mesh-based methods etc.~are discussed. Some valuing comments about the most important aspects can be found at the end of each section. This text was revised in 2004", "corpus_id": 67762778, "score": 0 }, { "doc_id": "6386792", "title": "Meshless methods: A review and computer implementation aspects", "abstract": "The aim of this manuscript is to give a practical overview of meshless methods (for solid mechanics) based on global weak forms through a simple and well-structured MATLAB code, to illustrate our discourse. The source code is available for download on our website and should help students and researchers get started with some of the basic meshless methods; it includes intrinsic and extrinsic enrichment, point collocation methods, several boundary condition enforcement schemes and corresponding test cases. Several one and two-dimensional examples in elastostatics are given including weak and strong discontinuities and testing different ways of enforcing essential boundary conditions.", "corpus_id": 6386792, "score": 0 }, { "doc_id": "120863760", "title": "Fracture and crack growth by element free Galerkin methods", "abstract": "Element free Galerkin (EFG) methods are methods for solving partial differential equations that require only nodal data and a description of the geometry; no element connectivity data are needed. This makes the method very attractive for the modeling of the propagation of cracks, as the number of data changes required is small and easily developed. The method is based on the use of moving least-squares interpolants with a Galerkin method, and it provides highly accurate solutions for elliptic problems. The implementation of the EFG method for problems of fracture and static crack growth is described. Numerical examples show that accurate stress intensity factors can be obtained Without any enrichment of the displacement field by a near-crack-tip singularity and that crack growth can be easily modeled since it requires hardly any remeshing.", "corpus_id": 120863760, "score": 0 }, { "doc_id": "120944503", "title": "Continuous meshless approximations for nonconvex bodies by diffraction and transparency", "abstract": "Continuous meshless approximations are developed for domains with non-convex boundaries, with emphasis on cracks. Two techniques are developed in the context of the element-free Galerkin method: a transparency method wherein smooth approximations are generated by making boundaries partially transparent, and a diffraction method, where the domain of influence wraps around a concave boundary. They are compared to the original method based on the visibility criterion in which the approximations are discontinuous in the vicinity of nonconvex boundaries. The performance of the methods is compared using two elastostatic examples: an infinite plate with a hole and a crack problem. The continuous approximations show only moderate imporvement in accuracy over the discontinous approximations, but yield significant improvements for enhanced bases, such as crack-tip singular functions.", "corpus_id": 120944503, "score": 0 }, { "doc_id": "122492107", "title": "Element-free galerkin methods for static and dynamic fracture", "abstract": "Abstract Element-free Galerkin (EFG) methods are presented and applied to static and dynamic fracture problems. EFG methods, which are based on moving least-square (MLS) interpolants, require only nodal data; no element connectivity is needed. The description of the geometry and numerical model of the problem consists only of a set of nodes and a description of exterior boundaries and interior boundaries from any cracks. This makes the method particularly attractive for growing crack problems, since only minimal remeshing is needed to follow crack growth. In moving least-square interpolants, the dependent variable at any point is obtained by minimizing a function in terms of the nodal values of the dependent variable in the domain of influence of the point. Numerical examples involving fatigue crack growth and dynamic crack propagation are presented to illustrate the performance and potential of this method.", "corpus_id": 122492107, "score": 0 }, { "doc_id": "18890969", "title": "Three-dimensional crack initiation, propagation, branching and junction in non-linear materials by an extended meshfree method without asymptotic enrichment", "abstract": "This paper presents a three-dimensional, extrinsically enriched meshfree method for initiation, branching, growth and coalescence of an arbitrary number of cracks in non-linear solids including large deformations, for statics and dynamics. The novelty of the methodology is that only an extrinsic discontinuous enrichment and no near-tip enrichment is required. Instead, a Lagrange multiplier field is added along the crack front to close the crack. This decreases the computational cost and removes difficulties involved with a branch enrichment. The results are compared to experimental data, and other simulations from the literature to show the robustness and accuracy of the method.", "corpus_id": 18890969, "score": 0 }, { "doc_id": "115397116", "title": "Meshless and Generalized Finite Element Methods: A Survey of Some Major Results", "abstract": "In this lecture, we discuss Meshless and Generalized Finite Element Methods. We survey major results in this area with a unified approach.", "corpus_id": 115397116, "score": 0 }, { "doc_id": "5806420", "title": "The partition of unity finite element method: Basic theory and applications", "abstract": "The paper presents the basic ideas and the mathematical foundation of the partition of unity finite element method (PUFEM). We will show how the PUFEM can be used to employ the structure of the differential equation under consideration to construct effective and robust methods. Although the method and its theory are valid in n dimensions, a detailed and illustrative analysis will be given for a one-dimensional model problem. We identify some classes of non-standard problems which can profit highly from the advantages of the PUFEM and conclude this paper with some open questions concerning implementational aspects of the PUFEM.", "corpus_id": 5806420, "score": 0 }, { "doc_id": "129037124", "title": "A clumped particle model for rock", "abstract": "Abstract Discrete element (particle) modeling is now often used to simulate the behavior of rock. While the method is attractive because it does not require the formulation of complex constitutive models, it requires extensive calibration with measured macro-scale results to determine the particle–contact parameters that will predict the macro-scale response. This calibration is usually carried out using the laboratory uniaxial compression test. The behavior of intact rock in compression is complex, resulting in a nonlinear failure envelope with high frictional resistance and a ratio of tensile to uniaxial compression strength of approximately 0.05–0.1. An extensive series of calibrations were carried out using a particle code to determine if the micro-parameters determined from uniaxial compression tests could be used to predict the intact rock response regardless of stress path, i.e., tension to triaxial compression. It is determined that the particle code cannot predict the failure envelope measured on laboratory samples, unless significant modifications are made. This study shows that adjusting the particle parameters had little effect on the macro-scale properties of compression and tension tests, but using a clumped-particle geometry improves the predictive capabilities of the particle code significantly. For both Lac du Bonnet granite and a weak synthetic rock, the particle code calibrated to uniaxial tests using the clumped-particle geometry predicts both the stress–strain behavior and the complete nonlinear failure envelope.", "corpus_id": 129037124, "score": 0 }, { "doc_id": "137435057", "title": "Simulations of instability in dynamic fracture by the cracking particles method", "abstract": "Crack instabilities and the phenomenon of crack speed saturation in a brittle material (PMMA) are studied with a meshfree cracking particle method. We reproduce the experimental observation that the computed terminal crack speeds attained in PMMA specimens are substantially lower than the Rayleigh wave speed; the computed crack speeds agree quite well with the reported experimental results. We also replicate repetitive microcrack branching along with the increased rate of energy dissipation after attainment of a critical crack speed, even in the absence of microstructural defects. We show that the presence of microdefects changes the response only a little. The computations reproduce many of the salient features of experimental observations.", "corpus_id": 137435057, "score": 0 }, { "doc_id": "54682115", "title": "Extended meshfree methods without branch enrichment for cohesive cracks", "abstract": "An extended meshless method for both static and dynamic cohesive cracks is proposed. This new method does not need any crack tip enrichment to guarantee that the crack closes at the tip. All cracked domains of influence are enriched by only the sign function. The domain of influence which includes a crack tip is modified so that the crack tip is always positioned at its edge. The modification is only applied for the discontinuous displacement field and the continuous field is kept unchanged. In addition to the new method, the use of Lagrange multiplier is explored to achieve the same goal. The crack is extended beyond the actual crack tip so that the domains of influence containing the crack tip are completely cut. It is enforced that the crack opening displacement vanishes along the extension of the crack. These methods are successfully applied to several well-known static and dynamic problems.", "corpus_id": 54682115, "score": 0 }, { "doc_id": "73591221", "title": "A new partition of unity finite element free from the linear dependence problem and possessing the delta property", "abstract": "Partition of unity based finite element methods (PUFEMs) have appealing capabilities for p-adaptivity and local refinement with minimal or even no remeshing of the problem domain. However, PUFEMs suffer from a number of problems that practically limit their application, namely the linear dependence (LD) problem, which leads to a singular global stiffness matrix, and the difficulty with which essential boundary conditions can be imposed due to the lack of the Kronecker delta property. In this paper we develop a new PU-based triangular element using a dual local approximation scheme by treating boundary and interior nodes separately. The present method is free from the LD problem and essential boundary conditions can be applied directly as in the FEM. The formulation uses triangular elements, however the essential idea is readily extendable to other types of meshed or meshless formulation based on a PU approximation. The computational cost of the present method is comparable to other PUFEM elements described in the literature. The proposed method can be simply understood as a PUFEM with composite shape functions possessing the delta property and appropriate compatibility.", "corpus_id": 73591221, "score": 0 }, { "doc_id": "17055921", "title": "A meshless method with enriched weight functions for three-dimensional crack propagation", "abstract": "The propagation of cracks in three dimensions is analysed by a meshless method. The cracks are modelled by a set of triangles that are added when the propagation occurs. Since the method is meshless, no remeshing of the domain is necessary during the propagation. To avoid using a large number of degrees of freedom, the stress singularity along the front of the cracks is taken into account by an enrichment of the shape functions of the meshless method by means of appropriate weight functions. This enrichment technique is an extension of the technique that proved to be successful in two dimensions in a previous paper. Several algorithms for efficiently implementing the meshless method in three dimensions are detailed. The accuracy of the enrichment is first assessed on simple examples and some results of non-planar propagation of multiple cracks are then presented. Copyright © 2005 John Wiley & Sons, Ltd.", "corpus_id": 17055921, "score": 0 }, { "doc_id": "123601659", "title": "A study of the representation of cracks with level sets", "abstract": "The level set method has been used for a few years to represent cracks in fracture mechanics simulations instead of an explicit description of the cracks faces geometry. This paper studies in detail the shape of the level set functions around a crack in two dimensions that is propagating with a sharp kink, obtained both with level set update methods found in the literature and with several innovative update methods developed by the author. A criterion based on the computation of a J integral of a virtual displacement field obtained with the values of the level set functions is proposed in order to assess the quality of these update methods. With the help of this criterion, two optimal approaches are identified, which predict an accurate evolution of the crack with smooth and consistent level set functions. These methods are then applied in three dimensions to the case of an initially penny-shaped crack that propagates out of its plane. Copyright © 2006 John Wiley & Sons, Ltd.", "corpus_id": 123601659, "score": 0 }, { "doc_id": "119552797", "title": "NON-PLANAR 3D CRACK GROWTH BY THE EXTENDED FINITE ELEMENT AND LEVEL SETS- PART II: LEVEL SET UPDATE", "abstract": "We present a level set method for treating the growth of non-planar three-dimensional cracks.The crack is defined by two almost-orthogonal level sets (signed distance functions). One of them describes the crack as a two-dimensional surface in a three-dimensional space, and the second is used to describe the one-dimensional crack front, which is the intersection of the two level sets. A Hamilton–Jacobi equation is used to update the level sets. A velocity extension is developed that preserves the old crack surface and can accurately generate the growing surface. The technique is coupled with the extended finite element method which approximates the displacement field with a discontinuous partition of unity. This displacement field is constructed directly in terms of the level sets, so the discretization by finite elements requires no explicit representation of the crack surface. Numerical experiments show the robustness of the method, both in accuracy and in treating cracks with significant changes in topology. Copyright © 2002 John Wiley & Sons, Ltd.", "corpus_id": 119552797, "score": 0 }, { "doc_id": "207078302", "title": "Fast Marching Methods", "abstract": "Fast Marching Methods are numerical schemes for computing solutions to the nonlinear Eikonal equation and related static Hamilton--Jacobi equations. Based on entropy-satisfying upwind schemes and fast sorting techniques, they yield consistent, accurate, and highly efficient algorithms. They are optimal in the sense that the computational complexity of the algorithms is O(N log N), where N is the total number of points in the domain. The schemes are of use in a variety of applications, including problems in shape offsetting, computing distances from complex curves and surfaces, shape-from-shading, photolithographic development, computing first arrivals in seismic travel times, construction of shortest geodesics on surfaces, optimal path planning around obstacles, and visibility and reflection calculations. In this paper, we review the development of these techniques, including the theoretical and numerical underpinnings; provide details of the computational schemes, including higher order versions; and demonstrate the techniques in a collection of different areas.", "corpus_id": 207078302, "score": 0 }, { "doc_id": "37807691", "title": "Solidification microstructures and solid-state parallels: Recent developments, future directions", "abstract": "Rapid advances in atomistic and phase-field modeling techniques as well as new experiments have led to major progress in solidification science during the first years of this century. Here we review the most important findings in this technologically important area that impact Our quantitative understanding of: (i) key anisotropic properties of the solid-liquid interface that govern solidification pattern evolution, including the solid-liquid interface free energy and the kinetic coefficient; (ii) dendritic solidification at small and large growth rates. with particular emphasis on orientation selection; (iii) regular and irregular eutectic and peritectic microstructures; (iv) effects of convection on microstructure formation; (v) solidification at a high Volume fraction of solid and the related formation of pores and hot cracks: and (vi) solid-state transformations as far as they relate to solidification models anti techniques. In light of this progress, critical issues that point to directions for future research in both solidification and solid-state transformations are identified. (C) 2008 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.", "corpus_id": 37807691, "score": 0 }, { "doc_id": "27352919", "title": "Three-dimensional phase-field simulation of micropore formation during solidification: Morphological analysis and pinching effect", "abstract": "A three-dimensional (3-D) multiphase-field model has been developed in order to study the formation of a micropore constrained to grow in a solid network (i.e. pinching effect). The model accounts for the pressure difference due to capillarity between liquid and gas, the equilibrium condition at triple (solid–liquid–pore) lines, and the partitioning and diffusion of dissolved gases such as hydrogen. From the predicted 3-D morphology of the pore, entities such as the interfacial shape distribution are plotted and analyzed. It is shown that the mean curvature of the pore–liquid surface, and thus also the pressure inside the pore, is uniform. The results are then compared with analytical pinching models. While predicting a similar trend, analytical models tend to underestimate the pore curvature at high solid fractions. Despite the complex morphology of pores reconstructed using high-resolution X-ray tomography, the present phase-field results suggest that a simple pinching model based on a spherical tip growing in between remaining liquid channels is a fairly good approximation.", "corpus_id": 27352919, "score": 0 }, { "doc_id": "9684740", "title": "Phase field method to optimize dielectric devices for electromagnetic wave propagation", "abstract": "We discuss a phase field method for shape optimization in the context of electromagnetic wave propagation. The proposed method has the same functional capabilities as the level set method for shape optimization. The first advantage of the method is the simplicity of computation, since extra operations such as re-initialization of functions are not required. The second is compatibility with the topology optimization method due to the similar domain representation and the sensitivity analysis. Structural shapes are represented by the phase field function defined in the design domain, and this function is optimized by solving a time-dependent reaction diffusion equation. The artificial double-well potential function used in the equation is derived from sensitivity analysis. We study four types of 2D or 2.5D (axisymmetric) optimization problems. Two are the classical problems of photonic crystal design based on the Bloch theory and photonic crystal wave guide design, and two are the recent topics of designing dielectric left-handed metamaterials and dielectric ring resonators.", "corpus_id": 9684740, "score": 0 }, { "doc_id": "137275923", "title": "Phase-field simulation of anisotropic crack propagation in ferroelectric single crystals: effect of microstructure on the fracture process", "abstract": "Crack propagation during the indentation test of a ferroelectric single crystal is simulated using a phase-field model. This model is based on variational formulations of brittle crack propagation and domain evolution in ferroelectric materials. Due to the high compressive stresses near the indenter contact faces, a modified regularized formulation of the variational brittle fracture is coupled with the material model to prevent crack formation and interpenetration in the compressed regions. The simulation results show that the radial cracks perpendicular to the poling direction of the material propagate faster than the parallel ones, which is in agreement with experimental observations. This anisotropy in the crack propagation is due to interactions between the material microstructure and the radial cracks, as captured by the phase-field simulation.", "corpus_id": 137275923, "score": 0 }, { "doc_id": "9874685", "title": "A real-space non-local phase-field model of ferroelectric domain patterns in complex geometries", "abstract": "Ferroelectric perovskites are used in various transducer, memory and optical applications due to their attractive properties. In these applications, the ferroelectric materials often have complex geometries and electrode arrangements, and are subjected to domain switching. Therefore, it is important to understand the domain pattern that forms in these geometries. However, models of domain evolution often make assumptions like periodicity and complete shielding which make them unrealistic for these applications. In this paper, we develop a phase-field approach that can study domain patterns and domain evolution in complex geometries with no a priori assumption on geometry, electrode arrangement, and dielectric properties. The key idea is a boundary element method to resolve the electrostatic fields. We illustrate the method by examining the closure domains that form at a free surface and domain switching under cyclic electric field in a device with interdigitated electrodes.", "corpus_id": 9874685, "score": 0 }, { "doc_id": "15612687", "title": "Revisiting brittle fracture as an energy minimization problem", "abstract": "Abstract A variational model of quasistatic crack evolution is proposed. Although close in spirit to Griffith’s theory of brittle fracture, the proposed model however frees itself of the usual constraints of that theory : a preexisting crack and a well-defined crack path. In contrast, crack initiation as well as crack path can be quantified, as demonstrated on explicitly computable examples. Furthermore the model lends itself to numerical implementation in more complex settings.", "corpus_id": 15612687, "score": 0 }, { "doc_id": "7842143", "title": "Numerical experiments in revisited brittle fracture", "abstract": "Abstract The numerical implementation of the model of brittle fracture developed in Francfort and Marigo (1998. J. Mech. Phys. Solids 46 (8), 1319–1342) is presented. Various computational methods based on variational approximations of the original functional are proposed. They are tested on several antiplanar and planar examples that are beyond the reach of the classical computational tools of fracture mechanics.", "corpus_id": 7842143, "score": 0 }, { "doc_id": "51695868", "title": "Regularized formulation of the variational brittle fracture with unilateral contact: Numerical experiments", "abstract": "Abstract This paper presents a modified regularized formulation of the Ambrosio–Tortorelli type to introduce the crack non-interpenetration condition in the variational approach to fracture mechanics proposed by Francfort and Marigo [1998. Revisiting brittle fracture as an energy minimization problem. J. Mech. Phys. Solids 46 (8), 1319–1342]. We focus on the linear elastic case where the contact condition appears as a local unilateral constraint on the displacement jump at the crack surfaces. The regularized model is obtained by splitting the strain energy in a spherical and a deviatoric parts and accounting for the sign of the local volume change. The numerical implementation is based on a standard finite element discretization and on the adaptation of an alternate minimization algorithm used in previous works. The new regularization avoids crack interpenetration and predicts asymmetric results in traction and in compression. Even though we do not exhibit any gamma-convergence proof toward the desired limit behavior, we illustrate through several numerical case studies the pertinence of the new model in comparison to other approaches.", "corpus_id": 51695868, "score": 0 }, { "doc_id": "123854583", "title": "A phase field model for rate-independent crack propagation: Robust algorithmic implementation based on operator splits", "abstract": "The computational modeling of failure mechanisms in solids due to fracture based on sharp crack discontinuities suffers in situations with complex crack topologies. This can be overcome by a diffusive crack modeling based on the introduction of a crack phase field. Following our recent work [C. Miehe, F. Welschinger, M. Hofacker, Thermodynamically-consistent phase field models of fracture: Variational principles and multi-field fe implementations, International Journal for Numerical Methods in Engineering DOI:10.1002/nme.2861] on phase-field-type fracture, we propose in this paper a new variational framework for rate-independent diffusive fracture that bases on the introduction of a local history field. It contains a maximum reference energy obtained in the deformation history, which may be considered as a measure for the maximum tensile strain obtained in history. It is shown that this local variable drives the evolution of the crack phase field. The introduction of the history field provides a very transparent representation of the balance equation that governs the diffusive crack topology. In particular, it allows for the construction of a new algorithmic treatment of diffusive fracture. Here, we propose an extremely robust operator split scheme that successively updates in a typical time step the history field, the crack phase field and finally the displacement field. A regularization based on a viscous crack resistance that even enhances the robustness of the algorithm may easily be added. The proposed algorithm is considered to be the canonically simple scheme for the treatment of diffusive fracture in elastic solids. We demonstrate the performance of the phase field formulation of fracture by means of representative numerical examples.", "corpus_id": 123854583, "score": 0 }, { "doc_id": "122604743", "title": "Thermodynamically consistent phase‐field models of fracture: Variational principles and multi‐field FE implementations", "abstract": "The computational modeling of failure mechanisms in solids due to fracture based on sharp crack discontinuities suffers in situations with complex crack topologies. This can be overcome by a diffusive crack modeling based on the introduction of a crack phase-field. In this paper, we outline a thermodynamically consistent framework for phase-field models of crack propagation in elastic solids, develop incremental variational principles and consider their numerical implementations by multi-field finite element methods. We start our investigation with an intuitive and descriptive derivation of a regularized crack surface functional that Γ-converges for vanishing length-scale parameter to a sharp crack topology functional. This functional provides the basis for the definition of suitable convex dissipation functions that govern the evolution of the crack phase-field. Here, we propose alternative rate-independent and viscous over-force models that ensure the local growth of the phase-field. Next, we define an energy storage function whose positive tensile part degrades with increasing phase-field. With these constitutive functionals at hand, we derive the coupled balances of quasi-static stress equilibrium and gradient-type phase-field evolution in the solid from the argument of virtual power. Here, we consider a canonical two-field setting for rate-independent response and a time-regularized three-field formulation with viscous over-force response. It is then shown that these balances follow as the Euler equations of incremental variational principles that govern the multi-field problems. These principles make the proposed formulation extremely compact and provide a perfect base for the finite element implementation, including features such as the symmetry of the monolithic tangent matrices. We demonstrate the performance of the proposed phase-field formulations of fracture by means of representative numerical examples. Copyright © 2010 John Wiley & Sons, Ltd.", "corpus_id": 122604743, "score": 0 }, { "doc_id": "11773968", "title": "Fractographic aspects of crack branching instability using a phase-field model.", "abstract": "A phase-field model of a crack front propagating in a three-dimensional brittle material is used to study the fractographic patterns induced by the branching instability. The numerical results of this model give rise to crack surfaces that are similar to those obtained in various experimental situations. Depending on applied loading configurations and initial conditions, we show that the branching instability is either restricted to a portion of the crack front or revealed through quasi-two-dimensional branches. For the former, the crack front leaves on the main broken surface either aligned or disordered parabolic marks. For the latter, fractography reveals the so called échelon cracks showing that branching instability can also induce crack front fragmentation.", "corpus_id": 11773968, "score": 0 }, { "doc_id": "136404357", "title": "Simulation of damage evolution in composites : A phase-field model", "abstract": "Abstract In this study, a phase-field model is introduced for the simulation of damage evolution in composite systems. The damage evolution in discontinuously reinforced and laminated composites, including elastic–plastic cases, was studied parametrically in order to establish its viability. The algorithm offers significant advantages to describe the microstructure and topological changes associated with the damage evolution in comparison to conventional simulation algorithms, due to the absence of formal meshing. The known damage mechanisms for specific composite systems naturally evolve from the algorithm with a simple evolution equation.", "corpus_id": 136404357, "score": 0 }, { "doc_id": "122265289", "title": "A continuum phase field model for fracture", "abstract": "A phase field model based on a regularized version of the variational formulation of brittle fracture is introduced. The influences of the regularization parameter that controls the interface width between broken and undamaged material and of the mobility constant of the evolution equation are studied in finite element simulations. A generalized Eshelby tensor is derived and analyzed for mode I loading in order to evaluate the energy release rate of the diffuse phase field cracks. The numerical implementation is performed with finite elements and an implicit time integration scheme. The configurational forces are computed in a postprocessing step after the coupled problem of mechanical balance equations and the evolution equation is solved. Some of the numerical results are compared to analytical results from classical Griffith theory.", "corpus_id": 122265289, "score": 0 }, { "doc_id": "120395192", "title": "Phase field approximation of dynamic brittle fracture", "abstract": "Numerical methods that are able to predict the failure of technical structures due to fracture are important in many engineering applications. One of these approaches, the so-called phase field method, represents cracks by means of an additional continuous field variable. This strategy avoids some of the main drawbacks of a sharp interface description of cracks. For example, it is not necessary to track or model crack faces explicitly, which allows a simple algorithmic treatment. The phase field model for brittle fracture presented in Kuhn and Müller (Eng Fract Mech 77(18):3625–3634, 2010) assumes quasi-static loading conditions. However dynamic effects have a great impact on the crack growth in many practical applications. Therefore this investigation presents an extension of the quasi-static phase field model for fracture from Kuhn and Müller (Eng Fract Mech 77(18):3625–3634, 2010) to the dynamic case. First of all Hamilton’s principle is applied to derive a coupled set of Euler-Lagrange equations that govern the mechanical behaviour of the body as well as the crack growth. Subsequently the model is implemented in a finite element scheme which allows to solve several test problems numerically. The numerical examples illustrate the capabilities of the developed approach to dynamic fracture in brittle materials.", "corpus_id": 120395192, "score": 0 }, { "doc_id": "122020674", "title": "On numerical aspects of phase field fracture modelling", "abstract": "Recently, a continuum model for crack propagation in brittle visco-elastic materials has been presented (M. Fleck et al., Phys. Rev. E 83, 046213 (2011)), in which fracture is described as an elastically induced nonequilibrium interfacial pattern formation process. The underlying mesoscopic description of a propagating crack results in a complicated moving boundary problem, that allows the self-consistent determination of the crack velocity as well as the entire time-dependent crack surface. Here we focus on the numerical aspects tied to the approximative solution of the arising moving boundary problem and discuss several strategies to develop efficient numerical schemes applying to it: i) a finite difference scheme, ii) a scheme based on the finite element method and iii) a scheme based on the multipole expansion method. The pros and cons of each method are elucidated in detail. Further, we present a comprehensive view on how the different approaches can be employed to validate each other in comparative studies, which is then illustrated for the example of crack propagation under mode I loading.", "corpus_id": 122020674, "score": 0 }, { "doc_id": "37480328", "title": "A phase-field description of dynamic brittle fracture", "abstract": "Abstract In contrast to discrete descriptions of fracture, phase-field descriptions do not require numerical tracking of discontinuities in the displacement field. This greatly reduces implementation complexity. In this work, we extend a phase-field model for quasi-static brittle fracture to the dynamic case. We introduce a phase-field approximation to the Lagrangian for discrete fracture problems and derive the coupled system of equations that govern the motion of the body and evolution of the phase-field. We study the behavior of the model in one dimension and show how it influences material properties. For the temporal discretization of the equations of motion, we present both a monolithic and staggered time integration scheme. We study the behavior of the dynamic model by performing a number of two and three dimensional numerical experiments. We also introduce a local adaptive refinement strategy and study its performance in the context of locally refined T-splines. We show that the combination of the phase-field model and local adaptive refinement provides an effective method for simulating fracture in three dimensions.", "corpus_id": 37480328, "score": 0 }, { "doc_id": "11224555", "title": "A geometrically nonlinear phase field theory of brittle fracture", "abstract": "Phase field theory is developed for solids undergoing potentially large deformation and fracture. The elastic potential depends on a finite measure of elastic strain. Surface energy associated with fracture can be anisotropic, enabling description of preferred cleavage planes in single crystals, or isotropic, applicable to amorphous solids such as glass. Incremental solution of the Euler–Lagrange equations corresponds to local minimization of an energy functional for the solid, enabling prediction of equilibrium crack morphologies. Predictions are in close agreement with analytical solutions for pure mode I or pure mode II loading, including the driving force for a crack to extend from a pre-existing plane onto a misoriented cleavage plane. In an isotropic matrix, the tendency for a crack to penetrate or deflect around an inclusion is shown to depend moderately on the ratio of elastic stiffness in matrix and inclusion and strongly on their ratio of surface energy. Cracks are attracted to (shielded by) inclusions softer (stiffer) than the surrounding matrix. The theory and results apparently report the first fully three-dimensional implementation of phase field theory of fracture accounting for simultaneous geometric nonlinearity, nonlinear elasticity, and surface energy anisotropy.", "corpus_id": 11224555, "score": 0 }, { "doc_id": "122255526", "title": "On three-dimensional modelling of crack growth using partition of unity methods", "abstract": "This paper reviews different crack tracking techniques in three-dimensions applicable in the context of partition of unity methods, especially meshfree methods. Issues such as describing and tracking the crack surface are addressed. A crack tracking procedure is proposed in detail and implemented in the context of the extended element-free Galerkin method (XEFG). Several three-dimensional cracking examples are compared to other results from the literature or the experimental data and show good agreement.", "corpus_id": 122255526, "score": 0 }, { "doc_id": "118868118", "title": "Phase field modeling of crack propagation", "abstract": "Fracture is a fundamental mechanism of materials failure. Propagating cracks can exhibit a rich dynamical behavior controlled by a subtle interplay between microscopic failure processes in the crack tip region and macroscopic elasticity. We review recent approaches to understand crack dynamics using the phase field method. This method, developed originally for phase transformations, has the well-known advantage of avoiding explicit front tracking by making material interfaces spatially diffuse. In a fracture context, this method is able to capture both the short-scale physics of failure and macroscopic linear elasticity within a self-consistent set of equations that can be simulated on experimentally relevant length and time scales. We discuss the relevance of different models, which stem from continuum field descriptions of brittle materials and crystals, to address questions concerning crack path selection and branching instabilities, as well as models that are based on mesoscale concepts for crack tip scale selection. Open questions which may be addressed using phase field models of fracture are summarized.", "corpus_id": 118868118, "score": 0 }, { "doc_id": "20816176", "title": "Phase-field models for brittle and cohesive fracture", "abstract": "In this paper we first recapitulate some basic notions of brittle and cohesive fracture models, as well as the phase-field approximation to fracture. Next, a critical assessment is made of the sensitivity of the phase-field approach to brittle fracture, in particular the degradation function, and the use of monolithic versus partitioned solution schemes. The last part of the paper makes extensions to a recently developed phase-field model for cohesive fracture, in particular for propagating cracks. Using some simple examples the current state of the cohesive phase-field model is shown.", "corpus_id": 20816176, "score": 0 }, { "doc_id": "119146314", "title": "Three-dimensional brittle fracture : configurational-force-driven crack propagation", "abstract": "SUMMARY \nThis paper presents a computational framework for quasi-static brittle fracture in three-dimensional solids. The paper sets out the theoretical basis for determining the initiation and direction of propagating cracks based on the concept of configurational mechanics, consistent with Griffith's theory. Resolution of the propagating crack by the FEM is achieved by restricting cracks to element faces and adapting the mesh to align it with the predicted crack direction. A local mesh improvement procedure is developed to maximise mesh quality in order to improve both accuracy and solution robustness and to remove the influence of the initial mesh on the direction of propagating cracks. An arc-length control technique is derived to enable the dissipative load path to be traced. A hierarchical hp-refinement strategy is implemented in order to improve both the approximation of displacements and crack geometry. The performance of this modelling approach is demonstrated on two numerical examples that qualitatively illustrate its ability to predict complex crack paths. All problems are three-dimensional, including a torsion problem that results in the accurate prediction of a doubly-curved crack. Copyright © 2013 John Wiley & Sons, Ltd.", "corpus_id": 119146314, "score": 1 }, { "doc_id": "121075479", "title": "A computational framework of three-dimensional configurational-force-driven brittle crack propagation", "abstract": "Abstract We consider a variational formulation of quasi-static brittle fracture and develop a new finite-element-based computational framework for propagation of cracks in three-dimensional bodies. We outline a consistent thermodynamical framework for crack propagation in elastic solids and show that both the elastic equilibrium response as well as the local crack evolution follow in a natural format by exploitation of a global Clausius–Planck inequality in the sense of Coleman’s method. Consequently, the crack propagation direction associated with the classical Griffith criterion is identified by the material configurational force which maximizes the local dissipation at the crack front. The variational formulation is realized numerically by a standard spatial discretization with finite elements which yields a discrete formulation of the global dissipation in terms configurational nodal forces. Therefore, the constitutive setting of crack propagation in the space-discretized finite element context is naturally related to discrete nodes of a typical finite element mesh. In a consistent way with the node-based setting, the discretization of the evolving crack discontinuity is performed by the doubling of critical nodes and interface facets of the mesh. The crucial step for the success of this procedure is its embedding into an r -adaptive crack-facet reorientation procedure based on configurational-force-based indicators in conjunction with crack front constraints. We propose a staggered solution procedure that results in a sequence of positive definite discrete subproblems with successively decreasing overall stiffness, providing a robust algorithmic setting in the postcritical range. The predictive capabilitiy of the proposed formulation is demonstrated by means of representative numerical simulations.", "corpus_id": 121075479, "score": 1 }, { "doc_id": "122560289", "title": "A robust algorithm for configurational-force-driven brittle crack propagation with R-adaptive mesh alignment", "abstract": "The paper considers a variational formulation of brittle fracture in elastic solids and proposes a numerical implementation by a finite element method. On the theoretical side, we outline a consistent thermodynamic framework for crack propagation in an elastic solid. It is shown that both the elastic equilibrium response as well as the local crack evolution follow in a natural format by exploitation of a global Clausius–Planck inequality in the sense of Coleman's method. Here, the canonical direction of the crack propagation associated with the classical Griffith criterion is the direction of the material configurational force which maximizes the local dissipation at the crack tip and minimizes the incremental energy release. On the numerical side, we exploit this variational structure in terms of crack-driving configurational forces. First, a standard finite element discretization in space yields a discrete formulation of the global dissipation in terms configurational nodal forces. As a consequence, the constitutive setting of crack propagation in the space-discretized finite element context is naturally related to discrete nodes of a typical finite element mesh. Next, consistent with the node-based setting, the discretization of the evolving crack discontinuity is performed by the doubling of critical nodes and interface segments of the mesh. Critical for the success of this procedure is its embedding into an r-adaptive crack-segment reorientation procedure with configurational-force-based directional indicator. Here, successive crack releases appear in discrete steps associated with the given space discretization. These are performed by a staggered loading–release algorithm of energy minimization at frozen crack state followed by the successive crack releases at frozen deformation. This constitutes a sequence of positive-definite discrete subproblems with successively decreasing overall stiffness, providing an extremely robust algorithmic setting in the postcritical range. We demonstrate the performance of the formulation by means of representative numerical simulations. Copyright © 2007 John Wiley & Sons, Ltd.", "corpus_id": 122560289, "score": 1 }, { "doc_id": "120697000", "title": "A computational framework of configurational-force-driven brittle fracture based on incremental energy minimization", "abstract": "A variational formulation of quasi-static brittle fracture in elastic solids at small strains is proposed and an associated finite element implementation is presented. On the theoretical side, a consistent thermodynamic framework for brittle crack propagation is outlined. It is shown that both the elastic equilibrium response as well as the local crack evolution follow in a natural format by exploitation of a global Clausius–Planck inequality. Here, the canonical direction of the crack propagation associated with the classical Griffith criterion is the direction of the material configurational force which maximizes the local dissipation at the crack tip. On the numerical side, we first consider a standard finite element discretization in the two-dimensional space which yields a discrete formulation of the global dissipation in terms of configurational nodal forces. Next, consistent with the node-based setting, the discretization of the evolving crack discontinuity for two-dimensional problems is performed by the doubling of critical nodes and interface segments of the mesh. A crucial step for the success of this procedure is its embedding into a r-adaptive crack-segment re-orientation algorithm governed by configurational-force-based directional indicators. Here, successive crack propagation is performed by a staggered loading-release algorithm of energy minimization at frozen crack state followed by nodal releases at frozen deformation. We compare results obtained by the proposed formulation with other crack propagation criteria. The computational method proposed is extremely robust and shows an excellent performance for representative numerical simulations.", "corpus_id": 120697000, "score": 1 }, { "doc_id": "120876929", "title": "Mechanics in Material Space: with Applications to Defect and Fracture Mechanics", "abstract": "1 Mathematical Preliminaries.- 1.1 General Remarks.- 1.2 What is a Conservation Law?.- 1.3 Trivial Conservation Laws.- 1.4 System with a Lagrangian Noether's Method.- 1.5 System without a Lagrangian Neutral-Action Method.- 1.6 Discussion.- 2 Linear Theory of Elasticity.- 2.1 General Remarks.- 2.2 Elements of Linear Elasticity.- 2.3 Conservation Laws of Linear Elastostatics.- 2.4 Alternative Derivations of Conservation Laws.- 3 Properties of the Eshelby Tensor.- 3.1 General Remarks 81.- 3.2 Physical Interpretation of the Components of the Eshelby Tensor.- 3.3 Invariants, Principal Values, Principal Directions and Extremal Values of the Eshelby Tensor.- 4 Linear Elasticity with Defects.- 4.1 General Remarks.- 4.2 Path-Independent Integrals and Energy-Release Rates.- 4.3 Example: Hole-Dislocation Interaction.- 4.4 Path-Independent Integrals of Fracture Mechanics.- 5 Inhomogeneous Elastostatics.- 5.1 General Remarks.- 5.2 Symmetry Transformations.- 5.3 The Homogeneous Case.- 5.4 The Inhomogeneous Case.- 5.5 Relation to Stress-Intensity Factors.- 5.6 Examples.- 6 Elastodynamics.- 6.1 General Remarks.- 6.2 Time t as an Additional Independent Variable.- 6.3 Convolution in Time.- 6.4 Domain-Independent Integrals.- 6.5 Energy-Release Rates.- 6.6 Wave Motion.- 7 Dissipative Systems.- 7.1 General Remarks.- 7.2 Diffusion Equation.- 7.3 Non-Linear Wave Equation.- 7.4 Viscoelasticity.- 8 Coupled Fields.- 8.1 General Remarks.- 8.2 Piezoelectricity.- 8.3 Thermoelasticity.- 8.4 Mechanics of a Porous Medium.- 9 Bars, Shafts and Beams.- 9.1 General Remarks.- 9.2 Elements of Strength-of-Materials.- 9.3 Balance and Conservation Laws for Bars and Shafts.- 9.4 Balance and Conservation Laws for Beams.- 9.5 Energy-Release Rates and Stress-Intensity Factors.- 9.6 Examples.- 10 Plates and Shells.- 10.1 General Remarks.- 10.2 Plate Theories.- 10.3 Conservation Laws for Elastostatics of Mindlin Plates.- 10.4 Reduction to the Classical Theory.- 10.5 Conservation Laws for Shells.- Appendix A.- Conservation Laws for Inhomogeneous Bars under Arbitrary Axial Loading.- Appendix B.- B.1 Elastodynamics of Inhomogeneous Bernoulli-Euler Beams.- B.2 Reduction to Statics.- Appendix C.- C.1 Elastodynamics of Inhomogeneous Mindlin Plates.- C.2 Reduction to Statics.- References.- Symbol Index.- Author Index.", "corpus_id": 120876929, "score": 0 }, { "doc_id": "120490279", "title": "Pseudomomentum and material forces in nonlinear elasticity: variational formulations and application to brittle fracture", "abstract": "SummaryThis work examines critically the various formulations of the balance of linear momentum innonlinear inhomogeneous elasticity. The corresponding variational formulations are presented. From the point of view of the theory of elastic inhomogeneities, the most interesting formulations are those which, being either completely material or mixed-Eulerian, exhibit explicitly the inhomogeneities in the form ofmaterial forces. They correspond to the balance ofpseudomomentum, a material covector which is seldom used but which we show to play a fundamental role in the Hamiltonian canonical formulation of nonlinear elasticity. The flux associated with pseudomomentum is none other than theEshelby material tensor. Applying this formulation to the case of an elastic body containing a crack of finite extent, the notion of suction force acting at the tip of the crack follows while afracture criterion à la Griffith can be deduced from a variational inequality. Possible extensions to higher-grade elastic materials and inelastic materials are indicated as well as the role played by pseudomomentum in the quantization of elastic vibrations.", "corpus_id": 120490279, "score": 0 }, { "doc_id": "120155999", "title": "Variational principles of nonlinear fracture mechanics", "abstract": "SummaryA variational principle of total energy is formulated for finite strain statics of a hyperelastic body whose initial configuration contains a gap. From this principle statical equations and boundary conditions for the gapped body are derived. The equilibrium condition at a gap tip is associated with the well-knownJ-integrals. By including the reaction of inertia and the flux of kinetic energy the principle of total energy is transformed to the variational inequality of evolution for dynamics of a hyperelastic body with a propagating crack. A closed system of dynamical equations, boundary conditions and additional conditions on the unknown contact crack surfaces and crack tip is obtained. As example the antiplane shear of an infinite gapped body is considered.", "corpus_id": 120155999, "score": 0 }, { "doc_id": "122444950", "title": "Studies in elastic fracture mechanics based on the material force method", "abstract": "The object of this work is to discuss a further improvement of the material force method for non-linear hyperelastostatic fracture mechanics. We investigate the accuracy of the material force method within a 'modified boundary layer'-formulation using a Ramberg-Osgood material type for the sake of comparison. The proposed improvement leads to a reliable and very accurate method to compute the vectorial J-integral in fracture mechanics.", "corpus_id": 122444950, "score": 0 }, { "doc_id": "122546662", "title": "Adaptive strategies and error control for computing material forces in fracture mechanics", "abstract": "The concept of material forces pertains to a variation of the inverse motion map while the placement field is kept fixed. From the weak formulation of the self-equilibrating Eshelby (material) stress tensor it turns out that the classical J-integral formulations in fracture mechanics are just special cases due to the choice of particular weight functions. In this contribution, we discuss a posteriori error control of the material forces as part of an adaptive strategy to reduce the discretization error to an acceptable level. The data of the dual problem involves the quite non-conventional tangent stiffness of the (material) Eshelby stress tensor with respect to a variation of the (physical) strain field. The suggested strategy is applied to the common fracture mechanics problem of a single-edged crack, whereby different strategies for computing the J-integral are compared. We also consider the case in which the crack edges are not parallel, i.e. a notch.", "corpus_id": 122546662, "score": 0 }, { "doc_id": "123076205", "title": "On Configurational forces in the context of the finite element method", "abstract": "The theory of configurational forces is briefly recast, together with the underlying balance laws. It is shown, that in the case of a homogeneous body without body forces the additional balance laws are identically satisfied if the standard force balance holds. In approximate solutions, for example obtained by finite elements, the equilibrium is not satisfied exactly, thus configurational forces occur on discretization nodes. An implementation of the configurational force balance into the finite element scheme is presented. The use of configurational forces is discussed with three main aspects. It is demonstrated how configurational forces can be used to check and to improve the finite element solution. Examples from fracture mechanics and problems with material inhomogeneities are discussed. Copyright © 2001 John Wiley & Sons, Ltd.", "corpus_id": 123076205, "score": 0 }, { "doc_id": "120338967", "title": "Application of material forces to hyperelastostatic fracture mechanics. II. Computational setting", "abstract": "Abstract The concern of this work is a novel algorithmic treatment of hyperelastostatic fracture mechanics problems consistent to the notion of material forces within the geometrically nonlinear setting of continuum mechanics. To this end, we consider the continuum mechanics of material forces, as outlined in Part I of this work (P. Steinmann, Int. J. Solid Struct. 37, 7371–7391), which act, contrary to the common physical forces, on the material manifold or rather in the material space. In the sequel it is proposed to discretize the corresponding quasi-static balance of pseudo momentum by a standard Galerkin finite element procedure. As a result we obtain global discrete node point quantities, the material node point forces, which prove to be of the same qualitative and quantitative importance for the assessment of fracture mechanics problems as the classical J -integral.", "corpus_id": 120338967, "score": 0 }, { "doc_id": "46300971", "title": "On material forces and finite element discretizations", "abstract": "Abstract The idea of using material forces also termed configurational forces in a computational setting is presented. The theory of material forces is briefly recast in the terms of a non-linear elastic solid. It is shown, how in a computational setting with finite elements (FE) the discrete configurational forces are calculated once the classical field equations are solved. This post-process calculation is performed in a way, which is consistent with the approximation of the classical field equations. Possible physical meanings of this configurational forces are discussed. A purely computational aspect of material forces is pointed out, where material forces act as an indicator to obtain softer discretizations.", "corpus_id": 46300971, "score": 0 }, { "doc_id": "121639055", "title": "Theory and numerics for finite deformation fracture modelling using strong discontinuities", "abstract": "A general finite element approach for the modelling of fracture is presented for the geometrically non-linear case. The kinematical representation is based on a strong discontinuity formulation in line with the concept of partition of unity for finite elements. Thus, the deformation map is defined in terms of one continuous and one discontinuous portion, considered as mutually independent, giving rise to a weak formulation of the equilibrium consisting of two coupled equations. In addition, two different fracture criteria are considered. Firstly, a principle stress criterion in terms of the material Mandel stress in conjunction with a material cohesive zone law, relating the cohesive Mandel traction to a material displacement ‘jump’ associated with the direct discontinuity. Secondly, a criterion of Griffith type is formulated in terms of the material-crack-driving force (MCDF) with the crack propagation direction determined by the direction of the force, corresponding to the direction of maximum energy release. Apart from the material modelling, the numerical treatment and aspects of computational implementation of the proposed approach is also thoroughly discussed and the paper is concluded with a few numerical examples illustrating the capabilities of the proposed approach and the connection between the two fracture criteria. Copyright © 2005 John Wiley & Sons, Ltd.", "corpus_id": 121639055, "score": 0 }, { "doc_id": "121512668", "title": "A framework for fracture modelling based on the material forces concept with XFEM kinematics", "abstract": "A theoretical and computational framework which covers both linear and non-linear fracture behaviour is presented. As a basis for the formulation, we use the material forces concept due to the close relation between on one hand the Eshelby energy–momentum tensor and on the other hand material defects like cracks and material inhomogeneities. By separating the discontinuous displacement from the continuous counterpart in line with the eXtended finite element method (XFEM), we are able to formulate the weak equilibrium in two coupled problems representing the total deformation. However, in contrast to standard XFEM, where the direct motion discontinuity is used to model the crack, we rather formulate an inverse motion discontinuity to model crack development. The resulting formulation thus couples the continuous direct motion to the inverse discontinuous motion, which may be used to simulate linear as well as non-linear fracture in one and the same formulation. In fact, the linear fracture formulation can be retrieved from the non-linear cohesive zone formulation simply by confining the cohesive zone to the crack tip. These features are clarified in the two numerical examples which conclude the paper. Copyright © 2005 John Wiley & Sons, Ltd.", "corpus_id": 121512668, "score": 0 }, { "doc_id": "122657429", "title": "On the numerical modelling of quasi-static crack growth in linear elastic fracture mechanics", "abstract": "In this paper we present a strategy for the simulation of a propagating crack under mixed mode linear elastic conditions using a discontinuous finite element method. A key issue is to accurately compute the incremental change in the kink angle of the propagating crack during subsequent steps. We have chosen to work with a domain formulation of the material force vector as a criteria for the propagation direction. We describe the theoretical background together with the numerical implementation in detail and show some results for different loading conditions. Copyright © 2005 John Wiley & Sons, Ltd.", "corpus_id": 122657429, "score": 0 }, { "doc_id": "137704796", "title": "On energetic changes due to configurational motion of standard continua", "abstract": "The appropriate thermodynamic setting for the combined configurational and deformational motion of standard continua is discussed in this paper. A key ingredient is an absolute (fixed) reference configuration, relative to which configurational and deformational changes (rates) with respect to the material (undeformed) and spatial (deformed) configurations, respectively, can be described in a unified fashion. In particular, we are interested in formulating the local as well as global measures of the energy dissipation due to configurational changes of a given physical system. It is believed that the presentation in this paper provides the following advantages: a unified kinematic and thermodynamic setting of the configurational and deformational motions, in particular the generic balance law accounting for configurational flux, increases the general clarity; the separation of the total dissipation in terms of the intrinsic change in elastic energy and in terms of the material dissipation that is induced by configurational changes becomes transparent. All results are obtained without any restrictions on dynamics, thermomechanical couplings, etc.", "corpus_id": 137704796, "score": 0 }, { "doc_id": "122723805", "title": "Fracture mechanical behaviour of visco-elastic materials: application to the so-called dwell-effect", "abstract": "The material force approach is an efficient, elegant, and accepted means to compute the J-integral as a fracture mechanical parameter for elastic and inelastic materials. With the formulation of a multiplicative split of the deformation gradient at hand, rate-dependent (visco-elastic) materials described for example by the physically based Bergstrom-Boyce model can be investigated. For these investigations, the so-called material volume forces have to be computed in order to separate the driving forces acting on the visco-elastic zone around the crack tip from the driving forces acting on the crack tip itself, representing the crack driving force. To illustrate the effectiveness of this approach, the so-called dwell-effect of elastomeric materials is investigated.", "corpus_id": 122723805, "score": 0 }, { "doc_id": "117233770", "title": "Material forces for inelastic models at large strains: application to fracture mechanics", "abstract": "Elastomeric materials show a wide range of different elastic and inelastic properties. Additionally, this class of materials is subjected to large deformations. Considering all these effects, fracture mechanical investigations are very challenging tasks and cannot be performed with standard approaches. Effects of inhomogeneities and discontinuities such as cracks can be investigated with the so-called material force approach in an efficient and elegant way. For comprehensive investigations of inelastic materials, the complete balance of the material motion problem has to be formulated. In this case, the material volume forces depend on the internal history variables which are required for the inelastic constitutive model. This paper derives a general formulation for rate-dependent and rate-independent inelastic materials based on a multiplicative split of the deformation gradient to cover viscoelastic and elastoplastic materials at finite deformations.", "corpus_id": 117233770, "score": 0 }, { "doc_id": "135501043", "title": "Evaluation of energy contributions in elasto-plastic fracture: A review of the configurational force approach", "abstract": "Abstract This paper discusses the role of the material or rather configurational force approach in elastic–plastic materials with a pre-cracked configuration and gives an overview of some recent numerical investigations of the crack tip field. On the theoretical side, a consistent thermodynamic framework for the combined configurational and deformational motion in elasto-plastic continua at small and finite strains is discussed. Furthermore, the study researches the separation of the total dissipation in terms of the change in elastic energy and in terms of the material dissipation by a configurational change obtained from the global energy momentum balance. On the numerical side, an equivalent general expression of the vectorial material forces is derived from the weak form of the energy momentum balance. For the sake of simplicity, all results are obtained neglecting dynamic and thermo-mechanical phenomena. The computations are applied to a stationary crack in a circular pre-cracked domain and a compact tension specimen under plasticity condition. The results show that the material force approach remains path independent only if all components of the momentum balance equation are properly included into the corresponding variational formulation. In addition, the cohesive fracture theory is combined with the material force approach in order to increase the clarity of the interpretation of the approach in engineering applications. Correspondingly, the results obtained from the compact tension specimen with three different free energy functions are compared to the conventional J-integral method and to experimental results available from a previous study. The contributions of this study are threefold. First, the path dependency of the material force approach in elasto-plastic continua is found to be considerably depending on the so-called material body forces. Secondly, interpretation of the induced material dissipation forces in the definition of the crack driving forces is not explicitly clear but they play an important role in case of path independency. Finally, with further analyses on compact tension examples, it is shown that the introduced energy functions in the material momentum balance yield a difference for the evaluation of the material force approach and the traditional J-integral.", "corpus_id": 135501043, "score": 0 }, { "doc_id": "122587920", "title": "On a solution strategy for energy-based mesh optimization in finite hyperelastostatics", "abstract": "The objective of this work is the development of a numerical solution strategy for energy-based mesh optimization in finite hyperelastostatics. In finite element computations that rely on the principle of minimum potential energy, the variational principle itself provides the basis for r-adaptive methods. The numerical solution can be improved by further minimizing the discrete potential energy with respect to the material node point positions. In this paper, we regard the mesh optimization as a nonlinear minimization problem with equality and inequality constraints. The equality constraints correspond to the spatial equilibrium condition, whereas the inequality constraints are given by the natural restriction that material elements with a negative volume (Jacobian) are inadmissible. Based on this interpretation, we develop a stable numerical solution strategy in which two approaches of nonlinear programming are combined. Applying a barrier method, the minimization problem is transformed into a sequence of problems without inequality constraints. Each problem of the sequence is solved by means of a Newton scheme that operates on the constrained surface given by the spatial equilibrium condition.", "corpus_id": 122587920, "score": 0 }, { "doc_id": "120481883", "title": "NUMERICAL MODELLING OF DISCONTINUA", "abstract": "Discrete element methods are numerical procedures for simulating the complete behaviour of systems of discrete, interacting bodies. Three important aspects of discrete element programs are examined: (1) the representation of contacts; (2) the representation of solid material; and (3) the scheme used to detect and revise the set of contacts. A proposal is made to define what constitutes a discrete element program, and four classes of such programs are described: the distinct element method, modal methods, discontinuous deformation analysis and the momentum‐exchange method. Several applications and examples are presented, and a list is given of suggestions for future developments.", "corpus_id": 120481883, "score": 0 }, { "doc_id": "131601997", "title": "A bonded-particle model for rock", "abstract": "A numerical model for rock is proposed in which the rock is represented by a dense packing of non-uniform-sized circular or spherical particles that are bonded together at their contact points and whose mechanical behavior is simulated by the distinct-element method using the two- and three-dimensional discontinuum programs PFC2D and PFC3D. The microproperties consist of stiffness and strength parameters for the particles and the bonds. Damage is represented explicitly as broken bonds, which form and coalesce into macroscopic fractures when load is applied. The model reproduces many features of rock behavior, including elasticity, fracturing, acoustic emission, damage accumulation producing material anisotropy, hysteresis, dilation, post-peak softening and strength increase with confinement. These behaviors are emergent properties of the model that arise from a relatively simple set of microproperties. A material-genesis procedure and microproperties to represent Lac du Bonnet granite are presented. The behavior of this model is described for two- and three-dimensional biaxial, triaxial and Brazilian tests and for two-dimensional tunnel simulations in which breakout notches form in the region of maximum compressive stress. The sensitivity of the results to microproperties, including particle size, is investigated. Particle size is not a free parameter that only controls resolution; instead, it affects the fracture toughness and thereby influences damage processes (such as notch formation) in which damage localizes at macrofracture tips experiencing extensile loading.", "corpus_id": 131601997, "score": 0 }, { "doc_id": "109485150", "title": "Simulation of blasting induced rock motion using spherical element models", "abstract": "Control of the rock motion associated with blasting can have significant economic benefits. For example, surface coal mining can be made more efficient if the overburden material can be cast further with explosives, leaving less work for mechanical equipment. The final muck pile shape in every type of surface and underground blasting is controlled by the blasting induced motion of the rock. A theoretically sound method of predicting rock motion will be beneficial to understanding the blasting process.", "corpus_id": 109485150, "score": 0 }, { "doc_id": "120937365", "title": "An alternating digital tree (ADT) algorithm for 3D geometric searching and intersection problems", "abstract": "A searching algorithm is presented for determining which members of a set of n points in an N dimensional space lie inside a prescribed space subregion. The algorithm is then extended to handle finite size objects as well as points. In this form it is capable of solving problems such as that of finding the objects from a given set which intersect with a prescribed object. The suitability of the algorithm is demonstrated for the problem of three dimensional unstructured mesh generation using the advancing front method.", "corpus_id": 120937365, "score": 0 }, { "doc_id": "123055686", "title": "A fast contact detection algorithm insensitive to object sizes", "abstract": "Presents a new contact detection algorithm based on double‐ended spatial sorting (DESS) that is insensitive to variations in object size. It was developed to address the problems that arise when objects with non‐spherical geometry and non‐uniform sizes are simulated using discrete element techniques. The algorithm is applicable to general spatial reasoning problems. While techniques based on spatial hashing (sometimes called bining methods) perform well for objects of similar size, they degrade significantly when the objects vary in size. The DESS algorithm overcomes this problem by using a spatial sorting technique applied to both ends of the object’s projection along each orthogonal axis. Discrete element test simulations comparing DESS and spatial hashing (NBS) are detailed. The results demonstrate that when object sizes vary significantly (size ratios greater than 8:1), DESS outperforms NBS up to around 100,000 objects. It is noted, however, that the superior scaling properties of NBS will always outperform DESS for some large numbers of objects.", "corpus_id": 123055686, "score": 0 }, { "doc_id": "138749550", "title": "Influence of the Main Contact Parameters in Finite Element Analysis of Elastic Bodies in Contact", "abstract": "One of the key issues in solving contact problems is the correct choice of the contact parameters. The contact stiffness, the penetration limit and the contact algorithm are some of the parameters that have to be adjusted. There are no methodologies available in the literature for choosing the contact parameters, relying only on the user experience for this important task. In this work we investigate how the contact parameters behave in a commercial finite element analysis software. We will show that while the contact stiffness has great influence on the finite element analysis, other parameters will not affect it significantly. Some contact examples are shown to illustrate the performance of the contact parameters during the solution of a contact problem.", "corpus_id": 138749550, "score": 0 }, { "doc_id": "140705154", "title": "A new discrete fracture modelling approach for rock masses", "abstract": "A method for modelling discrete fracture in rock masses under tensile and compressive stress fields is presented, based on a Mohr–Coulomb failure surface in compression and three independent anisotropic rotating crack models in tension. Extension fracturing is modelled by coupling the softening of the anisotropic rotating crack failure criterion to the compressive plastic strain evolution. An explicitly time-integrated coupled discrete element/finite element approach is employed with an explicit Lagrangian contact algorithm to enforce non-penetration of the surfaces created when the tensile strength is depleted. The geomechanical model is applied to naturally fractured rock masses, which are characterised by field mapping and borehole data integrated in a stochastic 3D discrete fracture network model. This approach maximises the utility of the field data and provides a direct approach to the determination of rock mass strength and deformability. It also provides a realistic insight into complex failure me...", "corpus_id": 140705154, "score": 0 }, { "doc_id": "55796607", "title": "The stability of a laminated Voussoir beam: Back analysis of a historic roof collapse using DDA", "abstract": "Abstract The stability of a horizontally bedded and vertically jointed roof, referred to here as a laminated Voussoir beam, is studied using careful documentation of a historic roof collapse, which occurred in an ancient underground water storage reservoir dated back to ca. 1000 B.C. The roof of the opening failed immediately after the excavation leaving a dome shaped loosened zone, with a span of 7 m and height of 2.5 m, consisting of horizontal beds and vertical joints with mean spacing of 50 and 25 cm, respectively. The ancient engineers erected a massive pillar at the center of the dome in order to passively support the failed roof and the opening remained in service for several hundred years following the failure. Analysis of the roof using iterative Voussoir beam procedure [Beer, G. and Meek, J. L., Design curves for roofs and hanging walls in bedded rock based on Voussoir beam and plate solutions. Trans. Inst. Min. Metall. , 1982, 91 , A18–22.] shows that the roof was more sensitive to failure by shear along the abutments rather than by crushing at hinge zones and that the required friction angle ( φ req. ) for stability would have been 36°. The available friction angle is estimated between 38.6° and 46.4° and, therefore, the result of the iterative solution is considered unconservatively wrong. Results of DDA [Shi, G. -H. and Goodman, R. E., Two-dimensional discontinuous deformation analysis. Int. J. Numer. Anal. Methods Geomech. , 1989, 13 , 359–380; Shi, G. -H., Block System Modeling by Discontinuous Deformation Analysis . Computational Mechanics Publications, Southampton, 1993, pp. 209.] however indicate that φ req. must have been greater than 60°, a shear strength which was not available at the time of construction, thus the immediate failure. Using DDA we further demonstrate that φ req. is related to joint spacing (or block length) in a parabolic function: with increasing joint spacing φ req. decreases to a minimum value and than increases with further increase in joint spacing. This result is attributed to the interaction of two competing forces: one is the stabilizing axial thrust which increases with increasing moment arm in individual blocks (a function of joint spacing or block length), the other is the destabilizing vertical load which increases with increasing weight of overlying blocks.", "corpus_id": 55796607, "score": 0 }, { "doc_id": "140163421", "title": "Stability of shallow karstic caverns in blocky rock masses", "abstract": "Abstract The limiting relationship is explored between underground opening span and required cover height for stability in blocky rock masses characterized by a network of horizontal bedding planes and vertical joints. Understanding this relationship is crucial for the design of mining excavations in karstic terrain as typically encountered in carbonate rock masses. We perform numerical analysis of multiple roof spans vs. cover height geometries using the DDA method to obtain the boundary curve between stable and unstable opening geometries. Our results indicate that for cavern spans of up to 18 m a low cover height vs. opening span ratio of h/B =0.33 is sufficient for stability. For spans greater than 18 m the demand for cover height rapidly increases and it appears to stabilize at h/B =1.0 for B =26 m and above. To validate our numerical analysis results, a unique case study is analyzed wherein a 40 m span karstic cavern, the Ayalon cave, has been preserved below an active open pit mine in central Israel with cover height of only 30 m, thus rendering the cave marginally stable according to our model prediction. Indeed there is ample evidence of partial collapse of the roof in the cave. The predictive capability of our model is further confirmed using two additional case studies in blocky rock masses, each of which possesses very different mechanical parameters such as intact rock strength, density, and deformability, suggesting that our model predictions remain valid as long the rock mass maintains a “blocky” structural configuration.", "corpus_id": 140163421, "score": 0 }, { "doc_id": "121500586", "title": "Review of validation of the discontinuous deformation analysis (DDA) method", "abstract": "Over the last decade, researchers in the discontinuous deformation analysis (DDA) community have dedicated a great deal of effort to document the accuracy of the method by performing validation studies. This paper contains a summary of more than 100 published and unpublished validation studies which comprise the body of DDA validation information to which the authors have access. The studies are grouped into three general categories: (a) validation with respect to analytical solutions, (b) validation with respect to results of other numerical techniques, and (c) validation with respect to laboratory and field data. Three general techniques for validation are described: qualitative assessment visually examining runtime behaviour of simulations, semi-quantitative assessment comparing numerical results of simulations, and quantitative where numerical simulation results are evaluated in detail with respect to similar analytical, laboratory or field results. We find that for many of the problems addressed by the papers in this review, DDA performs more than adequately for engineering analysis. Copyright © 2006 John Wiley & Sons, Ltd.", "corpus_id": 121500586, "score": 0 }, { "doc_id": "54901287", "title": "Tunnel roof deflection in blocky rock masses as a function of joint spacing and friction - A parametric study using discontinuous deformation analysis (DDA)", "abstract": "Abstract The stability of underground openings excavated in a blocky rock mass was studied using the discontinuous deformation analysis (DDA) method. The focus of the research was a kinematical analysis of the rock deformation as a function of joint spacing and friction. Two different opening geometries were studied: (1) span B  =  h t ; (2) B  = 1.5 h t ; where the opening height was h t  = 10 m for both configurations. Fifty individual simulations were performed for different values of joint spacing and friction angle. It was found that the extent of loosening above the excavation was predominantly controlled by the spacing of the joints, and only secondarily by the shear strength. The height of the loosening zone h r was found to be dependent upon the ratio between joint spacing and excavation span S j / B : (1) h r B for S j / B  ⩽ 2/10; (2) stable arching within the rock mass for S j / B  ⩾ 3/10. The results of this study provide explicit correlation between geometrical features of the rock mass, routinely collected during site investigation and excavation, and the expected extent of the loosening zone at the roof, which determines the required support.", "corpus_id": 54901287, "score": 0 }, { "doc_id": "121179217", "title": "Combined three-dimensional lattice Boltzmann method and discrete element method for modelling fluid-particle interactions with experimental assessment", "abstract": "A general algorithmic framework is established in this paper for numerical simulations of three-dimensional fluid–particle interaction problems with a large number of moving particles in turbulent flows using a combined lattice Boltzmann method (LBM) and discrete element method (DEM). In this approach, the fluid field is solved by the extended three-dimensional LBM with the incorporation of the Smagorinsky turbulence model, while particle interactions are modelled by the DEM. The hydrodynamic interactions between fluid and particles are realized through the extension of an existing two-dimensional fluid–particle hydrodynamic interaction scheme. The main computational aspects comprise the lattice Boltzmann formulation for the solution of fluid flows, the incorporation of a large eddy simulation-based turbulence model within the framework of the three-dimensional LBM for turbulent flows, the moving boundary condition for hydrodynamic interactions between fluid and moving particles, and the discrete element modelling of particle-particle interactions. To assess the solution accuracy of the proposed approach, a much simplified laboratory model of vacuum dredging systems for mineral recovery is employed. The numerical results are compared with the experimental data available. It shows that the overall correspondence between numerical results and experimental measurements is good and thus indicates, to a certain extent, the solution accuracy of the proposed methodology. Copyright © 2009 John Wiley & Sons, Ltd.", "corpus_id": 121179217, "score": 0 }, { "doc_id": "8122046", "title": "YADE‐OPEN DEM: an open‐source software using a discrete element method to simulate granular material", "abstract": "Purpose – YADE‐OPEN DEM is an open‐source software based on the discrete element method, (DEM) which uses object oriented programming techniques. The purpose of this paper is to describe the software architecture.Design/methodology/approach – The DEM chosen uses position, orientation, velocity and angular velocity as independent variables of simulated particles which are subject to explicit leapfrog time‐integration scheme (Lagrangian method). The three‐dimensional dynamics equations based on the classical Newtonian approach for the second law of motion are used. The track of forces and moments acting on each particle is kept at every time step. Contact forces depend on the particle geometry overlap and material properties. The normal, tangential and moment components of interaction force are included.Findings – An effort is undertaken to extract the underlying object oriented abstractions in the DEM. These abstractions are implemented in C++, conform to object oriented design principles and use design pa...", "corpus_id": 8122046, "score": 0 }, { "doc_id": "108776368", "title": "Y-Geo: New Combined Finite-Discrete Element Numerical Code for Geomechanical Applications", "abstract": "AbstractThe purpose of this paper is to present Y-Geo, a new numerical code for geomechanical applications based on the combined finite-discrete element method (FDEM). FDEM is an innovative numerical technique that combines the advantages of continuum-based modeling approaches and discrete element methods to overcome the inability of these methods to capture progressive damage and failure processes in rock. In particular, FDEM offers the ability to explicitly model the transition from continuum to discontinuous behavior by fracture and fragmentation processes. Several algorithmic developments have been implemented in Y-Geo to specifically address a broad range of rock mechanics problems. These features include (1) a quasi-static friction law, (2) the Mohr-Coulomb failure criterion, (3) a rock joint shear strength criterion, (4) a dissipative impact model, (5) an in situ stress initialization routine, (6) a material mapping function (for an exact representation of heterogeneous models), and (7) a tool to i...", "corpus_id": 108776368, "score": 0 }, { "doc_id": "129221963", "title": "Numerical Models in Discontinuous Media: Review of Advances for Rock Mechanics Applications", "abstract": "The paper presents a description of the methods used to model rock as discontinuous media. The objective of the work is to bring to the geomechanics community recent advances in numerical modeling in the field of rock mechanics. The following methods are included: (1) the distinct element method; (2) the discontinuous deformation analysis method; and (3) the bonded particle method. A brief description of the fundamental algorithms that apply to each method is included, as well as a simple case to illustrate their use.", "corpus_id": 129221963, "score": 0 }, { "doc_id": "122055539", "title": "Reformulation of Elasticity Theory for Discontinuities and Long-Range Forces", "abstract": "Some materials may naturally form discontinuities such as cracks as a result of deformation. As an aid to the modeling of such materials, a new framework for the basic equations of continuum mechanics, called the \"peridynamic\" formulation, is proposed. The propagation of linear stress waves in the new theory is discussed, and wave dispersion relations are derived. Material stability and its connection with wave propagation is investigated. It is demonstrated by an example that the reformulated approach permits the solution of fracture problems using the same equations either on or off the crack surface or crack tip. This is an advantage for modeling problems in which the location of a crack is not known in advance.", "corpus_id": 122055539, "score": 1 }, { "doc_id": "122387437", "title": "A meshfree method based on the peridynamic model of solid mechanics", "abstract": "An alternative theory of solid mechanics, known as the peridynamic theory, formulates problems in terms of integral equations rather than partial differential equations. This theory assumes that particles in a continuum interact with each other across a finite distance, as in molecular dynamics. Damage is incorporated in the theory at the level of these two-particle interactions, so localization and fracture occur as a natural outgrowth of the equation of motion and constitutive models. A numerical method for solving dynamic problems within the peridynamic theory is described. Accuracy and numerical stability are discussed. Examples illustrate the properties of the method for modeling brittle dynamic crack growth.", "corpus_id": 122387437, "score": 1 }, { "doc_id": "12461561", "title": "Combined finite element and peridynamic analyses for predicting failure in a stiffened composite curved panel with a central slot", "abstract": "This study presents an analysis approach based on a merger of the finite element method and the peridynamic theory. Its validity is established through qualitative and quantitative comparisons against the test results for a stiffened composite curved panel with a central slot under combined internal pressure and axial tension. The predicted initial and final failure loads, as well as the final failure modes, are in close agreement with the experimental observations. This approach demonstrates the capability of the PD approach to assess the durability of complex composite structures.", "corpus_id": 12461561, "score": 0 }, { "doc_id": "15182232", "title": "Peridynamic model for dynamic fracture in unidirectional fiber-reinforced composites", "abstract": "Abstract We propose a computational method for a homogenized peridynamics description of fiber-reinforced composites and we use it to simulate dynamic brittle fracture and damage in these materials. With this model we analyze the dynamic effects induced by different types of dynamic loading on the fracture and damage behavior of unidirectional fiber-reinforced composites. In contrast to the results expected from quasi-static loading, the simulations show that dynamic conditions can lead to co-existence of and transitions between fracture modes; matrix shattering can happen before a splitting crack propagates. We observe matrix–fiber splitting fracture, matrix cracking, and crack migration in the matrix, including crack branching in the matrix similar to what is observed in recent dynamic experiments. The new model works for arbitrary fiber orientation relative to a uniform discretization grid and also works with random discretizations. The peridynamic composite model captures significant differences in the crack propagation behavior when dynamic loadings of different intensities are applied. An interesting result is branching of a splitting crack into two matrix cracks in transversely loaded samples. These cracks branch as in an isotropic material but here they migrate over the “fiber bonds”, without breaking them. This behavior has been observed in recent experiments. The strong influence that elastic waves have on the matrix damage and crack propagation paths is discussed. No special criteria for splitting mode fracture (Mode II), crack curving, or crack arrest are needed, and yet we obtain all these modes of material failure as a direct result of the peridynamic simulations.", "corpus_id": 15182232, "score": 0 }, { "doc_id": "121593670", "title": "A peridynamic material model for the analysis of dynamic crack propagation in orthotropic media", "abstract": "Abstract A new material model for the dynamic fracture analysis of anisotropic materials has been proposed within the framework of the bond-based peridynamic theory. This model enables predicting complex fracture phenomena such as spontaneous crack nucleation and crack branching, curving and arrest, a capability inherited from the bond-based peridynamic theory. An important feature of the model is that the bond properties, i.e. the stiffness constant and critical stretch, are continuous functions of bond orientation in the principal material axes. This facilitates fracture analysis of anisotropic materials with random orientations, such as polycrystalline microstructures. Elastic and fracture behaviour of the model has been verified through simulating uniaxial tension of a composite plate and fracture of a cortical bone compact tension specimen, and making quantitative comparisons to analytical and experimental data. To further demonstrate the capabilities of the proposed model, dynamic fracture of a polycrystalline microstructure (alumina ceramic) has been simulated. The influence of the grain boundary and grain interior fracture energies on the interacting and competing fracture modes of polycrystalline materials, i.e. intergranular and transgranular fracture, has been studied.", "corpus_id": 121593670, "score": 1 }, { "doc_id": "30571789", "title": "Peridynamic States and Constitutive Modeling", "abstract": "A generalization of the original peridynamic framework for solid mechanics is proposed. This generalization permits the response of a material at a point to depend collectively on the deformation of all bonds connected to the point. This extends the types of material response that can be reproduced by peridynamic theory to include an explicit dependence on such collectively determined quantities as volume change or shear angle. To accomplish this generalization, a mathematical object called a deformation state is defined, a function that maps any bond onto its image under the deformation. A similar object called a force state is defined, which contains the forces within bonds of all lengths and orientation. The relation between the deformation state and force state is the constitutive model for the material. In addition to providing a more general capability for reproducing material response, the new framework provides a means to incorporate a constitutive model from the conventional theory of solid mechanics directly into a peridynamic model. It also allows the condition of plastic incompressibility to be enforced in a peridynamic material model for permanent deformation analogous to conventional plasticity theory.", "corpus_id": 30571789, "score": 1 }, { "doc_id": "135626352", "title": "A non-ordinary state-based peridynamic method to model solid material deformation and fracture", "abstract": "Abstract In this paper, we develop a new non-ordinary state-based peridynamic method to solve transient dynamic solid mechanics problems. This new peridynamic method has advantages over the previously developed bond-based and ordinary state-based peridynamic methods in that its bonds are not restricted to central forces, nor is it restricted to a Poisson’s ratio of 1/4 as with the bond-based method. First, we obtain non-local nodal deformation gradients that are used to define nodal strain tensors. The deformation gradient tensors are used with the nodal strain tensors to obtain rate of deformation tensors in the deformed configuration. The polar decomposition of the deformation gradient tensors are then used to obtain the nodal rotation tensors which are used to rotate the rate of deformation tensors and previous Cauchy stress tensors into an unrotated configuration. These are then used with conventional Cauchy stress constitutive models in the unrotated state where the unrotated Cauchy stress rate is objective. We then obtain the unrotated Cauchy nodal stress tensors and rotate them back into the deformed configuration where they are used to define the forces in the nodal connecting bonds. As a first example we quasi-statically stretch a bar, hold it, and then rotate it ninety degrees to illustrate the methods finite rotation capabilities. Next, we verify our new method by comparing small strain results from a bar fixed at one end and subjected to an initial velocity gradient with results obtained from the corresponding one-dimensional small strain analytical solution. As a last example, we show the fracture capabilities of the method using both a notched and un-notched bar.", "corpus_id": 135626352, "score": 0 }, { "doc_id": "121855323", "title": "Non-ordinary state-based peridynamic analysis of stationary crack problems", "abstract": "An implicit implementation of the non-ordinary state-based peridynamics formulation for quasi-static linearly elastic solids is presented. Emphasis is placed on assessing the accuracy of the numerical scheme in the vicinity of the crack front and other sources of stress concentration. We also present a comparative study of methods used to control the zero-energy modes inherent in the nonlocal definition of the strain tensor and reduce the spurious oscillations present particularly in regions of high strain gradients. The accuracy of the peridynamics scheme, including the impact of the lattice spacing and configuration, is assessed by performing an analysis of the near-tip stress and displacement fields (K-fields) for 2D problems. The manuscript also summarizes a verification study based on the classical 3D penny-shaped crack problem and a validation study of a 3D notched fracture specimen.", "corpus_id": 121855323, "score": 0 }, { "doc_id": "122698165", "title": "Higher‐order extended finite elements with harmonic enrichment functions for complex crack problems", "abstract": "SUMMARY In this paper, we analyze complex crack problems in elastic media using harmonic enrichment functions in a higher-order extended finite element implementation. The numerically computed enrichment function of a crack is the solution of the Laplace equation with discontinuous Dirichlet boundary condition along the crack, and its interaction with branches or other cracks is realized by imposing vanishing Neumann boundary conditions along those cracks. The classical finite element displacement approximation is enriched by adding the enrichment function of a crack through the framework of partition of unity. A nested subgrid mesh is used in the Laplace solve with a rasterized approximation of a crack, which simplifies the numerical integration—no partitioning of finite elements is required. Harmonic enrichment functions readily permit the extension to handle multiple interacting and branched cracks without any special treatment around the junction points. Several numerical examples are presented that arm the accuracy and eectiveness of the method when applied to complex crack", "corpus_id": 122698165, "score": 0 }, { "doc_id": "121647437", "title": "Modeling of dynamic crack branching by enhanced extended finite element method", "abstract": "The conventional extended finite element method (XFEM) is enhanced in this paper to simulate dynamic crack branching, which is a top challenge issue in fracture mechanics and finite element method. XFEM uses the enriched shape functions with special characteristics to represent the discontinuity in computation field. In order to describe branched cracks, it is necessary to set up the additional enrichment. Here we have developed two kinds of branched elements, namely the “element crossed by two separated cracks” and “element embedded by a junction”. Another series of enriched degrees of freedom are introduced to seize the additional discontinuity in the elements. A shifted enrichment scheme is used to avoid the treatment of blending element. Correspondingly a new mass lumping method is developed for the branched elements based on the kinetic conservation. The derivation of the mass matrix of a four-node quadrilateral element which contains two strong discontinuities is specially presented. Then by choosing crack speed as the branching criterion, the branching process of a single mode I crack is simulated. The results including the branching angle and propagation routes are compared with that obtained by the conventionally used element deletion method.", "corpus_id": 121647437, "score": 0 }, { "doc_id": "8462707", "title": "Studies of dynamic crack propagation and crack branching with peridynamics", "abstract": "In this paper we discuss the peridynamic analysis of dynamic crack branching in brittle materials and show results of convergence studies under uniform grid refinement (m-convergence) and under decreasing the peridynamic horizon (δ-convergence). Comparisons with experimentally obtained values are made for the crack-tip propagation speed with three different peridynamic horizons. We also analyze the influence of the particular shape of the micro-modulus function and of different materials (Duran 50 glass and soda-lime glass) on the crack propagation behavior. We show that the peridynamic solution for this problem captures all the main features, observed experimentally, of dynamic crack propagation and branching, as well as it obtains crack propagation speeds that compare well, qualitatively and quantitatively, with experimental results published in the literature. The branching patterns also correlate remarkably well with tests published in the literature that show several branching levels at higher stress levels reached when the initial notch starts propagating. We notice the strong influence reflecting stress waves from the boundaries have on the shape and structure of the crack paths in dynamic fracture. All these computational solutions are obtained by using the minimum amount of input information: density, elastic stiffness, and constant fracture energy. No special criteria for crack propagation, crack curving, or crack branching are used: dynamic crack propagation is obtained here as part of the solution. We conclude that peridynamics is a reliable formulation for modeling dynamic crack propagation.", "corpus_id": 8462707, "score": 0 }, { "doc_id": "44463470", "title": "Predicting crack initiation and propagation using XFEM, CZM and peridynamics: A comparative study", "abstract": "This study presents a comparison of extended finite elements (XFEM), cohesive zone model (CZM) and the peridynamic theory (PD). By comparisons against two experimental benchmark studies, the capability of these techniques to predict dynamic fracture is demonstrated through both qualitative and quantitative observations.", "corpus_id": 44463470, "score": 0 } ]

{ "doc_id": "40198893", "title": "Hydrophobia of gymnosperms: myth or reality? A global analysis", "abstract": "According to the classical textbooks, the gymnosperms are the only seed plants without aquatic species. Recently, however, a set of virtually complete compilations on gymnosperms has been published, enabling a new evaluation of the putative hydrophobia of gymnosperms. This synthesis aims at portraying the relation of all extant gymnosperm species to aquatic and wetland habitats. We present a database of all 986 extant gymnosperm species with their ecological characteristics including 291 cycads, 80 gnetophytes, one ginkgophyte and 614 conifers. We define four categories reflecting the level of hydrophobia and hydrophily of all species and their possible adaptation to wetlands and/or aquatic habitats. Eighty‐two percent (805) of the extant species of gymnosperms are clearly hydrophobic, but 18% (180) are classified as hydrophilic. The podocarp Retrophyllum minus is the only obligate inhabitant of aquatic habitats. This contribution classifies gymnosperms into four categories in reference to their physiological and morphological adaptation to a moisture gradient. It relativizes the putative hydrophobia of gymnosperms and provides new perspectives for research on gymnosperms.", "corpus_id": 40198893 }

[ { "doc_id": "6325911", "title": "Physiological and molecular basis of susceptibility and tolerance of rice plants to complete submergence.", "abstract": "Rice plants are much damaged by several days of total submergence. The effect can be a serious problem for rice farmers in the rainfed lowlands of Asia, and runs contrary to a widespread belief amongst plant biologists that rice is highly tolerant of submergence. This article assesses the characteristics of the underwater environment that may damage rice plants, examines various physiological mechanisms of injury, and reviews recent progress achieved using linkage mapping to locate quantitative traits loci (QTL) for tolerance inherited from a submergence-tolerant cultivar FR13A. Progress towards identifying the gene(s) involved through physical mapping of a dominant tolerance locus on chromosome 9 is also summarized. Available physiological evidence points away from responses to oxygen shortage as being inextricably involved in submergence injury. An imbalance between production and consumption of assimilates is seen as being especially harmful, and is exacerbated by strongly accelerated leaf extension and leaf senescence that are ethylene-mediated and largely absent from FR13A and related cultivars. DNA markers for a major QTL for tolerance are shown to be potentially useful in breeding programmes designed to improve submergence tolerance.", "corpus_id": 6325911, "score": 0 }, { "doc_id": "82867104", "title": "A Handbook of the World's Conifers", "abstract": "Foreword Preface The conifers of the world, an introduction The distribution and ecology of conifers The economic importance of conifers The conservation of conifer diversity Synopsis of families and genera Taxonomic treatment of families, with keys to families Taxonomic treatment of genera and species (in alphabetical order), with keys to sections, subsections and species Glossary References Lists of illustrations Index to botanical names of conifers", "corpus_id": 82867104, "score": 1 }, { "doc_id": "87702093", "title": "The botany of mangroves", "abstract": "Preface Acknowledgements Part I. General Account: 1. Ecology 2. Floristics 3. Biogeography 4. Shoot systems 5. Root systems 6. Water relations and salt balance 7. Flowering 8. Seedlings and seeds 9. Utilization and exploitation Part II. Detailed Descriptions by Family References Index.", "corpus_id": 87702093, "score": 0 }, { "doc_id": "128790350", "title": "The Biology of Mangroves and Seagrasses", "abstract": "1. Mangroves and seagrasses 2. Mangroves and their environment 3. Seagrasses and their environment 4. Community structure and dynamics 5. The mangrove community: terrestrial components 6. The mangrove community: marine components 7. Seagrass communities 8. Measuring and modelling 9. Comparisons and connections 10. Biodiversity and biogeography 11. Impacts 12. Global climate change", "corpus_id": 128790350, "score": 0 }, { "doc_id": "83630863", "title": "A comparitive study of the hydrophyte flora from the Alpine Rhine to the Middle Rhine. Application to the conservation of the Upper Rhine aquatic ecosystems", "abstract": "Abstract A typology of the main channel of the river Rhine according to its aquatic bryophyte and vascular hydrophyte assemblages is presented. The aquatic bryophytes are especially abundant in the main channel, having found stable, rocky habitats with variable water levels in the regulated river, and segregate longitudinally along a gradient of water quality. Conversely, the vascular hydrophytes are restricted to side channels with constant discharges and silt deposits, and segregate laterally along a gradient of connectivity with the main river. The hydrophytes have been affected by water eutrophication which became obvious in the 1960s–1970s. The oligotrophic groundwater-fed side-channels disconnected since the river canalization consequently include a relic reference flora. Important hydraulic works are currently in progress in order to protect the areas located downstream from the canalized Rhine from flooding by retaining the river waters in lateral systems during the discharge peaks and to recreate a functional alluvial floodplain by reconnecting the disconnected side-channels to the main river. The floodpulse caused by the suddent input of surface water in the disconnected brooks will probably wash out most of the hydrophytes and it is very likely that the rare species with their low recolonization strategies will disappear in these conditions. It is highly desirable to preserve from flooding the last oligotrophic brooks with their original hydrophyte assemblages. Those brooks which show a tendency to silt up can be re-dynamized by ecological engineering without disturbing the flowing drains of the watertable. In areas (including flowing drains of the watertable) that have already been designated for flood retention, the hydraulic works should allow, as far as possible, the preservation of the flowing oligotrophic streams by only permitting the input of surface water in the silted-up brooks. The disconnected side-channels could then continue their role as refugia from where the main channel, whose water quality has been improving for a decade, could be recolonized by its primary flora.", "corpus_id": 83630863, "score": 0 }, { "doc_id": "26911813", "title": "Fungal biodiversity in aquatic habitats", "abstract": "Fungal biodiversity in freshwater, brackish and marine habitats was estimated based on reports in the literature. The taxonomic groups treated were those with species commonly found on submerged substrates in aquatic habitats: Ascomycetes (exclusive of yeasts), Basidiomycetes, Chytridiomycetes, and the non-fungal Saprolegniales in the Class Oomycetes. Based on presence/absence data for a large number and variety of aquatic habitats, about 3,000 fungal species and 138 saprolegnialean species have been reported from aquatic habitats. The greatest number of taxa comprise the Ascomycetes, including mitosporic taxa, and Chytridiomycetes. Taxa of Basidiomycetes are, for the most part, excluded from aquatic habitats. The greatest biodiversity for all groups occurs in temperate areas, followed by Asian tropical areas. This pattern may be an artifact of the location of most of the sampling effort. The least sampled geographic areas include Africa, Australia, China, South America and boreal and tropical regions worldwide. Some species overlap occurs among terrestrial and freshwater taxa but little species overlap occurs among freshwater and marine taxa. We predict that many species remain to be discovered in aquatic habitats given the few taxonomic specialists studying these fungi, the few substrate types studied intensively, and the vast geographical area not yet sampled.", "corpus_id": 26911813, "score": 0 }, { "doc_id": "83223511", "title": "Cycads of the world", "abstract": "This is a comprehensive reference to the cycads of the world. Part One details their biology and cultivation, and pests and diseases to which they are susceptible. The second section provides concise descriptions of each plant, with information on its habitat and distribution, and horticultural information on seed germination, growing conditions and propagation methods where known. Species entries are accompanied by colour photographs and illustrations. This reference is designed to be of interest to scientists and to general readers interested in the conservation and cultivation of cyclads in public and private gardens.", "corpus_id": 83223511, "score": 1 }, { "doc_id": "83454718", "title": "Conifers of the World: The Complete Reference", "abstract": "Researched for more than three decades, this definitive work provides up-to-date descriptions of all the true conifers of the world, including 545 species of trees and shrubs. Written for accessibility to both horticultural and botanical audiences, it is the first comprehensive update of conifer taxonomy in nearly a century. Noted conifer taxonomist James E. Eckenwalder also discusses the relationships among the groups, practical usages, champion trees, fossil occurrences, and biology. New identification guides for the families and genera are based whenever possible on foliage features and thus should be easier to use than traditional conifer keys, which focus on seasonal, and often microscopic, cone characters. Eckenwalder shares the reasoning behind his taxonomic decisions, many of which are unique to this book, reflecting a comprehensive reevaluation of conifer classification. He also outlines the features sought in cultivars of each genus, particular cultivation concerns, and conifers recommended for cultivation under various conditions and to achieve different effects. Some 3,000 cultivars have been available in recent times, more than five times the total number of conifer species. Several hundred original illustrations include drawings of the seed cones for all genera as well as for representative species. Maps of the natural distribution of each genus allow for easy comparison of ranges. Handsome black-and-white photographs of species in their natural habitats and attractive color photos further enrich the volume. More than 100 images reproduce foliage of many genera as an aid in identification. With its unprecedented attention to detail and extensive bibliography, this major work is an essential reference for botanists, naturalists, and horticulturists.", "corpus_id": 83454718, "score": 0 }, { "doc_id": "128252666", "title": "Conifers Around the World: Conifers of the Temperate Zones and Adjacent Regions", "abstract": "Being a trailblazer at heart, I normally have little use for the plethora of hiking books on the market. But when Michael sent me of copy of Conifer Country, I couldn’t resist reading it. I was a little disappointed that the rest of the biota was left out, because botanical endemism is particularly high in the Klamath Range. Of course, the author had to focus his efforts and, with 39 conifers recorded in the region (even without the Del Norte pine, which is still in question), he had more to work with than in any other temperate mountain range of its size on the planet. The first part of the book covers climate, geology and the tree species. Well over half of the book is dedicated to Klamath conifers and their distribution and his maps are the best yet. I found some mis-statements in the section describing the conifers. For example, in the section for gray pine (Pinus sabiniana) (pages 84-86), the 500 to 2,500 ft. elevation range should be from nearly sea level to 7,000 feet elevation (at Sawtooth Peak, Inyo County), and that the pine is dependent on fire to regenerate is misleading because both birds and rodents are involved. The description of its distribution in Oregon as outlier populations that naturalized from plantings for food or landscaping in recent human history was refuted in a 2009 article in this journal (Kalmiopsis 16:1-14). On page 99, the author states that an underlying band of serpentine that runs east to west from the mountains to the coast north of the Chetco is an edaphic barrier to northward movement of redwoods. These serpentine belts actually run north to south; rather than inhibited by this substrate, coast redwood thrives on weathered serpentine-derived soils. Then on page 113, he comments that “Alaska-cedar trees do not reach significant size in the Siskiyous–I’ve never seen one more than 35’ tall.” I’ve seen Alaska cedars 70 feet tall and nearly 3 feet in diameter on Whiskey Peak in the Oregon Siskiyous. These and a few other errors will be corrected in the second edition, coming soon. The remainder of the book is all about hikes, but not to worry, none of these is anywhere as long as the Pacific Crest Trail or the Desert Trail, which both extend from the Mexican border and to the Canadian border. If you are a teacher, with a three month vacation, you might have enough time to complete the PCT in one season, or you can complete a half dozen of the 29 hikes listed in Conifer Country. The author is a teacher and clearly he has put his time to good use by writing this intriguing book (that is not only for teachers). The important thing to remember is to select hikes that are within your capability and time frame and be prepared to deal with the elements and strenuous climbs. Be sure to take time to smell the conifers and explore the geology and hydrology. When you are fit enough, you may want to do the Iron Man hike a.k.a. the 400-mile Bigfoot Trail mentioned at the end of the book. If you push so long and hard that you think you’ve just seen Bigfoot, it’s time to take a break! Is he really out there? Well, you will just have to take the trail and discover for yourself. This book is well written and very readable, the color photography is superb and just enough black and white photos to draw you into the mountains to see the real colors. Would I recommend that you buy the book, well no, not unless you get off your duff and put it to good use! This guide to the Klamath Mountains can give you an experience of a lifetime. Don’t pass up the opportunity, and be sure to take the book with you (carry it in a zip-lock bag to keep the elements out). –Frank Callahan, Siskiyou Chapter.", "corpus_id": 128252666, "score": 1 }, { "doc_id": "5174713", "title": "Phylogeny of seed plants based on all three genomic compartments: extant gymnosperms are monophyletic and Gnetales' closest relatives are conifers.", "abstract": "Efforts to resolve Darwin's \"abominable mystery\"-the origin of angiosperms-have led to the conclusion that Gnetales and various fossil groups are sister to angiosperms, forming the \"anthophytes.\" Morphological homologies, however, are difficult to interpret, and molecular data have not provided clear resolution of relationships among major groups of seed plants. We introduce two sequence data sets from slowly evolving mitochondrial genes, cox1 and atpA, which unambiguously reject the anthophyte hypothesis, favoring instead a close relationship between Gnetales and conifers. Parsimony- and likelihood-based analyses of plastid rbcL and nuclear 18S rDNA alone and with cox1 and atpA also strongly support a gnetophyte-conifer grouping. Surprisingly, three of four genes (all but nuclear rDNA) and combined three-genome analyses also suggest or strongly support Gnetales as derived conifers, sister to Pinaceae. Analyses with outgroups screened to avoid long branches consistently identify all gymnosperms as a monophyletic sister group to angiosperms. Combined three- and four-gene rooted analyses resolve the branching order for the remaining major groups-cycads separate from other gymnosperms first, followed by Ginkgo and then (Gnetales + Pinaceae) sister to a monophyletic group with all other conifer families. The molecular phylogeny strongly conflicts with current interpretations of seed plant morphology, and implies that many similarities between gnetophytes and angiosperms, such as \"flower-like\" reproductive structures and double fertilization, were independently derived, whereas other characters could emerge as synapomorphies for an expanded conifer group including Gnetales. An initial angiosperm-gymnosperm split implies a long stem lineage preceding the explosive Mesozoic radiation of flowering plants and suggests that angiosperm origins and homologies should be sought among extinct seed plant groups.", "corpus_id": 5174713, "score": 0 }, { "doc_id": "28339517", "title": "Seed plant phylogeny inferred from all three plant genomes: monophyly of extant gymnosperms and origin of Gnetales from conifers.", "abstract": "Phylogenetic relationships among the five groups of extant seed plants are presently quite unclear. For example, morphological studies consistently identify the Gnetales as the extant sister group to angiosperms (the so-called \"anthophyte\" hypothesis), whereas a number of molecular studies recover gymnosperm monophyly, and few agree with the morphology-based placement of Gnetales. To better resolve these and other unsettled issues, we have generated a new molecular data set of mitochondrial small subunit rRNA sequences, and have analyzed these data together with comparable data sets for the nuclear small subunit rRNA gene and the chloroplast rbcL gene. All nuclear analyses strongly ally Gnetales with a monophyletic conifers, whereas all mitochondrial analyses and those chloroplast analyses that take into account saturation of third-codon position transitions actually place Gnetales within conifers, as the sister group to the Pinaceae. Combined analyses of all three genes strongly support this latter relationship, which to our knowledge has never been suggested before. The combined analyses also strongly support monophyly of extant gymnosperms, with cycads identified as the basal-most group of gymnosperms, Ginkgo as the next basal, and all conifers except for Pinaceae as sister to the Gnetales + Pinaceae clade. According to these findings, the Gnetales may be viewed as extremely divergent conifers, and the many morphological similarities between angiosperms and Gnetales (e.g., double fertilization and flower-like reproductive structures) arose independently.", "corpus_id": 28339517, "score": 0 }, { "doc_id": "205834563", "title": "Fast evolution of the retroprocessed mitochondrial rps3 gene in Conifer II and further evidence for the phylogeny of gymnosperms.", "abstract": "The popular view that plant mitochondrial genome evolves slowly in sequence has been recently challenged by the extraordinarily high substitution rates of mtDNA documented mainly from several angiosperm genera, but high substitution rate acceleration accompanied with great length variation has been very rarely reported in plant mitochondrial genes. Here, we studied evolution of the mitochondrial rps3 gene that encodes the ribosomal small subunit protein 3 and found a dramatically high variation in both length and sequence of an exon region of it in Conifer II. A sequence comparison between cDNA and genomic DNA showed that there are no RNA editing sites in the Conifer II rps3 gene. Southern blotting analyses of the total DNA and mtDNA, together with the real-time PCR analysis, showed that rps3 exists as a single mitochondrial locus in gymnosperms. It is very likely that the Conifer II rps3 gene has experienced retroprocessing, i.e., the re-integration of its cDNA into the mitochondrial genome, followed by an evolutionary acceleration due to the intron loss. In addition, the phylogenetic analysis of rps3 supports the sister relationship between conifers and Gnetales. In particular, the monophyly of conifer II is strongly supported by the shared loss of two rps3 introns. Our results also indicate that the mitochondrial gene tree would be affected in topology when the \"edited\" paralogs are analyzed together with their genomic sequences.", "corpus_id": 205834563, "score": 0 }, { "doc_id": "82541322", "title": "A natural history of conifers", "abstract": "Conifers are the most diverse, interesting, beautiful trees in the world, so why is it that our gardens are home to so few species? Part of the reason lies in their economic importance which, by focusing attention on relatively few species, has limited our understanding of one of the most remarkable plant groups on earth. Leading expert Aljos Farjon provides a broader perspective with this compelling narrative that observes conifers from the standpoint of the curious naturalist. It starts with the basic question of what conifers are and continues to explore their evolution, taxonomy, ecology, distribution, human uses, and issues of conservation. As the story unfolds many popular misconceptions are dispelled, such as the notion that all conifers have cones (untrue), and the extraordinary diversity of conifers begins to dawn as Farjon describes the diminutive creeping shrub Microcachrys tetragona, whose strange seed cones resemble raspberries, and the prehistoric-looking Araucaria meulleri. The taxonomic diversity of conifers is huge and Farjon goes on to relate how, over the course of 300 million years, these trees and shrubs have adapted to survive geological upheavals, climatic extremes, and formidable competition from flowering plants. Scarcely less remarkable is his explanation of how conifers, with only 627 species, grew to occupy every continent on earth ranging from the high latitudes to the tropics. This illuminating review will fascinate plant lovers who wish to discover the extraordinary relatives of ordinary garden conifers, natural historians, who will relish seeing conifers reviewed in a broad context, and all who seek to learn more about the early history of life on our planet.", "corpus_id": 82541322, "score": 1 }, { "doc_id": "89233100", "title": "Out of China: distribution history of Ginkgo biloba L.", "abstract": "Gingko biloba L. is one of the most mysterious plant species, which continues to attract the interest of scientists and the public since many centuries. However, our knowledge of its evolutionary history and worldwide distribution is limited. Herein we are combining evidence from a previous phylogeographic analysis of Ginkgo biloba's range in China using cpDNA and AFLPs with new data from old, early introduced in Korea, Japan, Europe and Northern America with the aim to unravel the early human-mediated introduction history of this species. We provide evidence that Ginkgo biloba reached Japan via different routes from China during the last two millennia most likely by human-mediated dispersal. Based on AFLP data, all individuals originally introduced to Europe and North America (e.g., by Kaempfer in Europe in the 1720s) are genetically similar to one ofthe Korean accessions raising, the question ofthe validity of the origin of Kaempfer's original material, which was said to be brought from Japan to Europe in the early 18th century. Multiple introduction into Korea and Japan in concert with an out-crossing mating system has maintained high levels of gene diversity; this is also true for the European and North American trees. In addition, the trees outside the original Chinese Pleistocene refugia, due to their relatively small gene-pool, have a reduced number of AFLP fragments and no exclusive alleles.", "corpus_id": 89233100, "score": 0 }, { "doc_id": "9138505", "title": "The complete plastid genome sequence of Welwitschia mirabilis: an unusually compact plastome with accelerated divergence rates", "abstract": "BackgroundWelwitschia mirabilis is the only extant member of the family Welwitschiaceae, one of three lineages of gnetophytes, an enigmatic group of gymnosperms variously allied with flowering plants or conifers. Limited sequence data and rapid divergence rates have precluded consensus on the evolutionary placement of gnetophytes based on molecular characters. Here we report on the first complete gnetophyte chloroplast genome sequence, from Welwitschia mirabilis, as well as analyses on divergence rates of protein-coding genes, comparisons of gene content and order, and phylogenetic implications.ResultsThe chloroplast genome of Welwitschia mirabilis [GenBank: EU342371] is comprised of 119,726 base pairs and exhibits large and small single copy regions and two copies of the large inverted repeat (IR). Only 101 unique gene species are encoded. The Welwitschia plastome is the most compact photosynthetic land plant plastome sequenced to date; 66% of the sequence codes for product. The genome also exhibits a slightly expanded IR, a minimum of 9 inversions that modify gene order, and 19 genes that are lost or present as pseudogenes. Phylogenetic analyses, including one representative of each extant seed plant lineage and based on 57 concatenated protein-coding sequences, place Welwitschia at the base of all seed plants (distance, maximum parsimony) or as the sister to Pinus (the only conifer representative) in a monophyletic gymnosperm clade (maximum likelihood, bayesian). Relative rate tests on these gene sequences show the Welwitschia sequences to be evolving at faster rates than other seed plants. For these genes individually, a comparison of average pairwise distances indicates that relative divergence in Welwitschia ranges from amounts about equal to other seed plants to amounts almost three times greater than the average for non-gnetophyte seed plants.ConclusionAlthough the basic organization of the Welwitschia plastome is typical, its compactness, gene content and high nucleotide divergence rates are atypical. The current lack of additional conifer plastome sequences precludes any discrimination between the gnetifer and gnepine hypotheses of seed plant relationships. However, both phylogenetic analyses and shared genome features identified here are consistent with either of the hypotheses that link gnetophytes with conifers, but are inconsistent with the anthophyte hypothesis.", "corpus_id": 9138505, "score": 0 }, { "doc_id": "1692725", "title": "The origin and diversification of angiosperms.", "abstract": "The angiosperms, one of five groups of extant seed plants, are the largest group of land plants. Despite their relatively recent origin, this clade is extremely diverse morphologically and ecologically. However, angiosperms are clearly united by several synapomorphies. During the past 10 years, higher-level relationships of the angiosperms have been resolved. For example, most analyses are consistent in identifying Amborella, Nymphaeaceae, and Austrobaileyales as the basalmost branches of the angiosperm tree. Other basal lineages include Chloranthaceae, magnoliids, and monocots. Approximately three quarters of all angiosperm species belong to the eudicot clade, which is strongly supported by molecular data but united morphologically by a single synapomorphy-triaperturate pollen. Major clades of eudicots include Ranunculales, which are sister to all other eudicots, and a clade of core eudicots, the largest members of which are Saxifragales, Caryophyllales, rosids, and asterids. Despite rapid progress in resolving angiosperm relationships, several significant problems remain: (1) relationships among the monocots, Chloranthaceae, magnoliids, and eudicots, (2) branching order among basal eudicots, (3) relationships among the major clades of core eudicots, (4) relationships within rosids, (5) relationships of the many lineages of parasitic plants, and (6) integration of fossils with extant taxa into a comprehensive tree of angiosperm phylogeny.", "corpus_id": 1692725, "score": 0 }, { "doc_id": "83141441", "title": "Cypress knees: an enduring enigma.", "abstract": "less, throughout the nineteenth century and continuing to the present, botanists have put forth hypotheses about the function of these peculiar formations, hypotheses that have mcluded aeration of the root system, vegetative reproduction, mechanical support, nutrient accumulation, and carbohydrate storage. The aeration theory has been the most popular and, indeed, is presented without question in some botany texts, but in fact, no explanation has been generally accepted.’ 1", "corpus_id": 83141441, "score": 0 }, { "doc_id": "85324190", "title": "Why Are There So Many Kinds of Flowering Plants", "abstract": "The world is amazingly rich in the numbers of living species of plants and animals; understanding this diversity and explaining its origin continues to be a central issue in evolutionary biology. Whether working in the dry, but speciesrich, Sonoran Desert or in the epiphyteladen cloud forests in Central America, one is confronted by the same general question: What factors have caused such diverse communities to evolve? In a stimulating paper on animal diversity, Hutchinson (1959) pointed out that the species richness of the contemporary biota on land far exceeds species numbers in the oceans. He suggested that flowering plants have played a major role in the evolution of terrestrial diversity. There is no compelling evidence for the existence of angiosperms before the Cretaceous, but recently scientists have acquired a much more detailed understanding of their differentiation in the Middle Cretaceous (Dilcher 1979, Doyle 1977, Doyle and Hickey 1976). Since then, the flowering plants have come to dominate a great majority of the world's terrestrial ecosystems.", "corpus_id": 85324190, "score": 0 }, { "doc_id": "84891886", "title": "Why Are There So Many Species of Flowering Plants", "abstract": "This essay is in part a reply to the companion one by Burger and in part supplementary to it. Since the topic is to a large extent one of taxonomy or systematicsand reflects also the evolutionary history of a class of organisms over 120 million years-data from systematics are essential, and paleontological data must be considered when they are available. (Accepted for publication 30 April 1981)", "corpus_id": 84891886, "score": 0 }, { "doc_id": "84304909", "title": "The tortoise and the hare: ecology of angiosperm dominance and gymnosperm persistence", "abstract": "Gymnosperms, and conifers in particular, are sometimes very productive trees yet angiosperms dominate most temperate and tropical vegetation. Current explanations for angiosperm success emphasize the advantages of insect pollination and seed dispersal by animals for the colonization of isolated habitats. Differences between gymnosperm and angiosperm reproductive and vegetative growth rates have been largely ignored. Gymnosperms are all woody, perennial and usually have long reproductive cycles. Their leaves are not as fully vascularized as those of angiosperms and are more stereotyped in shape and size. Gymnosperm tracheids are generally more resistant to solute flow than angiosperm vessels. A consequence of the less efficient transport system is that maximum growth rates of gymnosperms are lower than maximum growth rates of angiosperms in well lit, well watered habitats. Gymnosperm seedlings may be particularly uncompetitive since their growth depends on a single cohort of relatively inefficient leaves. Later, some gymnosperms attain a higher productivity than co-occurring angiosperm trees by accumulating several cohorts of leaves with a higher total leaf area. \n \n \n \nThese functional constraints on gymnosperm growth rates suggest that gymnosperms will be restricted to areas where growth of angiosperm competitors is reduced, for example, by cold or nutrient shortages. Biogeographic evidence supports this prediction since conifers are largely confined to high latitudes and elevations or nutrient-poor soils. Experimental studies show that competition in the regeneration niche (between conifer seedlings and angiosperm herbs and shrubs) is common and significantly affects conifer growth and survival, Fast-growing angiosperms, especially herbs and shrubs, may also change the frequency of disturbance regimes thereby excluding slower-growing gymnosperms. \n \n \n \nShade-tolerant and early successional conifers share similar characteristics of slow initial growth and low plasticity to a change in resources. Shade-tolerant gymnosperms would be expected to occur only where forest openings are small or otherwise unsuitable for rapid filling by fast-growing angiosperm trees, lianas or shrubs. The limited evidence available suggests that shade-tolerant conifers are confined to forests with small gap sizes where large disturbances are very rare. \n \n \n \nThe regeneration hypothesis for gymnosperm exclusion by angiosperms is consistent with several aspects of the fossil record such as the early disappearance of gymnosperms from early successional environments where competition with angiosperms would have been most severe. However there are unresolved difficulties in interpreting process from paleoecological pattern which prevent the testing of alternative hypotheses.", "corpus_id": 84304909, "score": 1 }, { "doc_id": "82459053", "title": "Conifer Reproductive Biology", "abstract": "Prologue.- Glossary.- Section I. Conifer Reproductive Biology Overview. 1. Introducing Conifers.- 2. The Diplohaplontic Life Cycle.- Section II. Consequences of Heterospory. 3. Separate Female and Male Meioses.- 4. The Female Gametophyte Inside in the Ovule.- 5. The Male Gametophyte Enclosed in a Pollen Wall.- 6. Synchrony: Pollination and Fertilization.- 7. Syngamy, Embryo Development and Seed Dispersal.-Section III. Mating System Dynamics: Form and Chance. 8. The Dynamic Wind-Pollinated Mating System.- 9. The Embryo Lethal System.- Index.-", "corpus_id": 82459053, "score": 1 }, { "doc_id": "19753649", "title": "Threatened plants of New Caledonia: Is the system of protected areas adequate?", "abstract": "With 76% of its 3063 native species of flora endemic, the New Caledonia biodiversity hotspot has long been recognized as having a high potential for conservation. Under the new IUCN Red List categories, 25% of the endemic plants are at risk (Conservation Dependent, Vulnerable, Endangered, Critically Endangered), and five species are already extinct. A review of their distribution demonstrates that 83% of the threatened species do not occur at all in a conservation area, and only 11% have their conservation status improved by a protected area. The protected area network is geographically and floristically very unbalanced, with the rainforest and high altitude maquis in the south concentrating most of the conservation effort. Conversely, the middle and northern segments of the island, as well as all of the dry west coast, are left without adequate conservation area. Two vegetation types, the sclerophyll forest and the unique low/middle altitude maquis, are virtually totally unprotected. We conclude that the current network of protected areas needs to be considerably expanded, in terms of both geographical/floristic subregions within New Caledonia and vegetation type covered. With only 54% of the conservation area covered by strict mining restrictions, existing reserves need to have their conservation efficiency improved by a more vigorous enforcement of their status, and by extending mining bans to all of them.", "corpus_id": 19753649, "score": 0 }, { "doc_id": "7487407", "title": "Size and function in conifer tracheids and angiosperm vessels.", "abstract": "The wide size range of conifer tracheids and angiosperm vessels has important consequences for function. In both conduit types, bigger is better for conducting efficiency. The gain in efficiency with size is maximized by the control of conduit shape, which balances end-wall and lumen resistances. Although vessels are an order of magnitude longer than tracheids of the same diameter, they are not necessarily more efficient because they lack the low end-wall resistance of tracheids with torus-margo pits. Instead, vessels gain conducting efficiency over tracheids by achieving wider maximum diameters. End-walls contributed 56-64% to total xylem resistance in both conduit types, indicating that length limits conducting efficiency. Tracheid dimensions may be more limited by unicellularity and the need to supply strength to homoxylous wood than by the need to protect against cavitation. In contrast, the greater size of the multicellular vessel is facilitated by fibers that strengthen heteroxylous wood. Vessel dimensions may be most limited by the need to restrict intervessel pitting and cavitation by air-seeding. Stressful habitats that promote narrow vessels should favor coexistence of conifers and angiosperms. The evolution of vessels in angiosperm wood may have required early angiosperms to survive a phase of mechanic and hydraulic instability.", "corpus_id": 7487407, "score": 0 }, { "doc_id": "51841986", "title": "An overview of plant responses to soil waterlogging", "abstract": "Under natural conditions, plants are frequently exposed to transient or permanent soil waterlogging. Flooding drastically influences the soil physico-chemical properties, most notably soil redox potential, pH and O2 level. Thus, conditions of hypoxia or anoxia are commonly encountered by plant root systems. These O2 restrictive conditions dramatically affect plant growth, development and survival. One of the best characterised plant responses to soil waterlogging is the metabolic switch from aerobic respiration to anaerobic fermentation. In fact, most proteins induced during hypoxic conditions are enzymes involved in the establishment of this fermentative pathway. Because the plant cells need to keep a continuous ATP supply, the use of alternative electron acceptors and/or alternative pathways may be key elements of survival under soil waterlogging. The plant response may also include a reduction in stomatal conductance and photosynthesis, as well as root hydraulic conductivity. These physiological modifications may in turn affect carbohydrate reserves and translocation. In fact, efficient use of carbohydrates may discriminate between tolerant and intolerant species. Other observed adaptations include morphological changes which comprise the formation of hypertrophied lenticels, the initiation of adventitious roots and/or the development of aerenchyma. Our knowledge of the basic adaptive mechanisms of plants to soil waterlogging has benefited from large scale genomic and proteomic approaches, however, the diversity of the adaptive responses involved underlines the difficulty when studying this stress. This update reviews our current comprehension of the metabolic, physiological and morphological responses and adaptations of plants to soil waterlogging.", "corpus_id": 51841986, "score": 0 }, { "doc_id": "85920598", "title": "Waterlogging stress in plants: A review", "abstract": "Waterlogging is the major obstacle for sustainable agriculture. Plants subjected to waterlogging suffer from substantial yield losses. Under natural environmental conditions, plants often get exposed to transient or permanent waterlogging. Flooding induces a number of alterations in important soil physiochemical properties like soil pH, redox potential and oxygen level. Thus, the plants growing on the waterlogged soil face the stressful environment in terms of hypoxia (deficiency of O2) or anoxia (absence of O2). These oxygen deficient conditions substantially hamper plant growth, development and survival. Plants under O2-restrictive environment exhibit metabolic switch from aerobic respiration to anaerobic fermentation. It is evident from the available literature that most of the genes expressed under flooding stress are potentially involved in the synthesis of enzymes known to play active role in the establishment of this fermentative pathway. Plants undergo this metabolic change in order to get continuous supply of Adenosine triphosphate (ATP). Under waterlogged conditions, plants exhibit several responses including hampered stomata conductance, net CO2-assimilation rate and root hydraulic conductivity. Furthermore, plants grown under waterlogged conditions often face the oxidative damage induced by the generation of reactive oxygen species. These reactive oxygen species in turn affects the integrity of membranes and induce damage to the efficiency of photosystem II, thereby, causing considerable decrease in net photosynthetic rates. Moreover, these perturbations in physiological mechanisms may affect the carbohydrate reserves and translocations. In fact, waterlogging tolerant and sensitive plant species could be discriminated on the basis of their efficient carbohydrate utilization. Waterlogging is also known to induce adverse effects on several physiological and biochemical processes of plants by creating deficiency of essential nutrients like nitrogen, magnesium, potassium, calcium. Apart from these waterlogging-induced alterations in physiological mechanisms, plants growing under flooded conditions also exhibit certain morphological changes entailing the formation of adventitious roots, initiation of hypertrophied lenticels and/or establishment of aerenchyma. Therefore, the aim of this review is to highlight the major morphological, physiological and biochemical adaptations of plants to tolerate the flooding stress. \n \n Key words: Hypoxia, anoxia, fermentation, Adenosine triphosphate (ATP), reactive oxygen species (ROS), antioxidants.", "corpus_id": 85920598, "score": 0 }, { "doc_id": "84323924", "title": "Effect of flooding on growth, stem anatomy, and ethylene production of Pinushalepensis seedlings", "abstract": "Flooding of soil for 43 days greatly altered growth and stem anatomy and increased ethylene production by stems of 10-month-old Pinushalepensis seedlings. Flooding reduced the dry weight increment of seedlings primarily as a result of decay of roots and, to a lesser extent, inhibition of growth of roots and needles. Flooding did not influence height growth of seedlings but increased stem diameter, largely because of an increase in bark thickness at all stem heights and stem hypertrophy associated with proliferation of phloem parenchyma cells and an increased amount of intercellular space in the phloem. The effects of flooding on xylem increment varied appreciably with stem height. In the submerged portion of the stem, flooding greatly reduced the number of tracheids laid down per radial file. Flooding also slightly reduced the number of tracheids produced in the portion of the stem just above the water level. In the upper stem, however, flooding had little effect on xylem increment and on tracheid product...", "corpus_id": 84323924, "score": 0 }, { "doc_id": "15314720", "title": "Evolution of Water Transport and Xylem Structure", "abstract": "Land plants need water to replace the evaporation that occurs while atmospheric CO2 is diffusing into photosynthetic tissue. The water‐for‐carbon exchange rate is poor, and evolutionary history indicates a progression of innovations for cheap water transport—beginning in order with capillary suction at cell walls, stomatal regulation, hydroids, tracheids, secondary xylem, endodermis, and vessels. The radiation of plants in the Silurian and Devonian occurred when the need for water was at an all‐time low because of high CO2 concentration. Transport improvements appeared as water demand increased and CO2 dropped to current values in the Carboniferous and Permian. Stomatal regulation and high‐conductivity conduits permitted larger plants and a transition from poikilohydric to homoiohydric water relations. The evolution of conduits from hydroids through tracheids to vessels reflects the need to balance resistance to implosion and cavitation versus maximum hydraulic conductance and minimum conduit investment. Localization of rigidifying lignin away from the lumen surface and porous wall regions during tracheid evolution, and the origin of pits, acted to maintain wall strength and permeability while minimizing cavitation. Vessels mark the pinnacle of efficiency, making vines and dense, stiff woods possible without sacrificing conductivity or cavitation resistance. However, vessels make cavitation‐resistant wood more expensive and may compromise refilling efficiency versus tracheids. Vascular networks maximize hydraulic conductivity and protection from cavitation at minimum investment by following Murray’s law and localizing resistances to the periphery. A future challenge is to quantify the significance of xylem structure in terms of the carbon cost of transpiration and the net carbon profit via gas exchange.", "corpus_id": 15314720, "score": 0 }, { "doc_id": "83522872", "title": "THE CONCEPT OF A HYDROPHYTE FOR WETLAND IDENTIFICATION", "abstract": "deepwater aquatic systems and terrestrial systems. Although often found along rivers, lakes, ponds, and estuaries, wetlands also exist on gentle slopes or in isolated depressions surrounded by uplands. Wetlands can be considered to occur along a natural soil-moisture gradient between permanently flooded deepwater areas and dryland (Figure 1). Wetland hydrologic conditions, therefore, range from permanent inundation by shallow water or permanent soil saturation to periodic inundation or soil saturation.", "corpus_id": 83522872, "score": 0 }, { "doc_id": "55816391", "title": "Morphology, anatomy, and upland ecology of large cordaitalean trees from the Middle Pennsylvanian of Newfoundland", "abstract": "Abstract We describe the morphology and anatomy of large cordaitalean trees, preserved in Pennsylvanian (Bolsovian) alluvial deposits in southwest Newfoundland. Remains include more than one hundred calcite-permineralized stumps, trunks, and branches, including the largest cordaitalean trunk ever discovered, as well as common adpressed leaves. Reproductive organs are not preserved. We propose a sterile reconstruction of this tree based on directly attached organs and anatomical similarities between isolated, but facies-associated, organs. At ≤ 48.5 m high, mature cordaitaleans were the tallest trees in the Pennsylvanian tropical zone, and consisted of a straight, unbranched trunk topped by a dark, shading canopy, similar in gross morphology to extant araucarian conifers. A comprehensive review of the taphonomic occurrences of these large cordaitalean remains suggests that they grew in alluvial fan and extrabasinal terrains across Euramerica, and represent the earliest widespread upland forests.", "corpus_id": 55816391, "score": 0 }, { "doc_id": "128614691", "title": "Cordaiteans in paleotropical wetlands: An ecological re-evaluation", "abstract": "Abstract Cordaiteans in cordaite-dominated permineralized peat from Pennsylvanian coals in Iowa have been reconstructed as mangroves using root anatomy, peat taphonomy, and geochemical data. Macrofloral, palynofloral, and conodont biostratigraphy indicate that these peats come from the latest Atokan Blackoak coal and earliest Desmoinesian Cliffland coal (mid-Moscovian), both in the Kalo Formation. Thus, their depositional setting can be used to evaluate the mangrove hypothesis. In Recent mires, thick mangrove peats have accumulated in tropical to subtropical carbonate systems; in contrast, thick tropical freshwater peats have accumulated in siliclastic systems. Kalo Formation coals, which we interpret as freshwater deposits, formed in siliciclastic depositional settings, similar to those of modern tropical freshwater peat, and to other Pennsylvanian coals in North America interpreted as freshwater deposits. In the late Atokan and earliest Desmoinesian (mid-Moscovian), cordaiteans and tree ferns predominated in the Western Interior and Illinois Basins; lycopsids and cordaiteans predominated in the Appalachian and Donets Basins. The scarcity of lycopsid-only mires in North America during the late Atokan–earliest Desmoinesian (mid-Moscovian) suggests drier climates than during the mid-to-late Desmoinesian (late Moscovian). Rather than indicating mangrove swamps, cordaite-dominated peat may indicate climates with a ‘low-rain’ season. Although most plants in cordaite-dominated peat probably grew in freshwater, coastal mires in climate zones with seasons of ‘low-rain’ may harbor mangrove taxa. The Changuinola Swamp of Panama, a modern peat-accumulating wetland that has a ‘low-rain’ season, is a possible analog of ancient cordaite-dominated mires. In Changuinola, most plants require freshwater; however mangroves, sustained by salt-water influx into the swamp, grow along the seaward edge and along blackwater creeks. The ‘low-rain’ season hypothesis has implications for understanding rainfall amount and continuity during Pennsylvanian cyclothem deposition. The floral succession in diverse cordaite coals, from cordaiteans to tree ferns to lycopsids, suggests increasingly wet climate during coal accumulation. The position of these coals immediately above the sequence boundary suggests humid climate during early glacial melting for these cyclothems.", "corpus_id": 128614691, "score": 0 } ]

{ "doc_id": "14122823", "title": "Acquisition and loss of desiccation tolerance in seeds: from experimental model to biological relevance", "abstract": "AbstractMain conclusionBesides being an important model to study desiccation tolerance, the induction of desiccation tolerance in germinated seeds may also play an ecological role in seedling establishment.\n Desiccation tolerance (DT) is the ability of certain organisms to survive extreme water losses without accumulation of lethal damage. This was a key feature in the conquering of dry land and is currently found in all taxa including bacteria, fungi, roundworms and plants. Not surprisingly, studies in various fields have been performed to unravel this intriguing phenomenon. In flowering plants, DT is rare in whole plants (vegetative tissues), yet is common in seeds. In this review, we present our current understanding of the evolution of DT in plants. We focus on the acquisition of DT in seeds and the subsequent loss during and after germination by highlighting and comparing research in two model plants Medicago truncatula and Arabidopsis thaliana. Finally, we discuss the ability of seeds to re-establish DT during post-germination, the possible ecological meaning of this phenomenon, and the hypothesis that DT, in combination with dormancy, optimizes seedling establishment.", "corpus_id": 14122823 }

[ { "doc_id": "38268360", "title": "The Leeuwenhoek Lecture - The problem of anabiosis or latent life: history and current concept", "abstract": "The eight previous Leeuwenhoek Lectures covered a great variety of problems is bacteriology and virology, and each of the lecturers paid an enthusiastic tribute Antony van Leeuwenhoek as the founder of microbiology. When the Council honoured me by their invitation to deliver the ninth Leeuwen hoek Lecture I thought that it would be appropriate to devote it to the problem of anabiosis or latent life.", "corpus_id": 38268360, "score": 0 }, { "doc_id": "86520265", "title": "Desiccation tolerance: From genomics to the field", "abstract": "Abstract Desiccation tolerance is defined as the ability to survive the removal of all, or almost all the cellular water without irreversible damage. It confers to dried organisms the ability to survive extreme conditions of the environment and to stay alive in a suspended animation for long periods of time. The biotechnological potential of anhydrous biology has been recognized for more than 60 years. With the fast development of “omics” technologies, it is now possible to better appreciate the biotechnological promises that can be made from the understanding of desiccation tolerance. This review will discuss the impact of post-genomics tools on identifying genes or gene products, and will give a comprehensive overview of the agronomical and biotechnological applications. We propose the term desiccomics to define the approach consisting of combining “omics” approaches to address the specific issues associated with the dry state.", "corpus_id": 86520265, "score": 1 }, { "doc_id": "25917231", "title": "Desiccation Tolerance of Prokaryotes: Application of Principles to Human Cells1", "abstract": "Abstract The loss of water from cells is a stress that was likely imposed very early in evolution. An understanding of the sensitivity or tolerance of cells to depletion of intracellular water is relevant to the study of quiescence, longevity and aging, because one consequence of air-drying is full metabolic arrest, sometimes for extended periods. When considering the adaptation of cells to physiological extremes of pH, temperature or pressure, it is generally assumed that evolution is driven toward optimum function rather than maximum stability. However, adaptation to desiccation has the singular and crucial distinction that dried cells do not grow, and the time the cell is dried may represent the greater part of the life (the time the cell remains viable) of that cell and its component macromolecules. Is a consideration of “function” relevant in the context of desiccated cells? The response of prokaryotic cells to desiccation, and the mechanisms they employ to tolerate this stress at the level of the cell, genome and proteome are considered. Fundamental principles were then implemented in the design of strategies to achieve air-dry stabilization of sensitive eukaryotic (human) cells. The responses of the transcriptomes and proteomes of prokaryotic cells and eukaryotic cells (yeast and human) to drying in air are compared and contrasted to achieve an evolutionary context. The concept of the “desiccome” is developed to question whether there is common set of structural, physiological and molecular mechanisms that constitute desiccation tolerance.", "corpus_id": 25917231, "score": 0 }, { "doc_id": "8368960", "title": "Desiccation Tolerance in Bryophytes: A Reflection of the Primitive Strategy for Plant Survival in Dehydrating Habitats?1", "abstract": "Abstract Bryophytes are a non-monophyletic group of three major lineages (liverworts, hornworts, and mosses) that descend from the earliest branching events in the phylogeny of land plants. We postulate that desiccation tolerance is a primitive trait, thus mechanisms by which the first land plants achieved tolerance may be reflected in how extant desiccation-tolerant bryophytes survive drying. Evidence is consistent with extant bryophytes employing a tolerance strategy of constitutive cellular protection coupled with induction of a recovery/repair mechanism upon rehydration. Cellular structures appear intact in the desiccated state but are disrupted by rapid uptake of water upon rehydration, but cellular integrity is rapidly regained. The photosynthetic machinery appears to be protected such that photosynthetic activity recovers quickly. Gene expression responds following rehydration and not during drying. Gene expression is translationally controlled and results in the synthesis of a number of proteins, collectively called rehydrins. Some prominent rehydrins are similar to Late Embryogenesis Abundant (LEA) proteins, classically ascribed a protection function during desiccation. The role of LEA proteins in a rehydrating system is unknown but data indicates a function in stabilization and reconstitution of membranes. Phylogenetic studies using a Tortula ruralis LEA-like rehydrin led to a re-examination of the evolution of desiccation tolerance. A new phylogenetic analysis suggests that: (i) the basic mechanisms of tolerance seen in modern day bryophytes have changed little from the earliest manifestations of desiccation tolerance in land plants, and (ii) vegetative desiccation tolerance in the early land plants may have evolved from a mechanism present first in spores.", "corpus_id": 8368960, "score": 1 }, { "doc_id": "6779706", "title": "The Limits and Frontiers of Desiccation-Tolerant Life1", "abstract": "Abstract Drying to equilibrium with the air is lethal to most species of animals and plants, making drought (i.e., low external water potential) a central problem for terrestrial life and a major cause of agronomic failure and human famine. Surprisingly, a wide taxonomic variety of animals, microbes, and plants do tolerate complete desiccation, defined as water content below 0.1 g H2O g−1 dry mass. Species in five phyla of animals and four divisions of plants contain desiccation-tolerant adults, juveniles, seeds, or spores. There seem to be few inherent limits on desiccation tolerance, since tolerant organisms can survive extremely intense and prolonged desiccation. There seems to be little phylogenetic limitation of tolerance in plants but may be more in animals. Physical constraints may restrict tolerance of animals without rigid skeletons and to plants shorter than 3 m. Physiological constraints on tolerance in plants may include control by hormones with multiple effects that could link tolerance to slow growth. Tolerance tends to be lower in organisms from wetter habitats, and there may be selection against tolerance when water availability is high. Our current knowledge of limits to tolerance suggests that they pose few obstacles to engineering tolerance in prokaryotes and in isolated cells and tissues, and there has already been much success on this scientific frontier of desiccation tolerance. However, physical and physiological constraints and perhaps other limits may explain the lack of success in extending tolerance to whole, desiccation-sensitive, multicellular animals and plants. Deeper understanding of the limits to desiccation tolerance in living things may be needed to cross this next frontier.", "corpus_id": 6779706, "score": 0 }, { "doc_id": "7588524", "title": "Programming desiccation-tolerance: from plants to seeds to resurrection plants.", "abstract": "Desiccation-tolerance (DT) evolved as the key solution to survival on land by the early algal ancestors of terrestrial plants. This 'first' DT involved utilizing rapidly mobilisable repair mechanisms and is still found today in mosses, such as Tortula ruralis, and ferns, such as Mohria caffrorum. The first seed plants lost vegetative DT while investing their seeds with tolerance mechanisms improving their survival in unfavourable environments. The mechanisms of DT in seeds are strongly connected to their developmentally regulated maturation programs. We propose that angiosperm resurrection plants acquired tolerance by re-activating their innate DT mechanisms in their vegetative tissues. Here we review the current hypotheses regarding the genetic evidence for the evolution of DT in resurrection plants. We also present strong evidence showing the activation of seed specific genetic elements in the vegetative tissues of resurrection plants.", "corpus_id": 7588524, "score": 1 }, { "doc_id": "15168972", "title": "Molecular mechanisms of desiccation tolerance in resurrection plants", "abstract": "Resurrection plants are a small but diverse group of land plants characterized by their tolerance to extreme drought or desiccation. They have the unique ability to survive months to years without water, lose most of the free water in their vegetative tissues, fall into anabiosis, and, upon rewatering, quickly regain normal activity. Thus, they are fundamentally different from other drought-surviving plants such as succulents or ephemerals, which cope with drought by maintaining higher steady state water potential or via a short life cycle, respectively. This review describes the unique physiological and molecular adaptations of resurrection plants enabling them to withstand long periods of desiccation. The recent transcriptome analysis of Craterostigma plantagineum and Haberlea rhodopensis under drought, desiccation, and subsequent rehydration revealed common genetic pathways with other desiccation-tolerant species as well as unique genes that might contribute to the outstanding desiccation tolerance of the two resurrection species. While some of the molecular responses appear to be common for both drought stress and desiccation, resurrection plants also possess genes that are highly induced or repressed during desiccation with no apparent sequence homologies to genes of other species. Thus, resurrection plants are potential sources for gene discovery. Further proteome and metabolome analyses of the resurrection plants contributed to a better understanding of molecular mechanisms that are involved in surviving severe water loss. Understanding the cellular mechanisms of desiccation tolerance in this unique group of plants may enable future molecular improvement of drought tolerance in crop plants.", "corpus_id": 15168972, "score": 1 }, { "doc_id": "2917826", "title": "Constraints of tolerance: why are desiccation-tolerant organisms so small or rare?", "abstract": "SUMMARY Drying to equilibrium with the air kills nearly all animals and flowering plants, including livestock and crops. This makes drought a key ecological problem for terrestrial life and a major cause of human famine. However, the ability to tolerate complete desiccation is widespread in organisms that are either <5 mm long or found mainly where desiccation-sensitive organisms are scarce. This suggests that there is a trade-off between desiccation tolerance and growth. Recent molecular and biochemical research shows that organisms tolerate desiccation through a set of mechanisms, including sugars that replace water and form glasses, proteins that stabilize macromolecules and membranes, and anti-oxidants that counter damage by reactive oxygen species. These protections are often induced by drying, and some of the genes involved may be homologous in microbes, plants and animals. Understanding how mechanisms of desiccation tolerance may constrain growth might show how to undo the constraint in some economically important macroorganisms and elucidate the much-studied but elusive relationship between tolerance of stress and productivity.", "corpus_id": 2917826, "score": 1 }, { "doc_id": "556207", "title": "XVSAP1 from Xerophyta viscosa improves osmotic-, salinity- and high-temperature-stress tolerance in Arabidopsis.", "abstract": "XVSAP1, a gene isolated from a dehydrated Xerophyta viscosa cDNA library, was transformed into Arabidopsis thaliana by Ti plasmid-mediated transformation under the control of a cauliflower mosaic virus 35S promoter, a nos terminator and bar gene selection. Expression of XVSAP1 in Arabidopsis led to constitutive accumulation of the corresponding protein in the leaves. Transgenic Arabidopsis grown in tissue culture maintained higher growth rates during osmotic, high-salinity and high temperature stress, respectively. Non-transgenic plants had shorter roots, leaf expansion was inhibited and leaves were more chlorotic than those of the transgenic plants. This study demonstrates that XVSAP1 has a significant impact on dehydration, salinity and high-temperature stress tolerance in Arabidopsis.", "corpus_id": 556207, "score": 0 }, { "doc_id": "10530693", "title": "The Xerophyta viscosa Aldose Reductase (ALDRXV4) Confers Enhanced Drought and Salinity Tolerance to Transgenic Tobacco Plants by Scavenging Methylglyoxal and Reducing the Membrane Damage", "abstract": "We report the efficacy of an aldose reductase (ALDRXV4) enzyme from Xerophyta viscosa Baker in enhancing the prospects of plant’s survival under abiotic stress. Transgenic tobacco plants overexpressing ALDRXV4 cDNA showed alleviation of NaCl and mannitol-induced abiotic stress. The transgenic plants survived longer periods of water deficiency and salinity stress and exhibited improved recovery after rehydration as compared to the wild type plants. The increased synthesis of aldose reductase in transgenic plants correlated with reduced methylglyoxal and malondialdehyde accumulation and an elevated level of sorbitol under stress conditions. In addition, the transgenic lines showed better photosynthetic efficiency, less electrolyte damage, greater water retention, higher proline accumulation, and favorable ionic balance under stress conditions. Together, these findings suggest the potential of engineering aldose reductase levels for better performance of crop plants growing under drought and salt stress conditions.", "corpus_id": 10530693, "score": 0 }, { "doc_id": "23530876", "title": "Towards storage of cells and gametes in dry form.", "abstract": "We review published data on cell/gamete lyophilization. Most studies have utilized the same established protocols for cryopreservation (storage in liquid nitrogen) as for cell lyophilization (dehydration of frozen samples by water sublimation). Surveying natural lyoprotectants, we suggest trehalose and late embryogenesis abundant (LEA) proteins as ideal candidates for the reversible desiccation of mammalian cells/gametes. We find that despite the numerous water subtraction techniques, scientists have relied almost exclusively on lyophilization. There is thus room for improvement in both medium formulation and water subtraction strategies for dry cell/gamete storage. We believe the development of dry processing protocols for use in biobanks of cells/gametes, at reduced cost and with minimal carbon footprint, is within our grasp.", "corpus_id": 23530876, "score": 0 }, { "doc_id": "10116024", "title": "Loading red blood cells with trehalose: a step towards biostabilization.", "abstract": "A method for freeze-drying red blood cells (RBCs) while maintaining a high degree of viability has important implications in blood transfusion and clinical medicine. The disaccharide trehalose, found in animals capable of surviving dehydration can aid in this process. As a first step toward RBC preservation, we present a method for loading RBCs with trehalose. The method is based on the thermal properties of the RBC plasma membranes and provides efficient uptake of the sugar at 37 degrees C in a time span of 7 h. The data show that RBCs can be loaded with trehalose from the extracellular medium through a combination of osmotic imbalance and the phospholipid phase transition, resulting in intracellular trehalose concentrations of about 40 mM. During the loading period, the levels of ATP and 2,3-DPG are maintained close to the levels of fresh RBCs. Increasing the membrane fluidity through the use of a benzyl alcohol results in a higher concentration of intracellular trehalose, suggesting the importance of the membrane physical state for the uptake of the sugar. Osmotic fragility data show that trehalose exerts osmotic protection on RBCs. Flow cytometry data demonstrate that incubation of RBCs in a hypertonic trehalose solution results in a fraction of cells with different complexity and that it can be removed by washing and resuspending the RBCs in an iso-osmotic medium. The data provide an important first step in long-term preservation of RBCs.", "corpus_id": 10116024, "score": 0 }, { "doc_id": "20044230", "title": "A Regulatory Network-Based Approach Dissects Late Maturation Processes Related to the Acquisition of Desiccation Tolerance and Longevity of Medicago truncatula Seeds1[C][W][OPEN]", "abstract": "A network analysis approach to gene regulation during seed maturation of Medicago truncatula uncovers distinct temporal regulatory programs related to desiccation tolerance, longevity, and pod abscission and the key regulators governing these programs. In seeds, desiccation tolerance (DT) and the ability to survive the dry state for prolonged periods of time (longevity) are two essential traits for seed quality that are consecutively acquired during maturation. Using transcriptomic and metabolomic profiling together with a conditional-dependent network of global transcription interactions, we dissected the maturation events from the end of seed filling to final maturation drying during the last 3 weeks of seed development in Medicago truncatula. The network revealed distinct coexpression modules related to the acquisition of DT, longevity, and pod abscission. The acquisition of DT and dormancy module was associated with abiotic stress response genes, including late embryogenesis abundant (LEA) genes. The longevity module was enriched in genes involved in RNA processing and translation. Concomitantly, LEA polypeptides accumulated, displaying an 18-d delayed accumulation compared with transcripts. During maturation, gulose and stachyose levels increased and correlated with longevity. A seed-specific network identified known and putative transcriptional regulators of DT, including ABSCISIC ACID-INSENSITIVE3 (MtABI3), MtABI4, MtABI5, and APETALA2/ ETHYLENE RESPONSE ELEMENT BINDING PROTEIN (AtAP2/EREBP) transcription factor as major hubs. These transcriptional activators were highly connected to LEA genes. Longevity genes were highly connected to two MtAP2/EREBP and two basic leucine zipper transcription factors. A heat shock factor was found at the transition of DT and longevity modules, connecting to both gene sets. Gain- and loss-of-function approaches of MtABI3 confirmed 80% of its predicted targets, thereby experimentally validating the network. This study captures the coordinated regulation of seed maturation and identifies distinct regulatory networks underlying the preparation for the dry and quiescent states.", "corpus_id": 20044230, "score": 1 }, { "doc_id": "3347628", "title": "From Avicennia to Zizania: seed recalcitrance in perspective.", "abstract": "BACKGROUND\nConsidered only in terms of tolerance of, or sensitivity to, desiccation (which is an oversimplification), orthodox seeds are those which tolerate dehydration and are storable in this condition, while highly recalcitrant seeds are damaged by loss of only a small proportion of water and are unstorable for practical purposes. Between these extremes, however, there may be a gradation of the responses to dehydration--and also to other factors--suggesting perhaps that seed behaviour might be best considered as constituting a continuum subtended by extreme orthodoxy and the highest degree of recalcitrance. As the characteristics of seeds of an increasing number of species are elucidated, non-orthodox seed behaviour is emerging as considerably more commonplace--and its basis far more complex--than previously suspected.\n\n\nSCOPE\nWhatever the post-harvest responses of seeds of individual species may be, they are the outcome of the properties of pre-shedding development, and a full understanding of the subtleties of various degrees of non-orthodox behaviour must await the identification of, and interaction among, all the factors conferring extreme orthodoxy. Appreciation of the phenomenon of recalcitrance is confounded by intra- and interseasonal variability across species, as well as within individual species. However, recent evidence suggests that provenance is a pivotal factor in determining the degree of recalcitrant behaviour exhibited by seeds of individual species. Non-orthodox--and, in particular, recalcitrant--seed behaviour is not merely a matter of desiccation sensitivity: the primary basis is that the seeds are actively metabolic when they are shed, in contrast to orthodox types which are quiescent. This affects all aspects of the handling and storage of recalcitrant seeds. In the short to medium term, recalcitrant seeds should be stored in as hydrated a condition as when they are shed, and at the lowest temperature not diminishing vigour or viability. Such hydrated storage has attendant problems of fungal proliferation which, unless minimized, will inevitably and significantly affect seed quality. The life span of seeds in hydrated storage even under the best conditions is variable among species, but is curtailed (days to months), and various approaches attempting to extend non-orthodox seed longevity are discussed. Conservation of the genetic resources by means other than seed storage is then briefly considered, with detail on the potential for, and difficulties with, cryostorage highlighted.\n\n\nCONCLUSIONS\nThere appears to be little taxonomic relationship among species exhibiting the phenomenon of seed recalcitrance, suggesting that it is a derived trait, with tolerance having been lost a number of times. Although recalcitrant seededness is best represented in the mesic tropics, particularly among rainforest climax species, it does occur in cooler, drier and markedly seasonal habitats. The selective advantages of the trait are considered.", "corpus_id": 3347628, "score": 0 }, { "doc_id": "11395276", "title": "Desiccation tolerance in resurrection plants: new insights from transcriptome, proteome and metabolome analysis", "abstract": "Most higher plants are unable to survive desiccation to an air-dried state. An exception is a small group of vascular angiosperm plants, termed resurrection plants. They have evolved unique mechanisms of desiccation tolerance and thus can tolerate severe water loss, and mostly adjust their water content with the relative humidity in the environment. Desiccation tolerance is a complex phenomenon and depends on the regulated expression of numerous genes during dehydration and subsequent rehydration. Most of the resurrection plants have a large genome and are difficult to transform which makes them unsuitable for genetic approaches. However, technical advances have made it possible to analyze changes in gene expression on a large-scale. These approaches together with comparative studies with non-desiccation tolerant plants provide novel insights into the molecular processes required for desiccation tolerance and will shed light on identification of orphan genes with unknown functions. Here, we review large-scale recent transcriptomic, proteomic, and metabolomic studies that have been performed in desiccation tolerant plants and discuss how these studies contribute to understanding the molecular basis of desiccation tolerance.", "corpus_id": 11395276, "score": 0 }, { "doc_id": "12668210", "title": "Adaptations of higher plant cell walls to water loss: drought vs desiccation.", "abstract": "Water-deficit stress poses unique challenges to plant cells dependent on a hydrostatic skeleton and a polysaccharide-rich cell wall for growth and development. How the plant cell wall is adapted to loss of water is of interest in developing a general understanding of water stress tolerance in plants and of relevance in strategies related to crop improvement. Drought tolerance involves adaptations to growth under reduced water potential and the concomitant restructuring of the cell wall that allow growth processes to occur at lower water contents. Desiccation tolerance, by contrast, is the evolution of cell walls that are capable of losing the majority of cellular water without suffering permanent and irreversible damage to cell wall structure and polymer organization. This minireview highlights common features and differences between these two water-deficit responses observed in plants, emphasizing the role of the cell wall, while suggesting future research avenues that could benefit fundamental understanding in this area.", "corpus_id": 12668210, "score": 0 }, { "doc_id": "20030716", "title": "Drought, metabolites, and Arabidopsis natural variation: a promising combination for understanding adaptation to water-limited environments.", "abstract": "Drought elicits substantial changes in plant metabolism and it remains a challenge to determine which of these changes represent adaptive responses and which of them are merely neutral effects or even symptoms of damage. Arabidopsis primarily uses low water potential/dehydration avoidance strategies to respond to water limitation. The large variation in evolved stress responses among accessions can be a powerful tool to identify ecologically important and adaptive traits; however, collection of relevant phenotype data under controlled water stress is often a limiting factor. Quantitative genetics of Arabidopsis has great potential to find the genes underlying variation in drought-affected metabolic traits, for example proline metabolism, as well as overall adaptation.", "corpus_id": 20030716, "score": 1 }, { "doc_id": "5766114", "title": "Desiccation-Tolerant Flowering Plants in Southern Africa", "abstract": "The South African flora contains a unique abundance of higher plants which withstand virtually complete desiccation. Water potentials of fielddry leaves corresponded to 30 to 40 percent relative humidity. Mature leaves survived from 15 to approximately 0 percent relative humidity. Known examples were increased from 4 to 15 species, which for the first time included grasses.", "corpus_id": 5766114, "score": 0 }, { "doc_id": "35380541", "title": "An overview of mechanisms of desiccation tolerance in selected angiosperm resurrection plants", "abstract": "The vegetative tissues of resurrection plants, like seeds, can tolerate desiccation to 5% relative water content (RWC) for extended periods and yet resume full metabolic activity on re-watering. In this review we will illustrate how this is achieved in a variety of angiosperm resurrection plants, our studies ranging from the ecophysiological to the biochemical level. At the whole plant level, leaf folding and other anatomical changes serve to minimise light and mechanical stress associated with drying and rehydration. The mechanisms of cell wall folding are described for Craterostigma wilmsii and Myrothanmus flabellifolia. Free radicals, radical oxygen species (ROS) usually generated under water-deficit stress by photosynthesis, are minimised by either homoiochlorophylly (e.g. C. wilmsii and M. flabellifolia) or poikilochlorophylly (e.g. Xerophyta sp.). The antioxidant systems of these plants effectively deal with ROS generated by other metabolic processes. In addition to antioxidants common to most plants, resurrection plants also accumulate polyphenols such as 3, 4, 5 tri-O-galloylquinic acid in M. flabellifolia, and seed-associated antioxidants (e.g. 1-cys-peroxiredoxin and metallothionines) as effective ROS scavengers. Sucrose accumulates at low RWC, presumably protecting the sub-cellular milieu against desiccation-induced macromolecular denaturation. _____________________________________________________________________________________________________________", "corpus_id": 35380541, "score": 0 }, { "doc_id": "5033516", "title": "A comparison of mechanisms of desiccation tolerance among three angiosperm resurrection plant species", "abstract": "The mechanisms of protection against mechanical and oxidative stress were identified and compared in the angiosperm resurrection plants Craterostigma wilmsii, Myrothamnus flabellifolius and Xerophyta humilis. Drying-induced ultrastructural changes within mesophyll cells were followed to gain an understanding of the mechanisms of mechanical stabilisation. In all three species, water filled vacuoles present in hydrated cells were replaced by several smaller vacuoles filled with non-aqueous substances. In X. humilis, these occupied a large proportion of the cytoplasm, preventing plasmalemma withdrawal and cell wall collapse. In C. wilmsii, vacuoles were small but extensive cell wall folding occurred to prevent plasmalemma withdrawal. In M. flabellifolius, some degree of vacuolation and wall folding occurred, but neither were sufficient to prevent plasmalemma withdrawal. This membrane was not ruptured, possibly due to membrane repair at plasmodesmata junctions where tearing might have occurred. In addition, the extra-cytoplasmic compartment appeared to contain material (possibly similar to that in vacuoles) which could facilitate stabilisation of dry cells.Photosynthesis and respiration are particularly susceptible to oxidative stress during drying. Photosynthesis ceased at high water contents and it is proposed that a controlled shut down of this metabolism occurred in order to minimise the potential for photo-oxidation. The mechanisms whereby this was achieved varied among the species. In X. humilis, chlorophyll was degraded and thylakoid membranes dismantled during drying. In both C. wilmsii and M. flabellifolius, chlorophyll was retained, but photosynthesis was stopped due to chlorophyll shading from leaf folding and anthocyanin accumulation. Furthermore, in M. flabellifolius thylakoid membranes became unstacked during drying. All species continued respiration during drying to 10% relative water content, which is proposed to be necessary for energy to establish protection mechanisms. Activity of antioxidant enzymes increased during drying and remained high at low water contents in all species, ameliorating free radical damage from both photosynthesis and respiration. The nature and extent of antioxidant upregulation varied among the species. In C. wilmsii, only ascorbate peroxidise activity increased, but in M. flabellifolius and X. humilis ascorbate peroxidise, glutathione reductase and superoxide dismutase activity increased, to various extents, during drying. Anthocyanins accumulated in all species but this was more extensive in the homoiochlorophyllous types, possibly for protection against photo-oxidation.", "corpus_id": 5033516, "score": 0 }, { "doc_id": "23274853", "title": "Leaf Shrinkage with Dehydration: Coordination with Hydraulic Vulnerability and Drought Tolerance1[C][W][OPEN]", "abstract": "Leaf shrinkage is a potential driver of leaf hydraulic vulnerability, especially under mild stress, and carries strong ecological implications. Leaf shrinkage with dehydration has attracted attention for over 100 years, especially as it becomes visibly extreme during drought. However, little has been known of its correlation with physiology. Computer simulations of the leaf hydraulic system showed that a reduction of hydraulic conductance of the mesophyll pathways outside the xylem would cause a strong decline of leaf hydraulic conductance (Kleaf). For 14 diverse species, we tested the hypothesis that shrinkage during dehydration (i.e. in whole leaf, cell and airspace thickness, and leaf area) is associated with reduction in Kleaf at declining leaf water potential (Ψleaf). We tested hypotheses for the linkage of leaf shrinkage with structural and physiological water relations parameters, including modulus of elasticity, osmotic pressure at full turgor, turgor loss point (TLP), and cuticular conductance. Species originating from moist habitats showed substantial shrinkage during dehydration before reaching TLP, in contrast with species originating from dry habitats. Across species, the decline of Kleaf with mild dehydration (i.e. the initial slope of the Kleaf versus Ψleaf curve) correlated with the decline of leaf thickness (the slope of the leaf thickness versus Ψleaf curve), as expected based on predictions from computer simulations. Leaf thickness shrinkage before TLP correlated across species with lower modulus of elasticity and with less negative osmotic pressure at full turgor, as did leaf area shrinkage between full turgor and oven desiccation. These findings point to a role for leaf shrinkage in hydraulic decline during mild dehydration, with potential impacts on drought adaptation for cells and leaves, influencing plant ecological distributions.", "corpus_id": 23274853, "score": 0 }, { "doc_id": "29810968", "title": "A Modulating Role for Antioxidants in Desiccation Tolerance1", "abstract": "Abstract Most organisms depend on the availability of water. However, some life-forms, among them plants and fungi, but very few animals, can survive in the desiccated state. Here we discuss biochemical mechanisms that confer tolerance to desiccation in photosynthetic and non-photosynthetic organisms. We first consider damage caused by water removal and point out that free radicals are a major cause of death in intolerant tissue. Free radicals impair metabolism and necessitate protection and repair during desiccation and rehydration, respectively. As a consequence, desiccation tolerance and prolonged longevity in the desiccated state depend on the ability to scavenge free radicals, using antioxidants such as glutathione, ascorbate, tocopherols and free radical-processing enzymes. Some ‘classic’ antioxidants may be absent in lower plants and fungi. On the other hand, lichens and seeds often contain secondary phenolic products with antioxidant properties. The major intracellular antioxidant consistently found in all life forms is glutathione, making it essential to survive desiccation. We finally discuss the role of glutathione to act as a signal that initiates programmed cell death. The failure of the antioxidant system during long-term desiccation appears to trigger programmed cell death, causing ageing and eventual death of the organism. In turn, this suggests that a potent antioxidant machinery is one of the underlying mechanisms of desiccation tolerance.", "corpus_id": 29810968, "score": 0 }, { "doc_id": "6066284", "title": "Mechanisms of plant desiccation tolerance.", "abstract": "Anhydrobiosis (\"life without water\") is the remarkable ability of certain organisms to survive almost total dehydration. It requires a coordinated series of events during dehydration that are associated with preventing oxidative damage and maintaining the native structure of macromolecules and membranes. The preferential hydration of macromolecules is essential when there is still bulk water present, but replacement by sugars becomes important upon further drying. Recent advances in our understanding of the mechanism of anhydrobiosis include the downregulation of metabolism, dehydration-induced partitioning of amphiphilic compounds into membranes and immobilization of the cytoplasm in a stable multicomponent glassy matrix.", "corpus_id": 6066284, "score": 0 }, { "doc_id": "18617670", "title": "An emerging picture of the seed desiccome: confirmed regulators and newcomers identified using transcriptome comparison", "abstract": "Desiccation tolerance (DT) is the capacity to withstand total loss of cellular water. It is acquired during seed filling and lost just after germination. However, in many species, a germinated seed can regain DT under adverse conditions such as osmotic stress. The genes, proteins and metabolites that are required to establish this DT is referred to as the desiccome. It includes both a range of protective mechanisms and underlying regulatory pathways that remain poorly understood. As a first step toward the identification of the seed desiccome of Medicago truncatula, using updated microarrays we characterized the overlapping transcriptomes associated with acquisition of DT in developing seeds and the re-establishment of DT in germinated seeds using a polyethylene glycol treatment (−1.7 MPa). The resulting list contained 740 and 2829 transcripts whose levels, respectively, increased and decreased with DT. Fourty-eight transcription factors (TF) were identified including MtABI3, MtABI5 and many genes regulating flowering transition and cell identity. A promoter enrichment analysis revealed a strong over-representation of ABRE elements together with light-responsive cis-acting elements. In Mtabi5 Tnt1 insertion mutants, DT could no longer be re-established by an osmotic stress. Transcriptome analysis on Mtabi5 radicles during osmotic stress revealed that 13 and 15% of the up-regulated and down-regulated genes, respectively, are mis-regulated in the mutants and might be putative downstream targets of MtABI5 implicated in the re-establishment of DT. Likewise, transcriptome comparisons of the desiccation sensitive Mtabi3 mutants and hairy roots ectopically expressing MtABI3 revealed that 35 and 23% of the up-regulated and down-regulated genes are acting downstream of MtABI3. Our data suggest that ABI3 and ABI5 have complementary roles in DT. Whether DT evolved by co-opting existing pathways regulating flowering and cellular phase transition and cell identity is discussed.", "corpus_id": 18617670, "score": 1 }, { "doc_id": "25181981", "title": "Seed maturation in Arabidopsis thaliana is characterized by nuclear size reduction and increased chromatin condensation", "abstract": "Most plant species rely on seeds for their dispersal and survival under unfavorable environmental conditions. Seeds are characterized by their low moisture content and significantly reduced metabolic activities. During the maturation phase, seeds accumulate storage reserves and become desiccation-tolerant and dormant. Growth is resumed after release of dormancy and the occurrence of favorable environmental conditions. Here we show that embryonic cotyledon nuclei of Arabidopsis thaliana seeds have a significantly reduced nuclear size, which is established at the beginning of seed maturation. In addition, the chromatin of embryonic cotyledon nuclei from mature seeds is highly condensed. Nuclei regain their size and chromatin condensation level during germination. The reduction in nuclear size is controlled by the seed maturation regulator ABSCISIC ACID-INSENSITIVE 3, and the increase during germination requires two predicted nuclear matrix proteins, LITTLE NUCLEI 1 and LITTLE NUCLEI 2. Our results suggest that the specific properties of nuclei in ripe seeds are an adaptation to desiccation, independent of dormancy. We conclude that the changes in nuclear size and chromatin condensation in seeds are independent, developmentally controlled processes.", "corpus_id": 25181981, "score": 1 }, { "doc_id": "85941987", "title": "Desiccation-tolerance in bryophytes: a review", "abstract": "Abstract Desiccation-tolerance (DT), the ability to lose virtually all free intracellular water and then recover normal function upon rehydration, is one of the most remarkable features of bryophytes. The physiology of bryophytes differs in major respects from that of vascular plants by virtue of their smaller size; unlike vascular plants, the leafy shoots of bryophytes equilibrate rapidly with the water potential in their surroundings and tend to be either fully hydrated or desiccated and metabolically inactive. The time required to recover from desiccation increases and degree of recovery decreases with length of desiccation; both also depend upon temperature and intensity of desiccation. Tolerance in at least some species shows phenotypic plasticity. Recovery of respiration, photosynthesis and protein synthesis takes place within minutes or an hour or two; recovery of the cell cycle, food transport and the cytoskeleton may take 24 hours or more. Positive carbon balance is essential to survival of repeated cycles of drying and wetting; significant growth requires continuously wet periods of a few days or more. Male and female gametophytes, and gametophyte and sporophyte, may differ in tolerance. Desiccation-tolerance is essential to dispersal and establishment of spores and vegetative propagules. The mechanisms of DT in bryophytes, including expression of LEA proteins, high content of non-reducing sugars and effective antioxidant and photo-protection, are at least partly constitutive, allowing survival of rapid drying, but changes in gene expression resulting from mRNA sequestration and alterations in translational controls elicited upon rehydration are also important to repair processes following re-wetting. Phylogenetic and ecological considerations suggest that DT is a primitive character of land plants, lost in the course of evolution of the homoiohydric vascular-plant shoot system, but retained in spores, pollen and seeds, and re-evolved in the vegetative tissues of vascular “resurrection plants.” Bryophytes have retained the poikilohydry and DT that are probably the optimal pattern of adaptation at their scale, but modern bryophytes are specialized and diverse, and are removed by the same span of evolutionary time as the flowering plants from their primitive origins.", "corpus_id": 85941987, "score": 0 }, { "doc_id": "10138241", "title": "Evolution of Abscisic Acid Synthesis and Signaling Mechanisms", "abstract": "The plant hormone abscisic acid (ABA) mediates seed dormancy, controls seedling development and triggers tolerance to abiotic stresses, including drought. Core ABA signaling components consist of a recently identified group of ABA receptor proteins of the PYRABACTIN RESISTANCE (PYR)/REGULATORY COMPONENT OF ABA RECEPTOR (RCAR) family that act as negative regulators of members of the PROTEIN PHOSPHATASE 2C (PP2C) family. Inhibition of PP2C activity enables activation of SNF1-RELATED KINASE 2 (SnRK2) protein kinases, which target downstream components, including transcription factors, ion channels and NADPH oxidases. These and other components form a complex ABA signaling network. Here, an in depth analysis of the evolution of components in this ABA signaling network shows that (i) PYR/RCAR ABA receptor and ABF-type transcription factor families arose during land colonization of plants and are not found in algae and other species, (ii) ABA biosynthesis enzymes have evolved to plant- and fungal-specific forms, leading to different ABA synthesis pathways, (iii) existing stress signaling components, including PP2C phosphatases and SnRK kinases, were adapted for novel roles in this plant-specific network to respond to water limitation. In addition, evolutionarily conserved secondary structures in the PYR/RCAR ABA receptor family are visualized.", "corpus_id": 10138241, "score": 0 }, { "doc_id": "530301", "title": "Molecular Basis of the Core Regulatory Network in ABA Responses: Sensing, Signaling and Transport", "abstract": "ABA is a major phytohormone that regulates a broad range of plant traits and is especially important for adaptation to environmental conditions. Our understanding of the molecular basis of ABA responses in plants improved dramatically in 2009 and 2010, banner years for ABA research. There are three major components; PYR/PYL/ RCAR (an ABA receptor), type 2C protein phosphatase (PP2C; a negative regulator) and SNF1-related protein kinase 2 (SnRK2; a positive regulator), and they offer a double negative regulatory system, [PYR/PYL/RCAR—| PP2C—| SnRK2]. In the absence of ABA, PP2C inactivates SnRK2 by direct dephosphorylation. In response to environmental or developmental cues, ABA promotes the interaction of PYR/PYL/RCAR and PP2C, resulting in PP2C inhibition and SnRK2 activation. This signaling complex can work in both the nucleus and cytosol, as it has been shown that SnRK2 phosphorylates basic-domain leucine zipper (bZIP) transcription factors or membrane proteins. Several structural analyses of PYR/PYL/RCAR have provided the mechanistic basis for this ‘core signaling’ model, by elucidating the mechanism of ABA binding of receptors, or the ‘gate–latch–lock’ mechanism of interaction with PP2C in inhibiting activity. On the other hand, intercellular ABA transport had remained a major issue, as had intracellular ABA signaling. Recently, two plasma membrane-type ABC transporters were identified and shed light on the influx/efflux system of ABA, resolving how ABA is transported from cell to cell in plants. Our knowledge of ABA responses in plants has been greatly expanded from intracellular signaling to intercellular transport of ABA.", "corpus_id": 530301, "score": 0 }, { "doc_id": "5020962", "title": "Land Plants Acquired Active Stomatal Control Early in Their Evolutionary History", "abstract": "Stomata are pores that regulate plant gas exchange [1]. They evolved more than 400 million years ago [2, 3], but the origin of their active physiological responses to endogenous and environmental cues is unclear [2-6]. Recent research suggests that the stomata of lycophytes and ferns lack pore closure responses to abscisic acid (ABA) and CO(2). This evidence led to the hypothesis that a fundamental transition from passive to active control of plant water balance occurred after the divergence of ferns 360 million years ago [7, 8]. Here we show that stomatal responses of the lycophyte Selaginella [9] to ABA and CO(2) are directly comparable to those of the flowering plant Arabidopsis [10]. Furthermore, we show that the underlying intracellular signaling pathways responsible for stomatal aperture control are similar in both basal and modern vascular plant lineages. Our evidence challenges the hypothesis that acquisition of active stomatal control of plant carbon and water balance represents a critical turning point in land plant evolution [7, 8]. Instead, we suggest that the critical evolutionary development is represented by the innovation of stomata themselves and that physiologically active stomatal control originated at least as far back as the emergence of the lycophytes (circa 420 million years ago) [11].", "corpus_id": 5020962, "score": 0 }, { "doc_id": "21341737", "title": "Role of ABA and ABI3 in Desiccation Tolerance", "abstract": "The hormone pathway that stabilizes seeds may have served more primitive seedless plants in supporting desiccation tolerance. We show in bryophytes that abscisic acid (ABA) pretreatment of moss (Physcomitrella patens) cells confers desiccation tolerance. In angiosperms, both ABA and the transcriptional regulator ABSCISIC ACID INSENSITIVE 3 (ABI3) are required to protect the seed during desiccation. ABA was not able to protect moss cells in stable deletion lines of ABI3 (ΔPpabi3). Hence, moss has the same functional link between ABA, ABI3, and the desiccation tolerance phenotype that is found in angiosperms. Furthermore, we identified 22 genes that were induced during ABA pretreatment in wild-type lines. When their expression was compared with that of ΔPpabi3 during ABA pretreatment and immediately after desiccation, a new target of ABI3 action appears to be in the recovery period.", "corpus_id": 21341737, "score": 0 }, { "doc_id": "17519557", "title": "The Re-Establishment of Desiccation Tolerance in Germinated Arabidopsis thaliana Seeds and Its Associated Transcriptome", "abstract": "The combination of robust physiological models with “omics” studies holds promise for the discovery of genes and pathways linked to how organisms deal with drying. Here we used a transcriptomics approach in combination with an in vivo physiological model of re-establishment of desiccation tolerance (DT) in Arabidopsis thaliana seeds. We show that the incubation of desiccation sensitive (DS) germinated Arabidopsis seeds in a polyethylene glycol (PEG) solution re-induces the mechanisms necessary for expression of DT. Based on a SNP-tile array gene expression profile, our data indicates that the re-establishment of DT, in this system, is related to a programmed reversion from a metabolic active to a quiescent state similar to prior to germination. Our findings show that transcripts of germinated seeds after the PEG-treatment are dominated by those encoding LEA, seed storage and dormancy related proteins. On the other hand, a massive repression of genes belonging to many other classes such as photosynthesis, cell wall modification and energy metabolism occurs in parallel. Furthermore, comparison with a similar system for Medicago truncatula reveals a significant overlap between the two transcriptomes. Such overlap may highlight core mechanisms and key regulators of the trait DT. Taking into account the availability of the many genetic and molecular resources for Arabidopsis, the described system may prove useful for unraveling DT in higher plants.", "corpus_id": 17519557, "score": 0 }, { "doc_id": "42043519", "title": "The evolution of vegetative desiccation tolerance in land plants", "abstract": "Vegetative desiccation tolerance is a widespread but uncommon occurrence in the plant kingdom generally. The majority of vegetative desiccation-tolerant plants are found in the less complex clades that constitute the algae, lichens and bryophytes. However, within the larger and more complex groups of vascular land plants there are some 60 to 70 species of ferns and fern allies, and approximately 60 species of angiosperms that exhibit some degree of vegetative desiccation tolerance. In this report we analyze the evidence for the differing mechanisms of desiccation tolerance in different plants, including differences in cellular protection and cellular repair, and couple this evidence with a phylogenetic framework to generate a working hypothesis as to the evolution of desiccation tolerance in land plants. We hypothesize that the initial evolution of vegetative desiccation tolerance was a crucial step in the colonization of the land by primitive plants from an origin in fresh water. The primitive mechanism of tolerance probably involved constitutive cellular protection coupled with active cellular repair, similar to that described for modern-day desiccation-tolerant bryophytes. As plant species evolved, vegetative desiccation tolerance was lost as increased growth rates, structural and morphological complexity, and mechanisms that conserve water within the plant and maintain efficient carbon fixation were selected for. Genes that had evolved for cellular protection and repair were, in all likelihood, recruited for different but related processes such as response to water stress and the desiccation tolerance of reproductive propagules. We thus hypothesize that the mechanism of desiccation tolerance exhibited in seeds, a developmentally induced cellular protection system, evolved from the primitive form of vegetative desiccation tolerance. Once established in seeds, this system became available for induction in vegetative tissues by environmental cues related to drying. The more recent, modified vegetative desiccation tolerance mechanism in angiosperms evolved from that programmed into seed development as species spread into very arid environments. Most recently, certain desiccation-tolerant monocots evolved the strategy of poikilochlorophylly to survive and compete in marginal habitats with variability in water availability.", "corpus_id": 42043519, "score": 1 }, { "doc_id": "86199888", "title": "The evolution of desiccation tolerance in angiosperm plants: a rare yet common phenomenon.", "abstract": "In a minute proportion of angiosperm species, rehydrating foliage can revive from airdryness or even from equilibration with air of ~0% RH. Such desiccation tolerance is known from vegetative cells of some species of algae and of major groups close to the evolutionary path of the angiosperms. It is also found in the reproductive structures of some algae, moss spores and probably the aerial spores of other terrestrial cryptogamic taxa. The occurrence of desiccation tolerance in the seed plants is overwhelmingly in the aerial reproductive structures; the pollen and seed embryos. Spatially and temporally, pollen and embryos are close ontogenetic derivatives of the angiosperm microspores and megaspores respectively. This suggests that the desiccation tolerance of pollen and embryos derives from the desiccation tolerance of the spores of antecedent taxa and that the basic pollen/embryo mechanism of desiccation tolerance has eventually become expressed also in the vegetative tissue of certain angiosperm species whose drought avoidance is inadequate in micro-habitats that suffer extremely xeric episodes. The protective compounds and processes that contribute to desiccation tolerance in angiosperms are found in the modern groups related to the evolutionary path leading to the angiosperms and are also present in the algae and in the cyanobacteria. The mechanism of desiccation tolerance in the angiosperms thus appears to have its origins in algal ancestors and possibly in the endosymbiotic cyanobacteria-related progenitor of chloroplasts and the bacteria-related progenitor of mitochondria. The mechanism may involve the regulation and timing of the accumulation of protective compounds and of other contributing substances and processes.", "corpus_id": 86199888, "score": 1 }, { "doc_id": "83387148", "title": "Evolution, Diversity, and Habitats of Poikilohydrous Vascular Plants", "abstract": "Water stress is a common environmental constraint in terrestrial ecosystems. Among the various strategies to cope with temporal lack of water, poikilohydry is an important adaptive trait under specific habitat conditions. Desiccation tolerant vascular plants are particularly common among ferns, fern allies, and angiosperms that colonize forest canopies and mainly tropical rock outcrops (e.g., granitic/gneissic inselbergs, ferricretes) where environmental conditions (e.g., high temperatures, lack of water, and soil) are harsh.", "corpus_id": 83387148, "score": 0 }, { "doc_id": "15453242", "title": "The Signature of Seeds in Resurrection Plants: A Molecular and Physiological Comparison of Desiccation Tolerance in Seeds and Vegetative Tissues1", "abstract": "Abstract Desiccation-tolerance in vegetative tissues of angiosperms has a polyphyletic origin and could be due to 1) appropriation of the seed-specific program of gene expression that protects orthodox seeds against desiccation, and/or 2) a sustainable version of the abiotic stress response. We tested these hypotheses by comparing molecular and physiological data from the development of orthodox seeds, the response of desiccation-sensitive plants to abiotic stress, and the response of desiccation-tolerant plants to extreme water loss. Analysis of publicly-available gene expression data of 35 LEA proteins and 68 anti-oxidant enzymes in the desiccation-sensitive Arabidopsis thaliana identified 13 LEAs and 4 anti-oxidants exclusively expressed in seeds. Two (a LEA6 and 1-cys-peroxiredoxin) are not expressed in vegetative tissues in A. thaliana, but have orthologues that are specifically activated in desiccating leaves of Xerophyta humilis. A comparison of antioxidant enzyme activity in two desiccation-sensitive species of Eragrostis with the desiccation-tolerant E. nindensis showed equivalent responses upon initial dehydration, but activity was retained at low water content in E. nindensis only. We propose that these antioxidants are housekeeping enzymes and that they are protected from damage in the desiccation-tolerant species. Sucrose is considered an important protectant against desiccation in orthodox seeds, and we show that sucrose accumulates in drying leaves of E. nindensis, but not in the desiccation-sensitive Eragrostis species. The activation of “seed-specific” desiccation protection mechanisms (sucrose accumulation and expression of LEA6 and 1-cys-peroxiredoxin genes) in the vegetative tissues of desiccation-tolerant plants points towards acquisition of desiccation tolerance from seeds.", "corpus_id": 15453242, "score": 0 }, { "doc_id": "88572824", "title": "Flow Cytometric Determination of Nuclear Replication Stages in Tomato Seeds during Priming and Germination", "abstract": "We report relative nuclear DNA contents in tomato (Lycopersicon esculentum)seed and seedling tissues as measured with flow cytometry. We provide information about the replication stage of nuclei in cells of non-imbibed, hydrated and primed seeds and specify the tissue in which DNA replication occurs", "corpus_id": 88572824, "score": 1 }, { "doc_id": "23822237", "title": "Seed dormancy and the control of germination.", "abstract": "Seed dormancy is an innate seed property that defines the environmental conditions in which the seed is able to germinate. It is determined by genetics with a substantial environmental influence which is mediated, at least in part, by the plant hormones abscisic acid and gibberellins. Not only is the dormancy status influenced by the seed maturation environment, it is also continuously changing with time following shedding in a manner determined by the ambient environment. As dormancy is present throughout the higher plants in all major climatic regions, adaptation has resulted in divergent responses to the environment. Through this adaptation, germination is timed to avoid unfavourable weather for subsequent plant establishment and reproductive growth. In this review, we present an integrated view of the evolution, molecular genetics, physiology, biochemistry, ecology and modelling of seed dormancy mechanisms and their control of germination. We argue that adaptation has taken place on a theme rather than via fundamentally different paths and identify similarities underlying the extensive diversity in the dormancy response to the environment that controls germination.", "corpus_id": 23822237, "score": 0 }, { "doc_id": "13640408", "title": "The evolution of seed dormancy: environmental cues, evolutionary hubs, and diversification of the seed plants.", "abstract": "Seed dormancy, by controlling the timing of germination, can strongly affect plant survival. The kind of seed dormancy, therefore, can influence both population and species-level processes such as colonization, adaptation, speciation, and extinction. We used a dataset comprising over 14,000 taxa in 318 families across the seed plants to test hypotheses on the evolution of different kinds of seed dormancy and their association with lineage diversification. We found morphophysiological dormancy to be the most likely ancestral state of seed plants, suggesting that physiologically regulated dormancy in response to environmental cues was present at the origin of seed plants. Additionally, we found that physiological dormancy (PD), once disassociated from morphological dormancy, acted as an 'evolutionary hub' from which other dormancy classes evolved, and that it was associated with higher rates of lineage diversification via higher speciation rates. The environmental sensitivity provided by dormancy in general, and by PD in particular, appears to be a key trait in the diversification of seed plants.", "corpus_id": 13640408, "score": 0 }, { "doc_id": "86663179", "title": "Ecological aspects of seed desiccation sensitivity", "abstract": "Summary 1 The ability of seeds to survive desiccation is an important functional trait and is an integral part of plant regeneration ecology. Despite this, the topic has received relatively little attention from ecologists. In this study, we examine the relationships between seed desiccation tolerance and two important aspects of plant regeneration ecology: habitat and dormancy. This is done by comparative analysis of a data set of 886 tree and shrub species from 93 families. 2 The proportion of species displaying desiccation sensitive seeds declines as the habitat becomes drier, and possibly also cooler, although the latter observation requires cautious interpretation. Desiccation sensitivity is most common in moist, relatively aseasonal vegetation zones, but is infrequent in, though not absent from arid and highly seasonal habitats. 3 The highest frequency of desiccation sensitivity occurs in non-pioneer evergreen rain forest trees, although 48% of the species examined have desiccation tolerant seeds. In contrast, all pioneer taxa within the data set have drying tolerant seeds. 4 Desiccation sensitivity is more frequent in seeds that are non-dormant on shedding ( c. 31%), than dormant ( c. 9%). Highest frequencies of drying tolerance occur in seeds with physical or combinational dormancy, at 99% and 100%, respectively. 5 Although there is an association between non-dormancy and desiccation sensitivity in both tropical and temperate zones, the relationship does not appear to be causal. 6 Wo rking from the hypothesis that seed desiccation sensitivity represents a derived state in extant species, we use the results to investigate and discuss possible ecological trade-offs and associated fitness advantages. These may explain the hypothesized repeated loss of this trait. The frequent association between large seed size and desiccation sensitivity is also considered.", "corpus_id": 86663179, "score": 0 }, { "doc_id": "3943689", "title": "The evolution of seeds.", "abstract": "The evolution of the seed represents a remarkable life-history transition for photosynthetic organisms. Here, we review the recent literature and historical understanding of how and why seeds evolved. Answering the 'how' question involves a detailed understanding of the developmental morphology and anatomy of seeds, as well as the genetic programs that determine seed size. We complement this with a special emphasis on the evolution of dormancy, the characteristic of seeds that allows for long 'distance' time travel. Answering the 'why' question involves proposed hypotheses of how natural selection has operated to favor the seed life-history phenomenon. The recent flurry of research describing the comparative biology of seeds is discussed. The review will be divided into sections dealing with: (1) the development and anatomy of seeds; (2) the endosperm; (3) dormancy; (4) early seed-like structures and the transition to seeds; and (5) the evolution of seed size (mass). In many cases, a special distinction is made between angiosperm and gymnosperm seeds. Finally, we make some recommendations for future research in seed biology.", "corpus_id": 3943689, "score": 0 }, { "doc_id": "84378902", "title": "The evolution and biological significance of seeds", "abstract": "No evolutionary event in the colonization of the land by vascular plants is of greater significance than the appearance of the seed habit. What apparently began as an adaptation enhancing sexual reproduction in the absence of external free water has assumed a far broader importance in terms of survival and dispersal. The essential features of the seed habit are identified in relation to heterospory, megaspore retention, and endosporic gametophyte development and approaches to the seed habit by nonseed plants are reviewed. Seeds first appear in the fossil record of the Late Devonian Period and, in diverse forms and sizes, constitute a significant component of Carboniferous fossil floras. The rise to dominance of plants of gymnospermous affinity in the early Mesozoic and the appearance and rapid adaptive radiation of the angiosperms are discussed in relation to the significance of the seed habit. The structure and development of modern gymnosperm and angiosperm seeds are compared, and the contrasting patter...", "corpus_id": 84378902, "score": 0 }, { "doc_id": "54554217", "title": "Implications of the lack of desiccation tolerance in recalcitrant seeds", "abstract": "A suite of interacting processes and mechanisms enables tolerance of desiccation and storage (conservation) of orthodox seeds in the dry state. While this is a long-term option under optimized conditions, dry orthodox seeds are not immortal, with life spans having been characterized as short, intermediate and long. Factors facilitating desiccation tolerance are metabolic “switch-off” and intracellular dedifferentiation. Recalcitrant seeds lack these mechanisms, contributing significantly to their desiccation sensitivity. Consequently, recalcitrant seeds, which are shed at high water contents, can be stored only in the short-term, under conditions not allowing dehydration. The periods of such hydrated storage are constrained by germination that occurs without the need for extraneous water, and the proliferation of seed-associated fungi. Cryopreservation is viewed as the only option for long-term conservation of the germplasm of recalcitrant-seeded species. This is not easily achieved, as each of the necessary procedures imposes oxidative damage. Intact recalcitrant seeds cannot be cryopreserved, the common practice being to use excised embryos or embryonic axes as explants. Dehydration is a necessary procedure prior to exposure to cryogenic temperatures, but this is associated with metabolism-linked injury mediated by uncontrolled reactive oxygen species generation and failing anti-oxidant systems. While the extent to which this occurs can be curtailed by maximizing drying rate (flash drying) it cannot be completely obviated. Explant cooling for, and rewarming after, cryostorage must necessarily be rapid, to avoid ice crystallization. The ramifications of desiccation sensitivity are discussed, as are problems involved in cryostorage, particularly those accompanying dehydration and damage consequent upon ice crystallization. While desiccation sensitivity is a “fact” of seed recalcitrance, resolutions of the difficulties involved germplasm conservation are possible as discussed.", "corpus_id": 54554217, "score": 0 }, { "doc_id": "595899", "title": "Oleosins prevent oil-body coalescence during seed imbibition as suggested by a low-temperature scanning electron microscope study of desiccation-tolerant and -sensitive oilseeds", "abstract": "Abstract. In order to clarify further the physiological role of oleosins in seed development, we characterized the oil-body proteins of several oilseeds exhibiting a range of desiccation sensitivities from the recalcitrant (Theobroma cacao L., Quercus rubra L.), intermediate (Coffea arabica L., Azadirachta indica A. Juss.) and orthodox categories (Sterculia setigera Del., Brassica napus L.). The estimated ratio of putative oleosins to lipid in oil bodies of Q. rubra was less than 5% of the equivalent values for rapeseed oil bodies. No oleosin was detected in T. cacao oil bodies. In A. indica cotyledons, oil bodies contained very low amounts of putative oleosins. Oil bodies both from C. arabica and S. setigera exhibited a similar ratio of putative oleosins to lipid as found in rapeseed. In C. arabica seeds, the central domain of an oleosin was partially sequenced. Using a low temperature field-emission scanning electron microscope, the structural stability of oil bodies was investigated in seeds after drying, storage in cold conditions and rehydration. Despite the absence or relative dearth of oleosins in desiccation-sensitive, recalcitrant oilseeds, oil bodies remained relatively stable after slow or fast drying. In A. indica seeds exposed to a lethal cold storage treatment, no significant change in oil-body sizes was observed. In contrast, during imbibition of artificially dried seeds containing low amounts of putative oleosins, the oil bodies fused to form large droplets, resulting in the loss of cellular integrity. No damage to the oil bodies occurred in imbibed seeds of Q. rubra, C. arabica and S. setigera. Thus the rehydration phase appears to be detrimental to the stability of oil bodies when these are present in large amounts and are lacking oleosins. We therefore suggest that one of the functions of oleosins in oilseed development may be to stabilize oil bodies during seed imbibition prior to germination.", "corpus_id": 595899, "score": 0 }, { "doc_id": "910149", "title": "Arabidopsis Seed Development and Germination Is Associated with Temporally Distinct Metabolic Switches1[W]", "abstract": "While the metabolic networks in developing seeds during the period of reserve accumulation have been extensively characterized, much less is known about those present during seed desiccation and subsequent germination. Here we utilized metabolite profiling, in conjunction with selective mRNA and physiological profiling to characterize Arabidopsis (Arabidopsis thaliana) seeds throughout development and germination. Seed maturation was associated with a significant reduction of most sugars, organic acids, and amino acids, suggesting their efficient incorporation into storage reserves. The transition from reserve accumulation to seed desiccation was associated with a major metabolic switch, resulting in the accumulation of distinct sugars, organic acids, nitrogen-rich amino acids, and shikimate-derived metabolites. In contrast, seed vernalization was associated with a decrease in the content of several of the metabolic intermediates accumulated during seed desiccation, implying that these intermediates might support the metabolic reorganization needed for seed germination. Concomitantly, the levels of other metabolites significantly increased during vernalization and were boosted further during germination sensu stricto, implying their importance for germination and seedling establishment. The metabolic switches during seed maturation and germination were also associated with distinct patterns of expression of genes encoding metabolism-associated gene products, as determined by semiquantitative reverse transcription-polymerase chain reaction and analysis of publicly available microarray data. When taken together our results provide a comprehensive picture of the coordinated changes in primary metabolism that underlie seed development and germination in Arabidopsis. They furthermore imply that the metabolic preparation for germination and efficient seedling establishment initiates already during seed desiccation and continues by additional distinct metabolic switches during vernalization and early germination.", "corpus_id": 910149, "score": 0 }, { "doc_id": "21782546", "title": "Seed desiccation: a bridge between maturation and germination.", "abstract": "The development of orthodox seeds concludes by a desiccation phase. The dry seeds then enter a phase of dormancy, also called the after-ripening phase, and become competent for germination. We discuss physiological processes as well as gene expression and metabolic programs occurring during the desiccation phase in respect to their contribution to the desiccation tolerance, dormancy competence and successful germination of the dry seeds. The transition of developing seeds from the phase of reserve accumulation to desiccation is associated with distinct gene expression and metabolic switches. Interestingly, a significant proportion of the gene expression and metabolic signatures of seed desiccation resemble those characterizing seed germination, implying that the preparation of the seeds for germination begins already during seed desiccation.", "corpus_id": 21782546, "score": 0 }, { "doc_id": "25492149", "title": "Temporal profiling of the heat-stable proteome during late maturation of Medicago truncatula seeds identifies a restricted subset of late embryogenesis abundant proteins associated with longevity.", "abstract": "Developing seeds accumulate late embryogenesis abundant (LEA) proteins, a family of intrinsically disordered and hydrophilic proteins that confer cellular protection upon stress. Many different LEA proteins exist in seeds, but their relative contribution to seed desiccation tolerance or longevity (duration of survival) is not yet investigated. To address this, a reference map of LEA proteins was established by proteomics on a hydrophilic protein fraction from mature Medicago truncatula seeds and identified 35 polypeptides encoded by 16 LEA genes. Spatial and temporal expression profiles of the LEA polypeptides were obtained during the long maturation phase during which desiccation tolerance and longevity are sequentially acquired until pod abscission and final maturation drying occurs. Five LEA polypeptides, representing 6% of the total LEA intensity, accumulated upon acquisition of desiccation tolerance. The gradual 30-fold increase in longevity correlated with the accumulation of four LEA polypeptides, representing 35% of LEA in mature seeds, and with two chaperone-related polypeptides. The majority of LEA polypeptides increased around pod abscission during final maturation drying. The differential accumulation profiles of the LEA polypeptides suggest different roles in seed physiology, with a small subset of LEA and other proteins with chaperone-like functions correlating with desiccation tolerance and longevity.", "corpus_id": 25492149, "score": 0 }, { "doc_id": "85224408", "title": "An integrated overview of seed development in Arabidopsis thaliana ecotype WS", "abstract": "This work is part of a research program aiming at identifying and studying genes involved in Arabidopsis thaliana seed maturation. We focused here on the Wassilewskija ecotype seed development and linked physiological and biochemical data, including protein, oil, soluble sugars, starch and free amino acid measurements, to embryo development, to obtain a complete and thorough reference data set. A. thaliana seed development can be divided into three stages. During early embryogenesis (i.e. morphogenesis), seed weight and lipid content were low whereas important amounts of starch were transiently accumulated. In the second stage, or maturation phase, a rapid increase in seed dry weight was observed and storage oils and proteins were accumulated in large quantities, accounting for approximately 40% of dry matter each at the end of this stage. During the third and last stage (late maturation including acquisition of desiccation tolerance), seed dry weight remained constant while an acute loss of water took place in the seed. Storage compound synthesis ended concomitantly with sucrose, stachyose and raffinose accumulation. This study revealed the occurrence of metabolic activities such as protein synthesis, in the final phase of embryo desiccation. A striking correlation between peaks in hexose to sucrose ratio and transition phases during embryogenesis was observed.", "corpus_id": 85224408, "score": 0 }, { "doc_id": "12603829", "title": "The continuing conundrum of the LEA proteins", "abstract": "Research into late embryogenesis abundant (LEA) proteins has been ongoing for more than 20 years but, although there is a strong association of LEA proteins with abiotic stress tolerance particularly dehydration and cold stress, for most of that time, their function has been entirely obscure. After their initial discovery in plant seeds, three major groups (numbered 1, 2 and 3) of LEA proteins have been described in a range of different plants and plant tissues. Homologues of groups 1 and 3 proteins have also been found in bacteria and in certain invertebrates. In this review, we present some new data, survey the biochemistry, biophysics and bioinformatics of the LEA proteins and highlight several possible functions. These include roles as antioxidants and as membrane and protein stabilisers during water stress, either by direct interaction or by acting as molecular shields. Along with other hydrophilic proteins and compatible solutes, LEA proteins might also serve as “space fillers” to prevent cellular collapse at low water activities. This multifunctional capacity of the LEA proteins is probably attributable in part to their structural plasticity, as they are largely lacking in secondary structure in the fully hydrated state, but can become more folded during water stress and/or through association with membrane surfaces. The challenge now facing researchers investigating these enigmatic proteins is to make sense of the various in vitro defined functions in the living cell: Are the LEA proteins truly multi-talented, or are they still just misunderstood?", "corpus_id": 12603829, "score": 0 }, { "doc_id": "86253744", "title": "A review of recalcitrant seed physiology in relation to desiccation-tolerance mechanisms", "abstract": "A suite of mechanisms or processes that together have been implicated in the acquisition and maintenance of desiccation tolerance in orthodox seeds is discussed in the context of the behaviour of desiccation-sensitive seeds, and where appropriate, parallels are drawn with the situation in vegetative plant tissues that tolerate dehydration. Factors included are: physical characteristics of cells and intracellular constituents; insoluble reserve accumulation; intracellular de-differentiation; metabolic ‘switching off’; presence, and efficient operation, of antioxidant systems; accumulation of putatively protective substances including LEAs, sucrose and other oligosaccharides, as well as amphipathic molecules; the presence and role of oleosins; and the presence and operation of repair systems during rehydration. The variable response to dehydration shown by desiccation-sensitive seeds is considered in terms of the absence or incomplete expression of this suite of mechanisms or processes. Three categories of damage are envisaged: (i) reduction in cell volume which can lead to mechanical damage; (ii) aqueous-based degradative processes, probably consequent upon deranged metabolism at intermediate water contents. This is termed ‘metabolism-induced damage’ and its extent will depend upon the metabolic rate and the rate of dehydration; and (iii) the removal of water intimately associated with macromolecular surfaces leading to denaturation: this is referred to as desiccation damage sensu stricto . The effects of drying rate and the maturity status of seeds are considered in relation to the responses to dehydration, leading to the conclusion that the concept of critical water contents on a species basis is inappropriate. Viewing seed postharvest physiology in terms of a continuum of behaviour is considered to be more realistic than attempting precise categorization. Rapid dehydration of excised embryonic axes (or other explants) from desiccation-sensitive seeds permits retention of viability (in the short term) to water contents approaching the level of non-freezable water. This opens up the possibility of long-term conservation, by cryopreservation techniques, of the genetic resources of species producing non-orthodox seeds.", "corpus_id": 86253744, "score": 0 }, { "doc_id": "16179148", "title": "Regulation of the seed to seedling developmental phase transition by the LAFL and VAL transcription factor networks", "abstract": "In the seed, a fundamental transition between embryo and vegetative phases of plant development is coordinated by the interaction between the AFL and VAL sub‐clades of the plant specific B3 domain transcription factor family. The AFL B3 factors together with LEC1‐type HAP3 transcription factors promote embryo maturation; whereas the VAL B3 factors repress the LEC1/AFL (LAFL) network during seed germination. Recent advances reveal that genes in key developmental programs and hormone signaling pathways are downstream targets of the LAFL network highlighting the central role of the LAFL network in integration of intrinsic developmental and hormonal signals during plant development. The VAL B3 proteins are proposed to mediate repression by recruiting a histone deacetylase complex (HDAC) to LAFL genes that contain the Sph/RY cis‐element recognized by AFL and VAL B3‐DNA‐binding domains. In addition to VAL B3 factors, epigenetic mechanisms are implicated in maintaining repression of LAFL network during vegetative development. WIREs Dev Biol 2014, 3:135–145. doi: 10.1002/wdev.126", "corpus_id": 16179148, "score": 0 }, { "doc_id": "7360185", "title": "Isolation of the Arabidopsis ABI3 gene by positional cloning.", "abstract": "Arabidopsis abi3 mutants are altered in various aspects of seed development and germination that reflect a decreased responsiveness to the hormone abscisic acid. The ABI3 gene has been isolated by positional cloning. A detailed restriction fragment length polymorphism (RFLP) map of the abi3 region was constructed. An RFLP marker closely linked to the abi3 locus was identified, and by analyzing an overlapping set of cosmid clones containing this marker, the abi3 locus was localized within a 35-kb region. An 11-kb subfragment was then shown to complement the mutant phenotype in transgenic plants, thereby further delimiting the position of the locus. A candidate ABI3 gene was identified within this fragment as being expressed in developing fruits. The primary structure of the encoded protein was deduced from sequence analysis of a corresponding cDNA clone. In the most severe abi3-4 allele, the size of this predicted protein was reduced by 40% due to the presence of a point mutation that introduced a premature stop codon. The predicted ABI3 protein displays discrete regions of high similarity to the maize viviparous-1 protein.", "corpus_id": 7360185, "score": 0 }, { "doc_id": "16522018", "title": "Arabidopsis LEAFY COTYLEDON1 Is Sufficient to Induce Embryo Development in Vegetative Cells", "abstract": "The Arabidopsis LEAFY COTYLEDON1 (LEC1) gene is required for the specification of cotyledon identity and the completion of embryo maturation. We isolated the LEC1 gene and showed that it functions at an early developmental stage to maintain embryonic cell fate. The LEC1 gene encodes a transcription factor homolog, the CCAAT box-binding factor HAP3 subunit. LEC1 RNA accumulates only during seed development in embryo cell types and in endosperm tissue. Ectopic postembryonic expression of the LEC1 gene in vegetative cells induces the expression of embryo-specific genes and initiates formation of embryo-like structures. Our results suggest that LEC1 is an important regulator of embryo development that activates the transcription of genes required for both embryo morphogenesis and cellular differentiation.", "corpus_id": 16522018, "score": 0 }, { "doc_id": "24259393", "title": "FUSCA3 encodes a protein with a conserved VP1/AB13-like B3 domain which is of functional importance for the regulation of seed maturation in Arabidopsis thaliana.", "abstract": "Conditionally lethal mutant alleles of the FUSCA3 (FUS3) gene of Arabidopsis thaliana are specifically defective in the gene expression program responsible for seed maturation. FUS3 was isolated by map-based cloning and expression of the FUS3 cDNA resulted in complementation of the Fus3- phenotype. In the predicted FUS3 gene product, a continuous stretch of more than 100 amino acids shows significant sequence similarity to the B3 domains of the polypeptides encoded by ABI3 (Arabidopsis) and VP1 (maize). FUS3 transcription was detected mainly in siliques and was found to be developmentally regulated during embryogenesis. Transcripts of abnormal sizes were observed in fus3 mutants due to aberrant splicing caused by point mutations at intron termini. Sequence analysis of mutant and wild-type FUS3 alleles, as well as sequencing of fus3 cDNAs, revealed small inframe deletions at two different sites of the coding region. While a deletion between B3 and the C-terminus of the predicted polypeptide was found in conjunction with normal FUS3 function, another deletion located within the conserved B3 domain (as well as truncations therein) were associated with the Fus3- phenotype. It is apparent, therefore, that an intact B3 domain is essential for the regulation of seed maturation by FUS3.", "corpus_id": 24259393, "score": 0 }, { "doc_id": "26889629", "title": "LEAFY COTYLEDON2 encodes a B3 domain transcription factor that induces embryo development", "abstract": "The Arabidopsis LEAFY COTYLEDON2 (LEC2) gene is a central embryonic regulator that serves critical roles both early and late during embryo development. LEC2 is required for the maintenance of suspensor morphology, specification of cotyledon identity, progression through the maturation phase, and suppression of premature germination. We cloned the LEC2 gene on the basis of its chromosomal position and showed that the predicted polypeptide contains a B3 domain, a DNA-binding motif unique to plants that is characteristic of several transcription factors. We showed that LEC2 RNA accumulates primarily during seed development, consistent with our finding that LEC2 shares greatest similarity with the B3 domain transcription factors that act primarily in developing seeds, VIVIPAROUS1/ABA INSENSITIVE3 and FUSCA3. Ectopic, postembryonic expression of LEC2 in transgenic plants induces the formation of somatic embryos and other organ-like structures and often confers embryonic characteristics to seedlings. Together, these results suggest that LEC2 is a transcriptional regulator that establishes a cellular environment sufficient to initiate embryo development.", "corpus_id": 26889629, "score": 0 }, { "doc_id": "18956711", "title": "LEA polypeptide profiling of recalcitrant and orthodox legume seeds reveals ABI3-regulated LEA protein abundance linked to desiccation tolerance", "abstract": "In contrast to orthodox seeds that acquire desiccation tolerance during maturation, recalcitrant seeds are unable to survive drying. These desiccation-sensitive seeds constitute an interesting model for comparative analysis with phylogenetically close species that are desiccation tolerant. Considering the importance of LEA (late embryogenesis abundant) proteins as protective molecules both in drought and in desiccation tolerance, the heat-stable proteome was characterized in cotyledons of the legume Castanospermum australe and it was compared with that of the orthodox model legume Medicago truncatula. RNA sequencing identified transcripts of 16 homologues out of 17 LEA genes for which polypeptides are detected in M. truncatula seeds. It is shown that for 12 LEA genes, polypeptides were either absent or strongly reduced in C. australe cotyledons compared with M. truncatula seeds. Instead, osmotically responsive, non-seed-specific dehydrins accumulated to high levels in the recalcitrant cotyledons compared with orthodox seeds. Next, M. truncatula mutants of the ABSCISIC ACID INSENSITIVE3 (ABI3) gene were characterized. Mature Mtabi3 seeds were found to be desiccation sensitive when dried below a critical water content of 0.4g H2O g DW–1. Characterization of the LEA proteome of the Mtabi3 seeds revealed a subset of LEA proteins with severely reduced abundance that were also found to be reduced or absent in C. australe cotyledons. Transcripts of these genes were indeed shown to be ABI3 responsive. The results highlight those LEA proteins that are critical to desiccation tolerance and suggest that comparable regulatory pathways responsible for their accumulation are missing in both desiccation-sensitive genotypes, revealing new insights into the mechanistic basis of the recalcitrant trait in seeds.", "corpus_id": 18956711, "score": 0 }, { "doc_id": "20918739", "title": "ABI3 controls embryo degreening through Mendel's I locus", "abstract": "Significance Occurrence of mature green seeds in oil-seed crops such as canola and soybean causes severe losses in revenue. Retention of chlorophyll in seeds can be an undesirable trait as it affects seed maturation, seed oil, and meal quality. We show that the abscisic acid (ABA, plant hormone) dependent transcription factor ABSCISIC ACID INSENSITIVE 3 (ABI3), confers seed degreening by regulating Mendel’s stay-green genes. This study unveils a new role for ABI3 in removal of seed chlorophyll in addition to its functions in embryo maturation and conferring desiccation tolerance. This pathway could be manipulated to tackle the cold-induced green seed problem in oil-seed crops. Chlorophyll (chl) is essential for light capture and is the starting point that provides the energy for photosynthesis and thus plant growth. Obviously, for this reason, retention of the green chlorophyll pigment is considered a desirable crop trait. However, the presence of chlorophyll in mature seeds can be an undesirable trait that can affect seed maturation, seed oil quality, and meal quality. Occurrence of mature green seeds in oil crops such as canola and soybean due to unfavorable weather conditions during seed maturity is known to cause severe losses in revenue. One recently identified candidate that controls the chlorophyll degradation machinery is the stay-green gene, SGR1 that was mapped to Mendel’s I locus responsible for cotyledon color (yellow versus green) in peas. A defect in SGR1 leads to leaf stay-green phenotypes in Arabidopsis and rice, but the role of SGR1 in seed degreening and the signaling machinery that converges on SGR1 have remained elusive. To decipher the gene regulatory network that controls degreening in Arabidopsis, we have used an embryo stay-green mutant to demonstrate that embryo degreening is achieved by the SGR family and that this whole process is regulated by the phytohormone abscisic acid (ABA) through ABSCISIC ACID INSENSITIVE 3 (ABI3); a B3 domain transcription factor that has a highly conserved and essential role in seed maturation, conferring desiccation tolerance. Misexpression of ABI3 was sufficient to rescue cold-induced green seed phenotype in Arabidopsis. This finding reveals a mechanistic role for ABI3 during seed degreening and thus targeting of this pathway could provide a solution to the green seed problem in various oil-seed crops.", "corpus_id": 20918739, "score": 0 }, { "doc_id": "85378516", "title": "A mutant of Arabidopsis which is defective in seed development and storage protein accumulation is a new abi3 allele", "abstract": "Summary\r\nIn order to investigate the role of the plant hormones gibberellin (GA) and abscisic acid (ABA) in seed development and germination the GA biosynthetic inhibitor, Uniconazol, was used to isolate mutants with abnormal germination profiles. In one of these mutants, the ability to germinate on Uniconazol is due to a mutation in the ABI3 gene. However, unlike the previously reported abi3 mutant, this line displays an array of seed-specific developmental defects. The accumulation of seed reserve proteins is dramatically reduced due to reduced levels of the storage protein mRNA. The embryos remain green throughout development and are desiccation intolerant. However, immature seeds are completely non-dormant and grow normally. These results suggest the ABI3 gene is essential for the synthesis of seed storage proteins and for the protection of the embryo during desiccation.", "corpus_id": 85378516, "score": 0 }, { "doc_id": "89137398", "title": "A regulatory role for the ABI3 gene in the establishment of embryo maturation in Arabidopsis thaliana", "abstract": "The ABI3 gene product of Arabidopsis is essential for correct completion of seed maturation. A severe mutant allele at this locus results in seed that remain green, fail to establish desiccation tolerance, and that germinate at a developmental stage when wild-type seed will not. Moreover, the formation of leaf primordia and xylem differentiation, both characteristic of germinating wild-type seedlings, can be observed in embryos harvested 12 days after flowering. Thus, mature abi3 embryos reach a developmental state that more closely resembles the character of a developing seedling rather than that of a dormant embryo. Previous studies of this gene have resulted in the suggestion that ABI3 is a transducer of abscisic acid induced seed dormancy. Our results demonstrate that the ABI3 gene product can be most accurately described as one of the major regulators of the transition between embryo maturation and early seedling development, rather than simply a transducer of the abscisic acid signal.", "corpus_id": 89137398, "score": 0 }, { "doc_id": "205606156", "title": "Natural modifiers of seed longevity in the Arabidopsis mutants abscisic acid insensitive3-5 (abi3-5) and leafy cotyledon1-3 (lec1-3).", "abstract": "*Seed longevity is an important trait in many crops and is essential for the success of most land plant species. Current knowledge of its molecular regulation is limited. The Arabidopsis mutants abscisic acid insensitive3-5 (abi3-5) and leafy cotyledon1-3 (lec1-3) have impaired seed maturation and quickly lose seed viability. abi3-5 and lec1-3 were used as sensitized genetic backgrounds for the study of seed longevity. *We exploited the natural variation of Arabidopsis to create introgression lines from the Seis am Schlern and Shahdara accessions in, respectively, the abi3-5 and lec1-3 backgrounds. These lines carry natural modifiers of the abi3 and lec1 phenotypes. Longevity tests and a proteomic analysis were conducted to describe the seed physiology of each line. *The modifier lines showed improved seed longevity. The Shahdara modifiers can partially re-establish the seed developmental programs controlled by LEC1 and restore the accumulation of seed storage proteins that are reduced in abi3-5 and lec1-3. *The isolation and characterization of natural modifiers of the seed maturation mutants abi3-5 and lec1-3, and the analysis of their seed proteomes, advance our current understanding of seed longevity.", "corpus_id": 205606156, "score": 0 }, { "doc_id": "86705889", "title": "The re-establishment of desiccation tolerance in germinated radicles of Medicago truncatula Gaertn. seeds", "abstract": "Germinated seeds of Medicago truncatula Gaertn. with a protruded radicle length of 2.7 mm did not survive drying below 0.2 g H2O g–1 dw, as indicated by vital stain assays and the absence of growth resumption after rehydration. The re-establishment of desiccation tolerance was achieved using an osmotic treatment with polyethylene glycol (PEG), combined with a cold treatment. The ability to regain desiccation tolerance after germination was restricted to a period of growth characterized by radicle lengths between 1 and 3 mm. After PEG treatment of germinated seeds with 2.7 mm long radicles at –1.7 MPa at 10°C for 3 d and subsequent drying to 0.04 g H2O g–1 dw, 90% survived and developed into normal seedlings after rehydration. Desiccation tolerance could also be re-established in excised radicles, demonstrating that cotyledons were not essential for this process. Upon PEG incubation, sucrose accumulated rapidly prior to the re-establishment of desiccation tolerance in germinated radicles, regardless of the presence of cotyledons. Induction of MtDHN (a dehydrin) gene expression was correlated with the re-establishment of desiccation tolerance. Furthermore, the PEG-induced expression of MtDHN was repressed when fluridone was added to the PEG solution.", "corpus_id": 86705889, "score": 1 }, { "doc_id": "83886192", "title": "Loss of desiccation tolerance during germination in neo-tropical pioneer seeds: implications for seed mortality and germination characteristics†", "abstract": "Abstract Orthodox, desiccation-tolerant seeds lose desiccation tolerance during germination. Here, we quantify the timing of the loss of desiccation tolerance, and explore the implications of this event for seed mortality and the shape of germination progress curves for pioneer tree species. For the nine species studied, all seeds in a seedlot lost desiccation tolerance after the same fixed proportion of their time to germination, and this proportion was fairly constant across the species (0.63–0.70). The loss of desiccation tolerance after a fixed proportion of the time to germination has the implication that the maximum number of seeds in a seedlot that can be killed by a single drying event during germination (Mmax) increases with an increasing time to 50% germination (t50) and an increasing slope of the germination progress curve. Consequently, to prevent the seed population from becoming highly vulnerable to desiccation-induced mortality, species with a greater t50 would be expected to have a shallower germination progress curve. In conclusion, these data suggest that the loss of desiccation tolerance during germination may constitute a significant, but previously unexplored, source of mortality for seeds in seasonal environments with unpredictable rainfall.", "corpus_id": 83886192, "score": 0 }, { "doc_id": "85819579", "title": "Disappearance of desiccation tolerance of imbibed crop seeds is not associated with the decline of oligosaccharides", "abstract": "The relationship between sugar content and loss of desiccation tolerance of hydrated crop seeds (tomato, okra, snow pea, mung bean, and cucumber) was evaluated by imbibing seeds with or without ABA, followed by dehydration and germination. During the process of hydration, but before the seeds lost desiccation tolerance, monosaccharide content increased only slightly, sucrose increased in snow pea, mung bean and cucumber, but maintained its original level in other species and the oligosaccharides declined dramatically. At the time of losing desiccation tolerance, the sucrose content of imbibed seeds was 2-3 times higher than the original level in most species. Positive significant correlation coefficients (r) were found in many, but not all crop seeds between desiccation tolerance and the oligosaccharide mass, or oligo/sucrose ratio. The ratio of oligo/sucrose in intact seeds at the time of losing desiccation tolerance, however, was not a fixed value and varied among species. Oligosaccharides declined significantly in different seed parts of imbibed cucumber seeds while sucrose increased to a higher level in the radicle than in the hypocotyl. Radicles were far more sensitive to desiccation than hypocotyls. The same observation was found for cucumber seeds imbibed in 100 μM ABA, yet desiccation tolerance was largely maintained in hypocotyls and cotyledons. It is concluded that sucrose and oligosaccharides are not the determinants of the loss of desiccation tolerance in hydrated seeds. Imbibed seeds did not show any differences between seed parts in their ability to resynthesize sugars during the process of slow dehydration. Differences in sensitivity to desiccation among seed parts were not due to differences in the initial water content or to the rate of water content increase among seed parts. Physiological regulation of the loss of desiccation tolerance in crop seeds during hydration is discussed.", "corpus_id": 85819579, "score": 0 }, { "doc_id": "86639704", "title": "Induction of desiccation tolerance in germinated seeds", "abstract": "The induction of desiccation tolerance in germinated seeds by incubation in PEG for several days is reported. The induction coincided with an increased sucrose content and the formation of heat-soluble proteins. Germinated seeds can serve as a convenient model system in studies of desiccation tolerance. This finding may have important implications for the agricultural industry.", "corpus_id": 86639704, "score": 0 }, { "doc_id": "25524663", "title": "Abscisic acid (ABA) sensitivity regulates desiccation tolerance in germinated Arabidopsis seeds.", "abstract": "During germination, orthodox seeds lose their desiccation tolerance (DT) and become sensitive to extreme drying. Yet, DT can be rescued, in a well-defined developmental window, by the application of a mild osmotic stress before dehydration. A role for abscisic acid (ABA) has been implicated in this stress response and in DT re-establishment. However, the path from the sensing of an osmotic cue and its signaling to DT re-establishment is still largely unknown. Analyses of DT, ABA sensitivity, ABA content and gene expression were performed in desiccation-sensitive (DS) and desiccation-tolerant Arabidopsis thaliana seeds. Furthermore, loss and re-establishment of DT in germinated Arabidopsis seeds was studied in ABA-deficient and ABA-insensitive mutants. We demonstrate that the developmental window in which DT can be re-established correlates strongly with the window in which ABA sensitivity is still present. Using ABA biosynthesis and signaling mutants, we show that this hormone plays a key role in DT re-establishment. Surprisingly, re-establishment of DT depends on the modulation of ABA sensitivity rather than enhanced ABA content. In addition, the evaluation of several ABA-insensitive mutants, which can still produce normal desiccation-tolerant seeds, but are impaired in the re-establishment of DT, shows that the acquisition of DT during seed development is genetically different from its re-establishment during germination.", "corpus_id": 25524663, "score": 1 }, { "doc_id": "25716821", "title": "Stress-associated factors increase after desiccation of germinated seeds of Tabebuia impetiginosa Mart.", "abstract": "Improved re-establishment of desiccation tolerance was studied in germinated seeds of Tabebuia impetiginosa Mart. by exposing to a polyethylene glycol solution prior to desiccation. The effects of different osmotic potentials and drying rates were studied. In addition, temporary temperature stress and exogenous abscisic acid were applied to evaluate their effect on desiccation tolerance of the protruded radicle. An osmotic potential of −1.7 MPa at 5°C followed by slow drying was most effective in the re-establishment of desiccation tolerance in protruded radicles with a length up to 3 mm. An osmotic potential of −1.4 or −2.0 MPa was less effective. Fast drying completely prevented the re-induction of desiccation tolerance. Cold shock or heat shock prior to osmotic treatment as well as abscisic acid added to the osmotic solution improved desiccation tolerance of protruded radicles. Surprisingly, survival of the germinated seed did not depend on re-establishment of desiccation tolerance in the protruded radicle. Even after the protruded radicle became necrotic and died, the production of adventitious roots from the hypocotyls allowed for survival and the development of high quality seedlings. Thus, T. impetiginosa appeared to be well adapted to the seasonally dry biome in which the species thrives via mechanisms that offer protection against desiccation in the young seedling stage.", "corpus_id": 25716821, "score": 0 }, { "doc_id": "8202445", "title": "Metabolic dysfunction and unabated respiration precede the loss of membrane integrity during dehydration of germinating radicles.", "abstract": "This study shows that dehydration induces imbalanced metabolism before loss of membrane integrity in desiccation-sensitive germinated radicles. Using a photoacoustic detection system, responses of CO(2) emission and fermentation to drying were analyzed non-invasively in desiccation-tolerant and -intolerant radicles of cucumber (Cucumis sativa) and pea (Pisum sativum). Survival after drying and a membrane integrity assay showed that desiccation tolerance was present during early imbibition and lost in germinated radicles. However, tolerance could be re-induced in germinated cucumber radicles by incubation in polyethylene glycol before drying. Tolerant and polyethylene glycol (PEG)-induced tolerant radicles exhibited a much-reduced CO(2) production before dehydration compared with desiccation-sensitive radicles. This difference was maintained during dehydration. In desiccation-sensitive tissues, dehydration induced an increase in the emission of acetaldehyde and ethanol that peaked well before the loss of membrane integrity. Acetaldehyde emission from sensitive radicles was significantly reduced when dehydration occurred in 50% O(2) instead of air. Acetaldehyde/ethanol were not detected in dehydrating tolerant radicles of either species or in polyethylene glycol-induced tolerant cucumber radicles. Thus, a balance between down-regulation of metabolism during drying and O(2) availability appears to be associated with desiccation tolerance. Using Fourier transform infrared spectroscopy, acetaldehyde was found to disturb the phase behavior of phospholipid vesicles, suggesting that the products resulting from imbalanced metabolism in seeds may aggravate membrane damage induced by dehydration.", "corpus_id": 8202445, "score": 0 }, { "doc_id": "86164128", "title": "Desiccation and survival in the recalcitrant seeds of Avicennia marina: DNA replication, DNA repair and protein synthesis", "abstract": "Abstract An autoradiographic study was made of leucine and thymidine incorporation into the meristematic root primordia and hypocotyl tips of seeds of the recalcitrant mangrove species, Avicennia marina. The investigations show that although there is a temporary reduction of protein synthesis at shedding, root primordia and surrounding hypocotyl cells of the axis never wholly cease incorporation of [3H]leucine and regain pre-shedding levels of activity within a day. Precursor studies using methyl-[3H]thymidine show that, at shedding, there is a temporary cessation of incorporation into root meristem nuclei that lasts no longer than 48 h and, within a day, pre-shedding levels are regained in the meristem nuclei. Analysis of DNA fragmentation patterns in root tips at the time of shedding, and their ability to repair radiation-induced DNA damage, indicate that DNA repair processes are markedly compromised in these cells if water loss reaches 22%. Protein synthesis and DNA replication are reduced by more than half by a water loss of 18% and 16%, respectively. DNA replication does not fully recover on rehydration after only 8% water loss. DNA fragmentation to nucleosomes indicates a programme of cell death at a water loss of 10%. We suggest that the feature of continuous protein synthesis activity with only a temporary interruption in active cell cycling in A. marina root primordia helps to explain both the rapidity in seedling establishment and the extreme vulnerability to desiccation.", "corpus_id": 86164128, "score": 0 }, { "doc_id": "7390695", "title": "Changes in DNA and microtubules during loss and re-establishment of desiccation tolerance in germinating Medicago truncatula seeds.", "abstract": "Desiccation tolerance (DT) in orthodox seeds is acquired during seed development and lost upon imbibition/germination, purportedly upon the resumption of DNA synthesis in the radicle cells. In the present study, flow cytometric analyses and visualization of microtubules (MTs) in radicle cells of seedlings of Medicago truncatula showed that up to a radicle length of 2 mm, there is neither DNA synthesis nor cell division, which were first detected in radicles with a length of 3 mm. However, DT started to be lost well before the resumption of DNA synthesis, when germinating seeds were dried back. By applying an osmotic treatment with polyethylene glycol (PEG) before dehydration, it was possible to re-establish DT in seedlings with a radicle up to 2 mm long. Dehydration of seedlings with a 2 mm radicle, with or without PEG treatment, caused disassembly of MTs and appearance of tubulin granules. Subsequent pre-humidification led to an almost complete disappearance of both MTs and tubulin granules. Upon rehydration, neither MTs nor tubulin granules were detected in radicle cells of untreated seedlings, while PEG-treated seedlings were able to reconstitute the microtubular cytoskeleton and continue their normal development. Dehydration of untreated seedlings also led to an apoptotic-like DNA fragmentation in radicle cells, while in PEG-treated seedlings DNA integrity was maintained. The results showed that for different cellular components, desiccation-tolerant seedlings may apply distinct strategies to survive dehydration, either by avoidance or further repair of the damages.", "corpus_id": 7390695, "score": 0 }, { "doc_id": "86354364", "title": "DNA and desiccation tolerance", "abstract": "This article reviews mechanisms by which specialized cells of different life forms have overcome the lethal effects of dehydration and considers how the maintenance of genetic information is central to survival As a dynamic and hydrated molecule in vivo, DNA can assume different conformational structures depending upon the water activity, the base sequence and the presence of specific binding proteins The attainment of stable secondary structures that are resistant to degradation in vivo at low water potentials is proposed as a likely accompaniment to desiccation tolerance In addition, chemical modification of bases in DNA, the extent of methylation and conformational changes could determine the expression of different gene sequences as cells pass from desiccation-tolerant to desiccationintolerant states We monitored the integrity of extracted DNA in embryos of seeds and in winddispersed pollen during transition from their desiccation tolerance to desiccation intolerance on hydration and germination. We present evidence to show that the DNA of these two stages is different and that it is the DNA from desiccation-tolerant cells only that retains integrity when the cells are subjected to desiccation regimes We discuss these findings in relation to certain hydration-sensitive DNA structures and to other relevant biological systems", "corpus_id": 86354364, "score": 0 }, { "doc_id": "86799326", "title": "Influence of priming-induced nuclear replication activity on storability of pepper ( Capsicum annuum L.) seed", "abstract": "The effect of two priming treatments in PEG solutions on nuclear replication stages of pepper ( Capsicum annuum L.) embryos were evaluated using flow cytometry. Priming at −1.1 MPa for 10 d induced almost 40% of nuclei in the embryo root tips to enter the synthetic phase of nuclear division, while no DNA synthesis occurred during 6 d at−1.5 MPa and in less than 10% of the nuclei at 10 d. Both priming treatments effectively increased seed performance. A decrease of 2.7 d in mean germination time (MGT) was observed after priming in PEG solution at −1.1 MPa, while the treatment at−1.5 MPa lowered the MGT by 2.1 d. Primed and untreated seeds were subjected to controlled deterioration treatments by exposure to 45°C after equilibration at 75% RH. Both osmotic treatments considerably lowered seed tolerance to adverse storage conditions as compared with untreated seeds. However, seeds in which DNA replication was induced by priming were more sensitive to controlled deterioration than seeds in which priming did not induce nuclei to enter the synthetic phase. This could be a consequence of a higher DNA content, which is a more vulnerable target for mutation inducing factors. Alternatively the increased sensitivity could be a consequence of their more advanced progress in germinative events, making seeds less resistant to deteriorative factors imposed during storage. On the whole, from the present results it appears that the nucleic acid DNA content of the embryo only plays an additive role in influencing seed storability.", "corpus_id": 86799326, "score": 0 }, { "doc_id": "35080633", "title": "A plant DNA ligase is an important determinant of seed longevity.", "abstract": "DNA repair is important for maintaining genome integrity. In plants, DNA damage accumulated in the embryo of seeds is repaired early in imbibition, and is important for germination performance and seed longevity. An essential step in most repair pathways is the DNA ligase-mediated rejoining of single- and double-strand breaks. Eukaryotes possess multiple DNA ligase enzymes, each having distinct roles in cellular metabolism. Here, we report the characterization of DNA LIGASE VI, which is only found in plant species. The primary structure of this ligase shows a unique N-terminal region that contains a β-CASP motif, which is found in a number of repair proteins, including the DNA double-strand break (DSB) repair factor Artemis. Phenotypic analysis revealed a delay in the germination of atlig6 mutants compared with wild-type lines, and this delay becomes markedly exacerbated in the presence of the genotoxin menadione. Arabidopsis atlig6 and atlig6 atlig4 mutants display significant hypersensitivity to controlled seed ageing, resulting in delayed germination and reduced seed viability relative to wild-type lines. In addition, atlig6 and atlig6 atlig4 mutants display increased sensitivity to low-temperature stress, resulting in delayed germination and reduced seedling vigour upon transfer to standard growth conditions. Seeds display a rapid transcriptional DNA DSB response, which is activated in the earliest stages of water imbibition, providing evidence for the accumulation of cytotoxic DSBs in the quiescent seed. These results implicate AtLIG6 and AtLIG4 as major determinants of Arabidopsis seed quality and longevity.", "corpus_id": 35080633, "score": 0 }, { "doc_id": "6577999", "title": "The loss of desiccation tolerance during germination: An ultrastructural and biochemical approach", "abstract": "SummaryRye embryos of high viability and vigour can be imbibed for 1 hour, dehydrated and subsequently rehydrated without harm. However, extension of the imbibition period results in progressive structural damage to cells of both the embryonic root and the coleorhiza. Greatest sensitivity to this treatment is shown by the microtubule assembly system and the plasmalemma which loses its integrity permitting the egress of ribosomes and lipid towards the cell wall. Further stress results in fragmentation of the endoplasmic reticulum, disruption of plastid, mitochondrial and nuclear membranes and the dispersion of the contents of provacuoles. Damage is initiated during the drying of imbibed embryos but it is compounded by subsequent rehydration. Coleorhiza cells, particularly those distal to the root, which normally develop very rapidly during the early hours of germination are most sensitive to desiccation. The onset of sensitivity to desiccation (ca. 3 hours after imbibition) corresponds with a transitory halt in the increasing rate of protein synthesis and with the start of DNA replication. These results are discussed in relation to DNA repair and the “hardening” of seeds to stimulate rapid growth following rehydration.", "corpus_id": 6577999, "score": 0 }, { "doc_id": "35044476", "title": "Genetic Analysis of Desiccation Tolerance in Saccharomyces cerevisiae", "abstract": "Desiccation tolerance, the ability to survive nearly total dehydration, is a rare strategy for survival and reproduction observed in all taxa. However, the mechanism and regulation of this phenomenon are poorly understood. Correlations between desiccation tolerance and potential effectors have been reported in many species, but their physiological significance has not been established in vivo. Although the budding yeast Saccharomyces cerevisiae exhibits extreme desiccation tolerance, its usefulness has been hampered by an inability to reduce tolerance more than a few fold by physiological or genetic perturbations. Here we report that fewer than one in a million yeast cells from low-density logarithmic cultures survive desiccation, while 20–40% of cells from saturated cultures survive. Using this greatly expanded metric, we show that mutants defective in trehalose biosynthesis, hydrophilins, responses to hyperosmolarity, and hypersalinity, reactive oxygen species (ROS) scavenging and DNA damage repair nevertheless retain wild-type levels of desiccation tolerance, suggesting that this trait involves a unique constellation of stress factors. A genome-wide screen for mutants that render stationary cells as sensitive as log phase cells identifies only mutations that block respiration. Respiration as a prerequisite for acquiring desiccation tolerance is corroborated by respiration inhibition and by growth on nonfermentable carbon sources. Suppressors bypassing the respiration requirement for desiccation tolerance reveal at least two pathways, one of which, involving the Mediator transcription complex, is associated with the shift from fermentative to respiratory metabolism. Further study of these regulators and their targets should provide important clues to the sensors and effectors of desiccation tolerance.", "corpus_id": 35044476, "score": 0 }, { "doc_id": "8987036", "title": "TOR and RAS pathways regulate desiccation tolerance in Saccharomyces cerevisiae", "abstract": "Desiccation is thought to impose many stresses. Which of these stresses is responsible for desiccation-induced death and how the stress response is regulated are unknown, however. Here we use Saccharomyces cerevisiae to show that reduction of a 60S biogenesis intermediate via RAS or TOR down-regulation increases desiccation tolerance.", "corpus_id": 8987036, "score": 0 }, { "doc_id": "10410648", "title": "Comparative Analysis of the Heat Stable Proteome of Radicles of Medicago truncatula Seeds during Germination Identifies Late Embryogenesis Abundant Proteins Associated with Desiccation Tolerance1[W]", "abstract": "A proteomic analysis was performed on the heat stable protein fraction of imbibed radicles of Medicago truncatula seeds to investigate whether proteins can be identified that are specifically linked to desiccation tolerance (DT). Radicles were compared before and after emergence (2.8 mm long) in association with the loss of DT, and after reinduction of DT by an osmotic treatment. To separate proteins induced by the osmotic treatment from those linked with DT, the comparison was extended to 5 mm long emerged radicles for which DT could no longer be reinduced, albeit that drought tolerance was increased. The abundance of 15 polypeptides was linked with DT, out of which 11 were identified as late embryogenesis abundant proteins from different groups: MtEm6 (group 1), one isoform of DHN3 (dehydrins), MtPM25 (group 5), and three members of group 3 (MP2, an isoform of PM18, and all the isoforms of SBP65). In silico analysis revealed that their expression is likely seed specific, except for DHN3. Other isoforms of DNH3 and PM18 as well as three isoforms of the dehydrin Budcar5 were associated with drought tolerance. Changes in the abundance of MtEm6 and MtPM25 in imbibed cotyledons during the loss of DT and in developing embryos during the acquisition of DT confirmed the link of these two proteins with DT. Fourier transform infrared spectroscopy revealed that the recombinant MtPM25 and MtEm6 exhibited a certain degree of order in the hydrated state, but that they became more structured by adopting α helices and β sheets during drying. A model is presented in which DT-linked late embryogenesis abundant proteins might exert different protective functions at high and low hydration levels.", "corpus_id": 10410648, "score": 0 }, { "doc_id": "19994373", "title": "A postgermination developmental arrest checkpoint is mediated by abscisic acid and requires the ABI5 transcription factor in Arabidopsis", "abstract": "Seed dormancy is a trait of considerable adaptive significance because it maximizes seedling survival by preventing premature germination under unfavorable conditions. Understanding how seeds break dormancy and initiate growth is also of great agricultural and biotechnological interest. Abscisic acid (ABA) plays primary regulatory roles in the initiation and maintenance of seed dormancy. Here we report that the basic leucine zipper transcription factor ABI5 confers an enhanced response to exogenous ABA during germination, and seedling establishment, as well as subsequent vegetative growth. These responses correlate with total ABI5 levels. We show that ABI5 expression defines a narrow developmental window following germination, during which plants monitor the environmental osmotic status before initiating vegetative growth. ABI5 is necessary to maintain germinated embryos in a quiescent state thereby protecting plants from drought. As expected for a key player in ABA-triggered processes, ABI5 protein accumulation, phosphorylation, stability, and activity are highly regulated by ABA during germination and early seedling growth.", "corpus_id": 19994373, "score": 1 }, { "doc_id": "83589571", "title": "The isolation and characterization of abscisic acid-insensitive mutants of Arabidopsis thaliana", "abstract": "Abscisic acid (ABA) insensitive mutants of Arabidopsis thaliana (L.) Heynh. were isolated by selecting plants which grew well on a medium containing 10 μM ABA. From the progeny of approximately 3500 mutagen-treated seeds, five mutants of at least three different loci were isolated. Three mutants were characterized, moreover, by a reduced seed dormancy and by symptoms of withering, indicating disturbed water relations and, therefore, resembled phenotypically the ABA-deficient mutants we described earlier in this species. Two mutants showed in addition only a reduction of seed dormancy. Compared to wild type, all mutants showed similar or increased levels of endogenous ABA in developing seeds and fruits (siliquae). The role of the different genes involved is discussed in relation to the mechanism of ABA action.", "corpus_id": 83589571, "score": 0 }, { "doc_id": "8339093", "title": "The Arabidopsis Abscisic Acid Response Locus ABI4 Encodes an APETALA2 Domain Protein", "abstract": "Arabidopsis abscisic acid (ABA)–insensitive abi4 mutants have pleiotropic defects in seed development, including decreased sensitivity to ABA inhibition of germination and altered seed-specific gene expression. This phenotype is consistent with a role for ABI4 in regulating seed responses to ABA and/or seed-specific signals. We isolated the ABI4 gene by positional cloning and confirmed its identity by complementation analysis. The predicted protein product shows homology to a plant-specific family of transcriptional regulators characterized by a conserved DNA binding domain, the APETALA2 domain. The single mutant allele identified has a single base pair deletion, resulting in a frameshift that should disrupt the C-terminal half of the protein but leave the presumed DNA binding domain intact. Expression analyses showed that despite the seed-specific nature of the mutant phenotype, ABI4 expression is not seed specific.", "corpus_id": 8339093, "score": 0 }, { "doc_id": "86723474", "title": "Mutations at two new Arabidopsis ABA response loci are similar to the abi3 mutations", "abstract": "Summary \nTwo new Arabidopsis loci involved in ABA response, ABA-insensitive (ABI)4 and ABI5, have been identified by mutation. The abi4 and abi5 mutants were characterized in terms of ABA sensitivity of seed germination, dormancy, seed-specific gene expression and stomatal regulation. Their phenotypes are similar to mutations in ABI3, which is thought to encode a seed-specific transcriptional activator. Analysis of double mutants combining abi4 and abi5 mutations with abi1, abi2 or abi3 mutations also suggests that ABI4 and ABI5 act in the same transduction pathway as ABI3.", "corpus_id": 86723474, "score": 0 }, { "doc_id": "17044733", "title": "The Arabidopsis Abscisic Acid Response Gene ABI5 Encodes a Basic Leucine Zipper Transcription Factor", "abstract": "The Arabidopsis abscisic acid (ABA)–insensitive abi5 mutants have pleiotropic defects in ABA response, including decreased sensitivity to ABA inhibition of germination and altered expression of some ABA-regulated genes. We isolated the ABI5 gene by using a positional cloning approach and found that it encodes a member of the basic leucine zipper transcription factor family. The previously characterized abi5-1 allele encodes a protein that lacks the DNA binding and dimerization domains required for ABI5 function. Analyses of ABI5 expression provide evidence for ABA regulation, cross-regulation by other ABI genes, and possibly autoregulation. Comparison of seed and ABA-inducible vegetative gene expression in wild-type and abi5-1 plants indicates that ABI5 regulates a subset of late embryogenesis–abundant genes during both developmental stages.", "corpus_id": 17044733, "score": 0 }, { "doc_id": "15695194", "title": "A null mutation in a bZIP factor confers ABA-insensitivity in Arabidopsis thaliana.", "abstract": "We have used a modification of the classical ABA-insensitive screen (Koornneef et al. 1984) to isolate novel mutations in the ABA signal transduction pathway of Arabidopsis thaliana. In our screen, mutants were recovered on the basis of their growth-insensitivity to ABA (GIA) rather than germination-insensitivity. Here we present the isolation of the gia1 mutant as well as the identification of the gia1 gene by positional cloning and complementation studies. GIA1 is predicted to code for a bZIP transcription factor with high homology to previously characterized plant bZIP transcription factors (DPBF1, ABFs and TRAB1) known for their ability to bind ABA-responsive DNA elements. Our results provide in vivo evidence that a bZIP factor may indeed be involved in ABA signaling. Since GIA1 turned out to be identical to ABI5, we designated GIA1 as ABI5 in the present paper.", "corpus_id": 15695194, "score": 0 }, { "doc_id": "2480840", "title": "Toward the identification and regulation of the Arabidopsis thaliana ABI3 regulon", "abstract": "The plant-specific, B3 domain-containing transcription factor ABSCISIC ACID INSENSITIVE3 (ABI3) is an essential component of the regulatory network controlling the development and maturation of the Arabidopsis thaliana seed. Genome-wide chromatin immunoprecipitation (ChIP-chip), transcriptome analysis, quantitative reverse transcriptase–polymerase chain reaction and a transient promoter activation assay have been combined to identify a set of 98 ABI3 target genes. Most of these presumptive ABI3 targets require the presence of abscisic acid for their activation and are specifically expressed during seed maturation. ABI3 target promoters are enriched for G-box-like and RY-like elements. The general occurrence of these cis motifs in non-ABI3 target promoters suggests the existence of as yet unidentified regulatory signals, some of which may be associated with epigenetic control. Several members of the ABI3 regulon are also regulated by other transcription factors, including the seed-specific, B3 domain-containing FUS3 and LEC2. The data strengthen and extend the notion that ABI3 is essential for the protection of embryonic structures from desiccation and raise pertinent questions regarding the specificity of promoter recognition.", "corpus_id": 2480840, "score": 0 }, { "doc_id": "3955620", "title": "Abscisic acid: emergence of a core signaling network.", "abstract": "Abscisic acid (ABA) regulates numerous developmental processes and adaptive stress responses in plants. Many ABA signaling components have been identified, but their interconnections and a consensus on the structure of the ABA signaling network have eluded researchers. Recently, several advances have led to the identification of ABA receptors and their three-dimensional structures, and an understanding of how key regulatory phosphatase and kinase activities are controlled by ABA. A new model for ABA action has been proposed and validated, in which the soluble PYR/PYL/RCAR receptors function at the apex of a negative regulatory pathway to directly regulate PP2C phosphatases, which in turn directly regulate SnRK2 kinases. This model unifies many previously defined signaling components and highlights the importance of future work focused on defining the direct targets of SnRK2s and PP2Cs, dissecting the mechanisms of hormone interactions (i.e., cross talk) and defining connections between this new negative regulatory pathway and other factors implicated in ABA signaling.", "corpus_id": 3955620, "score": 0 }, { "doc_id": "7002572", "title": "In Vivo Inhibition of Seed Development and Reserve Protein Accumulation in Recombinants of Abscisic Acid Biosynthesis and Responsiveness Mutants in Arabidopsis thaliana.", "abstract": "In Arabidopsis thaliana, seed development in recombinants of the ABA-deficient aba mutant with the ABA response mutants abi1 or abi3 is compared to wild type and the monogenic parents. Aberrant seed development occurred in the aba,abi3 recombinant and was normal in aba,abi1, abi3 and aba,abi1 seeds. Embryos of the recombinant aba,abi3 seeds maintained the green color until maturity, the seeds kept a high water content, did not form the late abundant 2S and 12S storage proteins, were desiccation intolerant, and often showed viviparous germination. Application of ABA, and particularly of an ABA analog, to the roots of plants during seed development partially alleviated the aberrant phenotype. Seeds of aba,abi3 were normal when they developed on a mother plant heterozygous for Aba. In contrast to seed development, the induction of dormancy was blocked in all monogenic mutants and recombinants. Dormancy was only induced by embryonic ABA; it could not be increased by maternal ABA or ABA applied to the mother plant. It is concluded that endogenous ABA has at least two different effects in developing seeds. The nature of these responses and of the ABA response system is discussed.", "corpus_id": 7002572, "score": 0 }, { "doc_id": "574585", "title": "A mutational analysis of the ABA1 gene of Arabidopsis thaliana highlights the involvement of ABA in vegetative development.", "abstract": "Much of the literature on the phytohormone abscisic acid (ABA) describes it as a mediator in triggering plant responses to environmental stimuli, as well as a growth inhibitor. ABA-deficient mutants, however, display a stunted phenotype even under well-watered conditions and high relative humidity, which suggests that growth promotion may also be one of the roles of endogenous ABA. Zeaxanthin epoxidase, the product of the ABA1 gene of Arabidopsis thaliana, catalyses the epoxidation of zeaxanthin to antheraxanthin and violaxanthin, generating the epoxycarotenoid precursor of the ABA biosynthetic pathway. This paper gives a description of the molecular and phenotypic characterization of a large series of mutant alleles of the ABA1 gene, which cause different degrees of ABA deficiency, four of them previously isolated (aba1-1, aba1-3, aba1-4, and aba1-6) and the remaining five novel (sañ1-1, sañ1-2, sañ1-3, sañ1-4, and sre3). Molecular analysis of these alleles provides insights into the domains in which they compromise zeaxanthin epoxidase function. The size of the leaves, inflorescences, and flowers of these mutants is reduced, and their rosettes have lower fresh and dry weights than their wild types, as a result of a diminished cell size. Low concentrations of exogenous ABA increase the fresh weight of mutant and wild-type plants, as well as the dry weight of the mutants. The leaves of aba1 mutants are abnormally shaped and fail to develop clearly distinct spongy and palisade mesophyll layers. Taken together, these phenotypic traits indicate, as suggested by previous authors, that ABA acts as a growth promoter during vegetative development. The abnormal shape and internal structure of the leaves of aba1 mutants suggests, in addition, a role for ABA in organogenesis.", "corpus_id": 574585, "score": 0 }, { "doc_id": "40209364", "title": "Seed‐specific immunomodulation of abscisic acid activity induces a developmental switch", "abstract": "A single‐chain Fv antibody (scFv) gene, which has previously been used to immunomodulate abscisic acid (ABA) activity in transgenic tobacco to create a ‘wilty’ phenotype, was put under control of the seed‐specific USP promoter from Vicia faba and used to transform tobacco. Transformants were phenotypically similar to wild‐type plants apart from their seeds. Anti‐ABA scFv embryo development differed markedly from wild‐type embryo development. Seeds which accumulated similar levels of a scFv that binds to oxazolone, a hapten absent from plants, developed like wild‐type embryos. Anti‐ABA scFv embryos developed green cotyledons containing chloroplasts and accumulated photosynthetic pigments but produced less seed storage protein and oil bodies. Anti‐ABA scFv seeds germinated precociously if removed from seed capsules during development but were incapable of germination after drying. Total ABA levels were higher than in wild‐type seeds but calculated free ABA levels were near‐zero until 21 days after pollination. We show for the first time seed‐specific immunomodulation and the resulting switch from the seed maturation programme to a germination programme. We conclude that the immunomodulation of hormones can alter the development programme of target organs, allowing the study of the directly blocked endogenous molecules and manipulation of the system concerned.", "corpus_id": 40209364, "score": 0 }, { "doc_id": "205286390", "title": "Three Arabidopsis SnRK2 protein kinases, SRK2D/SnRK2.2, SRK2E/SnRK2.6/OST1 and SRK2I/SnRK2.3, involved in ABA signaling are essential for the control of seed development and dormancy.", "abstract": "ABA is an important phytohormone regulating various plant processes, including stress tolerance, seed development and germination. SRK2D/SnRK2.2, SRK2E/SnRK2.6/OST1 and SRK2I/SnRK2.3 are redundant ABA-activated SNF1-related protein kinases 2 (SnRK2s) in Arabidopsis thaliana. We examined the role of these protein kinases in seed development and germination. These SnRK2 proteins were mainly expressed in the nucleus during seed development and germination. The triple mutant (srk2d srk2e srk2i) was sensitive to desiccation and showed severe growth defects during seed development. It exhibited a loss of dormancy and elevated seed ABA content relative to wild-type plants. The severity of these phenotypes was far stronger than that of any single or double SRK2D, SRK2E and SRK2I mutants, including the srk2d srk2i mutant. The triple mutant had greatly reduced phosphorylation activity in in-gel kinase experiments using basic leucine zipper (bZIP) transcription factors including ABI5. Microarray experiments revealed that 48 and 30% of the down-regulated genes in abi5 and abi3 seeds were suppressed in the triple mutant seeds, respectively. Moreover, disruption of the three protein kinases induced global changes in the up-regulation of ABA-repressive gene expression, as well as the down-regulation of ABA-inducible gene expression. These alterations in gene expression result in a loss of dormancy and severe growth defects during seed development. Collectively, these results indicate that SRK2D, SRK2E and SRK2I protein kinases involved in ABA signaling are essential for the control of seed development and dormancy through the extensive control of gene expression.", "corpus_id": 205286390, "score": 0 }, { "doc_id": "18767810", "title": "Interaction between sugar and abscisic acid signalling during early seedling development in Arabidopsis", "abstract": "Sugars regulate important processes and affect the expression of many genes in plants. Characterization of Arabidopsis (Arabidopsis thaliana) mutants with altered sugar sensitivity revealed the function of abscisic acid (ABA) signalling in sugar responses. However, the exact interaction between sugar signalling and ABA is obscure. Therefore ABA deficient plants with constitutive ABI4 expression (aba2-1/35S::ABI4) were generated. Enhanced ABI4 expression did not rescue the glucose insensitive (gin) phenotype of aba2 seedlings indicating that other ABA regulated factors are essential as well. Interestingly, both glucose and ABA treatment of Arabidopsis seeds trigger a post-germination seedling developmental arrest. The glucose-arrested seedlings had a drought tolerant phenotype and showed glucose-induced expression of ABSCISIC ACID INSENSITIVE3 (ABI3), ABI5 and LATE EMBRYOGENESIS ABUNDANT (LEA) genes reminiscent of ABA signalling during early seedling development. ABI3 is a key regulator of the ABA-induced arrest and it is shown here that ABI3 functions in glucose signalling as well. Multiple abi3 alleles have a glucose insensitive (gin) phenotype comparable to that of other known gin mutants. Importantly, glucose-regulated gene expression is disturbed in the abi3 background. Moreover, abi3 was insensitive to sugars during germination and showed sugar insensitive (sis) and sucrose uncoupled (sun) phenotypes. Mutant analysis further identified the ABA response pathway genes ENHANCED RESPONSE TO ABA1 (ERA1) and ABI2 as intermediates in glucose signalling. Hence, three previously unidentified sugar signalling genes have been identified, showing that ABA and glucose signalling overlap to a larger extend than originally thought.", "corpus_id": 18767810, "score": 0 }, { "doc_id": "24100613", "title": "The sugar-insensitive1 (sis1) mutant of Arabidopsis is allelic to ctr1.", "abstract": "Soluble sugar levels affect a diverse array of plant developmental processes. For example, exposure to high levels of glucose or sucrose inhibits early seedling development of Arabidopsis thaliana (L.) Heynh. Media-shift experiments indicate that Arabidopsis seedlings lose their sensitivity to the inhibitory effects of high sugar levels on early development within approximately two days after the start of imbibition. The sugar-insensitive1 (sis1) mutant of Arabidopsis was isolated by screening for plants that are insensitive to the inhibitory effects of high concentrations of sucrose on early seedling development. The sis1 mutant also displays glucose and mannose resistant phenotypes and has an osmo-tolerant phenotype during early seedling development. The sis1 mutant is resistant to the negative effects of paclobutrazol, an inhibitor of gibberellin biosynthesis, on seed germination. Characterization of the sis1 mutant revealed that it is allelic to ctr1, a previously identified mutant with a constitutive response to ethylene.", "corpus_id": 24100613, "score": 0 }, { "doc_id": "2148303", "title": "Abscisic acid-induced rearrangement of intracellular structures associated with freezing and desiccation stress tolerance in the liverwort Marchantia polymorpha.", "abstract": "The plant growth regulator abscisic acid (ABA) is known to be involved in triggering responses to various environmental stresses such as freezing and desiccation in angiosperms, but little is known about its role in basal land plants, especially in liverworts, representing the earliest land plant lineage. We show here that survival rate after freezing and desiccation of Marchantia polymorpha gemmalings was increased by pretreatment with ABA in the presence of increasing concentrations of sucrose. ABA treatment increased accumulation of soluble sugars in gemmalings, and sugar accumulation was further increased by addition of sucrose to the culture medium. ABA treatment of gemmalings also induced accumulation of transcripts for proteins with similarity to late embryogenesis abundant (LEA) proteins, which accumulate in association with acquisition of desiccation tolerance in maturing seeds. Observation by light and electron microscopy indicated that the ABA treatment caused fragmentation of vacuoles with increased cytosolic volume, which was more prominent in the presence of a high concentration of external sucrose. ABA treatment also increased the density of chloroplast distribution and remarkably enlarged their volume. These results demonstrate that ABA induces drastic physiological changes in liverwort cells for stress tolerance, accompanied by accumulation of protectants against dehydration and rearrangement and morphological alterations of cellular organelles.", "corpus_id": 2148303, "score": 0 }, { "doc_id": "18458055", "title": "Role of the Arabidopsis Glucose Sensor HXK1 in Nutrient, Light, and Hormonal Signaling", "abstract": "Glucose modulates many vital processes in photosynthetic plants. Analyses of Arabidopsis glucose insensitive2(gin2) mutants define the physiological functions of a specific hexokinase (HXK1) in the plant glucose-signaling network. HXK1 coordinates intrinsic signals with extrinsic light intensity. HXK1 mutants lacking catalytic activity still support various signaling functions in gene expression, cell proliferation, root and inflorescence growth, and leaf expansion and senescence, thus demonstrating the uncoupling of glucose signaling from glucose metabolism. The gin2 mutants are also insensitive to auxin and hypersensitive to cytokinin. Plants use HXK as a glucose sensor to interrelate nutrient, light, and hormone signaling networks for controlling growth and development in response to the changing environment.", "corpus_id": 18458055, "score": 0 }, { "doc_id": "86122569", "title": "Annual changes in dormancy and germination in seeds of Sisymbrium officinale (L.) Scop.", "abstract": "SUMMARY \nThe effect of environmental conditions on changes in dormancy and germination of seeds of Sisymbrium officinale (L.) Scop, was studied. Seeds were buried in soil in the field or in incubators and at regular intervals, germination of exhumed seeds was tested over a range of conditions. Seeds that were buried in the field showed clear seasonal changes in dormancy. Fluctuations in soil moisture and nitrate content were not required for the changes in dormancy. Temperature seemed to be the only factor regulating these changes. Dormancy was relieved in periods of low temperatures and induced in periods of high temperatures. Fresh seeds and seeds buried for only a few months germinated best at elevated temperatures whereas seeds buried for a longer time germinated best at low-temperatures. Light, nitrate and desiccation stimulated germination of exhumed seeds. As a consequence, these treatments extended germination over a much longer period of the year. Germination of exhumed seeds in Petri dishes at field temperature was reasonably described by a model based on the dual role of temperature, in the regulation of both dormancy and subsequent germination.", "corpus_id": 86122569, "score": 0 }, { "doc_id": "84620601", "title": "Are Seasonal Dormancy Patterns in Arabidopsis thaliana Regulated by Changes in Seed Sensitivity to Light, Nitrate and Gibberellin?", "abstract": "Imbibed seeds of Arabidopsis thaliana (L.) Heynh., passed annually through a pattern of changes in dormancy. Dormancy was broken in summer and re-induced in autumn-winter. A second small germination flush occurred in early spring. The role of sensitivity to light, nitrate and gibberellins (GAs) in regulating annual dormancy patterns and germination was studied with the use of GA-deficient (gal-2) and wild-type seeds. Dark-incubated seeds were exposed to a natural temperature regime for periods up to 18 months and at regular intervals germination capacity of portions of seeds was tested at laboratory conditions. Germination data fitted as logistic dose response curves showed that sensitivity to light varied with the seasons in both genotypes. From interpretation of curve parameters, it is proposed that the observed sensitivity changes involve alterations in the number of receptors, in the binding characteristics of the receptors and/or in the response chain initiated by ligand-receptor interaction. In this response chain GA biosynthesis is stimulated (wild type) and sensitivity to GAs is enhanced (wild type, gal -2). GA sensitivity is also directly influenced by temperature, thus without the interference of light. However, the significance of direct regulation of GA requirement seemed to diminish with prolonged incubation outdoors, whereas reversible changes in light sensitivity remained clear. Therefore, we propose that seasonal dormancy patterns are mainly regulated by changes in sensitivity to light. GA sensitivity contributes to this pattern but is not primarily controlling dormancy. The GA requirement for germination is obvious as gal-2 seeds did not germinate at any time of the year when deprived of applied GAs. However, GA biosynthesis is not required for dormancy control, as a dormancy pattern was also observed in the absence of the capacity to synthesize GAs. Nitrate or sensitivity to nitrate did not contribute to the regulation of dormancy and germination of this species.", "corpus_id": 84620601, "score": 0 }, { "doc_id": "33035743", "title": "Dormancy cycling in Arabidopsis seeds is controlled by seasonally distinct hormone-signaling pathways", "abstract": "Seeds respond to environmental signals, tuning their dormancy cycles to the seasons and thereby determining the optimum time for plant establishment. The molecular regulation of dormancy cycling is unknown, but an extensive range of mechanisms have been identified in laboratory experiments. Using a targeted investigation of gene expression over the dormancy cycle of Arabidopsis seeds in the field, we investigated how these mechanisms are seasonally coordinated. Depth of dormancy and gene expression patterns were correlated with seasonal changes in soil temperature. The results were consistent with abscisic acid (ABA) signaling linked to deep dormancy in winter being repressed in spring concurrent with enhanced DELLA repression of germination as depth of dormancy decreased. Dormancy increased during winter as soil temperature declined and expression of ABA synthesis (NCED6) and gibberellic acid (GA) catabolism (GA2ox2) genes increased. This was linked to an increase in endogenous ABA that plateaus, but dormancy and DOG1 and MFT expression continued to increase. The expression of SNF1-related protein kinases, SnrK 2.1 and 2.4, also increased consistent with enhanced ABA signaling and sensitivity being modulated by seasonal soil temperature. Dormancy then declined in spring and summer. Endogenous ABA decreased along with positive ABA signaling as expression of ABI2, ABI4, and ABA catabolism (CYP707A2) and GA synthesis (GA3ox1) genes increased. However, during the low-dormancy phase in the summer, expression of transcripts for the germination repressors RGA and RGL2 increased. Unlike deep winter dormancy, this represson can be removed on exposure to light, enabling the completion of germination at the correct time of year.", "corpus_id": 33035743, "score": 1 }, { "doc_id": "8308969", "title": "Dual Effect of Light on the Gibberellin- and Nitrate-Stimulated Seed Germination of Sisymbrium officinale and Arabidopsis thaliana.", "abstract": "Red light (R) has a dual effect on the seed germination of the two related species Arabidopsis thaliana and Sisymbrium officinale. The two species provide different means to separate the light-effects. In S. officinale, stimulation of germination by R depends on the stimultaneous presence of nitrate (light-effect I). The effect of both factors is completely blocked by tetcyclacis, an inhibitor of gibberellin (GA)-biosynthesis. Addition of a mixture of gibberellins A(4) and A(7) (GA(4+7)) antagonizes the inhibition. In the absence of nitrate, R shifts germination to lower GA-requirement (light-effect II). In A. thaliana a similar second light-effect is seen on the GA-requirement of GA-deficient ga-1 mutant seeds. R stimulates germination of wild type seeds in water (light-effect I). For both species, light-effect I shows a fluence threshold value of approximately 10(-5) moles per square meter, which is independent of the nitrate concentration. Increasing nitrate concentrations narrow the fluence-range required for maximal germination whereby the product of nitrate concentration and fluence value determines the germination level, indicating a multiplicative interaction between R and nitrate. Fluence-response curves for light-effect II are similar for both species. Germination occurs in the range of 10(-6) to 10(-2) moles per square meter fluence. The maximal level of germination is determined by the level of dark-germination and light-effect II. Increasing GA(4+7) concentrations induce a shift to lower fluence values. It is shown that in the second effect the co-action of R and exogenous GA(4+7) is clearly additive. It is concluded that light-effect I induces a chain of events leading to GA biosynthesis. Light-effect II seems to enhance the sensitivity of the seeds to GAs.", "corpus_id": 8308969, "score": 0 }, { "doc_id": "84937173", "title": "LEAF-CANOPY-INDUCED SEED DORMANCY IN A GRASSLAND FLORA", "abstract": "SUMMARY \nThe germination of 27 species from calcareous grassland was tested in three light treatments in the laboratory: in darkness, under tungsten lamps and under a leaf-canopy. Germination was significantly lower under a leaf-canopy than in the dark in 17 species. The phenomena of leaf-canopy induced dormancy was not associated with the life-span of species, though there was a weak, negative relationship with seed weight amongst 20 perennials in the sample. It is suggested that the co-existence of species at high density in calcareous grasslands may, in part, be explained by differences in germination response to fine-grained variations in the light environment at the soil surface.", "corpus_id": 84937173, "score": 0 }, { "doc_id": "24942690", "title": "SOMNUS, a CCCH-Type Zinc Finger Protein in Arabidopsis, Negatively Regulates Light-Dependent Seed Germination Downstream of PIL5[W]", "abstract": "Light absorbed by seed phytochromes of Arabidopsis thaliana modulates abscisic acid (ABA) and gibberellic acid (GA) signaling pathways at least partly via PHYTOCHROME-INTERACTING FACTOR3-LIKE5 (PIL5), a phytochrome-interacting basic helix-loop-helix transcription factor. Here, we report a new mutant, somnus (som), that germinates in darkness, independently of various light regimens. SOM encodes a nucleus-localized CCCH-type zinc finger protein. The som mutant has lower levels of ABA and elevated levels of GA due to expressional changes in ABA and GA metabolic genes. Unlike PIL5, however, SOM does not regulate the expression of GA-INSENSITIVE and REPRESSOR OF GA1 (RGA/RGA1), two DELLA genes encoding GA negative signaling components. Our in vivo analysis shows that PIL5 activates the expression of SOM by binding directly to its promoter, suggesting that PIL5 regulates ABA and GA metabolic genes partly through SOM. In agreement with these results, we also observed that the reduced germination frequency of a PIL5 overexpression line is rescued by the som mutation and that this rescue is accompanied by expressional changes in ABA and GA metabolic genes. Taken together, our results indicate that SOM is a component in the phytochrome signal transduction pathway that regulates hormone metabolic genes downstream of PIL5 during seed germination.", "corpus_id": 24942690, "score": 0 }, { "doc_id": "7643409", "title": "Light activates the degradation of PIL5 protein to promote seed germination through gibberellin in Arabidopsis.", "abstract": "Angiosperm seeds integrate various environmental signals, such as water availability and light conditions, to make a proper decision to germinate. Once the optimal conditions are sensed, gibberellin (GA) is synthesized, triggering germination. Among environmental signals, light conditions are perceived by phytochromes. However, it is not well understood how phytochromes regulate GA biosynthesis. Here we investigated whether phytochromes regulate GA biosynthesis through PIL5, a phytochrome-interacting bHLH protein, in Arabidopsis. We found that pil5 seed germination was inhibited by paclobutrazol, the ga1 mutation was epistatic to the pil5 mutation, and the inhibitory effect of PIL5 overexpression on seed germination could be rescued by exogenous GA, collectively indicating that PIL5 regulates seed germination negatively through GA. Expression analysis revealed that PIL5 repressed the expression of GA biosynthetic genes (GA3ox1 and GA3ox2), and activated the expression of a GA catabolic gene (GA2ox) in both PHYA- and PHYB-dependent germination assays. Consistent with these gene-expression patterns, the amount of bioactive GA was higher in the pil5 mutant and lower in the PIL5 overexpression line. Lastly, we showed that red and far-red light signals trigger PIL5 protein degradation through the 26S proteasome, thus releasing the inhibition of bioactive GA biosynthesis by PIL5. Taken together, our data indicate that phytochromes promote seed germination by degrading PIL5, which leads to increased GA biosynthesis and decreased GA degradation.", "corpus_id": 7643409, "score": 0 }, { "doc_id": "7966296", "title": "Through form to function: root hair development and nutrient uptake.", "abstract": "Root hairs project from the surface of the root to aid nutrient and water uptake and to anchor the plant in the soil. Their formation involves the precise control of cell fate and localized cell growth. We are now beginning to unravel the complexities of the molecular interactions that underlie this developmental regulation. In addition, after years of speculation, nutrient transport by root hairs has been demonstrated clearly at the physiological and molecular level, with evidence for root hairs being intense sites of H(+)-ATPase activity and involved in the uptake of Ca(2+), K(+), NH(4)(+), NO(3)(-), Mn(2+), Zn(2+), Cl(-) and H(2)PO(4)(-).", "corpus_id": 7966296, "score": 0 }, { "doc_id": "2414463", "title": "ABI5 acts downstream of ABI3 to execute an ABA-dependent growth arrest during germination.", "abstract": "The development of a germinating embryo into an autotrophic seedling is arrested under conditions of water deficit. This ABA-mediated developmental checkpoint requires the bZIP transcription factor ABI5. Here, we used abi3-1, which is also unable to execute this checkpoint, to investigate the relative role of ABI3 and ABI5 in this process. In wild-type Arabidopsis plants, ABI3 expression and activity parallel those described for ABI5 following stratification. During this process, transcript levels of late embryogenesis genes such as AtEm1 and AtEm6 are also re-induced, which might be responsible for the acquired osmotic tolerance in germinated embryos whose growth is arrested. ABI5 expression is greatly reduced in abi3-1 mutants, which has low AtEm1 or AtEm6 expression. Cross complementation experiments showed that 35S-ABI5 could complement abi3-1, whereas 35S-ABI3 cannot complement abi5-4. These results indicate that ABI5 acts downstream of ABI3 to reactivate late embryogenesis programmes and to arrest growth of germinating embryos. Although ABI5 is consistently located in the nucleus, chromosomal immunoprecipitation (ChIP) experiments revealed that ABA increases ABI5 occupancy on the AtEm6 promoter.", "corpus_id": 2414463, "score": 0 }, { "doc_id": "42698817", "title": "The role of chromatin-remodeling factor PKL in balancing osmotic stress responses during Arabidopsis seed germination.", "abstract": "Embryogenesis in Arabidopsis results in mature, osmotolerant embryos within dry seeds. Late-embryogenesis programs involve the transcription factors ABI3 and ABI5, which are necessary for osmotolerance. ABI3 and ABI5 are degraded in seeds initiating germination, abolishing their protected state. However, during an early stage of germination, strong osmotic stresses, or ABA exposure maintain ABI3 and ABI5 expression, leading to growth arrest, and osmotolerance. Mild stress stimuli delay ABI3 and ABI5 disappearance, retarding germination but not preventing eventual closure of embryogenesis programs. PICKLE (PKL), a putative chromatin modifier, is necessary to repress ABI3 and ABI5 expression during germination in response to ABA. We show that pkl mutants display persistent high expression of ABI3 and ABI5 upon ABA stimulation. In turn, maintenance of ABI5 expression leads to hypersensitive germination responses to ABA in pkl seeds. We provide evidence that ABI3 and ABI5 are less associated with repressed chromatin in pkl mutants. Our results provide evidence that PKL-dependent repression of embryonic gene expression extends to late-embryogenesis genes and is associated with changes in chromatin. We suggest that effective closure of embryogenesis omostolerance programs during germination prevents excessive plant reactions to stress.", "corpus_id": 42698817, "score": 0 }, { "doc_id": "2322170", "title": "The Arabidopsis Histone Deacetylases HDA6 and HDA19 Contribute to the Repression of Embryonic Properties after Germination1[W]", "abstract": "Histone deacetylase (HDAC) is a chromatin-remodeling factor that contributes to transcriptional repression in eukaryotes. In Arabidopsis (Arabidopsis thaliana), the transcription factors LEAFY COTYLEDON1 (LEC1), FUSCA3 (FUS3), and ABSCISIC ACID INSENSITIVE3 (ABI3) play key roles in embryogenesis. Although the repression of embryogenesis-related genes during germination has been proposed to occur, the role of HDAC in this process has not been elucidated. To address this question, the effects of an HDAC inhibitor and suppression of the Arabidopsis HDAC genes on this process were investigated. Here, we show that treatment of an HDA6 repression line with the HDAC inhibitor trichostatin A resulted in growth arrest and elevated transcription of LEC1, FUS3, and ABI3 during germination. The growth-arrest phenotype of the repression line was suppressed by lec1, fus3, and abi3. An HDA6/HDA19 double-repression line displayed arrested growth after germination and the formation of embryo-like structures on the true leaves of 6-week-old plants even without trichostatin A. The growth-arrest phenotype of this line was rescued by lec1. These results suggest that during germination in Arabidopsis, HDA6 and HDA19 redundantly regulate the repression of embryonic properties directly or indirectly via repression of embryo-specific gene function.", "corpus_id": 2322170, "score": 0 }, { "doc_id": "206329716", "title": "HISTONE DEACETYLASE 9 represses seedling traits in Arabidopsis thaliana dry seeds.", "abstract": "Plant life is characterized by major phase changes. We studied the role of histone deacetylase (HDAC) activity in the transition from seed to seedling in Arabidopsis. Pharmacological inhibition of HDAC stimulated germination of freshly harvested seeds. Subsequent analysis revealed that histone deacetylase 9 (hda9) mutant alleles displayed reduced seed dormancy and faster germination than wild-type plants. Transcriptome meta-analysis comparisons between the hda9 dry seed transcriptome and published datasets demonstrated that transcripts of genes that are induced during imbibition in wild-type prematurely accumulated in hda9-1 dry seeds. This included several genes associated with photosynthesis and photoautotrophic growth such as RuBisCO and RuBisCO activase (RCA). Chromatin immunoprecipitation experiments demonstrated enhanced histone acetylation levels at their loci in young hda9-1 seedlings. Our observations suggest that HDA9 negatively influences germination and is involved in the suppression of seedling traits in dry seeds, probably by transcriptional repression via histone deacetylation. Accordingly, HDA9 transcript is abundant in dry seeds and becomes reduced during imbibition in wild-type seeds. The proposed function of HDA9 is opposite to that of its homologous genes HDA6 and HDA19, which have been reported to repress embryonic properties in germinated seedlings.", "corpus_id": 206329716, "score": 0 }, { "doc_id": "21192395", "title": "Triple Loss of Function of Protein Phosphatases Type 2C Leads to Partial Constitutive Response to Endogenous Abscisic Acid1[C][W][OA]", "abstract": "The phytohormone abscisic acid (ABA) is a key regulator of plant growth and development as well as plant responses to situations of decreased water availability. Protein phosphatases type 2C (PP2Cs) from group A, which includes the ABI1/HAB1 and PP2CA branches, are key negative regulators of ABA signaling. Specifically, HAB1, ABI1, ABI2, and PP2CA have been shown to affect both seed and vegetative responses to ABA. To further understand their contribution to ABA signaling and to unravel possible genetic interactions and functional redundancy among them, we have generated different combinations of double and triple mutants impaired in these PP2Cs. Interestingly, hab1-1pp2ca-1 and abi1-2pp2ca-1 double mutants showed reduced water loss and enhanced resistance to drought stress, which further supports the role of PP2CA in vegetative responses to ABA. Two triple hab1-1abi1-2abi2-2 and hab1-1abi1-2pp2ca-1 mutants were generated, which showed an extreme response to exogenous ABA, impaired growth, and partial constitutive response to endogenous ABA. Thus, transcriptomic analysis revealed a partial up-regulation/down-regulation of a subset of ABA-responsive genes in both triple mutants in the absence of exogenous ABA. Comparison of ABA responses in the different pp2c mutants showed that a progressive increase in ABA sensitivity could be obtained through combined inactivation of these PP2Cs. These results indicate that ABA response is finely tuned by the integrated action of these genes, which is required to prevent a constitutive response to endogenous ABA that might have a deleterious effect on growth and development in the absence of environmental stress.", "corpus_id": 21192395, "score": 0 }, { "doc_id": "29982939", "title": "Seed dormancy release in Arabidopsis Cvi by dry after-ripening, low temperature, nitrate and light shows common quantitative patterns of gene expression directed by environmentally specific sensing.", "abstract": "The depth of seed dormancy can be influenced by a number of different environmental signals, but whether a common mechanism underlies this apparently similar response has yet to be investigated. Full-genome microarrays were used for a global transcript analysis of Arabidopsis thaliana Cape Verde Island accession seeds exposed to dry after-ripening (AR), or low temperature, nitrate and light when imbibed. Germination studies showed that the sensitivity of imbibed seeds to low temperature, nitrate and light was dependent upon the length of time spent AR following harvest. Seeds had an absolute requirement for light to complete dormancy release in all conditions, but this effect required an exposure to a prior dormancy relieving environment. Principal component analyses of the expression patterns observed grouped physiological states in a way that related to the depth of seed dormancy, rather than the type of environmental exposure. Furthermore, opposite changes in transcript abundance of genes in sets associated with dormancy, or dormancy relief through AR, were also related to the depth of dormancy and common to different environments. Besides these common quantitative changes, environment-specific gene expression patterns during dormancy relief are also described. For example, higher transcript abundance for genes linked to the process of nitrate accumulation, and nitrate reduction was associated with dormancy relief. The quantity of GA3ox1 transcripts increased during dormancy relief in all conditions, in particular when dormancy relief was completed by exposure to light. This contrasts with transcripts linked to abscisic acid (ABA) synthesis, which declined. The results are consistent with a role for the ABA/gibberellic acid balance in integrating dormancy-relieving environmental signals.", "corpus_id": 29982939, "score": 0 }, { "doc_id": "12301303", "title": "ABA-dependent and ABA-independent signaling in response to osmotic stress in plants.", "abstract": "Plants have adaptive robustness to osmotic stresses such as drought and high salinity. Numerous genes functioning in stress response and tolerance are induced under osmotic conditions in diverse plants. Various signaling proteins, such as transcription factors, protein kinases and phosphatases, play signal transduction roles during plant adaptation to osmotic stress, with involvement ranging from stress signal perception to stress-responsive gene expression. Recent progress has been made in analyzing the complex cascades of gene expression during osmotic stress response, and especially in identifying specificity and crosstalk in abscisic acid (ABA)-dependent and ABA-independent signaling pathways. In this review, we highlight transcriptional regulation of gene expression governed by two key transcription factors: AREB/ABFs and DREB2A operating respectively in ABA-dependent and ABA-independent signaling pathways.", "corpus_id": 12301303, "score": 0 } ]

{ "doc_id": "22949834", "title": "Mutations in the Ty3 major homology region affect multiple steps in Ty3 retrotransposition", "abstract": "The Saccharomyces cerevisiae retroviruslike element Ty3 encodes the major structural proteins capsid (CA) and nucleocapsid in the GAG3 open reading frame. The Ty3 CA protein contains a sequence (QGX2EX5FX3LX3H, where H is a hydrophobic residue) which has not been observed in other retrotransposons but which is similar to the major homology region (MHR) described for retrovirus CA. In this study the effects of mutations in the Ty3 MHR on particle formation, processing, DNA synthesis, and transposition were examined. Each of the mutations tested resulted in severe defects in transposition, with disruption occurring prior to or at particle formation, subsequent to particle formation and prior to completion of DNA synthesis, and subsequent to DNA synthesis. Changing the Q in the motif to R had relatively little effect on particle formation but decreased transposition to about 13% of that of a wild-type element. Changing G to A or V almost completely eliminated the formation of intracellular particles, possibly by disruption of CA-CA interactions. Changes introduced at the position of E resulted in blocked processing, blocked DNA synthesis, or a block at some post-reverse transcription step, depending on the nature of the mutation introduced. These results showed that the integrity of the Ty3 MHR is required for multiple aspects of Ty3 replication involving CA. These functions are independent of extracellular budding and of infection, aspects of the retroviral life cycle which are not recapitulated in replication of the Ty3 retrotransposon.", "corpus_id": 22949834 }

[ { "doc_id": "173792", "title": "Ty3 GAG3 and POL3 genes encode the components of intracellular particles", "abstract": "Ty3 is a Saccharomyces cerevisiae retrotransposon that integrates near the transcription initiation sites of polymerase III-transcribed genes. It is distinct from the copialike Ty1 and Ty2 retrotransposons of S. cerevisiae in both the sequences of encoded proteins and gene order. It is a member of the gypsylike family of retrotransposons which resemble animal retroviruses. This study was undertaken to investigate the nucleocapsid particle of a transpositionally active gypsylike retrotransposon. Characterization of extracts from cells in which Ty3 expression was induced showed the presence of Ty3 nucleoprotein complexes, or viruslike particles, that migrated on linear sucrose gradients with a size of 156S. These particles are composed of Ty3 RNA, full-length, linear DNA, and proteins. In this study, antibodies raised against peptides predicted from the Ty3 sequence were used to identify Ty3-encoded proteins. These include the capsid (26 kDa), nucleocapsid (9 kDa), and reverse transcriptase (55 kDa) proteins. Ty3 integrase proteins of 61 and 58 kDa were identified previously (L. J. Hansen and S. B. Sandmeyer, J. Virol. 64:2599-2607, 1990). Reverse transcriptase activity associated with the particles was measured by using exogenous and endogenous primer-templates. Immunofluorescence studies of cells overexpressing Ty3 revealed cytoplasmic clusters of immunoreactive proteins. Transmission electron microscopy showed that Ty3 viruslike particles are about 50 nm in diameter. Thus, despite the unusual position specificity of Ty3 upstream of tRNA-coding regions, aspects of the Ty3 life cycle are fundamentally similar to those of retroviruses.", "corpus_id": 173792, "score": 1 }, { "doc_id": "22993434", "title": "Transposition of a Ty3 GAG3-POL3 fusion mutant is limited by availability of capsid protein", "abstract": "Ty3 encodes structural proteins in its upstream open reading frame (GAG3) and catalytic proteins in an overlapping open reading frame (POL3). As is the case for retroviruses, high levels of structural protein versus catalytic proteins are synthesized and we show here that catalytic proteins are derived from a GAG3-POL3 fusion polyprotein. To evaluate the relative contributions of structural and catalytic components of the Ty3 particle, we perturbed the balance of these proteins by fusing the GAG3 and POL3 frames. This fusion Ty3 was capable of complementing low levels of transposition of a donor Ty3 which contained only cis-acting sequences required for transposition. Examination of extracts of cells expressing the GAG3-POL3 fusion mutant showed that particle formation differed qualitatively and quantitatively from viruslike particle formation by wild-type Ty3. Suprisingly, expression of 238 codons of GAG3, encoding only capsid protein, complemented transposition and particle formation defects of the fusion mutant, showing that the limiting deficiency was in capsid, and not in nucleocapsid, function. In addition, protein containing the capsid domain expressed alone accumulated in the same particulate fraction as viruslike particles, showing that it was sufficient for particle formation. The activity of the Ty3 fusion mutant contrasts with the inviability of mutant retroviruses in which gag and pol frames were fused and argues that retrotransposons tolerate considerable variation in the nucleoprotein complexes that permit replication and integration.", "corpus_id": 22993434, "score": 1 }, { "doc_id": "1042580", "title": "The Cys-His motif of Ty3 NC can be contributed by Gag3 or Gag3-Pol3 polyproteins", "abstract": "The major structural proteins capsid and nucleocapsid (NC) of the Saccharomyces cerevisiae retroviruslike element Ty3 are produced as domains within the Gag3 and Gag3-Pol3 precursor polyproteins. Ty3 NC contains one copy of the conserved motif CX2CX4HX4C found in most retroviral NC proteins. We show here that NC proteins derived by processing of these different precursor species differ at their carboxyl termini. To determine whether the Cys-His motifs of these nascent NC domains contribute differently to replication, Gag3 and Gag3-Pol3 fusion proteins containing wild-type or mutant Cys-His domains were expressed from separate constructs. Although the Cys-His box was shown to be essential for polyprotein processing of a wild-type Ty3 element, this domain could be contributed from Gag3 or as part of Gag3-Pol3. These data suggest that the functions of the retroviral NC Cys-His domain contributed from Gag and Gag-Pol are redundant.", "corpus_id": 1042580, "score": 1 }, { "doc_id": "2936428", "title": "A single amino acid substitution within the matrix protein of a type D retrovirus converts its morphogenesis to that of a type C retrovirus", "abstract": "Two different morphogenic processes of retroviral capsid assembly have been observed: the capsid is either assembled at the plasma membrane during the budding process (type C), or preassembled within the cytoplasm (types B and D). We describe here a gag mutant of Mason-Pfizer monkey virus, a type D retrovirus, in which a tryptophan substituted for an arginine in the matrix protein results in efficient assembly of capsids at the plasma membrane through a morphogenic process similar to that of type C retroviruses. We conclude that a type D retrovirus Gag polyprotein contains an additional, dominant signal that prevents immediate transport of precursors from the site of biosynthesis to the plasma membrane. Instead, they are directed to and retained at a cytoplasmic site where a concentration sufficient for self-assembly into capsids occurs. Thus, capsid assembly processes for different retroviruses appear to differ only in the intracellular site to which capsid precursors are directed.", "corpus_id": 2936428, "score": 0 }, { "doc_id": "4250591", "title": "Crystal structure of SIV matrix antigen and implications for virus assembly", "abstract": "SIMIAN immunodeficiency virus (SIV) is closely related to human immunodeficiency virus (HIV)1, their matrix antigens (MAs) sharing some 50% sequence identity. MA is a component of PrSSGag, the sole protein required for assembly of the virion shell2. MA targets Pr55 to the plasma membrane3, and facilitates incorporation of the virus envelope protein4 and assembly of the PrSSGag shell5. Cleavage of PrSS by the viral protease produces the mature protein of relative molecular mass 17–18K, which underlies the host-derived membrane and is important in both virus entry6 and nuclear localization of the virion core7. Here we report the crystal structure of SIV MA. The molecule forms a trimer consistent with oligomerization in vitro8, the observed virion architecture9, and various biological properties of MA.", "corpus_id": 4250591, "score": 0 }, { "doc_id": "26028027", "title": "Assembly of the matrix protein of simian immunodeficiency virus into virus-like particles.", "abstract": "To obtain a better understanding of the processes of assembly and morphogenesis of simian immunodeficiency virus (SIV), recombinant vaccinia viruses containing regions of the gag-pol open reading frame were constructed and their intracellular expression as well as the ability of the Gag polypeptides to be released into the culture medium as constituents of virus-like particles were studied. Biochemical and electron microscopy analyses of cells infected with a recombinant expressing only the SIV matrix (MA) domain of the Gag polyprotein (v-p17 gag) showed that this protein self-assembles into 100-nm virus-like particles which are released into the culture medium. Interestingly, coexpression of SIV MA and Env proteins resulted in incorporation of gp120 and gp41 proteins into the recombinant p17-made particles. In addition when a positively charged domain of SIV MA (residues 26-33), which is highly conserved among all HIV and SIV MA proteins, was mutated into an acidic region, particle release was abolished without affecting protein expression, processing, or stability. Further characterization of the phenotype of this mutant by electron microscopy indicated that this mutant was blocked at the stage of assembly. These results suggest that SIV MA protein, along with its function in myristic acid-mediated membrane targeting, has intrinsic information for self-assembly as well as incorporation of viral Env glycoproteins into particles.", "corpus_id": 26028027, "score": 0 }, { "doc_id": "33488320", "title": "Single amino acid changes in the human immunodeficiency virus type 1 matrix protein block virus particle production", "abstract": "The matrix protein of human immunodeficiency virus type 1 is encoded by the amino-terminal portion of the Gag precursor and is postulated to be involved in a variety of functions in the virus life cycle. To define domains and specific amino acid residues of the matrix protein that are involved in virus particle assembly, we introduced 35 amino acid substitution mutations in the human immunodeficiency virus type 1 matrix protein. Using reverse transcriptase and radioimmunoprecipitation analyses and transmission electron microscopy, we assessed the mutants for their ability to form virus particles and to function in the infection process. This study has identified several domains of the matrix protein in which single amino acid substitutions dramatically reduce the efficiency of virus particle production. These domains include the six amino-terminal residues of matrix, the region of matrix between amino acids 55 and 59, and the region between amino acids 84 and 95. Single amino acid substitutions in one of these domains (between matrix amino acids 84 and 88) result in a redirection of the majority of virus particle formation to sites within cytoplasmic vacuoles.", "corpus_id": 33488320, "score": 0 }, { "doc_id": "18650765", "title": "A molecular determinant of human immunodeficiency virus particle assembly located in matrix antigen p17", "abstract": "We report single-point mutations that are located in the matrix protein domain of the gag gene of human immunodeficiency virus type 1 and that prevent Gag particle formation. We show that mutations of p17 that abolish human immunodeficiency virus particle assembly also prevent the dimerization of p17 protein, as measured directly by a protein-protein binding assay. In the three-dimensional structure of p17, mutations that abolish dimerization are located in a single alpha helix that forms part of a fingerlike projection from one side of the molecule. Peptides derived from this region of p17 also reduce the level of p17 dimer when they are added to p17-expressing cells and compete for p17 self-association when present in protein-protein binding assays. We propose that the dimerization of the Gag precursor that occurs by the interdigitation of alpha helices on adjacent matrix molecules is a key stage in virion assembly and that the prevention of such an interaction is the molecular basis of particle misassembly.", "corpus_id": 18650765, "score": 0 }, { "doc_id": "6338301", "title": "Structural role of the matrix protein of type D retroviruses in gag polyprotein stability and capsid assembly", "abstract": "To obtain a better understanding of the role of the gag gene-encoded matrix (MA) protein in the assembly and maturation of type D retroviruses, we have made five mutants with specific in-frame deletions within the p10-coding region by the use of oligonucleotide-directed mutagenesis. The changes in the Gag polyprotein made by these mutations resulted in almost identical phenotypes. In cells expressing mutant genomes, the mutant Gag polyproteins were synthesized and modified with myristic acid in a normal manner. However, they were so unstable that the bulk of the newly synthesized polyproteins was degraded within 1 h without being processed into mature structural polypeptides. In contrast, wild-type polyproteins have a processing half-life of 3.0 to 3.5 h. The mutant Gag polyproteins were assembled with very low efficiency into capsids in the cytoplasm of the mutant-infected cells. Moreover, the few capsids that formed were neither released from nor accumulated in the cells. These results suggest that the matrix protein plays an important role in guiding the correct folding of the Gag polyprotein, which is presumably crucial for both stabilizing the molecule and facilitating the intermolecular interactions that occur during assembly of immature capsids.", "corpus_id": 6338301, "score": 0 }, { "doc_id": "46247516", "title": "Suppression of retroviral MA deletions by the amino-terminal membrane-binding domain of p60src", "abstract": "The molecular mechanism by which retroviral Gag proteins are directed to the plasma membrane for the formation of particles (budding) is unknown, but it is widely believed that the MA domain, located at the amino terminus, plays a critical role. Consistent with this idea, we found that small deletions in this segment of the Rous sarcoma virus Gag protein completely blocked particle formation. The mutant proteins appear to have suffered only localized structural damage since they could be rescued (i.e., packaged into particles) when coexpressed with Gag proteins that are competent for particle formation. To our surprise, the effects of the MA deletions could be completely suppressed by fusing as few as seven residues of the myristylated amino terminus of the oncoprotein p60src to the beginning of the mutant Gag proteins. Particles produced by the chimeras were of the same density as the wild type. Two myristylated peptides having sequences distinct from that of p60src were entirely unable to suppress MA deletions, indicating that myristate alone is not a sufficient membrane targeting signal. We hypothesize that the amino terminus of p60src suppresses the effects of MA deletions by diverting the Rous sarcoma virus Gag protein from its normal site of assembly to the Src receptor for particle formation.", "corpus_id": 46247516, "score": 0 }, { "doc_id": "32722176", "title": "Efficient particle formation can occur if the matrix domain of human immunodeficiency virus type 1 Gag is substituted by a myristylation signal", "abstract": "Lentiviruses, such as human immunodeficiency virus type 1 (HIV-1), assemble at and bud through the cytoplasmic membrane. Both the matrix (MA) domain of Gag and its amino-terminal myristylation have been implicated in these processes. We have created HIV-1 proviruses lacking the entire matrix domain of gag which either lack or contain an amino-terminal myristate addition sequence at the beginning of the capsid domain. Myristate- and matrix-deficient [myr(-)MA(-)] viruses produced after transient transfection are still able to assemble into particles, although the majority do not form at the plasma membrane or bud efficiently. Myristylation of the amino terminus of the truncated Gag precursor permits a much more efficient release of the mutant virions. While myr(-)MA(-) particles were inefficient in proteolytic processing of the Gag precursor, myristylation enabled efficient proteolysis of the mutant Gag. All matrix-deficient viruses are noninfectious. Particles produced by matrix-deficient mutants contain low levels of glycoproteins, indicating the importance of matrix in either incorporation or stable retention of Env. Since matrix-deficient viruses contain a normal complement of viral genomic RNA, a role for MA in genomic incorporation can be excluded. Contrary to previous reports, the HIV-1 genome does not require sequences between the 5' splice donor site and the gag start codon for efficient packaging.", "corpus_id": 32722176, "score": 0 }, { "doc_id": "19442940", "title": "Identification of human immunodeficiency virus type 1 Gag protein domains essential to membrane binding and particle assembly", "abstract": "Assembly of human immunodeficiency virus type 1 (HIV-1) particles occurs at the plasma membrane of infected cells. Myristylation of HIV-1 Gag precursor polyprotein Pr55Gag is required for stable membrane binding and for assembly of viral particles. We expressed a series of proteins representing major regions of the HIV-1 Gag protein both with and without an intact myristyl acceptor glycine and performed subcellular fractionation studies to identify additional regions critical for membrane binding. Myristylation-dependent binding of Pr55Gag was demonstrated by using the vaccinia virus/T7 hybrid system for protein expression. Domains within the matrix protein (MA) region downstream of the initial 15 amino acids were required for membrane binding which was resistant to a high salt concentration (1 M NaCl). A myristylated construct lacking most of the matrix protein did not associate with the plasma membrane but formed intracellular retrovirus-like particles. A nonmyristylated construct lacking most of the MA region also was demonstrated by electron microscopy to form intracellular particles. Retrovirus-like extracellular particles were produced with a Gag protein construct lacking all of p6 and most of the nucleocapsid region. These studies suggest that a domain within the MA region downstream from the myristylation site is required for transport of Gag polyprotein to the plasma membrane and that stable plasma membrane binding requires both myristic acid and a downstream MA domain. The carboxyl-terminal p6 region and most of the nucleocapsid region are not required for retrovirus-like particle formation.", "corpus_id": 19442940, "score": 0 }, { "doc_id": "39368588", "title": "Conditional infectivity of a human immunodeficiency virus matrix domain deletion mutant", "abstract": "We constructed a human immunodeficiency virus (HIV) matrix (MA) deletion mutant by deletion of about 80% of the HIV type 1 Gag MA domain but retaining myristylation and proteolytic processing signals. The effects of this deletion matrix (dl.MA) mutant on HIV particle assembly, processing, and infectivity were analyzed. Surprisingly, the dl.MA mutant still could assemble and process virus particles, had a wild-type (wt) retrovirus particle density, and possessed wt reverse transcriptase activity. RNase protection experiments showed that dl.MA mutant particles preferentially packaged viral genomic RNA. When both mutant and wt particles were pseudotyped with an amphotropic murine leukemia virus envelope protein, mutant infectivity was about 10% of wt level. In contrast, infectivity of the dl.MA mutant was 1,000-fold less than that of wild-type when mutant and wt particles were pseudotyped with the HIV envelope protein. Protein analyses of pseudotyped virions indicated that there were no major differences between mutant and wt viruses in the efficiency of amphotropic murine leukemia virus envelope protein incorporation. In contrast, there was a reduction in the amount of mutant particle-associated HIV envelope protein gp120. Our results suggest that an intact HIV matrix domain is not absolutely required for reverse transcription, nuclear localization, or integration but is necessary for appropriate HIV envelope protein function.", "corpus_id": 39368588, "score": 0 }, { "doc_id": "19974774", "title": "Genetic analysis of the major homology region of the Rous sarcoma virus Gag protein", "abstract": "The mature cores of all retroviruses contain a major structural protein known as the CA (capsid) protein. Although it appears to form a shell around the ribonucleoprotein complex that contains the viral RNA, its function in viral replication is largely unknown. Little sequence similarity exists between the CA proteins of different retroviruses, except for a region of about 20 amino acids termed the major homology region (MHR). To examine the role of the CA protein in particle assembly and release, mutants of Rous sarcoma virus were created in which segments of CA were deleted or single conserved residues in the MHR were altered. The ability of the deletion mutants to release particles at rates similar to the wild-type protein demonstrated that the CA domain of Gag is not an essential component of the minimal budding machinery. Certain point mutations in the MHR region did block assembly and release in certain cell types, presumably by perturbing the global structure of the Gag precursor. Another group of MHR substitutions produced noninfectious or poorly infectious particles that were normal in their content of gag and pol gene products and viral RNA. The mutants were capable of initiating reverse transcription in vitro; however, the association of CA protein with the core was compromised, as indicated by its sensitivity to extraction with nonionic detergent. Prominent blebs on the virion envelope also indicated a disturbance at the membrane. Finally, an anti-peptide serum directed against MHR was found to react with the uncleaved Gag protein but not with mature CA, suggesting that MHR undergoes a dynamic rearrangement upon liberation from the polyprotein. We conclude that the MHR is involved in the very late steps in maturation of the virion (i.e., ones that occur after budding is initiated) and is essential for proper function of the core upon entry into a new host cell.", "corpus_id": 19974774, "score": 1 }, { "doc_id": "7537327", "title": "Functional domains of the capsid protein of human immunodeficiency virus type 1", "abstract": "A series of deletions was introduced into the CA domain of the human immunodeficiency virus type 1 Gag polyprotein to examine its role in virus particle and core formation. The mutations resulted in two phenotypes, indicating the existence of two functionally distinct regions within the CA domain. Deletions within a conserved stretch of 20 amino acids referred to as the major homology region (MHR) and deletions C terminal to this region blocked virus replication and significantly reduced the ability to form viral particles. Deletions N terminal to the MHR also prevented virus replication, but the mutants retained the ability to assemble and release viral particles with the same efficiency as the wild-type virus. The mutant particles contained circular rather than cone-shaped cores, and while they were of a density similar to that of wild-type particles, they were more heterogeneous in size. These results indicate that CA domain sequences N terminal to the MHR are essential for the morphogenesis of the mature cone-shaped core.", "corpus_id": 7537327, "score": 0 }, { "doc_id": "8675421", "title": "Role of the major homology region of human immunodeficiency virus type 1 in virion morphogenesis", "abstract": "Retroviral capsid (CA) proteins contain a uniquely conserved stretch of 20 amino acids which has been named the major homology region (MHR). To examine the role of this region in human immunodeficiency virus type 1 morphogenesis and replication, four highly conserved positions in the MHR were individually altered by site-directed mutagenesis. Conservative substitution of two invariant residues (glutamine 155 and glutamic acid 159) abolished viral replication and significantly reduced the particle-forming ability of the mutant gag gene products. Conservative substitution of the third invariant residue in the MHR (arginine 167) or of an invariably aromatic residue (tyrosine 164) had only a moderate effect. However, removal of the extended side chains of these amino acids by substitution with alanine prevented viral replication and affected virion morphogenesis. The replacement of tyrosine 164 with alanine substantially impaired viral particle production. By contrast, the substitution of arginine 167 with alanine had only a two- to threefold effect on particle yield but led to the formation of aberrant core structures. The MHR mutant which were severely defective for particle production had a dominant negative effect on particle formation by the wild-type Gag product. The role of the MHR in the incorporation of the Gag-Pol precursor was examined by expressing the Gag and Gag-Pol polyproteins individually from separate plasmids. Only when the two precursor polyproteins were coexpressed did processed Gag and Pol products appear in the external medium. The appearance of these products was unaffected or only moderately affected by substitutions in the MHR of the Gag-Pol precursor, suggesting that the mutant Gag-Pol precursors were efficiently incorporated into viral particles. The results of this study indicate that specific residues within the MHR are required both for human immunodeficiency virus type 1 particle assembly and for the correct assembly of the viral core. However, mutant Gag and Gag-Pol polyproteins with substitutions in the MHR retained the ability to interact with wild-type Gag protein.", "corpus_id": 8675421, "score": 0 }, { "doc_id": "46058550", "title": "Linker insertion mutations in the human immunodeficiency virus type 1 gag gene: effects on virion particle assembly, release, and infectivity", "abstract": "The phenotypes of a series of mutant human immunodeficiency virus type 1 proviruses with linker insertion and deletion mutations within the gag coding region were characterized. These mutants were tested for their ability to make and release viral particles in COS7 cells and for their viability in vivo. Of the 12 mutant proviruses, 4 did not make extracellular virion particles when transfected into COS7 cells. All four of these mutants had mutations in the C-terminal domain of CA. These mutants appeared to have defects both in the ability to accumulate high-molecular-weight intracellular structures containing Gag and Pol products and in the ability to release virion particles. Seven of the mutant proviruses retained the ability to make, release, and process virion particles from COS7 cells. These particles contained the Env glycoprotein, viral genomic RNA, and the mature products of the Gag and Gag-Pol polyproteins, yet they were noninfectious or poorly infectious. The defect in these mutants appears to be in one of the early steps of the viral life cycle. Thus, multiple regions throughout Gag appear to be important in mediating the early steps of the viral life cycle.", "corpus_id": 46058550, "score": 0 }, { "doc_id": "12180923", "title": "Characterization of deletion mutations in the capsid region of human immunodeficiency virus type 1 that affect particle formation and Gag-Pol precursor incorporation", "abstract": "The core of human immunodeficiency virus type 1 is derived from two precursor polyproteins, Pr55gag and Pr160gag-pol. The Gag precursor can assemble into immature virus-like particles when expressed by itself, while the Gag-Pol precursor lacks particle-forming ability. We have shown previously that the Gag precursor is able to \"rescue\" the Gag-Pol precursor into virus-like particles when the two polyproteins are expressed in the same cell by using separate simian virus 40-based plasmid expression vectors. To understand this interaction in greater detail, we have made deletion mutations in the capsid-coding regions of Gag- and Gag-Pol-expressing plasmids and assayed for the abilities of these precursors to assemble into virus-like particles. When we tested the abilities of Gag-Pol precursors to be incorporated into particles of Gag by coexpressing the precursors, we found that mutant Gag-Pol precursors lacking a conserved region in retroviral capsid proteins, the major homology region (MHR), were excluded from wild-type Gag particles. Mutant precursors lacking MHR were also less efficient in processing the Gag precursor in trans. These results suggest that the MHR is critical for interactions between Gag and Gag-Pol molecules. In contrast to these results, expression of mutated Gag precursors alone showed that deletions in the capsid region, including those which removed the MHR, reduced the efficiency of particle formation by only 40 to 50%. The mutant particles, however, were clearly lighter than the wild type in sucrose density gradients. These results indicate that the requirements for Gag particle formation differ from the ones essential for efficient incorporation of the Gag-Pol precursor into these particles.", "corpus_id": 12180923, "score": 1 }, { "doc_id": "29599966", "title": "Mutational analysis of the major homology region of Mason-Pfizer monkey virus by use of saturation mutagenesis", "abstract": "The major capsid (CA) protein of retroviruses possesses a stretch of 20 amino acids, called the major homology region (MHR), which is evolutionarily conserved and invariant in location within the primary sequence of the protein. The function of this region was investigated by examining the effect of random single-amino-acid substitutions within the central 13 positions of the MHR on the life cycle of Mason-Pfizer monkey virus (M-PMV), an immunosuppressive D-type retrovirus. When these mutants were subcloned into an M-PMV proviral vector and expressed in COS cells, one of two major phenotypes was observed. The first group, containing three mutants bearing drastic amino acid substitutions, was unable to assemble capsids in the cytoplasm of the host cell. The second and more common group of mutants was able to assemble and release virions, but these either displayed greatly reduced levels of infectivity or were completely noninfectious. Included within this second group were two mutants with unusual phenotypes; mutant D158Y exhibited a novel cleavage site for the viral protease that resulted in cleavage of the major capsid protein, p27 (CA), within the MHR, whereas mutant F156L appeared to have lost a major site for antibody recognition within the mature CA protein. The results of this mutagenic analysis suggest that changes in the MHR sequence can interfere with the assembly of viral capsids and block an early stage of the infection cycle of M-PMV.", "corpus_id": 29599966, "score": 0 }, { "doc_id": "6890213", "title": "Assembly, processing, and infectivity of human immunodeficiency virus type 1 gag mutants", "abstract": "We studied the effects of gag mutations on human immunodeficiency virus type 1 (HIV-1) assembly, processing, and infectivity by using a replication-defective HIV expression system. HIV mutants were screened for infectivity by transduction of a selectable marker and were examined for assembly by monitoring particle release from transfected cells. Gag protein processing and reverse transcriptase activities of mutant particles were also assayed. Surprisingly, most Gag protein mutants were assembled and processed. The two exceptions to this rule were a myristylation-minus mutant, and one gag matrix domain mutant which expressed proteins that were trapped intracellularly. Interestingly, a mutant with a 56-amino-acid deletion within the HIV gag capsid domain still could assemble and process virus particles, exhibited a wild-type retrovirus particle density, and had wild-type reverse transcriptase activity. Indeed, although most HIV-1 gag mutants were noninfectious or poorly infectious, they produced apparently normal particles which possessed significant reverse transcriptase activities. These results strongly support the notion that the HIV-1 Gag proteins are functionally involved in post-assembly, postprocessing stages of virus infectivity.", "corpus_id": 6890213, "score": 0 }, { "doc_id": "24964742", "title": "Transport and assembly of gag proteins into Moloney murine leukemia virus", "abstract": "We have studied the process of Moloney murine leukemia virus (M-MuLV) assembly by characterization of core (gag) protein mutants and analysis of wild-type (wt) gag proteins produced by cells in the presence of the ionophore monensin. Our genetic studies involved examination of linker insertion mutants of a Gag-beta-galactosidase (Gag-beta-gal) fusion protein, GBG2051, which is incorporated into virus particles when expressed in the presence of wt viral proteins. Analysis indicated that the amino-terminal two-thirds of the gag matrix domain is essential for targeting of proteins to the plasma membrane; mutant proteins localized to the cytoplasm or were trapped on intracellular membranes. Mutations through most of the coding region of the gag capsid domain generated proteins which were released from cells in membrane vesicles but not in virions. In contrast, linker insertions into p12gag or carboxy-terminal portions of the matrix or capsid coding regions did not affect assembly of fusion proteins into virus particles. Monensin, which blocks vesicular transport, inhibited gag protein intracellular transport and release from cells. Our results suggest that a significant proportion of M-MuLV myristylated gag proteins travel via vesicles to the cell surface. Specific matrix protein polypeptide regions and myristic acid modification are both necessary for appropriate gag protein transport, while capsid protein interactions appear to mediate the final phase of virion formation.", "corpus_id": 24964742, "score": 0 }, { "doc_id": "20534422", "title": "Assembly of recombinant human immunodeficiency virus type 1 capsid protein in vitro", "abstract": "The capsid protein (CA) (p24) of human immunodeficiency virus (HIV) type 1 expressed in Escherichia coli and purified to greater than 90% homogeneity was used to examine assembly in vitro and to probe the nature of interactions involved in the formation of capsid structures. The protein was detected in dimeric and oligomeric forms as indicated by molecular size measurements by gel filtration column chromatography, sedimentation through sucrose, and nondenaturing gel electrophoresis. Chemical cross-linking of CA molecules was observed with several homobifunctional reagents. Oligomer size was dependent on cross-linker concentration and exhibited a nonrandom pattern in which dimers and tetramers were more abundant than trimers and pentamers. Oligomers as large as dodecamers were detected in native polyacrylamide gels. These were stable in solutions of high ionic strength or in the presence of nonionic detergent, indicating that strong interactions were involved in oligomer stabilization. Limited tryptic digestion converted the putative dodecamers to octamers, suggesting that a region involved in CA protein multimerization was exposed in the structure. This region was mapped to the central portion of the protein. The recombinant CA proteins assembled in vitro into long rodlike structures and were disassembled into small irregular spheres by alterations in ionic strength and pH. The observation that assembly and disassembly of purified HIV type 1 CA protein can be induced in vitro suggests an approach for identifying possible control mechanisms involved in HIV viral core assembly.", "corpus_id": 20534422, "score": 0 }, { "doc_id": "5685311", "title": "Specificity and sequence requirements for interactions between various retroviral Gag proteins", "abstract": "We previously established a genetic assay for retroviral Gag polyprotein multimerization (J. Luban, K. B. Alin, K. L. Bossolt, T. Humaran, and S. P. Goff, J. Virol. 66:5157-5160, 1992). Here we use this assay to demonstrate homomeric interactions between Gag polyproteins encoded by six different retroviruses. Of the Gag polyproteins tested, only those encoded by closely related retroviruses formed heteromultimers. To determine the primary sequence requirements for human immunodeficiency virus type 1 Gag polyprotein multimerization, we studied the effects on multimerization of deletion and linker insertion mutations. Sequences necessary for this process were located between the C-terminal one-third of the capsid domain and the C terminus of the nucleocapsid domain.", "corpus_id": 5685311, "score": 0 }, { "doc_id": "7488298", "title": "Physical mapping of the Fv-1 tropism host range determinant of BALB/c murine leukemia viruses", "abstract": "The murine leukemia viruses (MuLVs) have different host ranges and were originally designated N-tropic and B-tropic if they replicated preferentially in vitro on NIH and BALB/c fibroblasts, respectively. It was later found that N-tropic MuLVs were in fact restricted in BALB/c cells, that B-tropic MuLVs were restricted in NIH cells, and that both viruses were restricted in (BALB X NIH) F1 cells. A single gene, Fv-1, with two alleles, Fv-1b and Fv-1n, determines this dominant restriction. A virus-encoded protein seems to carry the viral host range determinant which is recognized by the Fv-1 gene product. To map the viral DNA sequences encoding this determinant, we constructed viral DNA recombinants in vitro between the cloned infectious viral DNA genomes from BALB/c N-tropic and B-tropic MuLVs. Infectious recombinant MuLVs were recovered by microinjecting these recombinant DNAs into murine Fv-1- SC-1 cells and were subsequently tested in vitro for their host ranges (N- or B-tropic). We found that a short 302-base pair 5'-end fragment was necessary and sufficient to confer a specific host range to a recombinant. Our sequencing data revealed that this fragment codes for amino acid sequences in gag p30. They also showed that only two consecutive amino acid differences, Gln-ArgN- and Thr-GluB-, in p30 are responsible for the N- and B-tropic host ranges of the BALB/c MuLVs, respectively. Therefore, it appears that the Fv-1b and Fv-1n gene products can discriminate between these two p30 amino acid sequences.", "corpus_id": 7488298, "score": 0 }, { "doc_id": "43859444", "title": "Nucleotide sequences of gag-pol regions that determine the Fv-1 host range property of BALB/c N-tropic and B-tropic murine leukemia viruses", "abstract": "Previously, in vitro recombinant DNA studies demonstrated that genetic determinants of N-tropism and B-tropism, or Fv-1-related host range properties of murine leukemia viruses, were located in a BamHI-HindIII DNA segment derived from the 5' portion of the cloned viral genome. We sequenced this segment and its immediate 5' region from cloned DNA of two BALB/c mouse C-type viruses (WN1802N and WN1802B) and found base differences at 12 positions out of the otherwise identical 1,390-base-pair sequences. Analysis of the most likely reading frame showed that 6 of the 12 base differences would result in four encoded amino acid changes, three of which occur at positions 109 (glutamine in WN1802N versus threonine in WN1802B), 110 (arginine in WN1802N versus glutamic acid in WN1802B), and 159 (glutamic acid in WN1802N versus glycine in WN1802B) of the p30 protein. The remaining one is located at position 36 (threonine in WN1802N versus isoleucine in WN1802B) of the viral polymerase protein. Significant conformational alteration of the p30 protein could be predicted from these amino acid changes.", "corpus_id": 43859444, "score": 0 }, { "doc_id": "46469289", "title": "Analysis of the primary structure of the long terminal repeat and the gag and pol genes of the human spumaretrovirus", "abstract": "The nucleotide sequence of the human spumaretrovirus (HSRV) genome was determined. The 5' long terminal repeat region was analyzed by strong stop cDNA synthesis and S1 nuclease mapping. The length of the RU5 region was determined and found to be 346 nucleotides long. The 5' long terminal repeat is 1,123 base pairs long and is bound by an 18-base-pair primer-binding site complementary to the 3' end of mammalian lysine-1,2-specific tRNA. Open reading frames for gag and pol genes were identified. Surprisingly, the HSRV gag protein does not contain the cysteine motif of the nucleic acid-binding proteins found in and typical of all other retroviral gag proteins; instead the HSRV gag gene encodes a strongly basic protein reminiscent of those of hepatitis B virus and retrotransposons. The carboxy-terminal part of the HSRV gag gene products encodes a protease domain. The pol gene overlaps the gag gene and is postulated to be synthesized as a gag/pol precursor via translational frameshifting analogous to that of Rous sarcoma virus, with 7 nucleotides immediately upstream of the termination codons of gag conserved between the two viral genomes. The HSRV pol gene is 2,730 nucleotides long, and its deduced protein sequence is readily subdivided into three well-conserved domains, the reverse transcriptase, the RNase H, and the integrase. Although the degree of homology of the HSRV reverse transcriptase domain is highest to that of murine leukemia virus, the HSRV genomic organization is more similar to that of human and simian immunodeficiency viruses. The data justify classifying the spumaretroviruses as a third subfamily of Retroviridae.", "corpus_id": 46469289, "score": 0 }, { "doc_id": "37605722", "title": "Nucleotide sequence of a yeast Ty element: evidence for an unusual mechanism of gene expression.", "abstract": "We have determined the DNA sequence of the transposable element Ty912 of yeast. The 5918-base-pair element encodes two genes, tya912 and tyb912, which specify proteins similar to sequence-specific DNA-binding proteins of Escherichia coli and retroviral reverse transcriptases, respectively. The tyb912 gene is atypical of eukaryotic genes since (i) it begins 1336 nucleotides into the Ty912 mRNA (i.e., downstream of the tya912 gene) and (ii) the first in-frame AUG is 921 nucleotides into the coding frame. Protein blot analysis of Ty-lacZ fusions shows that the tyb912 gene is translated starting at the 5' end of the tya912 gene and that the primary translational product is a tya912::tyb912 fusion protein. We have shown that synthesis of this fusion protein probably does not occur by RNA splicing. The data are consistent with a mechanism of translational frameshifting occurring within the region of overlap between the 3' end of tya912 and the 5' end of tyb912.", "corpus_id": 37605722, "score": 0 }, { "doc_id": "20548581", "title": "Positive and negative regulatory elements control expression of the yeast retrotransposon Ty3.", "abstract": "We report the results of an analysis of Ty3 transcription and identification of Ty3 regions that mediate pheromone and mating-type regulation to coordinate its expression with the yeast life cycle. A set of strains was constructed which was isogenic except for the number of Ty3 elements, which varied from zero to three. Analysis of Ty3 expression in these strains showed that each of the three elements was transcribed and that each element was regulated. Dissection of the long terminal repeat regulatory region by Northern blot analysis of deletion mutants and reporter gene analysis showed that the upstream junction of Ty3 with flanking chromosomal sequences contained a negative control region. A 19-bp fragment (positions 56-74) containing one consensus copy and one 7 of 8-bp match to the pheromone response element (PRE) consensus was sufficient to mediate pheromone induction in either haploid cell type. Deletion of this region, however, did not abolish expression, indicating that other sequences also activate transcription. A 24-bp block immediately downstream of the PRE region contained a sequence similar to the a1-alpha 2 consensus that conferred mating-type control. A single base pair mutation in the region separating the PRE and a1-alpha 2 sequences blocked pheromone induction, but not mating-type control. Thus, the long terminal repeat of Ty3 is a compact, highly regulated, mobile promoter which is responsive to cell type and mating.", "corpus_id": 20548581, "score": 0 }, { "doc_id": "24651114", "title": "Ty3, a yeast retrotransposon associated with tRNA genes, has homology to animal retroviruses.", "abstract": "Ty3, a retrotransposon of Saccharomyces cerevisiae, is found within 20 base pairs (bp) of the 5' ends of different tRNA genes. Determination of the complete nucleotide sequence of one Ty3 retrotransposon (Ty3-2) shows that the element is composed of an internal domain 4,748 bp long flanked by long terminal repeats of the 340-bp sigma element. Three open reading frames (ORFs) longer than 100 codons are present in the sense strand. The first ORF, TYA3, encodes a protein with a motif found in the nucleic acid-binding protein of retroviruses. The second ORF, TYB3, has homology to retroviral pol genes. The deduced amino acid sequence of the reverse transcriptase domain shows the greatest similarity to Drosophila retrotransposon 17.6, with 43% identical residues. The inferred order of functional domains within TYB3--protease, reverse transcriptase, and endonuclease--resembles the order in Drosophila element 17.6 and in animal retroviruses but is different from that found in yeast elements Ty1 and Ty2. A second Ty3 element (Ty3-1) from a standard laboratory strain was overexpressed and shown to transpose.", "corpus_id": 24651114, "score": 0 }, { "doc_id": "35401110", "title": "Transposition of the yeast retroviruslike element Ty3 is dependent on the cell cycle.", "abstract": "Host cell cycle genes provide important functions to retroviruses and retroviruslike elements. To define some of these functions, the cell cycle dependence of transposition of the yeast retroviruslike element Ty3 was examined. Ty3 is unique among retroviruslike elements because of the specificity of its integration, which occurs upstream of genes transcribed by RNA polymerase III. A physical assay for Ty3 transposition which takes advantage of this position-specific integration was developed. The assay uses PCR to amplify a product of Ty3 integration into a target plasmid that carries a modified tRNA gene. By using the GAL1 upstream activating sequence to regulate expression of Ty3, transposition was detected within one generation of cell growth after Ty3 transcription was initiated. This physical assay was used to show that Ty3 did not transpose when yeast cells were arrested in G1 during treatment with the mating pheromone alpha-factor. The restriction of transposition was not due to changes in transcription of either Ty3 or tRNA genes or to aspects of the mating pheromone response unrelated to cell cycle arrest. The block of the Ty3 life cycle was reversed when cells were released from G1 arrest. Examination of Ty3 intermediates during G1 arrest indicated that Ty3 viruslike particles were present but that reverse transcription of the Ty3 genomic RNA into double-stranded DNA had not occurred. In G1, the Ty3 life cycle is blocked after particle assembly but before the completion of reverse transcription.", "corpus_id": 35401110, "score": 0 }, { "doc_id": "13279400", "title": "Saccharomyces cerevisiae SPT3 gene is required for transposition and transpositional recombination of chromosomal Ty elements.", "abstract": "Mutations in the Saccharomyces cerevisiae SPT3 gene have dramatic effects on the expression of Ty elements and genes adjacent to the element. The SPT3 gene is essential for Ty transposition, because transposition of chromosomal Ty elements ceased when the SPT3 gene was replaced with the frameshift mutation spt3-101. Presumably, the elimination of transposition was due to the effect of the SPT3 gene product on Ty transcription; the transcripts of chromosomal Ty elements were largely abolished in the spt3-101 strain (F. Winston, K. J. Durbin, and G. R. Fink, Cell 39:675-682, 1984). Ty transcription in an spt3-101 strain could be reestablished by introduction of the pGTyH3 plasmid, in which transcription of the Ty element TyH3 is under the control of the GAL1 promoter; these plasmid-derived Ty transcripts were SPT3-independent. Ty transposition resumed after galactose induction in spt3-101 strains containing the pGTyH3 plasmid. In spt3 mutants nearly all of the resulting transposition events derived from pGTyH3 plasmids and not from chromosomal elements.", "corpus_id": 13279400, "score": 0 }, { "doc_id": "205220215", "title": "Analysis of the yeast SPT3 gene and identification of its product, a positive regulator of Ty transcription.", "abstract": "Previous work has demonstrated that the yeast SPT3 gene is required for transcription from delta sequences, the long terminal repeats that flank yeast Ty elements. In spt3 null mutants, transcription fails to initiate in delta sequences and instead initiates farther downstream. Null mutations in SPT3 cause other mutant phenotypes, including defects in sporulation and diploid formation. In this paper we report further genetic and physical characterization of the SPT3 gene and protein. By extensive linker insertion mutagenesis, we have delimited the region necessary for SPT3 function. From DNA sequence analysis, SPT3 encodes a protein of 337 amino acids. We have identified this protein with an anti-SPT3 antibody. Finally, we show that overproduction of the SPT3 gene product does not alter the level of Ty transcription.", "corpus_id": 205220215, "score": 0 }, { "doc_id": "1376766", "title": "RNA from the yeast transposable element Ty1 has both ends in the direct repeats, a structure similar to retrovirus RNA.", "abstract": "The RNA homologous to the yeast transposable element Ty1 is one of the more abundant poly(A)+ RNAs in many strains of the yeast Saccharomyces cerevisiae. The 5' and 3' ends of Ty1 RNA have been determined from analysis of cDNA. The 5' end is 245 bases into the left delta sequence measured from the left side of the Ty1 element. The delta sequence is a direct repeat of about 340 base pairs present at each end of the Ty1 element. The Ty1 transcription includes 93-97 bases of the left delta sequence and continues through the entire internal portion of the element and through about 295 bases of the right delta sequence before reaching the 3' end located 38-46 bases from the right side of the right delta sequence. Because the delta sequences present at each end of a single Ty1 element have identical or very similar DNA sequences, these end points for Ty1 RNA raise several questions about the expression of Ty1 elements. First, what are the initiation and termination signals, because the Ty1 transcript must read through a DNA sequence that is identical to the 3' end at about 50 bases from the 5' end? Second, why is the direction of transcription of the Ty1 element opposite to that of genes that are overexpressed after the insertion of a Ty1 element? Third, because the Ty1 RNA itself has direct repeats of about 45 bases, a structure analogous to retrovirus RNAs, is the Ty1 RNA an intermediate in the transposition of Ty1?", "corpus_id": 1376766, "score": 0 }, { "doc_id": "40089077", "title": "The DNA intermediate in yeast Ty1 element transposition copurifies with virus-like particles: Cell-free Ty1 transposition", "abstract": "Yeast Ty1 elements are retrotransposons that transpose via an RNA intermediate found in a virus-like particle (Ty-VLP). A Ty-encoded reverse transcriptase activity found inside the particles is capable of giving rise to full-length reverse transcripts. The predominant form of these reverse transcripts is a full-length linear duplex DNA. We have developed a cell-free system for transposition of Ty1 DNA molecules into a bacteriophage lambda target. Purified Ty-VLPs and target DNA are the only macromolecular components required for the transposition reaction. A TYB-encoded protein, p90-TYB, contains amino acid sequences that are similar to those of retroviral integrase proteins. Mutations in the integrase coding region abolish transposition both in vivo and in vitro.", "corpus_id": 40089077, "score": 0 }, { "doc_id": "23657662", "title": "Proteolytic processing of Ty3 proteins is required for transposition", "abstract": "Ty3 is a retroviruslike element found in Saccharomyces cerevisiae. It encodes GAG3 and GAG3-POL3 polyproteins which are processed into mature proteins found in the Ty3 viruslike particle. In this study, the region encoding a protease that is homologous to retroviral aspartyl proteases was identified and shown to be required for production of mature Ty3 proteins and transposition. The Ty3 protease has the Asp-Ser-Gly consensus sequence found in copia, Ty1, and Rous sarcoma virus proteases, rather than the Asp-Thr-Gly found in most retroviral proteases. The Asp-Ser-Gly consensus is flanked by residues similar to those which flank the active sites of cellular aspartyl proteases. Mutations were made in the Ty3 active-site sequence to examine the role of the protease in Ty3 particle maturation and to test the functional significance of the Ser active-site variant in the consensus sequence. Mutation of the active-site Asp blocked processing of Gag3 and Gag3-Pol3 and allowed identification of a GAG3-POL3 polyprotein. This protein was turned over rapidly in cells expressing the mutant Ty3. Changing the active-site Ser to Thr caused only a modest reduction in the levels of certain Ty3 proteins. Five putative cleavage sites of this protease in Ty3 GAG3 and GAG3-POL3 polyproteins were defined by amino-terminal sequence analysis. The existence of an additional protein(s) of unknown function, encoded downstream of the protease-coding region, was deduced from the positions of these amino termini and the sizes of known Ty3 proteins. Although Ty3 protease cleavage sites do not correspond exactly to known retroviral protease cleavage sites, there are similarities. Residues P3 through P2' in the regions encompassing each of the five sites are uncharged, and no P1 position is occupied by an amino acid with a branched beta carbon.", "corpus_id": 23657662, "score": 0 }, { "doc_id": "31267558", "title": "Effect of Fv-1 gene product on proviral DNA formation and integration in cells infected with murine leukemia viruses.", "abstract": "The amounts of unintegrated murine leukemia virus-specific DNA detected by molecular hybridization in extracts of Fv-ln/n (strains NIH/3T3, SIM) or Fv-lb/b (strains JLS-V9, SIM.R) mouse cells after infection with N- or B-tropic viruses were found to be the same in both permissive and resistant cells. Therefore, formation of DNA products from the viral RNA template does not appear to be grossly affected by the Fv-l gene product. Integration of virus-specific DNA into chromosomal cellular DNA was assayed by hybridization of radioactive complementary DNA to DNA from infected cells. With either NIH/3T3 or SIM.R cells infected with N- or B-tropic viruses, integration of proviral DNA could be detected in permissive cells but not in nonpermissive cells. The Fv-l gene product therefore appears to prevent integration of proviral DNA.", "corpus_id": 31267558, "score": 0 }, { "doc_id": "39732010", "title": "Host restriction of Friend leukemia virus: synthesis and integration of the provirus.", "abstract": "Host restriction of exogenous infection by murine leukemia viruses is controlled in vitro predominantly by the murine Fv-1 locus. The mechanism of this host restriction was investigated by comparing the early events in the replication of N-tropic versus B-tropic Friend leukemia virus in NIH 3T3 cells. These cells, which are Fv-1nn in type, are permissive for the N-tropic strain, but nonpermissive for the B-tropic strain, which replicates permissively in Balb/c cells. We have studied the synthesis, intracellular location, and molecular form of virus-specific DNA early in replication by means of molecular hybridization with a virus-specific DNA probe. Our results suggest that in the permissive infection viral DNA rapidly becomes integrated with cellular DNA. However, in the nonpermissive infection, although almost equal amounts of both positive and negative strand viral DNA are synthesized, integration of the provirus does not occur.", "corpus_id": 39732010, "score": 0 }, { "doc_id": "38977686", "title": "Fv-1 restriction and its effects on murine leukemia virus integration in vivo and in vitro", "abstract": "We have investigated the mechanisms by which alleles at the mouse Fv-1 locus restrict replication of murine leukemia viruses. Inhibition of productive infection is closely paralleled by reduced accumulation of integrated proviral DNA as well as by reduced levels of linear viral DNA in a cytoplasmic fraction. Nevertheless, viral DNA is present at nearly normal levels in a nuclear fraction, and total amounts of viral DNA are only mildly affected in restrictive infections, suggesting a block in integration to account for reduced levels of proviral DNA. However, integrase (IN)-dependent trimming of 3' ends of viral DNA occurs normally in vivo during restrictive infections, demonstrating that not all IN-mediated events are prevented in vivo. Furthermore, viral integration complexes present in nuclear extracts of infected restrictive cells are fully competent to integrate their DNA into a heterologous target in vitro. Thus, the Fv-1-dependent activity that restricts integration in vivo may be lost in vitro; alternatively, Fv-1 restriction may prevent a step required for integration in vivo that is bypassed in vitro.", "corpus_id": 38977686, "score": 0 } ]

{ "doc_id": "13139105", "title": "Nanosensor Detection of an Immunoregulatory Tryptophan Influx/Kynurenine Efflux Cycle", "abstract": "Mammalian cells rely on cellular uptake of the essential amino acid tryptophan. Tryptophan sequestration by up-regulation of the key enzyme for tryptophan degradation, indoleamine 2,3-dioxygenase (IDO), e.g., in cancer and inflammation, is thought to suppress the immune response via T cell starvation. Additionally, the excreted tryptophan catabolites (kynurenines) induce apoptosis of lymphocytes. Whereas tryptophan transport systems have been identified, the molecular nature of kynurenine export remains unknown. To measure cytosolic tryptophan steady-state levels and flux in real time, we developed genetically encoded fluorescence resonance energy transfer nanosensors (FLIPW). The transport properties detected by FLIPW in KB cells, a human oral cancer cell line, and COS-7 cells implicate LAT1, a transporter that is present in proliferative tissues like cancer, in tryptophan uptake. Importantly, we found that this transport system mediates tryptophan/kynurenine exchange. The tryptophan influx/kynurenine efflux cycle couples tryptophan starvation to elevation of kynurenine serum levels, providing a two-pronged induction of apoptosis in neighboring cells. The strict coupling protects cells that overproduce IDO from kynurenine accumulation. Consequently, this mechanism may contribute to immunosuppression involved in autoimmunity and tumor immune escape.", "corpus_id": 13139105 }

[ { "doc_id": "204989591", "title": "Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT", "abstract": "Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12–13.1 (refs 3,4). We have identified a new transcript, encoding a protein (bo,+AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.", "corpus_id": 204989591, "score": 0 }, { "doc_id": "242877", "title": "The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location.", "abstract": "System T is a Na+-independent transport system that selectively transports aromatic amino acids. Here, we determined the structure of the human T-type amino-acid transporter-1 (TAT1) cDNA and gene (SLC16A10). The human TAT1 cDNA encoded a 515-amino-acid protein with 12 putative membrane-spanning domains. Human SLC16A10 was localized on human chromosome 6, mapped to 6q21-q22. SLC16A10 contains six exons spanning 136 kb. In contrast to rat TAT1, which is mainly present in the intestine, human TAT1 was strongly expressed in human kidney as well as in human intestine. Expression of human TAT1 in Xenopus laevis oocytes demonstrated the Na+-independent transport of tryptophan, tyrosine, phenylalanine, and L-dopa, indicating that human TAT1 is a transporter subserving system T. Because human TAT1 is proposed to be crucial to the efficient absorption of aromatic amino acids from intestine and kidney, its defect could be involved in the disruption of aromatic amino-acid transport, such as in blue diaper syndrome.", "corpus_id": 242877, "score": 0 }, { "doc_id": "32651163", "title": "Amino acid transport of y+L‐type by heterodimers of 4F2hc/CD98 and members of the glycoprotein‐associated amino acid transporter family", "abstract": "Amino acid transport across cellular membranes is mediated by multiple transporters with overlapping specificities. We recently have identified the vertebrate proteins which mediate Na+‐independent exchange of large neutral amino acids corresponding to transport system L. This transporter consists of a novel amino acid permease‐related protein (LAT1 or AmAT‐L‐lc) which for surface expression and function requires formation of disulfide‐linked heterodimers with the glycosylated heavy chain of the h4F2/CD98 surface antigen. We show that h4F2hc also associates with other mammalian light chains, e.g. y+LAT1 from mouse and human which are ∼48% identical with LAT1 and thus belong to the same family of glycoprotein‐associated amino acid transporters. The novel heterodimers form exchangers which mediate the cellular efflux of cationic amino acids and the Na+‐dependent uptake of large neutral amino acids. These transport characteristics and kinetic and pharmacological fingerprints identify them as y+L‐type transport systems. The mRNA encoding my+LAT1 is detectable in most adult tissues and expressed at high levels in kidney cortex and intestine. This suggests that the y+LAT1–4F2hc heterodimer, besides participating in amino acid uptake/secretion in many cell types, is the basolateral amino acid exchanger involved in transepithelial reabsorption of cationic amino acids; hence, its defect might be the cause of the human genetic disease lysinuric protein intolerance.", "corpus_id": 32651163, "score": 0 }, { "doc_id": "21447656", "title": "System L: heteromeric exchangers of large, neutral amino acids involved in directional transport", "abstract": "Abstract. The plasma membrane transport system L is in many cells the only (efficient) pathway for the import of large branched and aromatic neutral amino acids. The corresponding transporters are hetero(di)mers composed of a catalytic subunit (LAT1 or LAT2=light chain=glycoprotein-associated amino acid transporter) associated covalently with the glycoprotein 4F2hc/CD98 (heavy chain). The tissue distribution of LAT1 suggests that it is involved mainly in transporting amino acids into growing cells and across some endothelial/epithelial secretory barriers, whereas the localization of LAT2 indicates that it is mainly involved in the basolateral efflux step of transepithelial (re)absorptive amino acid transport. However, system L transporters are obligatory amino acid exchangers with 1:1 stoichiometry, with similar (but not identical) intra- and extracellular substrate selectivities and with highly asymmetrical apparent affinities (low affinity inside). Therefore, net directional transport of large, neutral amino acids by system L depends on the parallel expression of a unidirectional transporter with overlapping selectivity (for instance systems A or N) that provides/recycles amino acids that drive system L exchange function. By mediating the regulated flux of these exchange substrates, unidirectional transporters control the activity of system L.", "corpus_id": 21447656, "score": 1 }, { "doc_id": "43373439", "title": "LAT2, a New Basolateral 4F2hc/CD98-associated Amino Acid Transporter of Kidney and Intestine*", "abstract": "Glycoprotein-associated amino acid transporters (gpaAT) are permease-related proteins that require heterodimerization to express their function. So far, four vertebrate gpaATs have been shown to associate with 4F2hc/CD98 for functional expression, whereas one gpaAT specifically associates with rBAT. In this study, we characterized a novel gpaAT, LAT2, for which mouse and human cDNAs were identified by expressed sequence tag data base searches. The encoded ortholog proteins are 531 and 535 amino acids long and 92% identical. They share 52 and 48% residues with the gpaATs LAT1 and y+LAT1, respectively. When mouse LAT2 and human 4F2hc cRNAs were co-injected into Xenopus oocytes, disulfide-linked heterodimers were formed, and an l-type amino acid uptake was induced, which differed slightly from that produced by LAT1–4F2hc: the apparent affinity forl-phenylalanine was higher, and l-alanine was transported at physiological concentrations. In the presence of an external amino acid substrate, LAT2–4F2hc also mediated amino acid efflux. LAT2 mRNA is expressed mainly in kidney and intestine, whereas LAT1 mRNA is expressed widely. Immunofluorescence experiments showed colocalization of 4F2hc and LAT2 at the basolateral membrane of kidney proximal tubules and small intestine epithelia. In conclusion, LAT2 forms with LAT1 a subfamily of l-type gpaATs. We propose that LAT1 is involved in cellular amino acid uptake, whereas LAT2 plays a role in epithelial amino acid (re)absorption.", "corpus_id": 43373439, "score": 0 }, { "doc_id": "26990427", "title": "Identification of a Novel System L Amino Acid Transporter Structurally Distinct from Heterodimeric Amino Acid Transporters*", "abstract": "A cDNA that encodes a novel Na+-independent neutral amino acid transporter was isolated from FLC4 human hepatocarcinoma cells by expression cloning. When expressed in Xenopus oocytes, the encoded protein designated LAT3 (L-type amino acid transporter 3) transported neutral amino acids such as l-leucine, l-isoleucine, l-valine, and l-phenylalanine. The LAT3-mediated transport was Na+-independent and inhibited by 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, consistent with the properties of system L. Distinct from already known system L transporters LAT1 and LAT2, which form heterodimeric complex with 4F2 heavy chain, LAT3 was functional by itself in Xenopus oocytes. The deduced amino acid sequence of LAT3 was identical to the gene product of POV1 reported as a prostate cancer-up-regulated gene whose function was not determined, whereas it did not exhibit significant similarity to already identified transporters. The Eadie-Hofstee plots of LAT3-mediated transport were curvilinear, whereas the low affinity component is predominant at physiological plasma amino acid concentration. In addition to amino acid substrates, LAT3 recognized amino acid alcohols. The transport of l-leucine was electroneutral and mediated by a facilitated diffusion. In contrast, l-leucinol, l-valinol, and l-phenylalaninol, which have a net positive charge induced inward currents under voltage clamp, suggesting these compounds are transported by LAT3. LAT3-mediated transport was inhibited by the pretreatment with N-ethylmaleimide, consistent with the property of system L2 originally characterized in hepatocyte primary culture. Based on the substrate selectivity, affinity, and N-ethylmaleimide sensitivity, LAT3 is proposed to be a transporter subserving system L2. LAT3 should denote a new family of organic solute transporters.", "corpus_id": 26990427, "score": 0 }, { "doc_id": "9866298", "title": "Identification of LAT4, a Novel Amino Acid Transporter with System L Activity*", "abstract": "System L amino acid transporters mediate the movement of bulky neutral amino acids across cell membranes. Until now three proteins that induce system L activity have been identified: LAT1, LAT2, and LAT3. The former two proteins belong to the solute carrier family 7 (SLC7), whereas the latter belongs to SLC43. In the present study we present a new cDNA, designated LAT4, which also mediates system L activity when expressed in Xenopus laevis oocytes. Human LAT4 exhibits 57% identity to human LAT3. Like LAT3, the amino acid transport activity induced by LAT4 is sodium-, chloride- and pH-independent, is not trans-stimulated, and shows two kinetic components. The low affinity component of LAT4 induced activity is sensitive to the sulfhydryl-specific reagent N-ethylmaleimide but not that with high affinity. Mutation in LAT4 of the SLC43 conserved serine 297 to alanine abolishes sensitivity to N-ethylmaleimide. LAT4 activity is detected at the basolateral membrane of PCT kidney cells. In situ hybridization experiments show that LAT4 mRNA is restricted to the epithelial cells of the distal tubule and the collecting duct in the kidney. In the intestine, LAT4 is mainly present in the cells of the crypt.", "corpus_id": 9866298, "score": 0 }, { "doc_id": "26597086", "title": "Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime?", "abstract": "Relative to other neutral amino acid transporters, the expression levels of ASCT2 and LAT1, are coordinately elevated in a wide spectrum of primary human cancers, suggesting that they are frequently co-opted to support the \"tumor metabolome\". Each has recently been shown to play important roles in the growth and survival of cancer cell lines, making them potential targets for cancer therapy. The properties and putative relationship of these two amino acid exchangers are discussed in the context of their demonstrated utility in cancer biology, including cellular growth and survival signaling and integrated links to the mammalian target-of-rapamycin (mTOR) kinase.", "corpus_id": 26597086, "score": 0 }, { "doc_id": "206576595", "title": "Prevention of allogeneic fetal rejection by tryptophan catabolism.", "abstract": "In 1953 Medawar pointed out that survival of the genetically disparate (allogeneic) mammalian conceptus contradicts the laws of tissue transplantation. Rapid T cell-induced rejection of all allogeneic concepti occurred when pregnant mice were treated with a pharmacologic inhibitor of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme expressed by trophoblasts and macrophages. Thus, by catabolizing tryptophan, the mammalian conceptus suppresses T cell activity and defends itself against rejection.", "corpus_id": 206576595, "score": 0 }, { "doc_id": "7138934", "title": "Tryptophan catabolism and T cell responses.", "abstract": "Cells expressing indoleamine 2,3 dioxygenase (IDO) play key roles in regulating adaptive immune responses orchestrated by T cells. In this report we discuss our working model, the tryptophan depletion hypothesis, to explain links between IDO expression and inhibition of T cell responses. We posit that IDO+ cells, particularly professional antigen presenting cells (APCs) promote T cell entry but block cell cycle progression due to tryptophan catabolism. We discuss experimental evidence supporting predictions from the tryptophan depletion hypothesis and the implications that this model has for understanding the origin of tolerant states that explain immunological paradoxes, such as fetal survival, tumor persistence and failure to eradicate pathogens like HIV that cause persistent infections.", "corpus_id": 7138934, "score": 0 }, { "doc_id": "10618102", "title": "Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase", "abstract": "T lymphocytes undergo proliferation arrest when exposed to tryptophan shortage, which can be provoked by indoleamine 2,3-dioxygenase (IDO), an enzyme that is expressed in placenta and catalyzes tryptophan degradation. Here we show that most human tumors constitutively express IDO. We also observed that expression of IDO by immunogenic mouse tumor cells prevents their rejection by preimmunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These results suggest that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.", "corpus_id": 10618102, "score": 0 }, { "doc_id": "12338548", "title": "Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy", "abstract": "Immune escape is a crucial feature of cancer progression about which little is known. Elevation of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor cells can facilitate immune escape. Not known is how IDO becomes elevated or whether IDO inhibitors will be useful for cancer treatment. Here we show that IDO is under genetic control of Bin1, which is attenuated in many human malignancies. Mouse knockout studies indicate that Bin1 loss elevates the STAT1- and NF-κB-dependent expression of IDO, driving escape of oncogenically transformed cells from T cell–dependent antitumor immunity. In MMTV-Neu mice, an established breast cancer model, we show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to elicit regression of established tumors refractory to single-agent therapy. Our findings suggest that Bin1 loss promotes immune escape in cancer by deregulating IDO and that IDO inhibitors may improve responses to cancer chemotherapy.", "corpus_id": 12338548, "score": 0 }, { "doc_id": "25263268", "title": "Treatment of Autoimmune Neuroinflammation with a Synthetic Tryptophan Metabolite", "abstract": "Local catabolism of the amino acid tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. We show that IDO transcription was increased when myelin-specific T cells were stimulated with tolerogenic altered self-peptides. Catabolites of Trp suppressed proliferation of myelin-specific T cells and inhibited production of proinflammatory T helper–1 (TH1) cytokines. N-(3,4,-Dimethoxycinnamoyl) anthranilic acid (3,4-DAA), an orally active synthetic derivative of the Trp metabolite anthranilic acid, reversed paralysis in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Trp catabolites and their derivatives offer a new strategy for treating TH1-mediated autoimmune diseases such as MS.", "corpus_id": 25263268, "score": 0 }, { "doc_id": "31055428", "title": "In Vivo Imaging of the Dynamics of Glucose Uptake in the Cytosol of COS-7 Cells by Fluorescent Nanosensors*", "abstract": "Glucose homeostasis is a function of glucose supply, transport across the plasma membrane, and metabolism. To monitor glucose dynamics in individual cells, a glucose nanosensor was developed by flanking the Escherichia coli periplasmic glucose/galactose-binding protein with two different green fluorescent protein variants. Upon binding of substrate the FLIPglu-170n sensor showed a concentration-dependent decrease in fluorescence resonance energy transfer between the attached chromophores with a binding affinity for glucose of 170 nm. Fluorescence resonance energy transfer measurements with different sugars indicated a broad selectivity for monosaccharides. An affinity mutant with a Kd of ∼600 μm was generated, which showed higher substrate specificity, and thus allowed specific monitoring of reversible glucose dynamics in COS-7 cells in the physiological range. At external glucose concentrations between 0.5 and 10 mm, reflecting typical blood levels, free cytosolic glucose concentrations remained at ∼50% of external levels. The removal of glucose lead to reduced glucose levels in the cell, demonstrating reversibility and visualizing homeostasis. Glucose levels dropped even in the presence of the transport inhibitor cytochalasin B, indicating rapid metabolism. Consistently, the addition of 2-deoxyglucose, which is not recognized by the sensor, affects glucose uptake and metabolism rates. Within the physiological range, glucose utilization, i.e. hexokinase activity, was not limiting. Furthermore, the results show that in COS-7 cells, cytosolic glucose concentrations can vary over at least two orders of magnitude. The glucose nanosensor provides a novel tool with numerous scientific, medical, and environmental applications.", "corpus_id": 31055428, "score": 0 }, { "doc_id": "25932606", "title": "Visualization of maltose uptake in living yeast cells by fluorescent nanosensors", "abstract": "Compartmentation of metabolic reactions and thus transport within and between cells can be understood only if we know subcellular distribution based on nondestructive dynamic monitoring. Currently, methods are not available for in vivo metabolite imaging at cellular or subcellular levels. Limited information derives from methods requiring fixation or fractionation of tissue (1, 2). We thus developed a flexible strategy for designing protein-based nanosensors for a wide spectrum of solutes, allowing analysis of changes in solute concentration in living cells. We made use of bacterial periplasmic binding proteins (PBPs), where we show that, on binding of the substrate, PBPs transform their hinge–bend movement into increased fluorescence resonance energy transfer (FRET) between two coupled green fluorescent proteins. By using the maltose-binding protein as a prototype, nanosensors were constructed allowing in vitro determination of FRET changes in a concentration-dependent fashion. For physiological applications, mutants with different binding affinities were generated, allowing dynamic in vivo imaging of the increase in cytosolic maltose concentration in single yeast cells. Control sensors allow the exclusion of the effect from other cellular or environmental parameters on ratio imaging. Thus the myriad of PBPs recognizing a wide spectrum of different substrates is suitable for FRET-based in vivo detection, providing numerous scientific, medical, and environmental applications.", "corpus_id": 25932606, "score": 1 }, { "doc_id": "29228303", "title": "Development of a fluorescent nanosensor for ribose", "abstract": "To analyze ribose uptake and metabolism in living cells, nanosensors were engineered by flanking the Escherichia coli periplasmic ribose binding protein with two green fluorescent protein variants. Following binding of ribose, fluorescence resonance energy transfer decreased with increasing ribose concentration. Five affinity mutants were generated covering binding constants between 400 nM and 11.7 mM. Analysis of nanosensor response in COS‐7 cells showed that free ribose accumulates in the cell and is slowly metabolized. Inhibitor studies suggest that uptake is mediated by a monosaccharide transporter of the GLUT family, however, ribose taken up into the cell was not or only slowly released, indicating irreversibility of uptake.", "corpus_id": 29228303, "score": 0 }, { "doc_id": "10278381", "title": "Detection of glutamate release from neurons by genetically encoded surface-displayed FRET nanosensors.", "abstract": "Glutamate is the predominant excitatory neurotransmitter in the mammalian brain. Once released, its rapid removal from the synaptic cleft is critical for preventing excitotoxicity and spillover to neighboring synapses. Despite consensus on the role of glutamate in normal and disease physiology, technical issues limit our understanding of its metabolism in intact cells. To monitor glutamate levels inside and at the surface of living cells, genetically encoded nanosensors were developed. The fluorescent indicator protein for glutamate (FLIPE) consists of the glutamate/aspartate binding protein ybeJ from Escherichia coli fused to two variants of the green fluorescent protein. Three sensors with lower affinities for glutamate were created by mutation of residues peristeric to the ybeJ binding pocket. In the presence of ligands, FLIPEs show a concentration-dependent decrease in FRET efficiency. When expressed on the surface of rat hippocampal neurons or PC12 cells, the sensors respond to extracellular glutamate with a reversible concentration-dependent decrease in FRET efficiency. Depolarization of neurons leads to a reduction in FRET efficiency corresponding to 300 nM glutamate at the cell surface. No change in FRET was observed when cells expressing sensors in the cytosol were superfused with up to 20 mM glutamate, consistent with a minimal contribution of glutamate uptake to cytosolic glutamate levels. The results demonstrate that FLIPE sensors can be used for real-time monitoring of glutamate metabolism in living cells, in tissues, or in intact organisms, providing tools for studying metabolism or for drug discovery.", "corpus_id": 10278381, "score": 1 }, { "doc_id": "22444781", "title": "Purification and characterization of trp aporepressor.", "abstract": "We have isolated homogeneous trp aporepressor from an overproducing strain of Escherichia coli carrying a plasmid containing trpR preceded by tandem trp operon promoters. Dye-affinity and ion-exchange chromatography were used in conjunction with a gel electrophoresis assay in which the repressor, when bound to the trp operator, protects an Rsa I restriction site from endonuclease cleavage. Crystals suitable for x-ray diffraction studies were grown from a variety of concentrated salt solutions. Hydrodynamic properties and electrophoretic analysis of unmodified and covalently crosslinked aporepressor show that the free aporepressor has an isoelectric point of 5.9 and is a dimer containing two identical 12.5-kilodalton subunits in the presence or absence of L-tryptophan. The repressor . operator complex binds poorly to nitrocellulose filters, but restriction-site protection studies indicate that, in the presence of tryptophan, one dimer is bound to the operator site with an apparent dissociation constant less than 2 X 10(-9) M. Preliminary equilibrium dialysis experiments suggest that tryptophan binds to the aporepressor with a dissociation constant of 1.6 X 10(-5) M.", "corpus_id": 22444781, "score": 0 }, { "doc_id": "44837280", "title": "The structural basis for the interaction between L-tryptophan and the Escherichia coli trp aporepressor.", "abstract": "We have employed equilibrium dialysis to help study the mechanism by which the unliganded Escherichia coli trp aporepressor is activated by L-tryptophan to the liganded trp repressor. By measuring the relative affinity of L-tryptophan and various tryptophan analogues for the co-repressor's binding site, we have estimated the extent to which each of the functional groups of L-tryptophan contributes to the liganding process and discuss their role in the context of the crystal structures of the trp repressor and aporepressor. We have found that the indole ring and alpha carboxyl group of L-tryptophan are mainly responsible for its affinity to the aporepressor. The alpha amino group, however, has a small negative contribution to the affinity of L-tryptophan for the aporepressor which may be associated with its essential role in operator-specific binding.", "corpus_id": 44837280, "score": 1 }, { "doc_id": "31735300", "title": "Evidence for coupling of folding and function in trp repressor: physical characterization of the superrepressor mutant AV77.", "abstract": "The fine-control of gene expression in the trp repressor system is achieved through the thermodynamic linkage of multiple equilibria involving the trp repressor protein (TR), tryptophan (L-Trp) and DNA. We have undertaken studies of superrepressor mutants of TR as a means of dissecting the coupled equilibria that contribute to repressor function. Unlike all the other tested super-repressors that exhibit differences from wild-type TR DNA binding affinity or stoichiometry, the AV77 superrepressor (an alanine to valine substitution at position 77: AV77TR) has been indistinguishable from TR in vitro. The present studies using a variety of biophysical measurements comparing TR and AV77TR provide strong evidence that the helix-turn-helix (HTH) region of apoTR exists in a partially folded conformation. Far UV CD spectra of the two proteins reveal a 10% increase in helical content for the apoAV77TR compared to apoTR. Moreover, urea denaturation studies demonstrate that apoAV77TR is more stable to denaturation than apoTR. ApoTR binds large amounts of 1,8-ANS, a hydrophobic fluorescence probe used to detect protein folding intermediates, with high affinity, where apoAV77TR exhibits only marginal binding of this ligand. While the tryptophan affinities of the two proteins as measured by titration calorimetry are quite similar, the thermodynamic signatures are distinct, with a much reduced unfavorable entropic contribution for AV77TR. Finally, the allosteric effect of L-Trp on oligomerization is abolished by the AV77 mutation. Taken together these data support previous calorimetric studies implicating coupling of folding and L-Trp binding for TR. Moreover, they are consistent with NMR observations indicating partial disorder in the HTH region of apoTR. Based upon the distinct biophysical properties of TR and AV77TR, we propose a model in which folding of the HTH region accompanies ligand binding in TR. In this model distinct protein-protein interactions of the apo- and holoTR link this conformational change to apparent operator affinities, thereby modulating TR function in vivo.", "corpus_id": 31735300, "score": 0 }, { "doc_id": "32907689", "title": "Flexibility of dna binding domain of trp repressor required for recognition of different operator sequences", "abstract": "Trp repressor (25 kDa) is a regulatory protein that controls transcription initiation in the tryptophan biosynthetic operon and at least four other operons in Escherichia coli. An alanine to valine mutation (AV77) in the DNA binding domain is known to increase repressor activity at the trp operator in vivo, but not in vitro. We report here the amide proton exchange rates for the DNA‐binding domains of both the wild‐type and AV77 proteins. We find that the alanine to valine change stabilizes the flexible DNA‐binding domain of the repressor. We present in vivo data showing that, although the AV77 repressor is more inhibitory at the trp operator than the wild‐type repressor, it does not have increased activity at the aroH or trpR operator; repression at the aroH operator is, in fact, reduced. Our results suggest that the flexibility exhibited by the wild‐type repressor allows a broader range of repressor/DNA interactions, whereas the increased rigidity resulting from the AV77 change limits the repressor's effectiveness at some operators.", "corpus_id": 32907689, "score": 0 }, { "doc_id": "41395976", "title": "Principles of fluorescence spectroscopy", "abstract": "Fluorescence methods are being used increasingly in biochemical, medical, and chemical research. This is because of the inherent sensitivity of this technique. and the favorable time scale of the phenomenon of fluorescence. 8 Fluorescence emission occurs about 10- sec (10 nsec) after light absorp tion. During this period of time a wide range of molecular processes can occur, and these can effect the spectral characteristics of the fluorescent compound. This combination of sensitivity and a favorable time scale allows fluorescence methods to be generally useful for studies of proteins and membranes and their interactions with other macromolecules. This book describes the fundamental aspects of fluorescence. and the biochemical applications of this methodology. Each chapter starts with the -theoreticalbasis of each phenomenon of fluorescence, followed by examples which illustrate the use of the phenomenon in the study of biochemical problems. The book contains numerous figures. It is felt that such graphical presentations contribute to pleasurable reading and increased understand ing. Separate chapters are devoted to fluorescence polarization, lifetimes, quenching, energy transfer, solvent effects, and excited state reactions. To enhance the usefulness of this work as a textbook, problems are included which illustrate the concepts described in each chapter. Furthermore, a separate chapter is devoted to the instrumentation used in fluorescence spectroscopy. This chapter will be especially valuable for those perform ing or contemplating fluorescence measurements. Such measurements are easily compromised by failure to consider a number of simple principles.\"", "corpus_id": 41395976, "score": 0 }, { "doc_id": "9358980", "title": "Crystal structure of trp represser/operator complex at atomic resolution", "abstract": "The crystal structure of the trp repressor/operator complex shows an extensive contact surface, including 24 direct and 6 solvent-mediated hydrogen bonds to the phosphate groups of the DNA. There are no direct hydrogen bonds or non-polar contacts to the bases that can explain the repressor's specificity for the operator sequence. Rather, the sequence seems to be recognized indirectly through its effects on the geometry of the phosphate backbone, which in turn permits the formation of a stable interface. Water-mediated polar contacts to the bases also appear to contribute part of the specificity.", "corpus_id": 9358980, "score": 0 }, { "doc_id": "26998670", "title": "Construction and optimization of a family of genetically encoded metabolite sensors by semirational protein engineering", "abstract": "A family of genetically‐encoded metabolite sensors has been constructed using bacterial periplasmic binding proteins (PBPs) linearly fused to protein fluorophores. The ligand‐induced conformational change in a PBP allosterically regulates the relative distance and orientation of a fluorescence resonance energy transfer (FRET)‐compatible protein pair. Ligand binding is transduced into a macroscopic FRET observable, providing a reagent for in vitro and in vivo ligand‐measurement and visualization. Sensors with a higher FRET signal change are required to expand the dynamic range and allow visualization of subtle analyte changes under high noise conditions. Various observations suggest that factors other than inter‐fluorophore separation contribute to FRET transfer efficiency and the resulting ligand‐dependent spectral changes. Empirical and rational protein engineering leads to enhanced allosteric linkage between ligand binding and chromophore rearrangement; modifications predicted to decrease chromophore rotational averaging enhance the signal change, emphasizing the importance of the rotational freedom parameter κ2 to FRET efficiency. Tighter allosteric linkage of the PBP and the fluorophores by linker truncation or by insertion of chromophores into the binding protein at rationally designed sites gave rise to sensors with improved signal change. High‐response sensors were obtained with fluorescent proteins attached to the same binding PBP lobe, suggesting that indirect allosteric regulation during the hinge‐bending motion is sufficient to give rise to a FRET response. The optimization of sensors for glucose and glutamate, ligands of great clinical interest, provides a general framework for the manipulation of ligand‐dependent allosteric signal transduction mechanisms.", "corpus_id": 26998670, "score": 0 }, { "doc_id": "7657740", "title": "Identification of a Membrane Protein, LAT-2, That Co-expresses with 4F2 Heavy Chain, an L-type Amino Acid Transport Activity with Broad Specificity for Small and Large Zwitterionic Amino Acids*", "abstract": "We have identified a new human cDNA, L-amino acid transporter-2 (LAT-2), that induces a system L transport activity with 4F2hc (the heavy chain of the surface antigen 4F2, also named CD98) in oocytes. Human LAT-2 is the fourth member of the family of amino acid transporters that are subunits of 4F2hc. The amino acid transport activity induced by the co-expression of 4F2hc and LAT-2 was sodium-independent and showed broad specificity for small and large zwitterionic amino acids, as well as bulky analogs (e.g. BCH (2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid)). This transport activity was highlytrans-stimulated, suggesting an exchanger mechanism of transport. Expression of tagged N-myc-LAT-2 alone in oocytes did not induce amino acid transport, and the protein had an intracellular location. Co-expression of N-myc-LAT-2 and 4F2hc gave amino acid transport induction and expression of N-myc-LAT-2 at the plasma membrane of the oocytes. These data suggest that LAT-2 is an additional member of the family of 4F2 light chain subunits, which associates with 4F2hc to express a system L transport activity with broad specificity for zwitterionic amino acids. Human LAT-2 mRNA is expressed in kidney >>> placenta ≫ brain, liver > spleen, skeletal muscle, heart, small intestine, and lung. Human LAT-2 gene localizes at chromosome 14q11.2–13 (13 cR or ∼286 kb from marker D14S1349). The high expression of LAT-2 mRNA in epithelial cells of proximal tubules, the basolateral location of 4F2hc in these cells, and the amino acid transport activity of LAT-2 suggest that this transporter contributes to the renal reabsorption of neutral amino acids in the basolateral domain of epithelial proximal tubule cells.", "corpus_id": 7657740, "score": 0 }, { "doc_id": "37954360", "title": "Expression Cloning and Characterization of a Transporter for Large Neutral Amino Acids Activated by the Heavy Chain of 4F2 Antigen (CD98)*", "abstract": "A cDNA was isolated from rat C6 glioma cells by expression cloning which encodes a novel Na+-independent neutral amino acid transporter designated LAT1. For functional expression in Xenopusoocytes, LAT1 required the heavy chain of 4F2 cell surface antigen (CD98), a type II membrane glycoprotein. When co-expressed with 4F2 heavy chain, LAT1 transported neutral amino acids with branched or aromatic side chains and did not accept basic amino acids or acidic amino acids. The transport via LAT1 was Na+-independent and sensitive to a system L-specific inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. These functional properties correspond to those of the classically characterized amino acid transport system L, a major nutrient transporter. In in vitro translation, LAT1 was shown to be a nonglycosylated membrane protein consistent with the property of 4F2 light chain, suggesting LAT1 is at least one of the proteins formerly referred to as 4F2 light chain. LAT1 exhibits relatively low but significant amino acid sequence similarity to mammalian cationic amino acid transporters and amino acid permeases of bacteria and yeasts, indicating LAT1 is a new member of the APC superfamily. Because of highly regulated nature and high level of expression in tumor cell lines, LAT1 is thought to be up-regulated to support the high protein synthesis for cell growth and cell activation. The cloning of LAT1 is expected to facilitate the research on the protein-protein interaction in the transporter field and to provide a clue to the search for still unidentified transporters.", "corpus_id": 37954360, "score": 0 }, { "doc_id": "26050987", "title": "Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.", "abstract": "System L is a major nutrient transport system responsible for the transport of large neutral amino acids including several essential amino acids. We previously identified a transporter (L-type amino acid transporter 1: LAT1) subserving system L in C6 rat glioma cells and demonstrated that LAT1 requires 4F2 heavy chain (4F2hc) for its functional expression. Since its oncofetal expression was suggested in the rat liver, it has been proposed that LAT1 plays a critical role in cell growth and proliferation. In the present study, we have examined the function of human LAT1 (hLAT1) and its expression in human tissues and tumor cell lines. When expressed in Xenopus oocytes with human 4F2hc (h4F2hc), hLAT1 transports large neutral amino acids with high affinity (K(m)= approximately 15- approximately 50 microM) and L-glutamine and L-asparagine with low affinity (K(m)= approximately 1.5- approximately 2 mM). hLAT1 also transports D-amino acids such as D-leucine and D-phenylalanine. In addition, we show that hLAT1 accepts an amino acid-related anti-cancer agent melphalan. When loaded intracellularly, L-leucine and L-glutamine but not L-alanine are effluxed by extracellular substrates, confirming that hLAT1 mediates an amino acid exchange. hLAT1 mRNA is highly expressed in the human fetal liver, bone marrow, placenta, testis and brain. We have found that, while all the tumor cell lines examined express hLAT1 messages, the expression of h4F2hc is varied particularly in leukemia cell lines. In Western blot analysis, hLAT1 and h4F2hc have been confirmed to be linked to each other via a disulfide bond in T24 human bladder carcinoma cells. Finally, in in vitro translation, we show that hLAT1 is not a glycosylated protein even though an N-glycosylation site has been predicted in its extracellular loop, consistent with the property of the classical 4F2 light chain. The properties of the hLAT1/h4F2hc complex would support the roles of this transporter in providing cells with essential amino acids for cell growth and cellular responses, and in distributing amino acid-related compounds.", "corpus_id": 26050987, "score": 0 }, { "doc_id": "32173631", "title": "Activation of system L heterodimeric amino acid exchangers by intracellular substrates", "abstract": "System L‐type transport of large neutral amino acids is mediated by ubiquitous LAT1‐4F2hc and epithelial LAT2‐4F2hc. These heterodimers are thought to function as obligatory exchangers, but only influx properties have been studied in some detail up until now. Here we measured their intracellular substrate selectivity, affinity and exchange stoichiometry using the Xenopus oocyte expression system. Quantification of amino acid influx and efflux by HPLC demonstrated an obligatory amino acid exchange with 1:1 stoichiometry. Strong, differential trans‐stimulations of amino acid influx by injected amino acids showed that the intracellular substrate availability limits the transport rate and that the efflux selectivity range resembles that of influx. Compared with high extracellular apparent affinities, LAT1‐ and LAT2‐4F2hc displayed much lower intracellular apparent affinities (apparent Km in the millimolar range). Thus, the two system L amino acid transporters that are implicated in cell growth (LAT1‐4F2hc) and transcellular transport (LAT2‐4F2hc) are obligatory exchangers with relatively symmetrical substrate selectivities but strongly asymmetrical substrate affinities such that the intracellular amino acid concentration controls their activity.", "corpus_id": 32173631, "score": 0 }, { "doc_id": "19928871", "title": "Amino acid transport system L is differently expressed in human normal oral keratinocytes and human oral cancer cells.", "abstract": "Previously, we reported the expression and function of system L amino acid transporter in KB human oral epidermoid carcinoma cells. In the present study, therefore, we investigated the expression and function of system L amino acid transporter in human normal oral keratinocytes (HNOK) and compared the expressions and functions of system L amino acid transporters in HNOK and KB cells. The HNOK expressed L-type amino acid transporter 1 (LAT1) and L-type amino acid transporter 2 (LAT2) with their subunit 4F2hc in the plasma membrane but the expression of LAT1 was very weak, which is in contrast to the KB cells expressing LAT1 but not LAT2 with the 4F2hc in the plasma membrane. The [14C] L-leucine uptake by HNOK, as well as KB cells, was inhibited by the system L selective inhibitor BCH. The majority of [14C] L-leucine uptake was, therefore, mainly mediated by LAT2 in the HNOK and by LAT1 in the KB cells. These results suggest that the transport of neutral amino acids including several essential amino acids into the HNOK and KB cells are mainly mediated by LAT2 and LAT1, respectively. The specific inhibition of LAT1 in oral cancer cells could be a new rationale for anti-cancer therapy.", "corpus_id": 19928871, "score": 0 }, { "doc_id": "40107028", "title": "The RNA interference of amino acid transporter LAT1 inhibits the growth of KB human oral cancer cells.", "abstract": "BACKGROUND\nAmino acid transporters are essential for growth and proliferation in all living cells. Among the amino acid transporters, the system L amino acid transporters are the major nutrient transport system responsible for the Na+-independent transport of neutral amino acids, including several essential amino acids. The L-type amino acid transporter 1 (LAT1) is overexpressed to support cell growth in malignant tumors. Double-stranded RNA-mediated RNA interference (RNAi) analysis can be used in a wide variety of eukaryotes to induce the sequence-specific inhibition of gene expression. The current study attempted to investigate the effects of silencing LAT1 expression with small interfering RNA (siRNA) on cell growth in the KB human oral squamous cell carcinoma.\n\n\nMATERIALS AND METHODS\nThe effects of silencing LAT1 expression with siRNA KB on cell growth were examined using RT-PCR, Western blot analysis, amino acid transport measurement and the MTT assay.\n\n\nRESULTS\nIn the RT-PCR and Western blot analyses, the siRNA of LAT1 inhibited the expressions of LAT1 mRNA and protein. The uptake of [14C]L-leucine was also inhibited by the siRNA of LAT1. In the MTT assay, the siRNA of LAT1 inhibited the growth of the KB cells in a time-dependent manner, indicating that this growth inhibition was induced by the LAT1-mediated blocking of neutral amino acid transport.\n\n\nCONCLUSION\nThe transport of neutral amino acids, including several essential amino acids, into the KB human oral squamous cell carcinoma is mainly mediated by LAT1. Furthermore, LAT1 could be a new target for the inhibition of cancer cell growth.", "corpus_id": 40107028, "score": 0 }, { "doc_id": "31299670", "title": "T cell apoptosis by kynurenines.", "abstract": "Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that, expressed by different cell types, has regulatory effects on T cells resulting from tryptophan depletion in specific local tissue microenvironments. The discovery that inhibition of IDO activity reduces the survival of MHC-mismatched fetuses in mice and that the risk of fetal allograft rejection correlates with the degree of parental tissue incompatibility has led to the hypothesis that IDO activity protects fetal allografts from maternal T cell-mediated immunity. Different mechanisms, however, might contribute to IDO-dependent immune regulation. We have found that tryptophan metabolites in the kynurenine pathway, such as 3-hydroxyanthranilic and quinolinic acids, will induce the selective apoptosis in vitro of murine thymocytes and Th1 but not Th2 cells. T cell apoptosis was observed at relatively low concentrations of kynurenines, did not require Fas/Fas ligand interactions and was associated with the activation of casapase-8 and the release of cytochrome c from mitochondria. In vivo, the two kynurenines caused depletion of specific thymocyte subsets in a fashion qualitatively similar to dexamethasone. These data may represent the first experimental evidence for the involvement of tryptophan catabolism in the regulation of T cell apoptosis and maintenance of peripheral T cell tolerance.", "corpus_id": 31299670, "score": 0 }, { "doc_id": "6115549", "title": "Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase", "abstract": "Macrophages exposed to macrophage colony-stimulating factor acquire the capacity to suppress T cell proliferation; this effect is associated with de novo expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). We have purified IDO and tested its activity in in vitro models of T cell activation. IDO was able to inhibit proliferation of CD4+ T lymphocytes, CD8+ T lymphocytes, and natural killer (NK) cells; proliferation of B lymphocytes was not affected. The inhibitory role of tryptophan and of its catabolites was then tested. In the presence of tryptophan, only l-kynurenine and picolinic acid inhibit cell proliferation. In a tryptophan-free medium cell proliferation was not affected. In the absence of tryptophan inhibition induced by l-kynurenine and picolinic acid was observed at concentrations below the lowest concentration that was effective in the presence of tryptophan, and quinolinic acid acquired some inhibitory capacity. Inhibition of cell proliferation induced by the tryptophan catabolites resulting from IDO activity was selective, applying only to cells undergoing activation. Resting cells were not affected and could subsequently activate normally. We suggest that IDO exerts its effect on cell proliferation by (i) starting the cascade of biochemical reactions that produce the three catabolites and by (ii) enhancing their inhibitory potential by depriving the extracellular microenvironment of tryptophan.", "corpus_id": 6115549, "score": 1 }, { "doc_id": "15163397", "title": "Genetically encoded fluorescent indicator for intracellular hydrogen peroxide", "abstract": "We developed a genetically encoded, highly specific fluorescent probe for detecting hydrogen peroxide (H2O2) inside living cells. This probe, named HyPer, consists of circularly permuted yellow fluorescent protein (cpYFP) inserted into the regulatory domain of the prokaryotic H2O2-sensing protein, OxyR. Using HyPer we monitored H2O2 production at the single-cell level in the cytoplasm and mitochondria of HeLa cells treated with Apo2L/TRAIL. We found that an increase in H2O2 occurs in the cytoplasm in parallel with a drop in the mitochondrial transmembrane potential (ΔΨ) and a change in cell shape. We also observed local bursts in mitochondrial H2O2 production during ΔΨ oscillations in apoptotic HeLa cells. Moreover, sensitivity of the probe was sufficient to observe H2O2 increase upon physiological stimulation. Using HyPer we detected temporal increase in H2O2 in the cytoplasm of PC-12 cells stimulated with nerve growth factor.", "corpus_id": 15163397, "score": 0 }, { "doc_id": "9010716", "title": "Live Imaging of Glucose Homeostasis in Nuclei of COS-7 Cells", "abstract": "Measuring subcellular glucose levels deep in tissues can provide new insights into compartmentalization and specialization of glucose metabolism among different cells. As shown previously, a FRET-based glucose-sensor consisting of two GFP-variants and the Escherichia coli periplasmic glucose/galactose binding protein was successfully expressed in the cytosol of COS7-cells and used to determine cytosolic glucose levels. Recording cytosolic fluorescence intensities in cells located in deeper layers of tissues is often difficult due to loss of signal intensity caused by effects of other cell layers on excitation and emission light. These interfering effects may be reduced by restricting fluorophores to occupy only a fraction of the assayed tissue volume. This can be accomplished by confining fluorophores to a sub-compartment of each cell in the tissue, such as the nucleus. The glucose-sensor was targeted to nuclei of COS7-cells. To determine, whether nuclear glucose levels can be used to track cytosolic changes, nuclear glucose concentrations were quantified as the cells were challenged with external glucose over a range of 0.5 to 10 mM and compared to cytosolic levels. Internal glucose concentrations in both compartments were similar, corresponding to ∼50% of the external concentration. Taken together, these results indicate that nuclear glucose levels can be used to determine cytosolic levels indirectly, permitting more reliable quantification of fluorescence intensities and providing a tool for measurements not only in cell cultures but also in tissues.", "corpus_id": 9010716, "score": 0 }, { "doc_id": "32618780", "title": "Shining light on signaling and metabolic networks by genetically encoded biosensors.", "abstract": "Fluorescent labels have revolutionized cell biology. Signaling intermediates and metabolites can be measured in real time with subcellular spatial resolution. Most of these sensors are based on fluorescent proteins, and many report fluorescence resonance energy transfer. Because the biosensors are genetically encoded, a toolbox for addressing cell biological questions at the systems level is now available. Fluorescent biosensors are able to determine the localization of proteins and their dynamics, to reveal the cellular and subcellular localization of the respective interactions and activities, and to provide complementary data on the steady state levels of ions, metabolites, and signaling intermediates with high temporal and spatial resolution. They represent the basis for cell-based high-throughput assays that are necessary for a systems perspective on plant cell function.", "corpus_id": 32618780, "score": 0 }, { "doc_id": "24014529", "title": "Novel biosensors for the detection of estrogen receptor ligands", "abstract": "There exists a significant need for the detection of novel estrogen receptor (ER) ligands for pharmaceutical uses, especially for treating complications associated with menopause. We have developed fluorescence resonance energy transfer (FRET)-based biosensors that permit the direct in vitro detection of ER ligands. These biosensors contain an ER ligand-binding domain (LBD) flanked by the FRET donor fluorophore, cyan fluorescent protein (CFP), and the acceptor fluorophore, yellow fluorescent protein (YFP). The ER-LBD has been modified so that Ala 430 has been changed to Asp, which increases the magnitude of the FRET signal in response to ligand-binding by more than four-fold compared to the wild-type LBD. The binding of agonists can be distinguished from that of antagonists on the basis of the distinct ligand-induced conformations in the ER-LBD. The approach to binding equilibrium occurs within 30min, and the FRET signal is stable over 24h. The biosensor demonstrates a high signal-to-noise, with a Z' value (a statistical determinant of assay quality) of 0.72. The affinity of the ER for different ligands can be determined using a modified version of the biosensor in which a truncated YFP and an enhanced CFP are used. Thus, we have developed platforms for high-throughput screens for the identification of novel estrogen receptor ligands. Moreover, we have demonstrated that this FRET technology can be applied to other nuclear receptors, such as the androgen receptor.", "corpus_id": 24014529, "score": 0 }, { "doc_id": "20904514", "title": "FRET imaging", "abstract": "Förster (or Fluorescence) Resonance Energy Transfer (FRET) is unique in generating fluorescence signals sensitive to molecular conformation, association, and separation in the 1–10 nm range. We introduce a revised photophysical framework for the phenomenon and provide a systematic catalog of FRET techniques adapted to imaging systems, including new approaches proposed as suitable prospects for implementation. Applications extending from a single molecule to live cells will benefit from multidimensional microscopy techniques, particularly those adapted for optical sectioning and incorporating new algorithms for resolving the component contributions to images of complex molecular systems.", "corpus_id": 20904514, "score": 0 }, { "doc_id": "30529991", "title": "Recombinant Dicer efficiently converts large dsRNAs into siRNAs suitable for gene silencing", "abstract": "RNA interference (RNAi) is a powerful method for specifically silencing gene expression in diverse cell types. RNAi is mediated by ∼21-nucleotide small interfering RNAs (siRNAs), which are produced from larger double-stranded RNAs (dsRNAs) in vivo through the action of Dicer, an RNase III–family enzyme. Transfecting cells with siRNAs rather than larger dsRNAs avoids the nonspecific gene silencing of the interferon response, underscoring the importance of developing efficient methods for producing reliable siRNAs. Here we show that pools of 20- to 21-base pair (bp) siRNAs can be produced enzymatically in vitro using active recombinant Dicer. Yields of ≤ 70% are obtained, and the siRNAs can be easily separated from any residual large dsRNA by a series of spin columns or gel purification. Dicer-generated siRNAs (d-siRNAs) are effective in silencing transiently transfected reporter genes and endogenous genes, making in vitro dicing a useful, practical alternative for the production of siRNAs.", "corpus_id": 30529991, "score": 0 }, { "doc_id": "23730288", "title": "Indoleamine 2,3-dioxygenase in immune suppression and cancer.", "abstract": "The extrahepatic enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes tryptophan degradation in the first and rate-limiting step towards biosynthesis of the central metabolic co-factor nicotinamide adenine dinucleotide (NAD). While this pathway has been known for decades, the actual physiological role for IDO in mammals remained obscure, because (i.) most cell types do not express the downstream enzymes in the NAD biosynthesis pathway and (ii.) mammals salvage rather than synthesize NAD to meet their metabolic needs. An immunological role for IDO was hinted at with the observation that IDO expression is stimulated by interferon-gamma and subsequently confirmed by the discovery of its physiological importance in protecting the fetus from maternal immunity. Similarly, elevations in tryptophan catabolism in cancer patients were known since the 1950s, but the basis and meaning of this phenomenon were uncertain until it was shown that IDO, which is commonly elevated in tumors and draining lymph nodes, suppresses T cell immunity in the tumor microenvironment. Indeed, by creating peripheral tolerance to tumor antigens, IDO can undermine immune responses that thwart tumor cell survival in the context of an underlying inflammatory environment that facilitates tumor outgrowth. In preclinical studies, small molecule inhibitors of IDO compromise this mechanism of immunosuppression and strongly leverage the efficacy of a variety of classical chemotherapeutic agents, supporting the clinical development of IDO inhibitors as a therapeutic goal. This essay summarizes key findings that implicate IDO as an important mediator of peripheral tolerance and discusses the development of anti-cancer modalities that incorporate the use of IDO inhibitors.", "corpus_id": 23730288, "score": 0 }, { "doc_id": "28484846", "title": "Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma.", "abstract": "The antiproliferative effects of interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) were found to be cell-dependent. Among the human cell lines examined, IFN-gamma had a greater antiproliferative effect against cell lines that exhibited induction of indoleamine 2,3-dioxygenase, such as the KB oral carcinoma or WiDr colon adenocarcinoma, than against those that lacked the enzyme activity, such as the SW480 colon adenocarcinoma or NCI-H128 small-cell lung carcinoma. Induction of this dioxygenase showed a clear temporal relationship with increased metabolism of L-tryptophan and the depletion of this amino acid in the culture medium. While 70-80% of L-tryptophan remained in the medium of IFN-alpha- or vehicle-treated cells, virtually all of this amino acid was depleted in the medium of the IFN-gamma-treated group following 2-3 days of culture. Supplementing the growth medium with additional L-tryptophan reversed the antiproliferative effect of IFN-gamma against KB cells in a dose- and time-dependent manner. The antiproliferative effects of IFN-alpha and IFN-gamma on SW480 and NCI-H128 cells, which are independent of the dioxygenase activity, and the inability of added L-tryptophan to reverse the effects of IFN-gamma in WiDr cells suggest multiple mechanisms of action of the IFNs. The data show that the antiproliferative effect of IFN-gamma through induction of indoleamine 2,3-dioxygenase, with a consequent L-tryptophan deprivation, is an effective means of regulating cell growth.", "corpus_id": 28484846, "score": 0 }, { "doc_id": "17334989", "title": "A high‐affinity, tryptophan‐selective amino acid transport system in human macrophages", "abstract": "Tryptophan catabolism via the enzyme indoleamine 2,3‐dioxygenase (IDO) allows human monocyte‐derived macrophages (MDM) and other APC to suppress T cell proliferation. IDO helps protect murine fetuses from rejection by the maternal immune system and can promote tolerance and immunosuppression. For tryptophan to be catabolized by IDO, it must first enter the APC via transmembrane transport. It has been shown that MDM in vitro readily deplete tryptophan present in the extracellular medium to nanomolar levels via IDO activity; yet, no currently known amino acid transport system displays high affinity and specificity sufficiently to permit efficient uptake of tryptophan at these low concentrations. Here, we provide biochemical characterization of a novel transport system with nanomolar affinity and high selectivity for tryptophan. Tryptophan transport in MDM was predominantly sodium‐independent and occurred via two distinct systems: one consistent with the known system L transporter and a second system with 100‐fold higher affinity for tryptophan (Km<300 nM). Competition studies showed that the high‐affinity system did not correspond to any known transporter activity and displayed a marked selectivity for tryptophan over other amino acids and tryptophan analogs. This new system was expressed at low levels in fresh monocytes but underwent selective induction during MDM differentiation. In contrast, resting human T cells expressed only the conventional system L. We speculate that the high‐affinity, tryptophan‐specific transport system allows MDM to take up tryptophan efficiently under conditions of low substrate concentration, such as may occur during interaction between T cells and IDO‐expressing APC.", "corpus_id": 17334989, "score": 0 }, { "doc_id": "23719365", "title": "Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division", "abstract": "Cells expressing indoleamine 2,3‐dioxygenase (IDO), an enzyme which catabolizes tryptophan, prevent T‐cell proliferation in vitro, suppress maternal antifetal immunity during pregnancy and inhibit T‐cell‐mediated responses to tumour‐associated antigens. To examine the mechanistic basis of these phenomena we activated naïve murine T cells in chemically defined tryptophan‐free media. Under these conditions T cells expressed CD25 and CD69 and progressed through the first 12 hr of G0/G1 phase but did not express CD71, cyclin D3, cdk4, begin DNA synthesis, or differentiate into cytotoxic effector cells. In addition, activated T cells with their growth arrested by tryptophan deprivation exhibited enhanced tendencies to die via apoptosis when exposed to anti‐Fas antibodies. Apoptosis was inhibited by caspase inhibitor and was not observed when T cells originated from Fas‐deficient mice. These findings suggest that T cells activated in the absence of free tryptophan entered the cell cycle but cell cycle progression ceased in mid‐G1 phase and T cells became susceptible to death via apoptosis, in part though Fas‐mediated signalling. Thus, mature antigen‐presenting cells expressing IDO and Fas‐ligand may induce antigen‐specific T‐cell tolerance by blocking T‐cell cycle progression and by rapid induction of T‐cell activation induced cell death in local tissue microenvironments.", "corpus_id": 23719365, "score": 0 }, { "doc_id": "25744740", "title": "Nucleotide sequence and expression of Escherichia coli trpR, the structural gene for the trp aporepressor.", "abstract": "The nucleotide sequence of trpR of Escherichia coli was determined. This gene codes for a polypeptide (Mr 12,356) that is 108 amino acid residues in length. NH2-terminal, COOH-terminal, and total amino acid analyses of purified aporepressor agree with the deduced amino acid sequence and establish the translation start and stop codons of the structural gene. The transcription start site for trpR mRNA synthesis in vitro was shown to be 56 base pairs prior to the translation start site. The nucleotide sequence on either side of the transcription start site is homologous to the trp operon operator. Purified trp aporepressor, when activated by L-tryptophan, protects restriction sites in this region, the presumed trpR operator, from cleavage by the respective restriction endonucleases. Bound RNA polymerase protects the same restriction sites. These findings and the additional observation that trp repressor inhibits transcription initiation in vitro establish that there is a functional overlap of operator and promoter sequences in the regulatory region of the trpR operon. These findings indicate that expression of trpR is autoregulatory.", "corpus_id": 25744740, "score": 0 }, { "doc_id": "39460569", "title": "Spectroscopic approach for monitoring two-photon excited fluorescence resonance energy transfer from homodimers at the subcellular level.", "abstract": "We have employed a spectroscopic approach for monitoring fluorescence resonance energy transfer (FRET) in living cells. This method provides excellent spectral separation of green fluorescent protein (GFP) mutant signals within a subcellular imaging volume using two-photon excited fluorescence imaging and spectroscopy (TPIS-FRET). In contrast to current FRET-based methodologies, TPIS-FRET does not rely on the selection of optical filters, ratiometric image analysis, or bleedthrough correction algorithms. Utilizing the intrinsic optical sectioning capabilities of TPIS-FRET, we have identified protein-protein interactions within discrete subcellular domains. To illustrate the applicability of this technique to the detection of homodimer formation, we demonstrated the in vivo association of promyleocyte (PML) homodimers within their corresponding nuclear body.", "corpus_id": 39460569, "score": 0 } ]

{ "doc_id": "14256311", "title": "Agroecological weed control using a functional approach: a review of cropping systems diversity", "abstract": "Agriculture since the 1950s has shown pronounced trends toward specialisation and intensification. Intensive measures have been taken for crop protection against pests through the widespread use of chemical pesticides in order to reduce the loss of agriculture yield. Although crop protection practices have reduced the overall potential losses of 50 % to actual losses of about 30 %, crop losses due to pests still vary from 14 to 35 % according to the country. Moreover, consequences of this intensive agriculture are now well known with an important increase of atmospheric CO2 concentrations, water pollution and biodiversity loss. Current challenge is thus to design alternative sustainable cropping systems which maintain food production while reducing externalities. Application of ecological principles to agroecosystems has been proposed for that purpose. Nonetheless, it is difficult since crop systems are characterised by frequent and high disturbances, high nutrient input and high pressure of human activities. Here, we review the current knowledge in weed science and functional ecology and propose a conceptual framework to analyse weed community assembly in arable fields. Cropping systems are highly variable in their combination of agricultural techniques. We designed a trait-based approach of functional diversity (1) to establish a comparative description of the environmental gradients created by cropping systems and (2) to characterise the response of weeds to environmental gradients. We categorise the effects of cropping systems on the environment into disturbance and resource gradients. Disturbances induced by actual and previous agricultural practices are split into physical and chemical components, whose regime are defined by disturbance timing and frequency. Resource availability in arable fields is described by the value of effect traits of crops, such as plant height, that are related to their use of resources. Finally, we provide a list of relevant response traits of weeds to each component of the two gradients.", "corpus_id": 14256311 }

[ { "doc_id": "59291054", "title": "Post‐war changes in arable farming and biodiversity in Great Britain", "abstract": "Summary 1. Agriculture represents the dominant land use throughout much of western Europe, and a significant part of European biodiversity is associated with this habitat. We attempted to quantify the changes in agriculture and biodiversity in Britain since the 1940s. 2. There have been widespread declines in the populations of many groups of organisms associated with farmland in Britain and north-west Europe. The declines have been particularly marked amongst habitat specialists; many of the taxa still common on farmland are habitat generalists. 3. Farming practices have become increasingly intensive in the post-war period, with a dramatic reduction in landscape diversity. Since 1945, there has been a 65% decline in the number of farms, a 77% decline in farm labour and an almost fourfold increase in yield. Farms have become more specialized; the greatly increased use of machinery has made operations quicker and more efficient, but has resulted in the removal of 50% of the hedgerow stock. Autumn sowing of crops has become predominant, with winter stubbles now far less prevalent. The number and extent of chemical applications has increased greatly, but the net amount applied, and their persistence, has decreased in recent years. 4. Intensification has had a wide range of impacts on biodiversity, but data for many taxa are too scarce to permit a detailed assessment of the factors involved. Reduction in habitat diversity was important in the 1950s and 1960s; reduction in habitat quality is probably more important now. 5. As a case study, the declines in populations of seed-eating birds populations were assessed in relation to changing agricultural management. Generally, the declines were likely to be caused by a reduced food supply in the non-breeding season, although other factors may be important for particular species. 6. Agriculture will face a number of challenges in the medium term. While research into the mechanisms underlying species and habitat associations, and their interaction with scale, will be critical in under-pinning management, consideration of farmer attitudes and socio-economic factors is likely to be as important. Biodiversity may benefit from integrated farming techniques but these need to incorporate environmental objectives explicitly, rather than as a fringe benefit.", "corpus_id": 59291054, "score": 0 }, { "doc_id": "5496119", "title": "Global food demand and the sustainable intensification of agriculture", "abstract": "Global food demand is increasing rapidly, as are the environmental impacts of agricultural expansion. Here, we project global demand for crop production in 2050 and evaluate the environmental impacts of alternative ways that this demand might be met. We find that per capita demand for crops, when measured as caloric or protein content of all crops combined, has been a similarly increasing function of per capita real income since 1960. This relationship forecasts a 100–110% increase in global crop demand from 2005 to 2050. Quantitative assessments show that the environmental impacts of meeting this demand depend on how global agriculture expands. If current trends of greater agricultural intensification in richer nations and greater land clearing (extensification) in poorer nations were to continue, ∼1 billion ha of land would be cleared globally by 2050, with CO2-C equivalent greenhouse gas emissions reaching ∼3 Gt y−1 and N use ∼250 Mt y−1 by then. In contrast, if 2050 crop demand was met by moderate intensification focused on existing croplands of underyielding nations, adaptation and transfer of high-yielding technologies to these croplands, and global technological improvements, our analyses forecast land clearing of only ∼0.2 billion ha, greenhouse gas emissions of ∼1 Gt y−1, and global N use of ∼225 Mt y−1. Efficient management practices could substantially lower nitrogen use. Attainment of high yields on existing croplands of underyielding nations is of great importance if global crop demand is to be met with minimal environmental impacts.", "corpus_id": 5496119, "score": 0 }, { "doc_id": "10801536", "title": "The functional role of producer diversity in ecosystems.", "abstract": "Over the past several decades, a rapidly expanding field of research known as biodiversity and ecosystem functioning has begun to quantify how the world's biological diversity can, as an independent variable, control ecological processes that are both essential for, and fundamental to, the functioning of ecosystems. Research in this area has often been justified on grounds that (1) loss of biological diversity ranks among the most pronounced changes to the global environment and that (2) reductions in diversity, and corresponding changes in species composition, could alter important services that ecosystems provide to humanity (e.g., food production, pest/disease control, water purification). Here we review over two decades of experiments that have examined how species richness of primary producers influences the suite of ecological processes that are controlled by plants and algae in terrestrial, marine, and freshwater ecosystems. Using formal meta-analyses, we assess the balance of evidence for eight fundamental questions and corresponding hypotheses about the functional role of producer diversity in ecosystems. These include questions about how primary producer diversity influences the efficiency of resource use and biomass production in ecosystems, how primary producer diversity influences the transfer and recycling of biomass to other trophic groups in a food web, and the number of species and spatial /temporal scales at which diversity effects are most apparent. After summarizing the balance of evidence and stating our own confidence in the conclusions, we outline several new questions that must now be addressed if this field is going to evolve into a predictive science that can help conserve and manage ecological processes in ecosystems.", "corpus_id": 10801536, "score": 0 }, { "doc_id": "12056609", "title": "Ecological impacts of arable intensification in Europe.", "abstract": "Although arable landscapes have a long history, environmental problems have accelerated in recent decades. The effects of these changes are usually externalized, being greater for society as a whole than for the farms on which they operate, and incentives to correct them are therefore largely lacking. Arable landscapes are valued by society beyond the farming community, but increased mechanization and farm size, simplification of crop rotations, and loss of non-crop features, have led to a reduction in landscape diversity. Low intensity arable systems have evolved a characteristic and diverse fauna and flora, but development of high input, simplified arable systems has been associated with a decline in biodiversity. Arable intensification has resulted in loss of non-crop habitats and simplification of plant and animal communities within crops, with consequent disruption to food chains and declines in many farmland species. Abandonment of arable management has also led to the replacement of such wildlife with more common and widespread species. Soils have deteriorated as a result of erosion, compaction, loss of organic matter and contamination with pesticides, and in some areas, heavy metals. Impacts on water are closely related to those on soils as nutrient and pesticide pollution of water results from surface runoff and subsurface flow, often associated with soil particles, which themselves have economic and ecological impacts. Nitrates and some pesticides also enter groundwater following leaching from arable land. Greatest impacts are associated with simplified, high input arable systems. Intensification of arable farming has been associated with pollution of air by pesticides, NO2 and CO2, while the loss of soil organic matter has reduced the system's capacity for carbon sequestration. International trade contributes to global climate change through long distance transport of arable inputs and products. The EU Rural Development Regulation (1257/99) provides an opportunity to implement measures for alleviating ecological impacts of arable management through a combination of cross-compliance and agri-environment schemes. To alleviate the problems described in this paper, such measures should take account of opportunities for public/private partnerships and should integrate social, cultural, economic and ecological objectives for multifunctional land use.", "corpus_id": 12056609, "score": 0 }, { "doc_id": "51771047", "title": "Crop losses to pests", "abstract": "Productivity of crops grown for human consumption is at risk due to the incidence of pests, especially weeds, pathogens and animal pests. Crop losses due to these harmful organisms can be substantial and may be prevented, or reduced, by crop protection measures. An overview is given on different types of crop losses as well as on various methods of pest control developed during the last century. Estimates on potential and actual losses despite the current crop protection practices are given for wheat, rice, maize, potatoes, soybeans, and cotton for the period 2001–03 on a regional basis (19 regions) as well as for the global total. Among crops, the total global potential loss due to pests varied from about 50% in wheat to more than 80% in cotton production. The responses are estimated as losses of 26–29% for soybean, wheat and cotton, and 31, 37 and 40% for maize, rice and potatoes, respectively. Overall, weeds produced the highest potential loss (34%), with animal pests and pathogens being less important (losses of 18 and 16%). The efficacy of crop protection was higher in cash crops than in food crops. Weed control can be managed mechanically or chemically, therefore worldwide efficacy was considerably higher than for the control of animal pests or diseases, which rely heavily on synthetic chemicals. Regional differences in efficacy are outlined. Despite a clear increase in pesticide use, crop losses have not significantly decreased during the last 40 years. However, pesticide use has enabled farmers to modify production systems and to increase crop productivity without sustaining the higher losses likely to occur from an increased susceptibility to the damaging effect of pests. The concept of integrated pest/crop management includes a threshold concept for the application of pest control measures and reduction in the amount/frequency of pesticides applied to an economically and ecologically acceptable level. Often minor crop losses are economically acceptable; however, an increase in crop productivity without adequate crop protection does not make sense, because an increase in attainable yields is often associated with an increased vulnerability to damage inflicted by pests.", "corpus_id": 51771047, "score": 0 }, { "doc_id": "84285022", "title": "Spray retention, foliar uptake and translocation of glufosinate and glyphosate in Ambrosia artemisiifolia", "abstract": "Summary \n \nAmbrosia artemisiifolia plants exhibit stomata on both leaf surfaces and three types of trichomes: (i) small ( 80% of the applied label, and half maximum uptake being reached within 6 h. The foliar uptake of glyphosate was nearly complete and half of it was attained after 3 h. Glufosinate and glyphosate were ambimobile and their translocation out of the treated leaves amounted to 13–16% and 11–15% of the absorbed radioactive label respectively. Glufosinate was mainly directed to the apical developing tissues, with less amounts reaching the tissues below the treated leaves. Glyphosate was directed towards the sink tissues (apical developing tissues and roots). The sensitivity of A. artemisiifolia to glufosinate and glyphosate can be explained by high spray retention, rapid and important foliar uptake, and appreciable migration out of the parts of the plant hit by the spray.", "corpus_id": 84285022, "score": 0 }, { "doc_id": "52059376", "title": "Agroecology: A new research and development paradigm for world agriculture", "abstract": "Abstract In its several conceptions, agroecology has emerged as a scientific approach used to study, diagnose and propose alternative low-input management of agroecosystems. Solving the sustainability problem of agriculture is the primary aim of agroecology. It is maintained here, however, that simply focusing on the technological aspects of the problem, even though promoted technologies are low-input, obscures the fundamental problems that lie behing the technology-induced environmental crisis and rural poverty affecting the agricultural regions of the world. Agroecology can provide the ecological guidelines to point technological development in the right direction, but in the process, technological issues must assume their corresponding role within a strategy of rural development that incorporates social and economic problems.", "corpus_id": 52059376, "score": 0 }, { "doc_id": "97055219", "title": "Agroecology and the conversion of lárge‐scale conventional systems to sustainable management", "abstract": "This paper describes the agroecological principles necessary to guide the conversion of high‐input conventional systems to a low‐input management based on crop diversification and livestook integration schemes which break the monoculture nature of conventional systems. The new crop‐crop and crop‐animal combinations result in a series of synergisms and complementarities among farming system components which lead to optimal recycling of organic matter and nutrients, and to balanced pest‐natural enemy populations. Thus, agroecological design goes beyond “input‐substitution” by establishing systems capable of sponsoring their own soil fertility, crop protection and yield constancy. These new agroecosystems provide a sustainable level of productivity with minimal need for external (conventional or organic) resources. Biological structuring sponsors the functioning of the system.", "corpus_id": 97055219, "score": 0 }, { "doc_id": "140399717", "title": "Agroecology as a Science, a Movement and a Practice", "abstract": "Agroecology involves various approaches to solve actual challenges of agricultural production. Though agroecology initially dealt primarily with crop production and protection aspects, in recent decades new dimensions such as environmental, social, economic, ethical and development issues are becoming relevant. Today, the term ‘agroecology’ means either a scientific discipline, agricultural practice, or political or social movement. Here we study the different meanings of agroecology. For that we analyse the historical development of agroecology. We present examples from USA, Brazil, Germany, and France. We study and discuss the evolution of different meanings agroecology. The use of the term agroecology can be traced back to the 1930s. Until the 1960s agroecology referred only as a purely scientific discipline. Then, different branches of agroecology developed. Following environmental movements in the 1960s that went against industrial agriculture, agroecology evolved and fostered agroecological movements in the 1990s. Agroecology as an agricultural practice emerged in the 1980s, and was often intertwined with movements. Further, the scales and dimensions of agroecological investigations changed over the past 80 years from the plot and field scales to the farm and agroecosystem scales. Actually three approaches persist: (1) investigations at plot and field scales, (2) investigations at the agroecosystem and farm scales, and (3) investigations covering the whole food system. These different approaches of agroecological science can be explained by the history of nations. In France, agroecology was mainly understood as a farming practice and to certain extent as a movement, whereas the corresponding scientific discipline was agronomy. In Germany, agroecology has a long tradition as a scientific discipline. In the USA and in Brazil all three interpretations of agroecology occur, albeit with a predominance of agroecology as a science in the USA and a stronger emphasis on movement and agricultural practice in Brazil. These varied meanings of the term agroecology cause confusion among scientists and the public, and we recommend that those who publish using this term be explicit in their interpretation.", "corpus_id": 140399717, "score": 0 }, { "doc_id": "10639836", "title": "A model of plant strategies in fluvial hydrosystems", "abstract": "1. We propose a model of plant strategies in temperate fluvial hydrosystems that considers the hydraulic and geomorphic features that control plant recruitment, establishment and growth in river floodplains. 2. The model describes first how the disturbance gradient and the grain-size of the river bed load affect the relative proportion of erosion and deposition processes, and how the frequency of flood disturbance affects the intensity of such processes. 3. Secondly, the model predicts plant strategies according to direct and indirect effects of floods (disturbances through erosion versus deposition processes, and associated nutrient excess or limitation). 4. The relevance of the model as a prediction tool is discussed. Some proposals are made to validate the model, and traits are proposed that should be considered in future research for improving the predicting value of the model.", "corpus_id": 10639836, "score": 0 }, { "doc_id": "86147898", "title": "Can the seed bank be used for ecological restoration? An overview of seed bank characteristics in European communities", "abstract": "Abstract Question: Can seeds in the seed bank be considered as a potential source of material for the restoration of European plant communities including forest, marsh, grassland and heathland? Methods: This study reviews seed bank studies (1990–2006) to determine if they provide useful and reliable results to predict restoration success. We formally selected 102 seed bank studies and analyzed differences between four plant community types in several seed bank characteristics, such as seed density, species richness and similarity between seed bank and vegetation. We also assessed the dominant genera present in the seed bank in each plant community. Results: We observed remarkably consistent trends when comparing seed bank characteristics among community types. Seed density was lowest for grassland and forest communities and highest in marshes, whereas species richness, diversity and evenness of the seed bank community was lowest in heathland and highest in grassland. Similarity between seed bank and vegetation was low in forest, and high in grassland. There was a lot of overlap of the dominant genera of seed bank communities in all studies. Conclusions: The absence of target species and the high dominance of early successional species, in particular Juncus spp., indicate that restoration of target plant communities relying only on seed germination from the seed bank is in most cases not feasible. The exceptions are heathland and early successional plant communities occurring after temporally recurring disturbances. Restoration of plant communities composed of late successional species, such as woody species or herbaceous species typical of woodland or forest rely mainly on seed dispersal and not on in situ germination.", "corpus_id": 86147898, "score": 0 }, { "doc_id": "83954009", "title": "Identifying functional groups for response to disturbance in an abandoned pasture.", "abstract": "In an abandoned pasture in Brittany, we compared artificial small-scale disturbances to natural disturbances by wild boar and undisturbed vegetation. We developed a multivariate statistical approach which analyses how species biological attributes explain the response of community composition to disturbances. This technique, which reconciles the inductive and deductive approaches for functional classifications, identifies groups of species with similar responses to disturbance and characterizes their biological profiles. After 5 months of recolonization, artificial disturbances had a greater species richness than undisturbed vegetation as a result of recruitment of new species without the exclusion of pre-existing matrix species. Species morphology, described by canopy structure, canopy height and lateral spread, explained a large part (16 %) of community response to disturbance. Regeneration strategies, described by life history, seed mass, dispersal agent, dormancy and the existence of vegetative multiplication, explained a smaller part of community response to disturbance (8 %). Artificial disturbances were characterized by therophyte and compact rosettes with moderately dormant seeds, including a number of Asteraceae and other early successional species. Natural disturbances were colonized by leafy guerrilla species without seed dormancy. Few species were tightly related to undisturbed vegetation and were essentially grasses with a phalanx rosette morphology. The functional classification obtained is consistent with the classification of the community into fugitives, regenerators and persistors. These groups are structured according to Grubb's model for temperate grasslands, with regenerators and persistors in the matrix and fugitives taking advantage of gaps open by small-scale disturbances. The conjunction of functional diversity and species diversity within functional groups is the key to resilience to disturbance, an important ecosystem function.", "corpus_id": 83954009, "score": 0 }, { "doc_id": "84884235", "title": "The role of weeds in supporting biological diversity within crop fields", "abstract": "Weeds are major constraints on crop production, yet as part of the primary producers within farming systems, they may be important components of the agroecosystem. Using published literature, the role of weeds in arable systems for other above-ground trophic levels are examined. In the UK, there is evidence that weed flora have changed over the past century, with some species declining in abundance, whereas others have increased. There is also some evidence for a decline in the size of arable weed seedbanks. Some of these changes reflect improved agricultural efficiency, changes to more winter-sown crops in arable rotations and the use of more broad-spectrum herbicide combinations. Interrogation of a database of records of phytophagous insects associated with plant species in the UK reveals that many arable weed species support a high diversity of insect species. Reductions in abundances of host plants may affect associated insects and other taxa. A number of insect groups and farmland birds have shown marked population declines over the past 30 years. Correlational studies indicate that many of these declines are associated with changes in agricultural practices. Certainly reductions in food availability in winter and for nestling birds in spring are implicated in the declines of several bird species, notably the grey partridge, Perdix perdix . Thus weeds have a role within agroecosystems in supporting biodiversity more generally. An understanding of weed competitivity and the importance of weeds for insects and birds may allow the identification of the most important weed species. This may form the first step in balancing the needs for weed control with the requirements for biodiversity and more sustainable production methods.", "corpus_id": 84884235, "score": 0 }, { "doc_id": "11207837", "title": "Plant biodiversity enhances bees and other insect pollinators in agroecosystems. A review", "abstract": "Thirty-five percent of global production from crops including at least 800 cultivated plants depend on animal pollination. The transformation of agriculture in the past half-century has triggered a decline in bees and other insect pollinators. In North America, losses of bee colonies have accelerated since 2004, leaving the continent with fewer managed pollinators than at any time in the past 50 years. A number of factors linked to industrial modes of agriculture affect bee colonies and other pollinators around the world, ranging from habitat degradation due to monocultures with consequent declines in flowering plants and the use of damaging insecticides. Incentives should be offered to farmers to restore pollinator-friendly habitats, including flower provisioning within or around crop fields and elimination of use of insecticides by adopting agroecological production methods. Conventional farmers should be extremely cautious in the choice, timing, and application of insecticides and other chemicals. Here, we review the literature providing mounting evidence that the restoration of plant biodiversity within and around crop fields can improve habitat for domestic and wild bees as well as other insects and thus enhance pollination services in agroecosystems. Main findings are the following: (1) certain weed species within crop fields that provide food resources and refuge should be maintained at tolerable levels within crop fields to aid in the survival of viable populations of pollinators. (2) Careful manipulation strategies need to be defined in order to avoid weed competition with crops and interference with certain cultural practices. Economic thresholds of weed populations, as well as factors affecting crop–weed balance within a crop season, need to be defined for specific cropping systems. (3) More research is warranted to advance knowledge on identifying beneficial weed species and ways to sponsor them to attract pollinators while not reducing yields through interference. (4) In areas of intensive farming, field margins, field edges and paths, headlands, fence-lines, rights of way, and nearby uncultivated patches of land are important refuges for many pollinators. (5) Maintenance and restoration of hedgerows and other vegetation features at field borders is therefore essential for harboring pollinators. (6) Appropriate management of non-cropped areas to encourage wild pollinators may prove to be a cost-effective means of maximizing crop yield.", "corpus_id": 11207837, "score": 0 }, { "doc_id": "85614206", "title": "TILLAGE EFFECTS ON WEED SEED RETURN AND SEEDBANK COMPOSITION", "abstract": "Weed seed return and seedbank composition, with particular reference to common lambsquarters, were studied in four tillage systems established on a site near Fingal, Ontario. The tillage treatments were moldboard plow, chisel plow, ridge-till, and no-till. The cropping system was a corn- soybean rotation. Tillage effects on weed population compo- sition were assessed after all weed control measures had been implemented. More than 60% of the weed seedbank was concentrated in the upper 5 cm of soil in chisel plow and no-till. The seedbank of the moldboard plow system was more uniformly distributed over depth and larger than the other systems. Common lambsquarters comprised more than 50% of the seedbank in all systems except ridge-till, but only dominated the aboveground weed population in chisel plow. Seedbank populations of common lambsquarters with moldboard plowing were greater than those with ridge-till and no-till, and chisel plow seedbank populations were greater than those in ridge-till. Chisel and moldboard plow systems generally had higher aboveground plant populations of common lambsquarters than the other two systems. Seed production per plant by common lambsquarters was equiva- lent among the four systems, but estimated seed production per unit area was higher in moldboard plow and chisel plow systems than in the other systems. Populations of common lambsquarters and similar species may produce more seeds and persist in moldboard plow and chisel plow systems; these weeds may produce fewer seeds per unit area and be easier to manage in no-till and ridge-till systems. Nomenclature: Common lambsquarters, Chenopodium album L. #3 CHEAL; corn, Zea mays L.; soybean, Glycine max (L.) Merr. Additional index words: Conservation tillage, no-till, ridge- till, seedbank profile, weed spectrum, CHEAL.", "corpus_id": 85614206, "score": 0 }, { "doc_id": "85676481", "title": "An on-farm approach to investigate the impact of diversified crop rotations on weed species richness and composition in winter wheat", "abstract": "Weed species diversity may benefit from organic farming due to enhanced temporal diversification of crop species in a rotation and omission of herbicide applications. However, in intensively managed conventional systems, little evidence exists as to what extent diversified crop rotations contribute to higher weed species richness. Using an on-farm approach, the effect of crop rotation (organic, conventional diverse (CD) and conventional simple (CS) crop rotations) and weed control (with vs. without) on weed species richness, cover, community composition and crop biomass, was analysed in 24 winter wheat fields. Weed species with beneficial functions for invertebrates and birds were analysed separately. Weed species richness was higher in the organic crop rotation, but did not differ between CD and CS crop rotations. Weed control treatment reduced species richness in both conventional rotations, but not in the organic one. Redundancy analyses revealed that crop rotation intensity accounted for the largest part of the explained variation in weed species composition. Results from the study indicate that the maintenance of weed species richness and conservation of species with important ecological functions requires not only temporal diversification of crop species in the rotation, but also an adjustment of weed control strategies.", "corpus_id": 85676481, "score": 0 }, { "doc_id": "1710258", "title": "Consequences of organic farming and landscape heterogeneity for species richness and abundance of farmland birds", "abstract": "It has been suggested that organic farming may benefit farmland biodiversity more in landscapes that have lost a significant part of its former landscape heterogeneity. We tested this hypothesis by comparing bird species richness and abundance during the breeding season in organic and conventional farms, matched to eliminate all differences not directly linked to the farming practice, situated in either homogeneous plains with only a little semi-natural habitat or in heterogeneous farmland landscapes with abundant field borders and semi-natural grasslands. The effect of farm management on species richness interacted with landscape structure, such that there was a positive relationship between organic farming and diversity only in homogeneous landscapes. This pattern was mainly dependent on the species richness of passerine birds, in particular those that were invertebrate feeders. Species richness of non-passerines was positively related to organic farming independent of the landscape context. Bird abundance was positively related to landscape heterogeneity but not to farm management. This was mainly because the abundance of passerines, particularly invertebrate feeders, was positively related to landscape heterogeneity. We suggest that invertebrate feeders particularly benefit from organic farming because of improved foraging conditions through increased invertebrate abundances in otherwise depauperate homogeneous landscapes. Although many seed-eaters also benefit from increased insect abundance, they may also utilize crop seed resources in homogeneous landscapes and conventional farms. The occurrence of an interactive effect of organic farming and landscape heterogeneity on bird diversity will have consequences for the optimal allocation of resources to restore the diversity of farmland birds.", "corpus_id": 1710258, "score": 0 }, { "doc_id": "53985020", "title": "Seed traits in arable weed seed banks and their relationship to land-use changes", "abstract": "Abstract Recent studies have shown that relatively undisturbed plant communities, such as woodland and pasture, have generally low seed persistence, while seed longevity in frequently disturbed habitats, such as arable fields, is high. In addition, seed mass and shape were found to be closely linked to the living conditions of plants. The objective of the present study was to show how farming practice modifies these seed traits in the arable weed seed bank. On 67.4 ha of arable land at the Scheyern Research Station in Germany, conventional arable use was converted to organic farming, to a reduced-tillage system and to set-aside. During the six subsequent years, seed bank data were collected at 283 sampling points to analyse the effects of (1) the farming systems (long-term effects), (2) individual crops (short-term effects) and (3) vegetation cover. Set-aside arable land favoured a disk- or needle-like seed shape, greater mass and reduced seed longevity. Similarly, organic farming significantly increased seed mass and decreased longevity. Therefore, both types of land use reduced the selection for small and persistent seeds with a spherical shape. By contrast, an increasing persistence under reduced tillage suggested a higher selection pressure. The most consistent effect was that seed longevity increased with tillage frequency, independent from the farming system. Both high seed masses and a compact seed shape were frequently associated with a high crop cover. The results prove that beyond the properties of living plants the arable farming practice also significantly impacts the seed traits in the soil seed bank.", "corpus_id": 53985020, "score": 0 }, { "doc_id": "85966929", "title": "Management Filters and Species Traits: Weed Community Assembly in Long-Term Organic and Conventional Systems", "abstract": "Abstract Community assembly theory provides a useful framework to assess the response of weed communities to agricultural management systems and to improve the predictive power of weed science. Under this framework, weed community assembly is constrained by abiotic and biotic “filters” that act on species traits to determine community composition. We used an assembly approach to investigate the response of weed seed banks to 25 yr of management-related filtering in three different row-crop management systems in southeastern Pennsylvania: organic manure-based, organic legume-based, and conventional. Weed seed banks were sampled in April of 2005 and 2006 and quantified by direct germination in a greenhouse. We also assessed the filtering effects of weed management practices and relationships between assembled seed bank and emergent weed communities by allowing or excluding weed control practices within each management system and measuring emergent weed community response. Germinable weed seed bank densities and species richness in the final year of the study were over 40% and 15% higher, respectively, in the organic systems relative to the conventional system. Seed bank community structure in the organic systems was different from the conventional system, and the relationships between assembled seed banks and the emergent flora varied. Primary tillage, weed control, timing of planting, and fertility management appeared to be the main filters that differentiated weed seed banks in the three systems. Weed life history, emergence periodicity, seed size, and responsiveness to soil fertility and hydrology appeared to be the most important functional traits determining how weed species responded to management-related filters. Our results suggest that management systems can exert strong filtering effects that can persist over relatively long (greater than one growing season) time scales. Legacy effects of community-level filtering might be more important than previously assumed, and should be incorporated into predictive models of weed community assembly.", "corpus_id": 85966929, "score": 0 }, { "doc_id": "85374011", "title": "Environmental and management factors determining weed species composition and diversity in France", "abstract": "Multivariate analysis of data from approximately 700 arable fields from France was carried out to partition the respective importance of environmental factors versus management practices on weed species richness and composition. Overall, canonical correspondence analysis indicated that the major variations in species composition between fields were associated with human management factors; (1) the current crop type and (2) the preceding crop type. Three main weed communities were identified according to sowing season: winter, spring and summer-sown crops. The third most important gradient was associated with soil pH and soil texture to a lesser degree, resulting in highly contrasting weed communities on basic clay soils against those on acidic sandy soils. The influence of climate and geographical region was less pronounced and identified mainly through relationships with precipitation and longitude. Within individual crop types, the effect of other management practices became more prominent. Species richness is dependant on factors other than, or in addition to those influencing species composition, like those describing landscape organisation and/or tillage depth. Species richness (α-diversity) and community composition (β-diversity) had, for example, contrasting relationship to altitude: 300–450 m altitude giving high species richness but low species turnover. The variations observed in this large scale data set help to identify the agricultural practices which have had the most significant impact on the loss of species diversity in arable fields in recent decades.", "corpus_id": 85374011, "score": 1 }, { "doc_id": "7761749", "title": "Advances, challenges and a developing synthesis of ecological community assembly theory", "abstract": "Ecological approaches to community assembly have emphasized the interplay between neutral processes, niche-based environmental filtering and niche-based species sorting in an interactive milieu. Recently, progress has been made in terms of aligning our vocabulary with conceptual advances, assessing how trait-based community functional parameters differ from neutral expectation and assessing how traits vary along environmental gradients. Experiments have confirmed the influence of these processes on assembly and have addressed the role of dispersal in shaping local assemblages. Community phylogenetics has forged common ground between ecologists and biogeographers, but it is not a proxy for trait-based approaches. Community assembly theory is in need of a comparative synthesis that addresses how the relative importance of niche and neutral processes varies among taxa, along environmental gradients, and across scales. Towards that goal, we suggest a set of traits that probably confer increasing community neutrality and regionality and review the influences of stress, disturbance and scale on the importance of niche assembly. We advocate increasing the complexity of experiments in order to assess the relative importance of multiple processes. As an example, we provide evidence that dispersal, niche processes and trait interdependencies have about equal influence on trait-based assembly in an experimental grassland.", "corpus_id": 7761749, "score": 0 }, { "doc_id": "83166422", "title": "Trait-based approaches to unravelling the assembly of weed communities and their impact on agro-ecosystem functioning", "abstract": "Navas M-L (2012). Trait-based approaches to unravelling the assembly of weed communities and their impact on agro-ecosystem functioning. Weed Research52, 479–488. \n \nSummary \nThe trait-based approach to plant functional ecology has gained considerable attention over the last two decades, allowing ecologists to address questions relating to species distribution, community assembly and ecosystem functioning. We show here how this approach can be used to address these issues for weed ecology in a new way, allowing research to shift from purely weed control issues to a more global understanding of the impact of weed communities on the agro-ecosystem. We review how weed species are sorted by environmental factors and management according to the value of traits and the role thereof in the assembly of weed communities. How weed trait values and their distribution within communities affect agro-ecosystem processes is discussed in relation to loss of crop production. We also introduce the question of the impact of weed functional structure on ecosystem services and suggest some directions for research at species, community and agro-ecosystem levels.", "corpus_id": 83166422, "score": 1 }, { "doc_id": "85048135", "title": "A General Hypothesis of Species Diversity", "abstract": "A new hypothesis, based on differences in the rates at which populations of competing species approach competitive equilibrium (reduction or exclusion of some species), is proposed to explain patterns of species diversity. The hypothesis assumes that most communities exist in a state of nonequilibrium where competitive equilibrium is prevented by periodic population reductions and environmental fluctuations. When competitive equilibrium is prevented, a dynamic balance may be established between the rate of competitive displacement and the frequency of population reduction, which results in a stable level of diversity. Under conditions of infrequent reductions, an increase in the population growth rates of competitors generally results in decreased diversity. This model clarifies an underlying pattern of variation in diversity and points out the common elements of previous hypotheses. Rather than arguing that either competition, predation, or productivity control diversity, it demonstrates that all of these may contribute to the same basic mechanism. In doing so, it not only explains the correlations of the other hypotheses with patterns of diversity, but also explains the exceptions that these hypotheses could not explain. This hypothesis may be applied to variations of diversity both on a latitudinal gradient and within specific regions.", "corpus_id": 85048135, "score": 0 }, { "doc_id": "32641279", "title": "From Plant Traits to Plant Communities: A Statistical Mechanistic Approach to Biodiversity", "abstract": "We developed a quantitative method, analogous to those used in statistical mechanics, to predict how biodiversity will vary across environments, which plant species from a species pool will be found in which relative abundances in a given environment, and which plant traits determine community assembly. This provides a scaling from plant traits to ecological communities while bypassing the complications of population dynamics. Our method treats community development as a sorting process involving species that are ecologically equivalent except with respect to particular functional traits, which leads to a constrained random assembly of species; the relative abundance of each species adheres to a general exponential distribution as a function of its traits. Using data for eight functional traits of 30 herbaceous species and community-aggregated values of these traits in 12 sites along a 42-year chronosequence of secondary succession, we predicted 94% of the variance in the relative abundances.", "corpus_id": 32641279, "score": 0 }, { "doc_id": "37712779", "title": "Predicting changes in community composition and ecosystem functioning from plant traits: revisiting the Holy Grail", "abstract": "Summary 1. The concept of plant functional type proposes that species can be grouped according to common responses to the environment and/or common effects on ecosystem processes. However, the knowledge of relationships between traits associated with the response of plants to environmental factors such as resources and disturbances (response traits), and traits that determine effects of plants on ecosystem functions (effect traits), such as biogeochemical cycling or propensity to disturbance, remains rudimentary. 2. We present a framework using concepts and results from community ecology, ecosystem ecology and evolutionary biology to provide this linkage. Ecosystem functioning is the end result of the operation of multiple environmental filters in a hierarchy of scales which, by selecting individuals with appropriate responses, result in assemblages with varying trait composition. Functional linkages and trade-offs among traits, each of which relates to one or several processes, determine whether or not filtering by different factors gives a match, and whether ecosystem effects can be easily deduced", "corpus_id": 37712779, "score": 0 }, { "doc_id": "85779126", "title": "Scaling environmental change through the community-level: a trait-based response-and-effect framework for plants", "abstract": "Predicting ecosystem responses to global change is a major challenge in ecology. A critical step in that challenge is to understand how changing environmental conditions influence processes across levels of ecological organization. While direct scaling from individual to ecosystem dynamics can lead to robust and mechanistic predictions, new approaches are needed to appropriately translate questions through the community level. Species invasion, loss, and turnover all necessitate this scaling through community processes, but predicting how such changes may influence ecosystem function is notoriously difficult. We suggest that community-level dynamics can be incorporated into scaling predictions using a trait-based response-effect framework that differentiates the community response to environmental change (predicted by response traits) and the effect of that change on ecosystem processes (predicted by effect traits). We develop a response-and-effect functional framework, concentrating on how the relationships among species' response, effect, and abundance can lead to general predictions concerning the magnitude and direction of the influence of environmental change on function. We then detail several key research directions needed to better scale the effects of environmental change through the community level. These include (1) effect and response trait characterization, (2) linkages between response-and-effect traits, (3) the importance of species interactions on trait expression, and (4) incorporation of feedbacks across multiple temporal scales. Increasing rates of extinction and invasion that are modifying communities worldwide make such a research agenda imperative.", "corpus_id": 85779126, "score": 0 }, { "doc_id": "26916494", "title": "Patterns of plant traits in annual vegetation of man-made habitats in central Europe", "abstract": "Man-made habitats in central Europe can be broadly divided into arable land with weed vegetation, and settlements and their surroundings, harbouring ruderal vegetation. The former is a predictable environment with frequent, regular and large-scale disturbances, while the latter is an unpredictable environment with irregular disturbances of varying spatial extent producing heterogeneous mosaics of different successional stages. We hypothesize that these differences in disturbance regimes select for different sets of biological and ecological plant traits in these two habitats. A data set of 2715 vegetation plots sampled in man-made habitats dominated by annual plants in the Czech Republic was combined with data on biological and ecological traits of vascular plants, mostly taken from the BiolFlor database. Differences due to temporal variation and location of plots in different climatic zones were partialled out using partial canonical correspondence analysis. Then the differences in traits of the plants growing on arable fields and in settlements were analysed using logistic and least-square regression models, both with and without phylogenetic correction. Plants growing on arable land were more often annuals, R-strategists, with overwintering green leaves, insect or self-pollinated, reproducing by seeds, with persistent seed banks and archaeophytes (i.e. those aliens that arrived prior to 1500). Plants growing in human settlements were more often biennials or perennials, C-strategists, wind-pollinated, flowering in mid summer, reproducing both by seeds and vegetatively, dispersed by wind or humans, neophytes (i.e. those aliens that arrived after 1500), species with high demands for light and nutrients and with more continental distribution ranges. Most associations between plant traits and habitats did not change after taking phylogenetic relationships into account. Traits strongly linked to phylogeny were especially modes of pollination and dispersal. By contrast, traits weakly linked to phylogeny included life strategy and alien status.", "corpus_id": 26916494, "score": 0 }, { "doc_id": "86519098", "title": "A functional group approach to the management of UK arable weeds to support biological diversity", "abstract": "Weeds have an important role in maintaining farmland biodiversity. This needs to be balanced with their potential negative impact on crop yield and quality. Mechanistic models of crop-weed competition are an important tool in striking this balance. A range of common UK annual weeds were screened for the eco-physiological traits required by the models. Using multivariate techniques, a number of functional groups with a similar pattern of productivity and competition were identified, based on trade-offs between traits. A scheme was developed to assign species outside of the data set to one of the groups, based on life cycle, seed mass, maximum height and time of first flowering. As well as having a similar competitive ability, species within a group also appeared to have a similar ecosystem function, in terms of supporting higher trophic groups. Two beneficial groups of species were identified that combined a relatively low competitive ability with a high importance for invertebrates and birds. The identification of functional groups in the UK arable flora is a useful tool for assessing a weed community in the context of reconciling biodiversity provision with crop production. Preserving beneficial plant functional types within the crop would complement non-cropped wildlife refuges, such as field margins.", "corpus_id": 86519098, "score": 0 }, { "doc_id": "84748862", "title": "A functional analysis of large‐scale temporal shifts from 1970 to 2000 in weed assemblages of sunflower crops in France", "abstract": "Questions: What are the relationships between weed species traits and their change in distribution over a 30-year period? What does it tell us about factors that have driven shifts in the composition of weed communities? \n \nLocation: France. \n \nMethods: We analysed the links between change in the status of weed species in sunflower crops (decreasing or increasing) and a set of 17 traits using data sets collected in the 1970s and the 2000s, respectively. We analysed the contribution of traits to explain changes in the status of species both individually and in a multivariate way by mean of a clustering of species into functional groups. \n \nResults: 69% of the most widespread species had significantly changed their frequency rank status over the last 30 years. Nearly two thirds of the increasing species belonged to a single functional group, out of the five groups identified in this analysis. Overall, the weed flora occurring in sunflower crops has specialised since the 1970s in favour of ‘sunflower mimicking’ functional groups: increasing species were more nitrophilous, more heliophilous, less sensitive to sunflower herbicides and shared a rapid summer life cycle. \n \nConclusions: The individual trait approach gave some indication as to the environmental factors likely to have caused the shift in sunflower weed communities. The functional group approach seemed to outperform direct trait comparisons as it accounted for major traits combinations i.e. cases where a species has a number of favourable traits, but is severely disadvantaged by the possession of one or a few deleterious traits.", "corpus_id": 84748862, "score": 0 }, { "doc_id": "82887732", "title": "Functional traits relating arable weed communities to crop characteristics", "abstract": "Question: Which weed traits respond to the community assembly filters imposed by cropping regimes and how do they respond? Which crop characteristics (traits or aspects of field management) represent the strongest filters on weed traits? \n \nLocation: France. \n \nMethods: In 561 arable fields, we measured associations between crop characteristics and (i) mean values of quantitative weed traits at each site and (ii) composition of optimally defined weed functional types, based on both qualitative and quantitative weed traits and typologies. The crop characteristics included crop height, propagule size, family and sowing date; we also used basic types (winter wheat, maize, etc.) for comparison. \n \nResults: Crop sowing date was strongly related to many weed traits, whereas crop type was not the strongest predictor of any trait. With later sowing of crops, weeds started flowering later, germinated later and had shorter flowering periods. Sowing date was also associated with the distribution of Raunkiaer life forms, while crop architecture was associated with the distribution of weed heights and a C-S-R classification. \n \nConclusions: Cropping regimes can usefully be summarized by the crop sowing date. Phenological traits of weeds as well as classifications based on life form and C-S-R are important descriptors of weed community composition. Such findings may help predict the effects of particular crop rotations, novel crop varieties and invasive weed species.", "corpus_id": 82887732, "score": 1 }, { "doc_id": "84329315", "title": "Trajectories of weed communities explained by traits associated with species’ response to management practices", "abstract": "Abstract Two large-scale weed surveys conducted on winter wheat crops in France in the 1970s and the 2000s were used to determine the influence of management on weed communities. A trait-based approach was used to identify the mechanisms associated with the changing status of arable weeds over a 30 year period. A three-table ordination method (RLQ analysis) of the data set was performed to relate the environmental table to the species trait table using a species composition table to extract the joint structure (synchronic analysis). We then conducted a diachronic analysis to investigate the relationship between traits, alone or in combination, and the changing status of weeds. The synchronic analysis showed that tillage intensity filtered weeds according to height, seed weight, life forms and dispersal. Conversely, herbicides selected for species with delayed germination, which allows them to escape herbicide treatments. The diachronic analysis showed that successful weeds that have expanded were small plants, with rather light seeds, that can germinate over a long time frame during the vegetative period. This trait syndrome was probably favoured by profound changes in crop rotation and by increasing herbicide pressure. Our approach provides an excellent example of how future shifts in weed communities can be predicted and hence how weed management can be adapted so as to avoid promoting selection of problematic weeds.", "corpus_id": 84329315, "score": 1 }, { "doc_id": "196618158", "title": "A new model for the continuum concept", "abstract": "A reformulation of the continuum concept is presented after considering the implications of the community/continuum controversy and current niche theory. Community is a spatial concept dependent on landscape pattern while the continuum is an environmental concept referring to an abstract space. When applying niche theory to plants, the mechanisms of competition are ill-defined and the assumption of bell-shaped response curves for species unrealistic.", "corpus_id": 196618158, "score": 0 }, { "doc_id": "40600127", "title": "Remarkable changes of weed species in Spanish cereal fields from 1976 to 2007", "abstract": "Management practices, geographical gradients and climatic factors are factors explaining weed species composition and richness in cereal fields from Northern and Central Europe. In the Mediterranean area, the precise factors responsible for weed distribution are less known due to the lack of data and surveys. The existence of weed survey data of year 1976 in the Zaragoza province of the Aragón region, Spain, offered us the opportunity to compare present weed species with weed species growing 30 years ago. No detailed comparison of changes in weed species composition in cereal fields in that period of time has been conducted in the Mediterranean area. Here a survey was conducted in the Aragón region from 2005 to 2007. Weeds were surveyed in 138 winter cereal fields in ten survey areas where winter cereals are the main crops, using the same methodology applied 30 years ago. In the Zaragoza province, 36 fields were chosen in the same municipalities than in the previous survey. Several management, geographic and climatic variables of each field were recorded and related to weed species with multivariate analysis. Diversity index were calculated and related to survey area and altitude. Our results show that out of the 175 species only 26 species were found in more than 10% of the surveyed fields. The main species were Papaver rhoeas, Lolium rigidum, Avena sterilis and Convolvulus arvensis found in more than half of the surveyed fields. L. rigidum was related to dryland, while the other species were found overall. Furthermore, we found that management, geographical and climatic factors were significantly related to weed species distribution. In particular altitude, survey areas, irrigation and herbicide use in post-emergence were the most driving factors explaining weed species distribution. Species richness was higher in survey areas with extensive management practices and increased with altitude excepting a very productive area with intensive management practices at high altitude where richness was as low as in the irrigated lowlands. The main differences found between the 1976 and the 2005–2007 surveys were (1) the striking increase of grass weeds, (2) the high decrease of mean weed species number found in each field declining from 9 to 3 and (3) the frequency decrease of many weed species probably caused by agriculture intensification in that period of time. The growing importance of other weed species is probably related to their adaptation to minimum tillage, which is a widespread technique nowadays.", "corpus_id": 40600127, "score": 0 }, { "doc_id": "84849852", "title": "Floristic and ecological differences between recent and ancient forests growing on non-acidic soils", "abstract": "Abstract The aim of this work was to investigate differences in soil chemistry and understory composition between recent forests (sites afforested in the last 170 years) and ancient forests growing on non-acidic soils. The study was carried out on hardwood forests at moderate elevation (400–600 m asl) in the Jura Mountains (N.E. France) on four main pedological substrates with different characteristics. The floristic composition of 127 stands from recent forests (n = 65) or ancient forests (n = 62) was surveyed. Some functional traits and the Ellenberg indicator values of the surveyed species were recorded. In addition, the topsoil from 30 stands was analysed. The composition of the flora was analysed by Detrended Correspondence Analysis and the species which were typical of one class of forest age were identified using a chi-square (χ2) test. The difference between forest classes for plant traits, their indicator values, or soil chemistry was tested using the generalized linear model and Bonferroni t-tests (or Kruskall–Wallis tests). The floristic composition of the ancient forests was significantly different from that of the recent forests and was characterized by a high occurrence of shrub species in recent forests. These differences were associated with higher specific leaf area, low-range seeds dispersal, and some life forms like geophytes. There was no clear difference in soil chemistry between the two classes of forests, except for δ15N values. The weakness of the difference in the soil between ancient and recent forests suggested that changes in soil chemistry caused by a former agricultural land use were not responsible for the differences in understory composition recorded. The differences in functional traits between the two forest classes supported this conclusion. We finally concluded that (i) past land use modifies the vegetation composition of current forests, even on neutral soils and that (ii) in our context, biological filters were probably responsible for these changes.", "corpus_id": 84849852, "score": 0 }, { "doc_id": "53997541", "title": "Relative climatic, edaphic and management controls of plant functional trait signatures", "abstract": "To identify the relative roles of climatic, edaphic and management factors in controlling the weighted mean traits of vegetation. Eleven sites in Europe and one in Israel undergoing transitions in land use. Standardised methods were used to collect information on species traits and attributes from plots covering a range of land uses at each site. This was combined with abundance data to create a plot x trait matrix. Variance partitioning was used to identify the relative roles of climate, soil and management on the weighted and unweighted mean traits of the vegetation in the full data set, and the data set divided into vegetative traits (including life-form, clonality, defence and a range of leaf traits) and traits linked to regeneration via seeds (including seed mass, dispersal and pollination mechanism). Variance partitioning of the full data set showed that climate (18.7%), explained more variance in the weighted mean traits of the vegetation than climate and soil together (9.2), soil (6.9) and management (6.1). There was a similar distribution of variance explained for both vegetative and regeneration via seed traits, although more variance was explained for the latter. This restricted set of climatic, edaphic and management variables could explain 45-50% of the variance in the weighted mean traits of the vegetation between plots. There were only small differences between analyses of the weighted and unweighted data. Despite large variations in climate and soils between sites, there was still a separate and recognisable impact of management on the mean weighted traits of the vegetation. There was also a degree of shared variation between the three groups of factors, indicating that the response of plant traits to one group of factors may not be predictable because they may be modulated by their response to other groups.", "corpus_id": 53997541, "score": 0 }, { "doc_id": "87154152", "title": "Dynamics of weed populations", "abstract": "Dynamics of weed populations , Dynamics of weed populations , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی", "corpus_id": 87154152, "score": 0 }, { "doc_id": "53600331", "title": "Seed supply, drought, and grazing determine spatio-temporal patterns of recruitment for native and introduced invasive pines in grasslands", "abstract": "Aim The rate of grassland invasion by trees depends on the ability of the species to invade, i.e. their invasiveness, and on the susceptibility of the environments to invasion, i.e. their invasibility. Knowledge of the invasiveness of native and introduced tree species and of the environmental factors that contribute to invasibility is necessary to understand landscape evolution and assess required management measures. Our main aim was to explore this by estimating the separate effects of propagule pressure and environmental factors on the spatio-temporal patterns of sapling recruitment, a key stage in the tree life cycle. Location Causse Mejean calcareous plateau (southern France). Methods The effects of seed supply and environmental variables (grazing, geological substrate, and duration or intensity of drought) on the spatio-temporal patterns of sapling recruitment were assessed for the native Scots pine ( Pinus sylvestris L.) and the introduced black pine ( Pinus nigra Arn. ssp. nigra ). Estimates were derived by inverse modelling with data of locations and ages of 4- to 20-year-old saplings and seed-bearing trees in 32 sites. Yearly indices of drought were derived from a soil‐water content model. Results For both species, seed supply was as important as the whole set of environmental factors in explaining sapling recruitment rates. Grazing and the duration of drought from July to August decreased sapling recruitment rates, which were also lower on hard limestone than on dolomite. Dispersal distances and effective fecundities were higher for the introduced P. nigra , which was less susceptible to drought but more affected by grazing than the native P. sylvestris . In grazed grasslands, shrubs facilitated sapling establishment of both species. Main conclusions This study shows how seed supply and environmental factors shape spatio-temporal patterns of sapling recruitment for trees invading grasslands. Implications for landscape evolution and management, of the difference in invasiveness of the two pine species and of the hierarchy of environmental factors in determining invasibility, are discussed.", "corpus_id": 53600331, "score": 0 }, { "doc_id": "205604951", "title": "Plant response traits mediate the effects of subalpine grasslands on soil moisture.", "abstract": "* In subalpine grasslands, changes in abiotic conditions with decreased management intensity alter the functional composition of plant communities, leading to modifications of ecosystem properties. Here, it is hypothesized that the nature of plant feedbacks on soil moisture is determined by the values of key traits at the community level. * As community functional parameters of grasslands change along a gradient of land uses, those traits that respond most to differences in abiotic conditions produced by land use changes were identified. A vegetation removal experiment was then conducted to determine how each plant community affected soil moisture. * Soil moisture was negatively correlated with community root length and positively correlated with canopy height, whereas average leaf area was associated with productivity. These traits were successfully used to predict the effects on soil moisture of each plant community in the removal experiment. This result was validated using data from an additional set of fields. * These findings demonstrate that the modification of soil moisture following land use change in subalpine grasslands can be mediated through those plant functional traits that respond to water availability.", "corpus_id": 205604951, "score": 0 }, { "doc_id": "128233192", "title": "Physiological Plant Ecology: Ecophysiology and Stress Physiology of Functional Groups", "abstract": "Plant ecophysiology is the science of the vital processes of plants in interaction with the environment. This advanced text offers insights into the laws governing the carbon, nitrogen, mineral and water balance, development, vital capacity and adaptability of plants. An extensive chapter deals with the effects of natural and anthropogenic stress factors. The book focuses on the ways the different plant species and functional types react in various locations and in all climatic zones.", "corpus_id": 128233192, "score": 0 }, { "doc_id": "83591894", "title": "Plant traits related to competition: how do they shape the functional diversity of communities?", "abstract": "The identification of functional traits critical to plant responses to the environment promotes our understanding of assembly of communities which relies on environmental filtering. However, the recent trait-community approaches mostly ignore the influence of plant-plant interactions by mainly focusing on traits related to abiotic filtering processes. The conceptual framework we propose aims to clarify how the functional diversity of communities depends on the filtering effect of competition on relevant traits. We define two types of competition-related traits: competitive effect traits reflect the changes in local resource levels due to plant activity while competitive response traits are related to plant response to these resource depletions. We then suggest that the contribution of both types of competition-related traits to functional diversity depends on the importance of competition, previously defined as the effect of competition on plant fitness relative to that of other environmental factors. The...", "corpus_id": 83591894, "score": 1 }, { "doc_id": "86402914", "title": "Intraspecific seed trait variations and competition: passive or adaptive response?", "abstract": "Summary 1. The phenotype of offspring depends on the abiotic and biotic environment in which the parents developed. However, the direct effects of competition experienced by parent plants on single-seed traits are poorly documented despite their impact on plant fitness. 2. We hypothesize that single-seed traits can differentially respond to the resource deficiencies of parent plants due to competition: seed quality may decrease as seed number does, magnifying the negative effects of competition for offspring ('passive response' hypothesis), or increase and then enhance offspring fitness to offset the reduction in offspring number ('adaptive response' hypothesis). Here we tested these hypotheses for four single-seed traits. We assessed the sensibility of their responses to changes in competition intensity due to species with different competitive effects and to contrasting soil nitrogen conditions. 3. In a common-garden experiment, four single-seed traits related to fitness - seed mass, seed nitrogen concentration (SNC), germinability and the timing of germination - were measured on a phytometer species transplanted in 14 different neighbours grown in monoculture with and without soil nitrogen limitation. 4. Under nitrogen-limiting conditions, the responses of SNC and of the timing of germination were passive and mainly related to the effects of neighbours on soil nitrogen availability, as shown by the increase in SNC with N-fixing neighbours. Within-individual seed mass variability decreased with increasing competition intensity, as an adaptive response to counterbalance the reduction in seed production. With nitrogen supplementation, competitors had no detectable effect on single-seed traits despite an overall increase in SNC and germination rate, confirming their nitrogen-dependent passive responses to competition. Germinability did not change among treatments. 5. The impact of competition on single-seed traits depends on both phytometer trait identity and resource modulation by neighbours. The passive response of seed chemical composition to competitors may magnify the competitive effects on offspring. By contrast, the adaptive response of seed size variability may offset these competitive effects. As a consequence, experiments looking at the fitness consequences of competition should not only consider the effects on fitness parameters of a target plant but also on the offspring.", "corpus_id": 86402914, "score": 1 }, { "doc_id": "21897339", "title": "Asymmetric competition in plant populations.", "abstract": "Recently there has been much interest in the hypothesis that competition between individual plants is asymmetric or onesided: larger individuals obtain a disproportionate share of the resources (for their relative size) and suppress the growth of smaller individuals. This has important implications for population structure, for the analysis of competition between plants at the individual, population and community levels, and for our understanding of competition as a selective force in the evolution of plant populations.", "corpus_id": 21897339, "score": 0 }, { "doc_id": "8174453", "title": "Evolutionary Agroecology: the potential for cooperative, high density, weed-suppressing cereals", "abstract": "Evolutionary theory can be applied to improve agricultural yields and/or sustainability, an approach we call Evolutionary Agroecology. The basic idea is that plant breeding is unlikely to improve attributes already favored by millions of years of natural selection, whereas there may be unutilized potential in selecting for attributes that increase total crop yield but reduce plants’ individual fitness. In other words, plant breeding should be based on group selection. We explore this approach in relation to crop‐weed competition, and argue that it should be possible to develop high density cereals that can utilize their initial size advantage over weeds to suppress them much better than under current practices, thus reducing or eliminating the need for chemical or mechanical weed control. We emphasize the role of density in applying group selection to crops: it is competition among individuals that generates the ‘Tragedy of the Commons’, providing opportunities to improve plant production by selecting for attributes that natural selection would not favor. When there is competition for light, natural selection of individuals favors a defensive strategy of ‘shade avoidance’, but a collective, offensive ‘shading’ strategy could increase weed suppression and yield in the high density, high uniformity cropping systems we envision.", "corpus_id": 8174453, "score": 0 }, { "doc_id": "42561861", "title": "Decomposition Analysis of Competitive Symmetry and Size Structure Dynamics", "abstract": "Abstract An analysis is introduced, based on the decomposition of relative growth rates, to examine the mode of competition (i.e. whether competition is symmetric or asymmetric), the size-dependence of growth, and their interdependence. In particular, the basis for two commonly held views is examined: (1) that the type of resource limitation determines the mode of competition, and (2) that asymmetric competition always leads to size-divergence between unequal competitors. It is shown that in field-grown millet plants, competition for light was symmetric at low density and asymmetric at high density. However, size variation at low density decreased during growth, because small plants had greater relative growth rates than larger plants. Size variation stayed constant at high density, since plants of all sizes had equal average relative growth rates. Based on these results and a general discussion, it is proposed that the type of resource limitation does not determine the mode of competition. Competition for light can be symmetric, and foraging for heterogeneously distributed soil resources can produce asymmetric competition below-ground. Furthermore, the mode of competition alone does not determine size structure dynamics. Size-dependence of resource conversion efficiency and allocation can modify the effects of resource uptake on growth.", "corpus_id": 42561861, "score": 0 }, { "doc_id": "8859190", "title": "Plant Ecological Strategies: Some Leading Dimensions of Variation Between Species", "abstract": "▪ Abstract An important aim of plant ecology is to identify leading dimensions of ecological variation among species and to understand the basis for them. Dimensions that can readily be measured would be especially useful, because they might offer a path towards improved worldwide synthesis across the thousands of field experiments and ecophysiological studies that use just a few species each. Four dimensions are reviewed here. The leaf mass per area–leaf lifespan (LMA-LL) dimension expresses slow turnover of plant parts (at high LMA and long LL), long nutrient residence times, and slow response to favorable growth conditions. The seed mass–seed output (SM-SO) dimension is an important predictor of dispersal to establishment opportunities (seed output) and of establishment success in the face of hazards (seed mass). The LMA-LL and SM-SO dimensions are each underpinned by a single, comprehensible tradeoff, and their consequences are fairly well understood. The leaf size–twig size (LS-TS) spectrum has obvio...", "corpus_id": 8859190, "score": 0 }, { "doc_id": "16985738", "title": "A handbook of protocols for standardised and easy measurement of plant functional traits worldwide", "abstract": "There is growing recognition that classifying terrestrial plant species on the basis of their function (into 'functional types') rather than their higher taxonomic identity, is a promising way forward for tackling important ecological questions at the scale of ecosystems, landscapes or biomes. These questions include those on vegetation responses to and vegetation effects on, environmental changes (e.g. changes in climate, atmospheric chemistry, land use or other disturbances). There is also growing consensus about a shortlist of plant traits that should underlie such functional plant classifications, because they have strong predictive power of important ecosystem responses to environmental change and/or they themselves have strong impacts on ecosystem processes. The most favoured traits are those that are also relatively easy and inexpensive to measure for large numbers of plant species. Large international research efforts, promoted by the IGBP–GCTE Programme, are underway to screen predominant plant species in various ecosystems and biomes worldwide for such traits. This paper provides an international methodological protocol aimed at standardising this research effort, based on consensus among a broad group of scientists in this field. It features a practical handbook with step-by-step recipes, with relatively brief information about the ecological context, for 28 functional traits recognised as critical for tackling large-scale ecological questions.", "corpus_id": 16985738, "score": 0 }, { "doc_id": "83617857", "title": "Can traits predict the competitive response of herbaceous Mediterranean species", "abstract": "This study tested whether (i) functional traits, measured on individually grown plants, can be used to predict species response to competition; (ii) species competitive response depends on the standing biomass of neighbouring vegetation. Nine herbaceous Mediterranean species (targets) were grown as isolated plants or in mixture with one of three grasses (neighbours) differing in RGR, in pots during 4 months. Ten traits of targets, related to plant size, resource acquisition and conservation ability, and the above-ground biomass of neighbours were measured. Species with large basal area when individually grown were least suppressed by competition. No relationship was found between species competitive response and other traits measured on plants grown in isolation, including height and RGR. This result suggests that plant basal area could be used to predict the competitive ability of species in herbaceous communities. The competitive response of targets varied with the standing biomass of neighbours: it decreased with increasing neighbour biomass for low-productive mixtures, then reached a minimal value as neighbour biomass became larger, whatever the identity of neighbours. The implications of this relationship are discussed.", "corpus_id": 83617857, "score": 0 }, { "doc_id": "86336417", "title": "Leaf dry matter content and lateral spread predict response to land use change for six subalpine grassland species", "abstract": "Abstract Question: Land-use change has a major impact on terrestrial plant communities by affecting fertility and disturbance. We test how particular combinations of plant functional traits can predict species responses to these factors and their abundance in the field by examining whether trade-offs at the trait level (fundamental trade-offs) are linked to trade-offs at the response level (secondary trade-offs). Location: Central French Alps. Methods: We conducted a pot experiment in which we characterized plant trait syndromes by measuring whole plant and leaf traits for six dominant species, originating from contrasting subalpine grassland types. We characterized their response to nutrient availability, shading and clipping. We quantified factors linked with different land usage in the field to test the relevance of our experimental treatments. Results: We showed that land management affected nutrient concentration in soil, light availability and disturbance intensity. We identified particular suites of traits linked to plant stature and leaf structure which were associated with species responses to these environmental factors. Leaf dry matter content separates fast and slow growing species. Height and lateral spread separated tolerant and intolerant species to shade and clipping. Discussion and Conclusion: Two fundamental trade-offs based on stature traits and leaf traits were linked to two secondary trade-offs based on response to fertilization shade and mowing. Based on these trade-offs, we discuss four different species strategies which could explain and predict species distributions and traits syndrome at community scale under different land-uses in subalpine grasslands. Nomenclature: Tutin et al. (1964–1980).", "corpus_id": 86336417, "score": 0 }, { "doc_id": "53663223", "title": "Let the concept of trait be functional", "abstract": "In its simplest definition, a trait is a surrogate of organismal performance, and this meaning of the term has been used by evolutionists for a long time. Over the last three decades, developments in community and ecosystem ecology have forced the concept of trait beyond these original boundaries, and trait-based approaches are now widely used in studies ranging from the level of organisms to that of ecosystems. Despite some attempts to fix the terminology, especially in plant ecology, there is currently a high degree of confusion in the use, not only of the term \"trait\" itself, but also in the underlying concepts it refers to. We therefore give an unambiguous definition of plant trait, with a particular emphasis on functional trait. A hierarchical perspective is proposed, extending the \"performance paradigm\" to plant ecology. \"Functional traits\" are defined as morpho-physiophenological traits which impact fitness indirectly via their effects on growth, reproduction and survival, the three components of individual performance. We finally present an integrative framework explaining how changes in trait values due to environmental variations are translated into organismal performance, and how these changes may influence processes at higher organizational levels. We argue that this can be achieved by developing \"integration functions\" which can be grouped into functional response (community level) and effect (ecosystem level) algorithms.", "corpus_id": 53663223, "score": 0 }, { "doc_id": "30602307", "title": "Flowering phenology and height growth pattern are associated with maximum plant height, relative growth rate and stem tissue mass density in herbaceous grassland species", "abstract": "Summary 1. We hypothesize that flowering phenology correlates with plant height growth pattern and that the pattern is associated with functional traits including maximum plant height (Hmax), RGR, stem tissue mass density (SD), hollow ratio (proportion of central hollow of stem cross-sectional area) and leaf mass per area (LMA) in grassland herbaceous species. 2. We investigated plant height growth trajectories and flower phenology, and measured LMA, SD and hollow ratio for 25 herbaceous species including 20 dicot forb species and five monocot species in an old-field grassland of New England, USA. Hmax, RGR, T10 and T90 (Julian day when plant height was 10% and 90% Hmax respectively) were derived from a logistic function for each species and were analysed in relation to LMA and SD. 3. Hmax was positively correlated with T10, T90 and flowering onset time (Julian day when the first 10% of flowers were blossoming) across species and across evolutionary-correlated divergences. Early growing and flowering species were shorter than late ones, and species reaching Hmax earlier flowered earlier than their counterparts. 4. There was a positive relationship between T90 and RGR, in which early growing species were usually at mid-to-high levels of RGR, while late-growing ones had widely varied RGR. A similar relationship was found between flowering onset time and RGR. RGR was significantly negatively correlated with SD and LMA but positively with hollow ratio, as indicated by correlation analysis and phylogenetically independent comparative analysis. 5. Based on the above results, we propose that herbaceous species have two major dimensions of height growth strategies (early vs. late and fast vs. slow growth), collectively resulting in three extreme cases (early and fast, late and slow, and late and fast). Different height growth trajectories resulting from these strategies may reduce asymmetric competition among co-existing species in dense grasslands. 6. Synthesis. Flowering phenology and height growth patterns are significantly associated with functional traits such as RGR, LMA and hollow ratio in herbaceous grassland species. The difference in height growth trajectories and associated functional traits may allow species coexistence possibly at both plant and consumer trophic levels.", "corpus_id": 30602307, "score": 0 }, { "doc_id": "84258379", "title": "The influence of sowing rate and row spacing on the plant density and yield of red beet", "abstract": "Three experiments examined the effects of sowing rate and between-row spacing on the plant density and yield of red beet. The proportion of seeds which produced mature plants decreased when the mean distance to the nearest neighbour was less than 5 cm. In these experiments, this distance was governed by within-row spacing. Thus, plots with narrow-spaced rows achieved a higher plant density than those with wide-spaced rows, when sown with the same weight of seed. Total yield of beet per unit area decreased with increasing plant density. Maximum yields per unit area of small beet were achieved at high plant densities, whereas maximum yields of large beet were achieved at low plant densities. The effect of between-row spacing on yield was much smaller than that of density, and was important only for crops harvested early. Shoot yield per unit area was measured in two experiments and was not affected by row spacing in either. Shoot yield was not affected by plant density in one experiment, but, in the other, tended to a maximum value with increasing plant density.", "corpus_id": 84258379, "score": 0 }, { "doc_id": "56043044", "title": "A parsimonious combination of functional traits predicting plant response to disturbance and soil fertility", "abstract": "Abstract Questions: 1. How many traits associated with persistence and regeneration are necessary to predict the response of plants to soil fertility and disturbance? 2. Are correlated changes in trait expressions linked to the response of functional groups to fertility and disturbance? Location: Lower Frankonia, Germany. Methods: On 120 plots located in managed and abandoned grasslands, fields, and vineyards, we recorded species composition, disturbance intensity, soil water and nutrients, and ten candidate traits for 75 species. We used a novel method which is based on three steps: (1) logistic regression to separate responsive from non-responsive species; (2) iterative clustering of all possible combinations of the candidate traits including regression of each cluster in response to the environmental variables; (3) selection of the trait combination that performed best with respect to goodness of fit of all clusters from this combination. Bivariate trait relationships across functional groups were analysed with reduced major axis regression (RMA). Results: The parsimonious trait combination consisted of life span, specific leaf area (SLA), canopy height, and seed number. The ‘acquisitive’ functional groups in terms of SLA and height were linked to higher fertility and earlier disturbance, while the ‘retentive’ groups related to lower fertility and later disturbance. Investment in reproduction, however, displayed a reverse relation. SLA and canopy height showed correlated shifts in two pairs of co-occurring functional groups. Conclusions: A small number of traits is sufficient to predict the response of species. Plants need a higher increment in SLA to reach the same height, if start of disturbance is earlier. Linkages between traits shift from generative to vegetative with increasing fertility and earlier start of disturbance. Functional groups enable shifts in scaling relationships between traits to be analysed, in contrast to the analysis of single traits. Nomenclature: Rothmaler (1994).", "corpus_id": 56043044, "score": 0 }, { "doc_id": "87864445", "title": "Weed seedbank response to tillage, herbicides, and crop rotation sequence.", "abstract": "Changes in the weed seedbank due to crop production practices are an important determinant of subsequent weed problems. Research was conducted to evaluate effects of primary tillage (moldboard plowing and chisel plowing), secondary tillage (row cultivation), and herbicides on weed species changes in the soil seedbank in three irrigated row crop rotational sequences over a 3-yr period. The cropping sequences consisted of continuous corn for 3 yr, continuous pinto beans for 3 yr, or sugarbeets for 2 yr followed by corn in the third year. Cropping sequence was the most dominant factor in- fluencing species composition in the seedbank. This was partly due to herbicide use in each cropping sequence producing a shift in the weed seedbank in favor of species less susceptible to applied herbicides. A comparison between moldboard and chisel plowing indicated that weed seed of predominant species were more prevalent near the soil surface after chisel plowing. The number of predominant annual weed seed over the 3-yr period increased more rapidly in the seedbank after chisel plowing compared to moldboard plowing unless effective weed control could be maintained to produce a decline in seedbank number. In this case, seedbank decline was generally more rapid after moldboard plowing. Row cultivation generally reduced seedbanks of most species compared to uncultivated plots in the pinto bean and sugarbeet sequences. A simple model was developed to validate the observation that rate of change in the weed seedbank is influenced by type of tillage and weed control effectiveness. Nomenclature: Corn, Zea mays L.; pinto beans, Phaseolus vulgaris L.; sugarbeets, Beta vulgaris L. Additional index words: Weed shifts, reduced tillage, conservation tillage, population dynamics, modeling, KCHSC, AMARE, CHEAL, SOLSA, SETVI, ERACN.", "corpus_id": 87864445, "score": 0 }, { "doc_id": "85336254", "title": "Integrated Weed Management systems allow reduced reliance on herbicides and long-term weed control", "abstract": "Current concerns about the environmental impacts of pesticide use in agriculture require the investigation of novel cropping systems that would reduce their reliance on pesticides. In this paper, we report on an experiment carried out over 6 years to assess the performance of four cropping systems based on Integrated Weed Management (IWM) as compared to a reference standard system. Systems differed in crop rotations, soil tillage, mechanical and chemical weeding and crop management. Fewer herbicides were applied in IWM-based systems as compared to the reference, resulting in a lower environmental impact. Over the 6 years, we detected no significant increase in the density of winter or summer annual broad-leaved, and of grassy weeds in IWM systems, with one exception that is discussed. These results indicate that the combination of various IWM techniques allow both the long-term control of arable weeds and a significantly reduced reliance on herbicides.", "corpus_id": 85336254, "score": 0 }, { "doc_id": "82315172", "title": "Modelling rotations: can crop sequences explain arable weed seedbank abundance?", "abstract": "We investigated the effects of crop sequences on monocotyledon, dicotyledon and total weed seedbank abundance. Using seedbank data sampled from the conventionally cropped part of the GB farm-scale evaluations of genetically modified, herbicide-tolerant (GMHT) crops, we asked whether it is possible to identify crop sequence effects, to identify their duration and to simplify crop sequences into crop management classes with similar effects on weed seedbanks. This work showed that it is possible to detect historical effects of past crops, sown in sequence, on weed seedbanks for up to 3 years and that crop sequences may be simplified to crop management classes describing the season of sowing, crop type and weed target for herbicide application. Model estimates for the seedbanks were validated against an independent, follow-up seedbank data set. The analysis provided abundance estimates that ranged over 3 and 1.7 orders of magnitude for the monocotyledon and dicotyledon weed seedbanks for different crop sequences. This work yields a methodology for estimating seedbank abundance in current crop sequences, potentially allowing sequences to be identified that better reconcile the competing needs for weed control to maintain crop productivity and the demand for increased farmland biodiversity.", "corpus_id": 82315172, "score": 0 }, { "doc_id": "85162329", "title": "Weed seed predation increases with vegetation cover in perennial forage crops", "abstract": "Vegetation cover may affect weed seed predation by modifying the habitat quality for predatory organisms. Post-dispersal weed seed predation was measured by placing ‘seed cards’ in two perennial crops (alfalfa, cocksfoot) with and without crop cutting and in plots with bare soil. Each treatment was repeated four times in a randomized complete block design. Vegetation cover was measured by canopy light interception. Predation trials lasted two weeks and were repeated three times. Seed predation rates varied among three weed species (highest for Viola arvensis, intermediate for Alopecurus myosuroides, lowest for Sinapis arvensis). Vertebrate exclusion cages (12 mm × 12 mm openings) strongly reduced seed predation rates. Positive relationships were observed between vegetation cover and seed predation rates by both vertebrates and invertebrates for all weed species and trials, except when overall predation rates were very low. Predation rates were highest in uncut alfalfa, lowest on bare soil, but 16–64% of this variation could equally be explained by vegetation cover. The factorial design indicated that cutting had a stronger impact than crop species (legume or grass). Results suggest that weed seed predation may be enhanced by maintaining a high and temporally extended vegetation cover.", "corpus_id": 85162329, "score": 0 }, { "doc_id": "86231483", "title": "Timing of tillage is an important filter on the assembly of weed communities", "abstract": "Abstract A trait-based community assembly approach to weed management may enhance our understanding of how weed communities respond to specific management practices and increase the utility of weed management based on ecological principles. Therefore, identifying management practices that operate as assembly filters and the species traits upon which they act is an important first step in developing a more predictive weed science. Here, I report results from a 3-yr investigation of the effects of timing of annual tillage (spring vs. fall) on the annual assembly of arable weed communities. The timing of tillage had consistent and dramatic effects on the composition of weed communities; spring tillage led to weed communities dominated by early emerging spring annual forbs and C4 grasses, and fall tillage led to communities dominated by later-emerging forbs and C3 grasses. Traits determining a species' susceptibility to tillage time likely include germination syndrome and life cycle, both of which influence how species respond to changes in soil resource levels and light availability driven by seasonal disturbance regime. Manipulating the timing of tillage and other major soil disturbances may therefore be an important tool for managers interested in influencing community composition or targeting species with similar germination and life-history traits.", "corpus_id": 86231483, "score": 0 }, { "doc_id": "86546950", "title": "Timing of disturbance and vegetation development: how sowing date affects the weed flora in spring‐sown crops", "abstract": "The number of annual weeds were recorded in 752 field experiments in spring-sown cereal crops conducted in Sweden 1972-1993. Two null hypotheses were tested regard- ing how the sowing date influenced the weed flora. 1. There is no relationship between the weed flora composition and sow- ing date. A pCCA (with geographic regions, crop species and soil types as covariables) clearly refuted this hypothesis. Hence, the composition of the weed flora varied depending on so wing date. 2. Species classified as summer annuals, winter annuals and germination generalists (that can germinate substantially in both spring and autumn) do not differ in their placement along the first ordination axis in the pCCA, i.e. according to sowing date. An ANOVA was unable to reject this hypothesis. Hence, germina- tion syndrome classification did not explain the observed com- munity differences related to sowing date. These results illustrate the importance of the date of disturbance for any secondary succession involving a seed bank and also the importance of annual dormancy cycles in seed banks.", "corpus_id": 86546950, "score": 0 }, { "doc_id": "40754718", "title": "The Search for Generality in Studies of Disturbance and Ecosystem Dynamics", "abstract": "Studies of disturbance have a long tradition in vegetation ecology (Cooper 1926; Raup 1941; White 1979) and have increased lly during the last 30 years (Dayton 1971; Heinselman 1973; Levin and Paine 1974; Borman and Likens 1979; Sousa 1979a,b, 1984; Pickett 1980; Pickett and White 1985; Van der Maarel 1993; Bornette and Amoros 1996; Paine et al. 1998; Freiich and Reich 1999; White et al. 1999). We have learned a tremendous amount about the significance of disturbance as an ecological factor in various habitats and communities (Knapp 1974; Grubb 1977; Miles 1979; Oliver 1981; Pickett and White 1985; Goldberg 1988; Frelich and Lorimer 1991; Milton et al. 1997), about disturbance regimes (Romme 1982; Turner et al. 1993; White et al. 1999), about functional adaptations of plants (Garcia-Mora et al. 1999; Walker et al. 1999), about responses of ecosystems (Bornette and Amoros 1996; Johnson et al. 1998; Engelmark et al. 1999) and about restoring disturbance as an ecosystem process (White and Walker 1997; Covington et al. 1999). During this period, a few theories and synthetic concepts have been proposed, but we do not yet have an inclusive general paradigm for this important body of work.", "corpus_id": 40754718, "score": 0 }, { "doc_id": "83607984", "title": "Characteristics of seeds and seedlings from weeds treated with sublethal herbicide doses", "abstract": "Summary \n \nSize, germination and viability of seeds as well as growth of seedlings derived from three weed species were studied in a pot trial. Fallopin convolvulus (L.) A. Loeve, Galium. spurium L. and Thlaspi arvense L. were treated with MCPA or tribenuron-methyl at four doses and at five growth stages, from seedling stage to flowering, In G. spurium subnormal doses of tribenuron-methyl, applied at intermediate growth stages, greatly reduced seed weight, gennination, viability, seedling shoot biomass and root biomass. Germination and viability, as well as the shoot biomass and root biomass of seedlings, were highly correlated with seed weight. In addition, but to a smaller extent, seed weight was reduced in F. convolvidus and T. arvense by tribenuron-methyl and in G. spurium by MCPA. Germination was reduced in F. convolvulus by MCPA and in T. arvense by tribenuron-methyl. However, the effects varied greatly depending on the growth stage at application.", "corpus_id": 83607984, "score": 0 }, { "doc_id": "129645744", "title": "Morphological characterisation of soil structure in tilled fields: from a diagnosis method to the modelling of structural changes over time", "abstract": "Characterisation of soil structure within the tilled layer of cultivated fields is crucial because the importance of this soil characteristic on the biological, chemical and physical properties of the soil and its repercussions on water cycle, root growth and functioning. We present in this paper a method for field characterisation of soil structure. This method, practised since the 1970s, was designed for field diagnosis of the effects of cropping systems on soil structure. It is based on a stratification of the observation face of a pit dug perpendicular to the direction of tillage and traffic: spatial compartments are distinguished, according to the nature of the mechanical stresses they have been submitted to during tillage and crop management. Characterisation of soil structure is performed on a morphological basis, using two criteria, each of them addressing a specific organisation level of the soil: firstly, clods size distribution, proportion of fine soil and the way the clods are brought together are considered; then, secondly, the clods are classified in three types, on the basis of the importance and the origin of their internal structural porosity. Physical measurements (bulk density, compaction test, and water retention) are presented, which demonstrate that physical behaviour is different between clod types. These results justify the use of the method to model changes with time in soil structure, under the effects of the main factors affecting soil structure dynamics in tilled fields: compaction, fragmentation, climate and biological activity. A model which simulates at the field scale the changes over time of the proportion of compacted clods within the tilled layer is presented. In this model, the tilled layer is represented as a set of 1 cm 2 pixels, regularly located on a square grid. Each pixel is defined by its co-ordinates and a specific structure, compacted or non compacted. The pixel co-ordinates are modified during ploughing, for which the model calculates the lateral and vertical displacement of the soil. The structure of any individual pixel can be changed, depending on the soil condition and the operation type. This model was evaluated by comparing its outcomes to measurements obtained from a long term field experiment designed to study soil structure dynamics.", "corpus_id": 129645744, "score": 0 }, { "doc_id": "34439305", "title": "Integration of soil structure variations with time and space into models for crop management. A review", "abstract": "Soil structure plays a major role in the design of new crop management systems. For instance, the transition from conventional to no-tillage changes soil structure, which, in turn, has implications on crop yield greenhouse gas emissions, and pesticide and nitrate leaching. Modelling soil structure at field scale faces two main issues: (1) the spatial variability and (2) the temporal variability. Here, we review how spatial variability of soil structure is taken into account in water transfer models at field scale. We discuss the effects of soil structure on hydraulic properties. We present options to model soil structure effects using pedotransfer functions or calculations based on pore network geometry. Then we review studies on water transfer. Here, we show the utility of one-dimensional (1-D) and 2-D models, and the range of soil profile partitions. In the second part, we study a mean to model the temporal variation of soil structure. We propose an indicator of soil structure dynamics based on the proportion of compacted clods in the tilled layer. This indicator was measured from the observation face of soil pits. We studied this indicator in a long-term field experiment involving various risks of compaction. The results showed that this indicator gave a more precise description of the time course changes in soil structure than the mean soil bulk density measured on the same experimental plots. Lastly, we discuss the principles of a model that predicts the evolution of this indicator under different soil tillage and climatic conditions. This model can be used to evaluate the effects of different crop management systems on soil structure and soil water transfer.", "corpus_id": 34439305, "score": 0 }, { "doc_id": "84907612", "title": "Weed seedling emergence and seed survival: separating the effects of seed position and soil modification by tillage", "abstract": "Summary \nTillage causes both vertical redistribution of weed seeds and changes in soil physical properties. These two factors are rarely distinguished in studies of the impact of tillage on seedling emergence or seed survival. In this study, seeds of Chenopodium album L., Amaranthus retroflexus L., and Abutilon theophrasti Medik, were planted at particular depths in pots of undisturbed or stirred soil to separate these effects. Emergence and survival data were analysed by non-linear regression to determine the nature of significant differences between treatments. Emergence increased with slight burial and then decreased exponentially at greater depths. Average emergence over all depths was generally greater in tilled sou than in unfilled soil, particularly for C. album and A. retroflexus. Seed survival approached a maximum with increasing depth. Average survival of seeds that did not produce emerged seedlings was greater in tilled soil than in untilled soil for C. album and A. retroflexus. Thus, tillage affects emergence and seed survival of weeds through changes in soil conditions independently of effects resulting from redistribution of seeds in the soil profile.", "corpus_id": 84907612, "score": 0 }, { "doc_id": "83706903", "title": "Effects of soil depth and aggregate size on weed seed distribution and viability in a silt loam soil", "abstract": "Abstract The position of weed seeds within the soil matrix plays an important role in seedling emergence and seed survival. The relationship of weed seeds with soil aggregates and soil depth was evaluated in a Waukegon silt loam soil that had been under a long-term, conventional tillage, annual crop management system. Soil aggregates were separated and classified into eight size classes from ≤5 to >12 mm and weed seeds were extracted from the aggregates. Amaranthus spp., Chenopodium album L. (common lambsquarters), Polygonum pensylvanicum L. (Pennsylvania smartweed), Setaria faberi Herrm. (giant foxtail), and Solanum ptycanthum Dun. (eastern black nightshade) accounted for the majority of seeds recovered. In general, seed viability declined from April to June, but increased in October following seed deposition. Seeds of individual species were most abundant in the aggregate size class most closely matching its seed size. However, seeds were commonly found associated with aggregates larger than 9 mm. Highest seed viability was found in the aggregate fraction closest to the seed size, however, S. faberi viability was also high in the >12 mm aggregate size class. Regardless of aggregate size, seed numbers were generally greatest in the upper 5 cm of soil. The results of this research were species-dependent and variable and demonstrated the complexity of weed seed/soil aggregate associations. However, they did show that seed placement within the soil matrix may play an important role in weed population dynamics.", "corpus_id": 83706903, "score": 0 }, { "doc_id": "84755035", "title": "Effects of seed depth and soil aggregates on the emergence of weeds with contrasting seed traits", "abstract": "Gardarin A, Durr C & Colbach N (2010). Effects of seed depth and soil aggregates on the emergence of weeds with contrasting seed traits. Weed Research50, 91–101. \n \n \n \nSummary \n \nTillage has a strong impact on weed emergence by burying seeds in the soil and modifying soil structure. Its influence can vary according to seed and seedling characteristics. This article focuses on shoot and radicle elongation in the soil and on seedling mortality caused by soil obstacles. Germinated seeds of nine contrasting weeds were planted in pots and grown in the dark to measure shoot and radicle elongation. Second, the proportion of seedlings blocked under aggregates (20–50 mm) was measured. Shoot growth rate, maximal shoot and radicle lengths were positively correlated with seed mass. Large-seeded species (e.g. Avena fatua) were more likely to emerge from greater depths (exceeding 20 cm deep). Seedling mortality increased with increasing obstacle size for all species; it was greater for monocotyledonous than for dicotyledonous species and decreased with the shoot diameter. Weed seed depth and soil structure influence emergence of weed species differently, depending on seed mass, shoot diameter and taxa. Including the results of this study in a cropping system-weed dynamics model would help to predict responses of weeds species to tillage.", "corpus_id": 84755035, "score": 0 }, { "doc_id": "83525889", "title": "Seasonal restrictions of bud growth on roots of Cirsium arvense and Sonchus arvensis and rhizomes of Elymus repens", "abstract": "Brandsaeter LO, Fogelfors H, Fykse H, Graglia E, Jensen RK, Melander B, Salonen J & Vanhala P (2010). Seasonal restrictions of bud growth on roots of Cirsium arvense and Sonchus arvensis and rhizomes of Elymus repens. Weed Research50, 102–109. \n \n \n \nSummary \n \nThe success of weed management aimed at depleting the regenerative structures of perennial weeds depends largely on the sprouting activity of rhizome and root buds. Seasonal variation in sprouting of these buds on Cirsium arvense, Sonchus arvensis and Elymus repens was studied for plants collected from Denmark, Finland, Norway and Sweden. At 2-week intervals from July to October, 5-cm fragments of roots or rhizomes were cut from plants grown in buckets and planted into soil in pots, half of which were placed immediately into growth chambers at 18°C for 4 weeks. The other half of the pots were initially placed in a dark room at 2°C for 4 weeks before being transferred to the same growth chamber, also for 4 weeks. During the growth chamber period, the numbers of emerged shoots in each pot were counted weekly. The sprouting activity of C. arvense and E. repens was relatively uniform during this period and bud dormancy was not apparent. In all ecotypes of S. arvensis, innate bud dormancy developed during the latter part of the growing season. For all three species, differences in sprouting readiness were found among ecotypes. The results imply that C. arvense and E. repens are more likely to be controlled by mechanical measures in autumn than S. arvensis.", "corpus_id": 83525889, "score": 0 }, { "doc_id": "129785748", "title": "Cumulative effect of annually repeated passes of heavy agricultural machinery on soil structural properties and sugar beet yield under two tillage systems", "abstract": "Abstract The aim of this study was to determine potential cumulative effects of repeated passes with current heavy agricultural machinery on topsoil (0–0.3 m) and subsoil (below 0.3 m) physical properties of a Luvisol as affected by long-term tillage (annual mouldboard ploughing to 0.3 m depth (MP), shallow-mixing conservation tillage to 0.1 m depth (SM) with a wing-bladed rigid tine cultivator). Moreover, sugar beet yield was determined. Wheeling was conducted with a six-row self-propelled sugar beet harvester representing contemporary heavy agricultural machinery (wheel load 7.8–11.7 Mg, average ground contact pressure 100–145 kPa). Wheeling was applied once per year over three consecutive years after harvest of sugar beet, cereal and cereal, and moreover, independent from regular plot management with light experimental machinery. Soil moisture at wheeling (0–0.6 m depth) was around 100% field capacity in most years, which was secured by irrigation before wheeling if necessary. Repeated wheeling negatively affected penetration resistance, macropore volume (equivalent diameter >50 μm) and air permeability of topsoil (0.05–0.1 m, 0.18–0.23 m) and subsoil (0.4–0.45 m) layers, while biopore number and surface water infiltration remained unaffected. SM compared to MP tillage increased penetration resistance while decreasing macropore volume and air permeability in the 0.18–0.23 m layer, whereas reverse effects occurred in 0.4–0.45 m depth. Sugar beet yield was decreased by wheeling and SM tillage compared to the control treatments. No significant interactions between wheeling and tillage occurred in any parameter investigated. Conclusively, SM tillage did not provide better subsoil resistance against compaction compared to MP treatment under wheeling and soil conditions prevalent in our experiment. Repeated wheeling with heavy agricultural harvest machinery is obviously at risk to exceed the bearing capacity of susceptible soils. Although (i) under regular harvest conditions just small parts of arable fields (except headlands) are wheeled with high loads, (ii) harvest is by far not every year conducted under high soil moisture, and (iii) effects in the subsoil were small, such risks have to be taken into account. Reduction of tillage depth to", "corpus_id": 129785748, "score": 0 }, { "doc_id": "128797866", "title": "Weeds and Weed Management on Arable Land: An Ecological Approach", "abstract": "Classification of plants based on traits of ecological significance annual and perennial crops weed commodities looked upon as early stages in secondary vegetation succession weeds with diverse life forms in various types of crop germination, emergence and establishment of crop and weed plants competition in plant stands of short duration weed flora and weed plant adaption to environment and competitive conditions measurements of competition and competitiveness in plant stands of short duration soil tillage effects on weeds chemical weed control as an element in the cropping system special management measures knowledge of importance for understanding the occurrence and rational management of weeds. (Part contents)", "corpus_id": 128797866, "score": 0 }, { "doc_id": "54025533", "title": "Challenging Theophrastus: A common core list of plant traits for functional ecology", "abstract": "Abstract. Ecologists need a common language of plant traits in order to make comparisons across regions and scales, pool data, and maximize the utility of the data. To develop such a set of traits we began with the primary challenges faced by plants: dispersal, establishment, and persistence in order to identify fundamental traits. Most of these traits are hard to measure, but advances in comparative ecology have suggested a number of easy to measure analogs. Unfortunately, some of the fundamental traits have no simple analog. The common core list includes: seed mass, seed shape, dispersal mode, clonality, specific leaf area, leaf water content, height, above-ground biomass, life history, onset of flowering, stem density, and resprouting ability. Most of the traits can be measured quantitatively, but several traits on the list must still be measured qualitatively due to logistical problems or lack of an easy analog. Key problem areas include: dispersal ability, capacity for vegetative spread, germination, palatability, plasticity, and all the various below-ground traits. Comparative studies need to address these problem areas. The common core list is suggested as a common starting point for studies of functional ecology. The idiosyncrasies of regional floras and specific research agendas will dictate which traits can be ignored and those that need to be added.", "corpus_id": 54025533, "score": 0 }, { "doc_id": "32555721", "title": "A leaf-height-seed (LHS) plant ecology strategy scheme", "abstract": "A leaf-height-seed (LHS) plant ecology strategy scheme is proposed. The axes would be specific leaf area SLA (light-capturing area deployed per dry mass allocated), height of the plant's canopy at maturity, and seed mass. All axes would be log-scaled. The strategy of a species would be described by its position in the volume formed by the three axes.The advantages of the LHS scheme can be understood by comparing it to Grime's CSR scheme, which has Competitors, Stress-tolerators and Ruderals at the corners of a triangle. The CSR triangle is widely cited as expressing important strategic variation between species. The C–S axis reflects variation in responsiveness to opportunities for rapid growth; in the LHS scheme, SLA reflects the same type of variation. The R axis reflects coping with disturbance; in the LHS scheme, height and seed mass reflect separate aspects of coping with disturbance.A plant ecology strategy scheme that permitted any species worldwide to be readily positioned within the scheme could bring substantial benefits for improved meta-analysis of experimental results, for placing detailed ecophysiology in context, and for coping with questions posed by global change. In the CSR triangle the axes are defined by reference to concepts, there is no simple protocol for positioning species beyond the reference datasets within the scheme, and consequently benefits of worldwide comparison have not materialized. LHS does permit any vascular land plant species to be positioned within the scheme, without time-consuming measurement of metabolic rates or of field performance relative to other species. The merits of the LHS scheme reside (it is argued) in this potential for worldwide comparison, more than in superior explanatory power within any particular vegetation region.The LHS scheme avoids also two other difficulties with the CSR scheme: (a) It does not prejudge that there are no viable strategies under high stress and high disturbance (the missing quadrant in the CSR triangle compared to a two-axis rectangle); (b) It separates out two distinct aspects of the response to disturbance, height at maturity expressing the amount of growth attempted between disturbances, and seed mass (inverse of seed output per unit reproductive effort) expressing the capacity to colonize growth opportunities at a distance.The advantage of LHS axes defined through a single readily-measured variable needs to be weighed against the disadvantage that single plant traits may not capture as much strategy variation as CSR's multi-trait axes. It is argued that the benefits of potential worldwide comparison do actually outweigh any decrease in the proportion of meaningful variation between species that is captured. Further, the LHS scheme opens the path to quantifying what proportion of variation in any other ecologically-relevant trait is correlated with the LHS axes. This quantification could help us to move forward from unprofitable debates of the past 30 years, where CSR opponents have emphasized patterns that were not accommodated within the scheme, while CSR proponents have emphasized patterns that the scheme did account for.", "corpus_id": 32555721, "score": 0 }, { "doc_id": "84903724", "title": "Evidence for the Existence of Three Primary Strategies in Plants and Its Relevance to Ecological and Evolutionary Theory", "abstract": "It is suggested that evolution in plants may be associated with the emergence of three primary strategies, each of which may be identified by reference to a number of characteristics including morphological features, resource allocation, phenology, and response to stress. The competitive strategy prevails in productive, relatively undisturbed vegetation, the stress-tolerant strategy is associated with continuously unproductive conditions, and the ruderal strategy is characteristic of severely disturbed but potentially productive habitats. A triangular model based upon the three strategies may be reconciled with the theory of r- and K-selection, provides an insight into the processes of vegetation succession and dominance, and appears to be capable of extension to fungi and to animals.", "corpus_id": 84903724, "score": 0 }, { "doc_id": "133206075", "title": "Distribution and Survival of Quackgrass (Elytrigia repens) Rhizome Buds1", "abstract": "An experiment was established at three sites to determine the longevity and distribution of rhizome buds of two quackgrass biotypes in the soil profile under two tillage systems (no-till or fall-plow). The experiments were established in May 1987 at sites initially free of quackgrass. Rhizome segments with three nodes were planted 2 to 5 cm deep to give an initial density of 21 buds m-2. Production of new buds was prevented in subsequent years. Rhizome bud populations were sampled every 6 mo between October 1987 and October 1989. Buds were produced until snow cover, indicating the need to control quackgrass until late fall to prevent a bud population increase. Under no-till conditions, 94% of quackgrass buds occurred in the top 10 cm of soil while 68 and 19% were found below 10 and 20 cm, respectively, in the fallplow treatments. A control program against quackgrass should aim at keeping the majority of rhizomes in the top 10 cm in order to facilitate control by having most shoots emerging at the same time. There was no statistically significant difference in bud longevity between biotypes, sites, and tillage systems. Viability of the rhizome buds declined rapidly during the first year. In most cases it took 2 yr for the bud populations to reach extinction although 0.6% of buds of one biotype survived as long as 30 mo in one of the three sites. Therefore, a minimum of 2 yr of total control would be required to eradicate quackgrass from most locations. Nomenclature: Bromoxynil, 3,5-dibromo-4-hydroxybenzonitrile; dicamba, 3,6-dichloro-2-methoxybenzoic acid; paraquat, 1,1'dimethyl-4,4'-bipyridinium ion; quackgrass, Elytrigia repens (L.) Nevski #3 AGRRE. Additional index words: Agropyron repens, Elymus repens, rhizome bud longevity, AGRRE.", "corpus_id": 133206075, "score": 0 }, { "doc_id": "84234574", "title": "Ecological interpretation of weed flora dynamics under different tillage systems", "abstract": "In northern Italy, on soil managed with three different tillage systems (conventional tillage, ridge tillage, and no-tillage) and submitted to standard cultural practices (crop rotation, and chemical weed control), the weed vegetation was assessed at the beginning of the trial (1987) and after six, and eight years. The aims were to evaluate (1) the effect of tillage systems on the weeds; and (2) the possibility of linking the floristic changes under reduced disturbance to the theory of ecological succession. The weeds were categorised according to life-forms (biological groups), periodicity types (ecophysiological groups), dispersal types and seed longevity. Data were analysed using Sorenson's Indices of Similarity, the Independence test, and Principal Components Analysis. The tillage systems profoundly altered the weed community: in undisturbed soils the importance of the geophyte and hemicryptophyte species, and among the annuals, Digitaria sanguinalis, Conyza canadensis and Kickxia elatine increased, as well as that of the wind-dispersed weeds. The species linked to disturbance were annuals and in particular Amaranthus spp., Chenopodium album and Echinochloa crus-galli. After eight years the floristic evolution in the reduced tillage system can be interpreted on the basis of ecological succession. The community that has formed assumes, from the quantitative point of view, characteristics of a pioneer community of secondary succession with a predominance of annual species and a large number of wind-dispersed plants. Qualitatively there is a movement towards a more mature community that could become similar to that of the woodland edge, with more perennial species, shrubs, and bird-dispersed plants. The implications of these conclusions are discussed in terms of weed management.", "corpus_id": 84234574, "score": 0 }, { "doc_id": "85751609", "title": "Management in a modified no-tillage corn–soybean–wheat rotation influences weed population and community dynamics", "abstract": "Abstract Conservation tillage systems, such as no-tillage, are ecologically advantageous because they reduce soil erosion; however, they rely heavily on herbicide use. Our goal was to determine how weed communities of no-tillage systems are affected when the system is modified to reduce herbicide use through a combination of banded herbicides and interrow cultivation. To this end, we conducted a 9-yr study in a no-tillage corn–soybean–winter wheat rotation. All management systems had a preplant application of glyphosate, followed by either broadcast PRE herbicides (conventional no-tillage), interrow cultivation with banded PRE herbicides, or interrow cultivation alone. Aboveground weed densities were assessed each year and data were grouped into early (1991 to 1993) and late (1996 to 1998) time periods. Over time, weed communities became more distinct, showing a strong response to management and crop. In the early years, weed communities separated more in response to management than crop. In the late years, this was reversed. Weed communities in systems with interrow cultivation were more diverse than those in conventional no-tillage. The response to weed management system and crop was species specific. For example, the abundance of yellow foxtail was higher when interrow cultivation was employed, but abundance was equal in all crops. Dandelion was more abundant in conventional no-tillage of corn and soybean; however, it was equally abundant in all management systems in wheat. Seed bank species richness increased over time and was highest in systems with interrow cultivation. Herbicide use can be reduced in a modified no-tillage corn–soybean–wheat rotation by incorporating interrow cultivation, with or without banded herbicides, into the management plan. The weed community trajectory changes, and the weed community becomes more diverse. A more diverse weed community will not necessarily alter how we manage weeds. Nomenclature: Glyphosate; yellow foxtail, Setaria glauca (L.) Beauv.; dandelion, Taraxacum officinale Weber; corn, Zea mays L.; soybean, Glycine max (L.) Merr.; wheat, Triticum aestivum L.", "corpus_id": 85751609, "score": 0 }, { "doc_id": "86034544", "title": "The Selective Memory of Weed Seedbanks after 18 Years of Conservation Tillage", "abstract": "A conservation tillage study provided the opportunity to test whether tillage effects on the germinable weed seedbank would be consistent across different crop rotations and to investigate the potential residual effects of herbicide treatments terminated 12 yr earlier. Our objective was to measure the effects of tillage (moldboard plow [MP] vs. chisel plow [CP] vs. no-till [NT]), crop rotation (2-yr barley–red clover followed by 4-yr barley–canola–wheat–soybean rotation, compared to a cereal monoculture), and of a prior weed management factor (three intensity levels of herbicide use) on the density, diversity, and community structure of weed seedbanks. Species richness, evenness (Shannon's E), and diversity (Shannon's H′) of spring seedbanks varied little across treatments and over time. Total seedbank density generally increased as tillage was reduced, with some variations due to weed management in 1993 and crop rotation in 2006. Crop rotations generally had smaller seedbanks with fewer species than the monoculture. In 1993, seedbanks with minimum weed management were twice as dense as those with intensive or moderate weed management (approximately 6,000 vs. 3,000 seed m−2). By 2006, seed density averaged 6,838 seed m−2 across intensive and moderate weed management regardless of tillage, but was nearly twice as large in NT (12,188 seed m−2) compared to MP (4,770 seed m−2) and CP (7,117 seed m−2) with minimum weed management (LSD0.005  =  4488). Species with abundant seedbanks responded differently to treatments. Barnyardgrass and green foxtail had larger seedbanks in the monoculture than in the rotation. Common lambsquarters and pigweed species had large seedbanks in tilled treatments in the rotation, whereas yellow foxtail and field pennycress contributed to the large seedbanks observed in NT treatments. The latter two species were also associated with residual effects of weed management treatments (terminated 12 yr earlier) in NT. The differential seedbank response of weed species, attributed in part to contrasting weed emergence patterns and agronomic practice effects on seed rain, explained some of the weak treatment effects observed for total seedbank density and diversity. The large weed seedbanks observed in NT plots after 18 yr confirms the importance of seed rain and seedbank management for the sustainability of NT systems. Nomenclature: Barnyardgrass, Echinochloa crus-galli (L.) Beauv.; common lambsquarters, Chenopodium album L.; green foxtail, Setaria viridis (L.) Beauv.; field pennycress, Thlaspi arvense L.; pigweed species, Amaranthus sp.; yellow foxtail, Setaria pumila (Poir.) Roem & Schult.", "corpus_id": 86034544, "score": 0 }, { "doc_id": "84205913", "title": "Weed surveys in different tillage systems in southwestern Ontario field crops", "abstract": "A weed survey of 593 corn, soybean and winter wheat fields in southwestern Ontario was conducted during 1988 and 1989 to determine the abundance and distribution of weeds under a variety of tillage systems. The survey was conducted after all weed-control measures had been carried out. A total of 82 weed species and groups of species were recorded. Many weeds were found infrequently. The most abundant weeds were green foxtail (Setaria viridis (L.) Beauv.), lamb’s-quarters (Chenopodium album L.), quack grass (Agropyron repens (L.) Beauv.), redroot pigweed (Amaranthus retroflexus L.), common ragweed (Ambrosia artemisiifolia L.) and dandelion (Taraxacum officinale Weber). These weeds accounted for 54% of the total relative abundance. Weed communities in individual fields were highly variable. Most fields had fewer than 10 species, and nearly half of the fields had fewer than 6 weeds m−2. Six weeds, yellow foxtail (Setaria glauca (L.) Beauv.), quack grass, crab grass spp. (Digitaria spp.), lamb’s-quarters, gre...", "corpus_id": 84205913, "score": 0 }, { "doc_id": "83548997", "title": "Using phenology prediction in weed management: a review", "abstract": "Summary \n \nThe success of weed management based on ecological principles and weed biology will depend on a better understanding of the effect of environment on lift history strategies, growth, and competition of weeds; and crops, and particularly upon the ability to predict weed and crop phenology, This paper reviews the importance of phenotypic plasticity to weed and crop competition and other biological interactions. We also discuss the utility of phenological predictions in weed management and review current weed phenology models that are based on thermal time. By understanding the variables that drive plant phenotypic responses, new approaches and more long-term solutions for weed problems can be developed.", "corpus_id": 83548997, "score": 0 }, { "doc_id": "4326028", "title": "The worldwide leaf economics spectrum", "abstract": "Bringing together leaf trait data spanning 2,548 species and 175 sites we describe, for the first time at global scale, a universal spectrum of leaf economics consisting of key chemical, structural and physiological properties. The spectrum runs from quick to slow return on investments of nutrients and dry mass in leaves, and operates largely independently of growth form, plant functional type or biome. Categories along the spectrum would, in general, describe leaf economic variation at the global scale better than plant functional types, because functional types overlap substantially in their leaf traits. Overall, modulation of leaf traits and trait relationships by climate is surprisingly modest, although some striking and significant patterns can be seen. Reliable quantification of the leaf economics spectrum and its interaction with climate will prove valuable for modelling nutrient fluxes and vegetation boundaries under changing land-use and climate.", "corpus_id": 4326028, "score": 0 }, { "doc_id": "85085725", "title": "Modelling assimilation rates of 14 temperate arable weed species as a function of the environment and leaf traits", "abstract": "Information on the response of assimilation rate to environmental factors is lacking for many less competitive weed species that need to be considered in the context of increasing farm biodiversity. A pot experiment was sown to parameterize gross assimilation rate at light saturation and initial light use efficiency for 14 common UK annual weeds and winter wheat at four leaf temperatures. Field experiments were also sown to measure inter-specific differences in specific leaf area (SLA), leaf nitrogen content and assimilation rates in the field at near-optimum temperatures. A generic relationship describing the response of assimilation rate to temperature and light using SLA and leaf nitrogen content as conversion factors successfully predicted inter-specific differences in assimilation rates in the field. This relationship could be incorporated into weed-crop competition models to predict the productivity and competitive impact of weed mixtures, including species outside the current data set. Assimilation rates at light saturation in the field were determined largely by SLA. This trait was variable between species and within a species across the growing season and needs to be well described in mechanistic competition models to accurately calculate instantaneous assimilation rates.", "corpus_id": 85085725, "score": 0 }, { "doc_id": "23386578", "title": "Competition, traits and resource depletion in plant communities", "abstract": "Although of primary importance to explain plant community structure, general relationships between plant traits, resource depletion and competitive outcomes remain to be quantified across species. Here, we used a comparative approach to test whether instantaneous measurements of plant traits can capture both the amount of resources depleted under plant cover over time (competitive effect) and the way competitors perceived this resource depletion (competitive response). We performed a large competition experiment in which phytometers from a single grass species were transplanted within 18 different monocultures grown in a common-garden experiment, with a time-integrative quantification of light and water depletion over the phytometers’ growing season. Resource-capturing traits were measured on both phytometers (competitive response traits) and monocultures (competitive effect traits). The total amounts of depleted light and water availabilities over the season strongly differed among monocultures; they were best estimated by instantaneous measurements of height and rooting depth, respectively, performed when either light or water became limiting. Specific leaf area and leaf water potential, two competitive response traits measured at the leaf level, were good predictors of changes in phytometer performance under competition, and reflected the amount of light and water, respectively, perceived by plants throughout their lifespan. Our results demonstrated the relevance of instantaneous measures of plant traits as indicators of resource depletion over time, validating the trait-based approach for competition ecology.", "corpus_id": 23386578, "score": 0 }, { "doc_id": "86798143", "title": "Seed mass and the competition/colonization trade-off: Competitive interactions and spatial patterns in a guild of annual plants", "abstract": "Summary 1 We used neighbourhood modelling to estimate individual-level competition coefficients for seven annuals growing in limestone grassland over 2 years. We calculated the relative strength of intra- and interspecific competition and related this to differences in seed size and plant size between targets and neighbours. 2 Significant differences in the impact of neighbours on each target species were observed in half the models fitted, allowing us to reject a null hypothesis of competitive equivalence. 3 In one year we found that as the seed size or plant size of neighbours increased relative to targets, so did their competitive effect. Although this is consistent with the competition/colonization trade-off model the competitive interactions were not sufficiently asymmetric to allow coexistence. In a second year we found only weak interspecific competition and no relationship with plant or seed size. 4 We found no overall relationship between competition coefficients and the degree of segregation, contradicting the spatial segregation hypothesis for coexistence. However, segregation was linked to differences in plant traits: when targets were smaller than neighbours the degree of segregation increased with relative neighbour size. 5 Most species were positively associated with each other due to a shared preference for otherwise unvegetated patches. The degree of association was negatively correlated with differences in plant and seed size, particularly when interspecific competition was weak. This might reflect (i) decreasing overlap in microhabitat use with increasing trait divergence or (ii) density-dependent mortality. 6 Seed size is a key trait within this group of species, determining both competitive and colonizing ability. The presence of such a competition/colonization trade-off undoubtedly stabilizes community dynamics although other mechanisms may also be at work.", "corpus_id": 86798143, "score": 0 }, { "doc_id": "44664190", "title": "Early season height differences as robust predictors of weed growth potential in maize: new avenues for adaptive management?", "abstract": "Summary Weed interference in annual cropping systems can be highly variable from year-to-year, as well as spatially heterogeneous. These factors have confounded efforts to develop simple methods for predicting competitive outcomes early in the growing season. A 2-year study was conducted with maize in competition with four annual weed species (Setaria faberi, Abutilon theophrasti, Chenopodium album and Amaranthus retroflexus) to: (i) characterise the relationship between early crop–weed height differences and weed growth potential, and (ii) assess threshold-type decision rules based on these relationships. Analysis of 742 weed individuals suggests that early season height disparities are robust predictors of season-long growth. For example, weeds £8 cm tall when maize canopy was 60 cm tall had a very low probability (c. 2%) of growing larger than 150 cm and this applied across weed species, relative emergence dates and spatial proximity to the maize row. In our dataset, weeds less than 150 cm tall were associated with low crop yield losses and weed fecundity. Precision management of weed individuals based on early season height differences may provide a reliable and practical basis for selective post-emergence weed control that is relevant to both yield loss and longer-term seedbank", "corpus_id": 44664190, "score": 0 }, { "doc_id": "83800744", "title": "Differential response to competition in weedy biotypes of proso millet", "abstract": "Five weedy biotypes of proso millet (Panicum miliaceum L.) were grown under conditions of both intra- and inter-biotype competition. These biotypes represent the range of weediness from crop-like, large, white-seeded types with dense, drooping panicles to the most weed-like strain, which produces small, dormant, black seeds and has open, shattering panicles. Under noncompetitive conditions, the five biotypes of proso millet (WHITE, GOLDEN, ORANGE, CROWN and BLACK) differ strikingly in plant size, fresh weight distribution patterns, flowering time, and seed size. All biotypes showed decreased biomass per plant and delayed flowering time with increasing density when grown in monoculture. Variation in total biomass among individuals in each biotype was reduced at increasing densities resulting in positively skewed frequency distributions. The crop-like biotypes (WHITE and GOLDEN) demonstrated the greatest intrabiotype competitive effects, i.e., were the least tolerant of increased density in monoculture show...", "corpus_id": 83800744, "score": 0 }, { "doc_id": "86618707", "title": "Life-history variation in the annual arable weed Diplotaxis erucoides (Cruciferae)", "abstract": "Variation in life-history traits such as emergence, survival, time of flowering, and fecundity were studied in Diplotaxis erucoides, a mediterranean winter annual weed, by analyzing cohorts that emerged in autumn, early spring, and spring. The response of the plants to the environment, as reflected by plant architecture and pattern of biomass allocation, was also studied. Seedlings that germinate in autumn produced from 3 to 10 times more seeds than those that germinated in spring. The main factor affecting the number of seeds produced appears to be the life-span. Reduction of the growing period led to a decrease in both number and length of modular units, which resulted in decreased numbers of leaves, flowers, and fruits of each module. In semelparous D. erucoides plants, differences in the pattern of biomass allocation to reproduction are related to plant size. Our field data indicate that an increase of reproductive effort with size occurs in small individuals; however, a decrease occurs for vegetative...", "corpus_id": 86618707, "score": 0 }, { "doc_id": "85646317", "title": "Morphological analysis of herbaceous communities under different grazing regimes", "abstract": "A methodology for the morphological analysis of herbaceous communities is presented, together with an exam- ple of its application in montane grasslands in the province of C6rdoba (Argentina) subject to grazing and burning. The method, based on multivariate ordination and classifi- cation techniques, enabled the detection of morphological changes at three levels in response to disturbance: (a) charac- terization of the spatial structure of the vegetation; (b) identi- fication of morphological plant groups; and (c) quantification of morphological shifts among different individuals of a single species. The architecture of the vegetation changed toward a pro- gressive miniaturization of photosynthetic structures and con- centration of biomass close to the ground, as disturbance intensity increased. Six morphological plant groups (modes of response) showing different behaviour in relation to competi- tion for light and pressure from large herbivores were identi- fied. Some species, highly preferred by ungulate grazers, showed high morphological variability among morphs grow- ing in different grazing situations, whereas some others were morphologically uniform.", "corpus_id": 85646317, "score": 0 }, { "doc_id": "86067511", "title": "Quantifying trait selection driving community assembly: a test in herbaceous plant communities under contrasted land use regimes", "abstract": "Plant traits are particularly important in determining plant community structure. However, how can one identify which traits are the most important in driving community assembly? Here we propose a method 1) to quantify the direction and strength of trait selection during community assembly and 2) to obtain parsimonious lists of traits that can predict species relative abundances in plant communities. We tested our method using floristic data from 32 plots experiencing different treatments (fertilisation and grazing) in southern France. Twelve functional traits were measured on 68 species. We determined the direction and strength of selection on these 12 traits using a metric derived from a maximum entropy model (i.e. lambda). We then determined our parsimonious list of traits using a backward selection of traits based on these lambda values (for all treatments and in each treatment separately). We finally compared our method to two other methods: one based on iterative RLQ and the other based on an entropy-based forward selection of traits. We found major differences in the direction and strength of selection across the 12 traits and treatments. From the 12 traits, plant vegetative and reproductive heights, leaf dry matter content leaf nitrogen content, specific leaf area, and leaf phosphorus content were particularly important for predicting species relative abundances when considering all treatments together. Our method yielded results similar to those produced by the entropy-based approach but differed from those produced by the iterative RLQ, whose selected traits could not significantly predict species relative abundances. Together these results suggest that the assembly of these communities is primarily driven by a small number of key functional traits. We argue that our method provides an objective way of determining a parsimonious list of traits that together accurately predict community structure and which, despite its complementarities with entropy-based method, offers significant advantages.", "corpus_id": 86067511, "score": 0 }, { "doc_id": "84785610", "title": "Seed mass and the competition/colonization trade-off: a sowing experiment", "abstract": "Summary \n \n1  A seed-addition experiment using seven co-occurring annual plant species with a range of seed masses was carried out in a limestone grassland in South Wales. \n \n \n \n2  If seedlings compete for establishment sites, then large seed size may confer enhanced competitive ability. However, the simple reciprocal relationship found between seed mass and per capita seed output showed that species producing larger seeds suffer reduced fecundity. Seed size may therefore act as a surrogate in a competition/colonization trade-off. \n \n \n \n3  Equal numbers of seeds of all species were sown in a mixture over a range of densities. As sowing density increases, all species should reach a higher proportion of the available microsites. If large-seeded species are the best competitors they are expected to win all the sites they reach, and hence to occupy an increasing proportion of sites as sowing density increases. \n \n \n \n4  The three species with the largest seeds made up 49% of individuals at low-density sown plots but 83% of individuals in high-density sown plots. In addition, seed mass and plant density were not correlated in unsown plots, but were strongly correlated in high-density sown plots. However, all small-seeded species maintained a presence in sown plots. \n \n \n \n5  Although species were sown at random with respect to one another, individuals were up to five times more likely than expected to have a conspecific as a nearest neighbour. This could be caused by interspecific competition and/or by environmental heterogeneity that favours different species in different patches. \n \n \n \n6  The results suggest that seedlings do compete for establishment sites and that large-seeded species generally win when in direct competition. In unsown areas small-seeded species win many sites by forfeit (because large-seeded species are strongly recruitment limited) but there may be a restricted subset of potential sites for which they are the best competitors and which they can win outright.", "corpus_id": 84785610, "score": 0 }, { "doc_id": "59385694", "title": "Seedling survival and seed size: a synthesis of the literature", "abstract": "Summary \n1Large-seeded species have long been known to have higher survivorship during establishment than small-seeded species. Here, we assessed the size of this advantage by compiling published data on survival through seedling emergence, seedling establishment and sapling establishment. \n2We found no relationship between seed mass and survival through the transition from viable seed in or on the soil to newly emerged seedlings (P = 0.47, n = 33 species). \n3Synthesis of data from experimental studies on the advantages of large-seeded species establishing under particular hazards (such as shade, drought or herbivory) confirmed that seedlings of large-seeded species perform better than those of small-seeded species in most situations. However, the magnitude of this advantage was not sufficient to counterbalance the greater number of seeds produced by small-seeded species m−2 of canopy outline year−1. \n4Synthesis of data from field studies of populations under natural conditions also showed that large-seeded species have higher survival through early seedling establishment than small-seeded species (P = 0.006, n = 112 species). However, the magnitude of this advantage would only be sufficient to counterbalance the greater number of seeds produced by small-seeded species m−2 of canopy outline year−1 if mortality continued at the same rate for some time. \n5The time required for a species with 10-fold larger seeds to recoup the advantage gained by a smaller-seeded species during seed production ranged from 8.8 weeks for the smallest seeded species in the data set, up to an implausible 4.2 years for the largest-seeded species. Thus, while large-seeded species do have a survival advantage over small-seeded species during seedling establishment, the available evidence suggests that advantages must also accrue during other stages in the life cycle. One possibility is that the greater seed production of small-seeded species (m−2 of canopy outline year−1) is partly offset by larger canopies and longer reproductive life spans in large-seeded species.", "corpus_id": 59385694, "score": 0 }, { "doc_id": "83665203", "title": "Which model species for weed seedbank and emergence studies? A review", "abstract": "Gardarin A, Durr C & Colbach N (2009). Which model species for weed seedbank and emergence studies? A review. Weed Research49, 117–130. \n \n \n \nSummary \n \nModels predicting the effects of cropping systems on weed demography are important tools for testing new rules for integrated weed management that may reduce the use of herbicides and preserve the biodiversity of agro-ecosystems. Such models already exist for a few species and should now be extended to a larger flora, in order to predict and understand the effects of agricultural practices on the evolution of weed communities. This review analysed the literature from 1973 to 2006, focusing on 45 species, to identify past reasons for choosing particular species when modelling the effects of cropping systems on the processes leading to seedling emergence. The frequency or harmfulness of the species were the main reason for studying them. It appears that the studied species were mainly autumn-emerging in north-western Europe cropping systems and summer-emerging in North America; the effects of deep soil tillage were studied mainly in Europe, as simplified sowing techniques are more often practised in North America. A voluminous literature exists on seed persistence in the soil, dormancy, germination and emergence, but rarely with the attempt of establishing generic relationships between species characteristics and model parameters. Until now, such an approach has been mostly developed in ecological studies. Taxa, as well as ecological preferences, seed size and the relationships of these characteristics with weed emergence model parameters should be considered when selecting a range of species for multi-specific modelling purposes.", "corpus_id": 83665203, "score": 0 }, { "doc_id": "87033937", "title": "Game-Theoretical Evolution of Seed Mass in Multi-Species Ecological Models", "abstract": "Within plant communities seed mass often varies over 3 to 5 orders of magnitude, yet simple evolutionary models predict a single optimum seed mass. Here we explore a class of models where seed mass determines 1) the number of seeds produced via a size-number trade-off and 2) competitive ability - plants arising from large seeds are assumed to have a competitive advantage over those derived from small seeds. In this setting the existence of a single-species global ESS seed mass requires the competitive advantage of large seeds over small ones to be unbounded. If there is a limit on the competitive advantage that large seeds obtain then it is always possible to find a smaller seed mass that will successfully invade. In such circumstances there might be a multi-species coevolutionarily stable coalition of several species each with a different seed mass. In this way a wide range of seed masses could be promoted by evolution. In general the adaptive landscape generated by these models is extremely flat leading to slow evolutionary dynamics. The implications of these results for the interpretation of observational, comparative and experimental studies are discussed.", "corpus_id": 87033937, "score": 0 }, { "doc_id": "86231889", "title": "Seed size, shape and vertical distribution in the soil: indicators of seed longevity", "abstract": "1. We investigated the vertical distribution of seeds in the soil, using data from nine studies in five European countries. We discovered significant correlations between seed shape and distributio ...", "corpus_id": 86231889, "score": 0 }, { "doc_id": "85891847", "title": "Seed mortality in the soil is related to seed coat thickness", "abstract": "Abstract Models that quantify the effects of cropping systems on weed dynamics are useful tools for testing innovative cropping systems. In these models, seed mortality in the soil is a key parameter to account for the cumulated effect of cropping systems over time via the soil seed-bank. Since seed mortality is difficult to measure, our objective was to develop a method to estimate it from easily accessible information. Seeds of 13 weed species were buried 30 cm deep in fields and were recovered regularly for 2 years to measure their viability. Seed mass, dimensions, shape, and protein and lipid contents as well as coat thickness were measured. To estimate seed mortality of species not included in the study, we searched for relationships between mortality rates and seed traits. Seed viability mainly decreased during the second year of burial, with mortality rates ranging from 0.01 to 0.63 seeds·seeds− 1·year− 1, depending on the species. Seed mortality decreased with increasing seed coat thickness. No correlation was found with other measured traits or with seed persistence data in the literature. These results were confirmed when the effects of phylogenetic relatedness with phylogenetically independent contrasts were included. The thickness of the seed coat, which varied between 17 and 231 μm over the range of species studied, can protect the seed from external attacks in the soil and slow down seed decay. This trait can be easily measured via X-ray images and could be used to estimate the seed mortality rate for a wider range of species.", "corpus_id": 85891847, "score": 0 }, { "doc_id": "88645901", "title": "Seeds Ecology Biogeography And Evolution Of Dormancy And Germination", "abstract": "Thank you very much for downloading seeds ecology biogeography and evolution of dormancy and germination. As you may know, people have look hundreds times for their favorite novels like this seeds ecology biogeography and evolution of dormancy and germination, but end up in malicious downloads. Rather than reading a good book with a cup of tea in the afternoon, instead they cope with some harmful bugs inside their desktop computer.", "corpus_id": 88645901, "score": 0 }, { "doc_id": "11980169", "title": "Hydrophobic trichome layers and epicuticular wax powders in Bromeliaceae.", "abstract": "The distinctive foliar trichome of Bromeliaceae has promoted the evolution of an epiphytic habit in certain taxa by allowing the shoot to assume a significant role in the uptake of water and mineral nutrients. Despite the profound ecophysiological and taxonomic importance of this epidermal structure, the functions of nonabsorbent trichomes in remaining Bromeliaceae are not fully understood. The hypothesis that light reflection from these trichome layers provides photoprotection was not supported by spectroradiometry and fluorimetry in the present study; the mean reflectance of visible light from trichome layers did not exceed 6.4% on the adaxial surfaces of species representing a range of ecophysiological types nor was significant photoprotection provided by their presence. Several reports suggesting water repellency in some terrestrial Bromeliaceae were investigated. Scanning electron microscopy (SEM) and a new technique-fluorographic dimensional imaging (FDI)-were used to assess the interaction between aqueous droplets and the leaf surfaces of 86 species from 25 genera. In the majority of cases a dense layer of overlapping, stellate or peltate trichomes held water off the leaf epidermis proper. In the case of hydrophobic tank-forming tillandsioideae, a powdery epicuticular wax layer provided water repellency. The irregular architecture of these indumenta resulted in relatively little contact with water droplets. Most mesic terrestrial Pitcairnioideae examined either possessed glabrous leaf blades or hydrophobic layers of confluent trichomes on the abaxial surface. Thus, the present study indicates that an important ancestral function of the foliar trichome in Bromeliaceae was water repellency. The ecophysiological consequences of hydrophobia are discussed.", "corpus_id": 11980169, "score": 0 }, { "doc_id": "83656452", "title": "Herbicide deposition on leaf surfaces.", "abstract": "Leaf surface morphology and physical characteristics of herbicide deposits on leaf surfaces can influence herbicide performance. Leaf surface topography, the degree and type of epicuticular wax formation, and the presence, type, and distribution of trichomes all influence the distribution of a given herbicide formulation sprayed onto a leaf surface. Depressions above anticlinal cell walls accumulate herbicide, thus lessening uniform distribution. As the amount of particulate wax increases, the size of individual spray drop deposits on the leaf decreases, thus resulting in reduced coverage. In many instances the presence of trichomes reduces optimal epidermal coverage by intercepting spray drops before they reach the epidermal surface. Adjuvants reduce the adverse influence of leaf topography, epicuticular wax, and trichomes on herbicide distribution, but their use usually does not yield an even coating over the entire leaf surface. Many herbicides, in pure form, are solids (i.e., crystals) rather than liquids. For most applications, herbicides are dissolved, dispersed, or emulsified in a water-based spray solution. After spraying, water and any solvents evaporate from the leaf surface and herbicides often return to their solid crystalline form. In the few cases that have been studied, less herbicide is absorbed when present on the leaf surface as a solid rather than as a liquid. In many instances, greater effectiveness of a postemergence herbicide may be obtained if attention is given to optimizing the distribution and physical form on sprayed leaf surfaces.", "corpus_id": 83656452, "score": 0 }, { "doc_id": "666134", "title": "Managing arable weeds for biodiversity.", "abstract": "As a result of the recent intensification of crop production, the abundance and diversity of UK arable weeds adapted to cultivated land have declined, with an associated reduction in farmland birds. A number of questions need to be addressed when considering how these declines can be reversed. Firstly, can the delivery of crop production and biodiversity be reconciled by spatially separating cropping from designated wildlife areas? A number of subsidised environmental schemes in the UK take this approach and are focused on establishing vegetation cover on uncropped land. However, because of the lack of regular disturbance in these habitats, they are dominated by perennials and they therefore have limited potential for promoting the recovery of annual weed populations. A number of farmland bird species also rely on the provision of resources in field centres, and it is therefore likely that the recovery of their populations will rely on weed management options targeted at the cropped areas of the field. This raises two further questions. Firstly, is it possible to identify beneficial weed species that are relatively poor competitors with the crop and also have biodiversity value? Secondly, are the tools available to manage these species at acceptable levels while controlling pernicious weeds? A number of approaches are being employed to answer these questions, including predicting yield loss from weed competition models and exploiting herbicide selectivity. The further development of these tools is crucial if farmer opposition to managing weeds in crops is to be overcome.", "corpus_id": 666134, "score": 0 }, { "doc_id": "30906161", "title": "Towards an assessment of multiple ecosystem processes and services via functional traits", "abstract": "Managing ecosystems to ensure the provision of multiple ecosystem services is a key challenge for applied ecology. Functional traits are receiving increasing attention as the main ecological attributes by which different organisms and biological communities influence ecosystem services through their effects on underlying ecosystem processes. Here we synthesize concepts and empirical evidence on linkages between functional traits and ecosystem services across different trophic levels. Most of the 247 studies reviewed considered plants and soil invertebrates, but quantitative trait–service associations have been documented for a range of organisms and ecosystems, illustrating the wide applicability of the trait approach. Within each trophic level, specific processes are affected by a combination of traits while particular key traits are simultaneously involved in the control of multiple processes. These multiple associations between traits and ecosystem processes can help to identify predictable trait–service clusters that depend on several trophic levels, such as clusters of traits of plants and soil organisms that underlie nutrient cycling, herbivory, and fodder and fibre production. We propose that the assessment of trait–service clusters will represent a crucial step in ecosystem service monitoring and in balancing the delivery of multiple, and sometimes conflicting, services in ecosystem management.", "corpus_id": 30906161, "score": 0 }, { "doc_id": "6410974", "title": "The strength of seeds and their destruction by granivorous insects", "abstract": "The influence of seed structure and strength on their destruction by granivores is central to understanding the dynamics of granivore-plant interactions. For up to nine seed species, the effects of seed size (cm3), mass (mg), density (mg/cm3) and coat strength (MPa) on the damage inflicted by three post-dispersal granivores (Harpalus pensylvanicus, Anisodactylus sanctaecrucis, and Gryllus pennsylvanicus) were evaluated. Seed destruction rates by G. pennsylvanicus were statistically unrelated to the size and toughness of the seeds. Seed densities significantly affected their destruction by A. sanctaecrucis and H. pensylvanicus, as did seed size, mass, and strength in H. pensylvanicus under choice conditions. The carabid beetles destroyed more of the small, denser seeds with stronger seed coats. The results show that different granivores are able to distinguish the structural strength and physical density of seeds as well as seed size. The relative ability of granivores to detect these seed characteristics offers a way in which diverse communities of post-dispersal insect granivores can persist within a single habitat. The authors redefine how the strength of biological structures should be evaluated in ecological studies, using guidelines commonplace in the field of engineering.", "corpus_id": 6410974, "score": 0 } ]

{ "doc_id": "4008107", "title": "Retrospective study of freestyle perforator-based peninsular flaps", "abstract": "Abstract This study aimed to present a simple, fast, and safe technique, called freestyle perforator-based peninsular flap (FPBPF), for pressure sore reconstruction. Among the 21 patients who underwent pressure sore reconstruction between May 2013 and October 2016, 12 patients (Group A) and 9 patients (Group B) were subjected to perforator-based island flap (PBIF) and FPBPF, respectively. We retrospectively reviewed and statistically analyzed the data of both groups. All flaps completely survived in both groups. No significant differences were found in patient demographics, complications, hospital stay, and follow-up period. The mean arc of rotation (102.50 ± 17.645° vs 83.33 ± 14.142°; P = .01), mean flap harvest time (35.83 ± 2.552 minutes vs 20.88 ± 1.763 minutes; P < .001), and mean operative time (145.41 ± 6.788 minutes vs 131.66 ± 10.770 minutes; P = .002) were significantly decreased in Group B compared with Group A. The FPBPF is a simpler and faster technique than the PBIF. FPBPF is a good modality with a few complications for sore reconstruction.", "corpus_id": 4008107 }

[ { "doc_id": "5724360", "title": "Gluteal perforator flaps for coverage of pressure sores at various locations.", "abstract": "Management of pressure sores is one of the most formidable challenges confronting the reconstructive plastic surgeon. Traditionally, muscle and musculocutaneous flaps were used for the treatment of pressure sores. However, this clinical approach of using the “pressure dispersing” effects of muscle appears to conflict with certain experimental observations. In the 1960s, Kosiak1 and Keane2 demonstrated that muscle is more susceptible to the effects of pressure than either skin or subcutaneous tissue. Keane2 demonstrated that body weight is borne on superficial bony prominences covered only by skin and subcutaneous tissue, thus protecting muscle from the effects of ischemia. In normal weight-bearing positions over bony prominences, muscle is rarely interposed between bone and skin. When muscle and musculocutaneous flaps are used, the use of adjacent flaps is often obviated because of violation of vascular territories. Furthermore, muscle, and its function are sacrificed, which is especially important in ambulatory patients. In the late 1980s, Kroll and Rosenfield3 introduced the concept of perforator flaps. Perforator flaps, supplied by musculocutaneous perforators, obviate the need for muscle or musculocutaneous flaps, thus minimizing donor-site morbidity. These flaps have gained popularity during the past decade with their current application to pressure sore management by the authors. The rationale for the use of fasciocutaneous perforator flaps can be found in some of the earlier literature on flap physiology.1,2 Fasciocutaneous perforator flaps are durable, safe, and reliable; can be elevated in various locations; permit freedom in flap design; and are associated with low donor-site morbidity. The donor site can often be closed directly. Coşkunfırat and Özgentaş are to be congratulated for their impressive experience with 35 gluteal perforator flaps for coverage of 22 sacral, seven ischial, and six trochanteric pressure sores in 32 patients including 18 who were plegic and five who were bedridden. The authors report an excellent survival rate, with only one flap loss, two wound dehiscences treated by secondary closure, and only one recurrence during the 13.6-month follow-up period. These results are quite remarkable because the factors contributing to recurrence following surgery are often beyond the surgeon’s control. Soft-tissue integrity ultimately depends on the patient’s ability to restore blood flow following ischemia and the avoidance of prolonged pressure. Malnutrition, anemia, concomitant medical problems, shear forces, spasm, infection, and patient compliance are the major variables in the equation. Perhaps the most frustrating aspect of pressure sore management is the high incidence of recurrence, which tremendously increases medical costs and patient morbidity. The authors’ results are outstanding, especially when one considers their exceptionally low incidence of recurrence. Although the follow-up period is short, the recurrence rate is nevertheless the lowest of which I am aware for a similar series. In 1956, Conway and Griffith4 reported on 1000 ischial pressure sore patients, consisting predominantly of plegic and bed-dependent patients. Regardless of the type of treatment (surgical or nonsurgical), recurrence rates were 75 to 77 percent. In 1992, Disa et al.5 reported a 61 percent recurrence rate after", "corpus_id": 5724360, "score": 0 }, { "doc_id": "23462781", "title": "The Pacman Perforator-Based V-Y Advancement Flap for Reconstruction of Pressure Sores at Different Locations", "abstract": "BackgroundMany procedures have been proposed for the treatment of pressure sores, and V-Y advancement flaps are widely used to repair a defect. Unfortunately, the degree of mobility of a V-Y advancement flap is dependent on the laxity of the underlying subcutaneous tissue. This is an important disadvantage of traditional V-Y advancement flap and limits its use.We used V-Y advancement flaps as perforator-based to overcome mobility restriction problem, with a further modification (Pacman-like shape) to improve the covering surface area of the flap. MethodsBetween January 2012 and December 2014, the authors used 37 V-Y Pacman perforator-based flaps in 33 consecutive patients for coverage of defects located at sacral (n = 21), ischial (n = 13), trochanter (n = 1) regions. There were 27 male and 6 female patients with a mean age of 49.9 years (range, 15–74 years). ResultsAll flaps survived completely (92.3%) except 3 in which one of them had undergone total necrosis due to hematoma and the other 2 had partial necrosis. No venous congestion was observed. The mean follow-up period was 14.9 months (range, 2–38 months). No flap surgery-related mortality or recurrence of pressure sores was noted. ConclusionsThe V-Y Pacman perforator-based advancement flaps are safe and very effective for reconstruction of pressure sores at various regions. The advantage of our modification procedure include shorter operative time, lesser pedicle dissection, low donor site morbidity, good preservation of muscle, and offers remarkable excursion to the V-Y flap, which make the V-Y Pacman perforator-based flaps an excellent choice for large pressure sore coverage.", "corpus_id": 23462781, "score": 0 }, { "doc_id": "41950222", "title": "The gluteal perforator-based flap for repair of sacral pressure sores.", "abstract": "A gluteal perforator-based flap employing the gluteus maximus muscle perforators located around the sacrum is described. A cadaveric study disclosed the existence of several significant perforators all around the gluteal region. Among these, the parasacral perforators originating from the internal pudendal artery and lateral sacral artery have proven useful for the repair of sacral pressure sores. A total of eight decubitus in seven patients were treated with gluteal perforator-based flaps. There were no postoperative complications, such as flap necrosis and wound infection, with the exception of fistula formation in one case. This flap requires no transection or sacrifice of the gluteus maximus muscle, and elevation time for the flap is short. However, the perforators are located at various sites and thus require some careful dissection.", "corpus_id": 41950222, "score": 0 }, { "doc_id": "7683757", "title": "Modified lumbar artery perforator flaps for gluteal pressure sore reconstruction", "abstract": "Gluteal perforator flaps (GPFs) are the most useful for gluteal region pressure sore reconstruction. However, application is difficult if the surrounding area has scar tissue from previous operations or trauma, especially with recurrent sores. We describe the use of modified lumbar artery perforator flaps when GPFs cannot be used.", "corpus_id": 7683757, "score": 0 }, { "doc_id": "2386858", "title": "Perineal Perforator–Based Island Flaps: The Next Frontier in Perineal Reconstruction", "abstract": "Background: Perineal reconstruction is a challenging prospect. Conventional flap reconstruction often involves the sacrifice of a source artery and muscle, resulting in significant donor morbidity. Perforator flaps sought to overcome this but required tedious dissection. In this article, the authors introduce a new concept in perineal reconstruction using perforator-based island flaps. Methods: The perineal perforator-based island flap is raised based on perforators that most commonly arise from the perineal artery. The flap is designed in the inguinal and gluteal folds in order to achieve aesthetic, tension-free primary closure of the donor site. Eleven patients underwent perineal reconstruction using this approach. Patients ranged in age from 8 to 75 years, with a female-to-male ratio of 10:1. Results: All 11 operations were performed by a single surgeon (S.Y.M.H.). There were no cases of flap loss or donor-site complications, as defined by wound infection, dehiscence, or keloid formation. All 11 patients reported excellent satisfaction with regard to donor-site aesthetics. Conclusions: Perineal perforator-based island flaps represent one of the most successful outcomes of the perforator concept. There is no sacrifice of donor vessels or muscle and minimal donor morbidity. The flap is also easily harvested and allows for challenging free-form flap design because it is based on reliable perforators. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.", "corpus_id": 2386858, "score": 1 }, { "doc_id": "36888893", "title": "Perineal reconstruction using a bilobed pudendal artery perforator flap.", "abstract": "BACKGROUND\nTo reconstruct the perineal region, including the urogenital and anal triangle that differ from each other in tissue characteristics and function, we applied pudendal artery perforator flaps with a bilobed flap design. This bilobed flap design could improve the arc of flap rotation and the mobility of the flap so it could cover wide and deep defects. Moreover, it could preserve the characteristics of each triangle.\n\n\nMETHODS\nThis study enrolled a total of 15 female patients who had undergone perineal reconstruction with pudendal artery perforator flaps. Seven of them had vulva cancer, seven others had extramammary Paget's disease and the remaining one patient had rectovaginal fistula. We examined the location and shape of the defects, flap designs and their clinical courses.\n\n\nRESULTS\nAll flaps survived during the entire follow-up period. The flap sizes ranged from 3x4 to 13x12 cm, and the follow-up period was 4.6 months on average. Bilobed flaps were used in nine patients, and unilobed flaps were used in six patients. The reconstructed areas were in good functional and aesthetic conditions.\n\n\nCONCLUSION\nWe used a bilobed pudendal artery perforator flap according to the location and shape of defect areas in the perineal region. As a result, we could preserve the functional, morphological and cosmetic characteristics of the defect areas.", "corpus_id": 36888893, "score": 0 }, { "doc_id": "5096170", "title": "Perineal reconstruction with multiple perforator flaps based on anatomical divisions", "abstract": "Reconstruction of perineal defects remains a challenge because such defects can be extensive, complex, and three‐dimensional. This report presents a retrospective review of our past 5 years of experience in perineal reconstruction, and suggests a simple algorithmic approach according to anatomical divisions with multiple pedicled perforator flaps for extensive perineal defects.", "corpus_id": 5096170, "score": 1 }, { "doc_id": "25322759", "title": "Perfecting the Design of the Gluteus Maximus Perforator–Based Island Flap for Coverage of Buttock Defects", "abstract": "Background: The new design of the gluteus maximus perforator–based island flap for coverage of gluteal defects has the distinct advantage of being able to use customizable tissue components for coverage and at the same time sparing the source vessel. This adds a further option for use in reconstruction. Methods: After excisional débridement of the lesion, a perforator adjacent to the defect is selected. The tissue of the donor region is pinched to simulate closure. The change in shape of the recipient defect is noted and the dimensions of this new shape are measured. This will serve as the new dimensions of the donor tissue. The tissue components required to fill the defect are then analyzed and the flap is raised. It can be either muscle-sparing, muscle-splitting, or muscle-inclusive. A 1- to 2-cm diameter of soft tissue around the perforator is preserved. The flap is islanded and transposed, and the donor site is closed primarily, acting as a “locking barrier” to the flap. Tension-free closure of the recipient flap is then carried out. Seventy-five patients underwent closure of varying defects of the gluteal region using this technique. Results: The authors had a total of three minor complications. The rest of the patients healed well, with no recurrence at a mean follow-up of 15 months. Conclusions: The flap design for coverage of gluteal defects has a great impact on recurrence and complications. This design is novel and the flap is simple to elevate. This is an ideal flap in any high-risk patient in whom the risk of recurrence is high.", "corpus_id": 25322759, "score": 1 }, { "doc_id": "41132203", "title": "An Improved Perforator–Based Island Flap: The Heart Balloon Flap", "abstract": "Background: Reconstructive surgery has entered a “perforator flap era” with more surgeons performing successful perforator flap procedures. The perforator-based island flap is an extension of this perforator concept and one of the most successful. In perforator-rich or -reliable areas, this allows for primary closure of the donor site and the construction of highly customized flaps with little tissue waste. Methods: The authors present a design modification of the perforator-based island flap used in 73 patients who underwent heart balloon perforator-based island flap reconstruction between 2008 and 2012. Results: There were no reported cases of total flap necrosis. Marginal necrosis of the flap was noted in three cases, which resolved with simple dressings. The donor sites were closed primarily in all cases. Conclusions: The heart balloon perforator-based island flap enables tension-free closure of the donor site, reduces donor-site complications, and minimizes tissue waste. The resulting shape resembles a heart and gives rise to the flap’s name. Key principles for success are perforators close to the defect, a flap axis that allows for primary donor-site closure, flap border adjacent to the defect that is smaller than the postresection defect, flap harvest until an adequate arc of rotation is obtained, primary closure of the donor site before flap inset, and preservation of a triangular area between the proximal apex of the flap and the defect. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.", "corpus_id": 41132203, "score": 1 }, { "doc_id": "1143005", "title": "Freestyle Pedicle Perforator Flaps: Clinical Results and Vascular Anatomy", "abstract": "Background: Perforator flaps have increased in use, with advantages such as sparing of the underlying muscle with resultant decreased donor-site morbidity and the possibility of improving aesthetic outcome. Theoretically, a flap can be based on any perforator, whether free or pedicled, based on the perforasome theory. In this study, the principle of free-style perforator flaps was used to harvest pedicled flaps. Methods: The authors report the cumulative experience with freestyle perforator flaps of two medical centers (Hôpital Maisonneuve-Rosemont and University of Texas Southwestern Medical Center). Fifty-three pedicled perforator flaps were performed on 49 patients for local reconstruction of a range of defects at various anatomical locations: head and neck (n = 3), anterior trunk (n = 13), posterior trunk (n = 9), perineal/gluteal (n = 4), lower limb (n = 20), and upper limb (n = 4). Results: Complete flap survival was obtained in 48 of 53 flaps. Complications included three cases of partial flap necrosis and two total flap failures, the latter in high-risk patients. Complete primary closure of the donor site was possible in 37 cases, especially in the trunk. Twelve patients had partial primary closure complemented by skin grafting, three cases required complete skin grafting, and one donor site required another local flap for closure. Five clinical examples are given—anterior trunk, posterior trunk, cervical region, lower limb, and upper limb. Conclusions: This is a large series on clinical applications of the freestyle pedicled perforator flap. Because of its many advantages and its versatility, the authors believe it will find its place as a valued reconstructive option and, when indicated, a simpler alternative to free flaps.", "corpus_id": 1143005, "score": 0 }, { "doc_id": "52871031", "title": "Modification of the superior gluteal artery perforator flap for reconstruction of sacral sores.", "abstract": "BACKGROUND\nDespite advances in reconstruction techniques, the treatment of sacral sores remains challenging to plastic surgeons. The superior gluteal artery perforator (SGAP) flap is reliable and preserves the entire contralateral side as a future donor site. The ipsilateral gluteal muscle is preserved, and the inferior gluteal artery flaps are viable. However, dissection of the perforator is tedious and may compromise the perforator vessels.\n\n\nMETHODS\nBetween April 2003 and March 2013, we performed two modified flap-harvesting techniques: a rotational and a tunnel method, with only a short pedicle dissection to cover 30 sacral defects. Patient characteristics including sex, age, cause of sacral defect, flap size, perforator number, use and postoperative complications were recorded.\n\n\nRESULTS\nAll flaps survived except two, which developed partial flap necrosis and were finally treated by contralateral V-Y advancement flap coverage. The mean follow-up period was 14.8 months (range, 3-24 months). No flap surgery-related mortality or recurrence of sacral pressure sores or infected pilonidal cysts were noted.\n\n\nCONCLUSIONS\nPerforator-based flaps have become popular in modern reconstructive surgery because of low donor-site morbidity and good preservation of muscle. The advantages of our modification procedure include shorter operative time, lesser bleeding and lesser pedicle trauma, which make the SGAP flaps an excellent choice for sacral sore coverage.", "corpus_id": 52871031, "score": 0 }, { "doc_id": "46642214", "title": "Free-Style Free Flaps", "abstract": "Free-tissue transfer has become the accepted standard for reconstruction of complex defects. With the growth of this field, anatomic studies and clinical work have added many flaps to the armamentarium of the microvascular surgeon. Further advancements and experience with techniques of perforator flap surgery have allowed for the harvest of flaps in a free-style manner, where a flap is harvested based only on the preoperative knowledge of Doppler signals present in a specific region. Between June of 2002 and September of 2003, 13 free-style free flaps were harvested from the region of the thigh. All patients presented with an oral or pharyngeal cancer and underwent resection and immediate reconstruction of these flaps. All flaps were cutaneous and were harvested in a suprafascial plane. The average size of the flaps was 108 cm2 (range, 36 to 187 cm2), and the average length of the vascular pedicle was 10 cm (range, 9 to 12 cm). All flaps were successful in achieving wound coverage and functional outcomes without any vascular compromise necessitating re-exploration. Free-style free flaps have become a clinical reality. The concepts and techniques used to harvest a free-style free flap will aid in dealing with anatomic variations that are encountered during conventional flap harvest. Future trends in flap selection will focus mainly on choosing tissue with appropriate texture, thickness, and pliability to match requirements at the recipient site while minimizing donor-site morbidity.", "corpus_id": 46642214, "score": 0 }, { "doc_id": "21833460", "title": "Reverse Sural Artery Island Flap With Skin Extension Along the Pedicle.", "abstract": "The distally based sural flap is an efficient flap for reconstruction of soft tissues defects of lower limb. The unstable vascular pedicle, however, is prone to compression by the subcutaneous tunnel, especially when a long pedicle covers the distal area of the foot. The aim of the present study was to introduce a modified surgical technique that leaves the skin extension over the pedicle and to report the clinical results of this modification. A total of 25 consecutive patients with a mean age of 51.7 ± 14.7 years underwent surgery. We modified the conventional sural flap technique by leaving a skin extension over the entire length of the pedicle, creating a fasciocutaneous vascular pedicle. The postoperative flap survival rates, complications, and the characteristics of the flaps such as flap size, pedicle length, and the most distal area that could be covered with this modification, were reviewed. At the last clinical follow-up examination, all the flaps survived, although partial necrosis was observed in 2 (8%) cases. Four cases of venous congestion developed but healed without additional complications. The mean flap size was 5.9 ± 1.8 × 9.2 ± 2.7 cm. With this modification, the sural flap could cover the defect located in extreme distal areas, such as the medial forefoot and dorsum of the first metatarsophalangeal joint, with a longer pedicle (≤27 cm) in 7 patients (28%). A skin extension along the pedicle achieved the favorable survival rate of the sural flap and successfully extended the surgical indications to more distal areas.", "corpus_id": 21833460, "score": 0 }, { "doc_id": "23728308", "title": "Safe dissection of the distally based anterolateral thigh flap.", "abstract": "BACKGROUND\nThe distally based anterolateral thigh (ALT) flap is an interesting reconstructive solution for complex soft tissue defects of the knee. In spite of a low donor site morbidity and wide covering surface as well as arch of rotation, it has never gained popularity among reconstructive surgeons. Venous congestion and difficult flap dissection in the presence of a variable anatomy of the vascular pedicle are the possible reasons.\n\n\nMETHODS\nAn anatomical study of 15 cadaver legs was performed to further clarify the blood supply of the distally based ALT. Our early experience with the use of preoperative angiography and a safe flap design modification that avoids distal intramuscular skeletonization of the vascular pedicle and includes a subcutaneous strip ranging from the distal end of the flap to the pivot point is presented.\n\n\nRESULTS\nThe distally based ALT presents a constant and reliable retrograde vascular contribution from the superior genicular artery. Preoperative angiography reliably identified and avoided critical Shieh Type II pedicled flaps. The preservation of a subcutaneous strip ranging from the distal flap end to the upper knee was associated with the absence of venous congestion in a short case series.\n\n\nCONCLUSIONS\nPreoperative angiography and a flap design modification are proposed to allow the safe transfer of the distally based ALT to reconstruct soft tissue defects of the knee.", "corpus_id": 23728308, "score": 0 }, { "doc_id": "38155793", "title": "Increasing versatility of the distally based sural flap.", "abstract": "Repairing distal lower limb soft tissue defects remains challenging for reconstructive surgeons. Relatively few procedures have real efficiency and low morbidity. Since its initial description, the distally based sural flap has been used increasingly for this indication. However, controversy exists about the upper limit of the skin paddle of the sural flap. In the present series, 11 patients underwent surgery with distally based sural flaps. In 6 patients, the flap skin paddle was partially or totally placed beyond this controversial limit on the proximal calf region. To increase the skin irrigation of this region, whole mesenteric tissue under the deep fascia of the leg was included in the flap. Venous congestion and distal tip necrosis can impair the success of flap surgery. To overcome these problems, the flap pedicle was not passed through the subcutaneous tunnel. All flaps survived completely, and no cases of venous congestion developed. Thus, extending the donor area to the upper part of the leg is a reliable maneuver to repair more distal defects of the leg and foot, and abstaining from passing the pedicle through a subcutaneous tunnel could contribute to a decreased risk of venous congestion.", "corpus_id": 38155793, "score": 0 }, { "doc_id": "2025038", "title": "Free-style local perforator flaps: concept and classification system.", "abstract": "BACKGROUND\nDefect reconstruction according to the free-style concept applied to perforator flaps allows flap harvesting in any anatomical region where an audible Doppler signal of a perforator is detected. We report the results of a study in which local perforator flaps were selected for reconstruction in different anatomical areas and were harvested using the free-style concept.\n\n\nMETHODS\nDuring a 2-year period, defect coverage was carried out in 21 patients (n=21) in the following anatomical areas: cervical (n=3), sternal/parasternal (n=4), axillary (n=2), tibial (n=5), trochanteric (n=2) and sacral/gluteal (n=5). The mean age of patients (15 male and six female) was 57.8 years. Flap selection was based solely on preoperative Doppler mapping in areas adjacent to soft-tissue defects. The mean follow-up period was 1 year.\n\n\nRESULTS\nAll flaps survived, demonstrating postoperatively acceptable aesthetic results with good patient satisfaction. The donor sites were closed primarily in 17 patients; four patients required skin grafting. Two patients required surgical revision due to flap-margin dehiscence. There was no loss of function at donor sites. Increased flap mobility could be achieved through extended perforator dissection. One perforator-based flaps offered the widest arc of rotation serving as propeller flaps. If more than one perforator vessel was preserved, flap mobility was limited, but still allowed sufficient flap movement either as a rotation or advancement flap or as a combination of both. A classification is proposed according to the number of perforator vessels preserved and to the type of flap movement.\n\n\nCONCLUSIONS\nThe concept of free-style local perforator flaps represents a safe, versatile and reliable surgical procedure. It not only offers a greater freedom in flap selection but also provides good aesthetic results. The classification proposed might aid in the decision-making process involved in order to achieve adequate results with this procedure.", "corpus_id": 2025038, "score": 0 }, { "doc_id": "316654", "title": "The Effect of Twisting on Perforator Flap Viability: An Experimental Study in Rats", "abstract": "Perforator flaps increasingly find acceptance and use in the field of reconstructive surgery due to their decreased donor-site morbidity and increased like-tissue coverage. Nevertheless, they are more prone to vascular compromise, especially when the meticulous technique they require is not employed. Pedicle twisting is a condition occasionally encountered in flap procedures, sometimes inadvertently, sometimes inevitably. In this study, circulatory comprise induced by twisting of the pedicle on a true perforator flap in a rat model is investigated. Thirty-eight Wistar-Albino rats were randomized into 4 groups, and cranial epigastric artery true perforator flaps were elevated on a single perforator. The flaps were returned as they were in the control group (n = 9), and with 90°, 180°, and 270° of torsion in groups 2 (n = 9), 3 (n = 10), and 4 (n = 10), respectively. The flaps were evaluated by their flap survival area, weight, and histopathological appearance by the end of the first week. The mean flap survival ratios for groups 1, 2, 3, and 4 were 97.78 ± 4.41%, 72.22 ± 44.10%, 73.50 ± 30.46%, and 30 ± 30.18% (mean ± SD), respectively. The degree of degenerative changes in group 4 was found to be statistically significant (P < 0.016). Our histopathological examinations indicate that vascular compromise was moderate in group 3 and severe in group 4. Our findings suggest that under normal conditions, the pedicle of a true perforator flap must not be twisted more than 180°.", "corpus_id": 316654, "score": 0 }, { "doc_id": "28162960", "title": "Risk Factor Analysis of Freestyle Propeller Flaps", "abstract": "Background Freestyle propeller flaps have been widely used as a reconstructive option for both trunk and extremities. It offers the advantage of “like‐with‐like” reconstruction with an adjacent tissue with no dissection to the source vessels. However, there is the risk of vascular complications. In the present study, the authors investigated the incidence of vascular complications and their risk factors following freestyle propeller flap in the trunk and extremities. Methods The authors conducted a retrospective review of 50 patients who underwent soft tissue reconstruction of the trunk and the extremities with 55 freestyle propeller flaps from 2004 to 2015. Data regarding patient demographics, surgical details, including the arc of rotation, and flap complications were collected from a prospectively maintained database and analyzed. Results There were 10 flap complications (18.2%), including 7 superficial partial necrosis, 2 full‐thickness partial necrosis, and 1 total necrosis from the 55 freestyle propeller flaps harvested. Previous irradiation was a significant risk factor for flap complications and the propeller flap harvested from the extremities showed a significantly higher rate of complications compared with those harvested from the trunk. Complication rates were higher in flaps with the arc of rotation between 150 and 180 degrees with marginal significance compared with flaps with the arc of rotation less than 150 degrees. Conclusions Freestyle propeller flaps proved to be a valid and reliable option for reconstruction of defects in the trunk, while complication rate was quite high in the extremities. A prudent preoperative evaluation and preparation may be necessary before performing this surgical technique in the extremities.", "corpus_id": 28162960, "score": 1 }, { "doc_id": "16266636", "title": "Nonlinear Finite Element Simulations to Elucidate the Determinants of Perforator Patency in Propeller Flaps", "abstract": "The propeller-type flap design is increasingly used in reconstructive surgery for various regions of the body. To date, determinants of perforator patency when subjected to twisting have not been elucidated. We propose a simulation model to study parameters affecting perforator patency under such conditions. Nonlinear finite element procedure was used to simulate a perforator consisting of an artery and a vein with both ends fixed. A rigid body was attached to the top of the perforator for applying prescribed angular displacement. The effect of the following parameters on the pedicle patency was determined: (1) increasing angle of twist, (2) vessel stiffness, (3) vessel length, (4) diameter, (5) intraluminal pressure, and (6) the presence or absence of blood flow during twisting. Simulation results were reported in effective stress and strain on the twisted pedicle. In the context of perforator patency, effective strain, which is a measure of vessel deformation or collapse, is the more relevant outcome. The vein was more prone to occlusion because of its weaker wall and lower intraluminal pressure. Four factors that affected perforator patency were identified: angle of twist, intraluminal blood pressure, and perforator diameter and length. There was no significant difference whether twisting was performed prior to or after restoration of blood flow (P > 0.05). Therefore, to optimize condition for maintaining perforator patency, the angle of twist should be kept <180 degrees, perioperative blood pressure should be kept stable (avoiding periods of hypotension), and the selected perforator should be approximately 1 mm in diameter and >30 mm in length. We found that the propeller flap is a feasible design. This study defined the determinants of perforator patency and will serve as a useful guide when performing such flaps.", "corpus_id": 16266636, "score": 0 } ]

{ "doc_id": "22162115", "title": "Prognostic value of disability on mortality: 15-year follow-up of the Bambuí cohort study of aging.", "abstract": "BACKGROUND\nDisability is a concern in the context of population ageing. The extent of an individual's disability is a major determinant of whether or not they require long-term care or survival time. We investigated the effect of three disability domains as predictors of all-cause mortality over 15-year follow-up in a Brazilian socioeconomically disadvantaged and multiracial older adult population.\n\n\nMETHODS\nWe estimated Cox proportional hazards models using data from 1333 community-dwelling individuals aged 60 and older from the Bambuí Cohort Study of Ageing. Disability was defined as a great difficulty or not being able to perform one and two or more activities in each domain: mobility, instrumental activities of daily living (IADL) and basic activities of daily living (BADL).\n\n\nRESULTS\nThe overall mortality rate was 46.1 per 1000 person-years at risk (pyrs) and it was higher in men. Among men, the fully adjusted Hazard Ratios (HRs) were 1.92 (95%CI: 1.43-2.58), 2.07 (95%CI: 1.53-2.79) and 1.65 (95%CI: 1.11-2.45), and among women 1.75 (95%CI: 1.38-2.21), 1.43 (95%CI: 1.11-1.84) and 1.43 (95%CI: 1.05-1.95), for two or more disability in mobility tasks, IADLs and BADLs, respectively, compared to those with no difficulty or some difficulty to perform all the tasks.\n\n\nCONCLUSION\nA similar risk of death for mobility, IADL and BADL in both genders was found, suggesting that any of these domains can be used to identify risk of all-cause mortality among older adults. The number of activities with limitations in each domain was an important factor.", "corpus_id": 22162115 }

[ { "doc_id": "23480426", "title": "Risk factors for functional status decline in community-living elderly people: a systematic literature review.", "abstract": "To lay the groundwork for devising, improving and implementing strategies to prevent or delay the onset of disability in the elderly, we conducted a systematic literature review of longitudinal studies published between 1985 and 1997 that reported statistical associations between individual base-line risk factors and subsequent functional status in community-living older persons. Functional status decline was defined as disability or physical function limitation. We used MEDLINE, PSYCINFO, SOCA, EMBASE, bibliographies and expert consultation to select the articles, 78 of which met the selection criteria. Risk factors were categorized into 14 domains and coded by two independent abstractors. Based on the methodological quality of the statistical analyses between risk factors and functional outcomes (e.g. control for base-line functional status, control for confounding, attrition rate), the strength of evidence was derived for each risk factor. The association of functional decline with medical findings was also analyzed. The highest strength of evidence for an increased risk in functional status decline was found for (alphabetical order) cognitive impairment, depression, disease burden (comorbidity), increased and decreased body mass index, lower extremity functional limitation, low frequency of social contacts, low level of physical activity, no alcohol use compared to moderate use, poor self-perceived health, smoking and vision impairment. The review revealed that some risk factors (e.g. nutrition, physical environment) have been neglected in past research. This review will help investigators set priorities for future research of the Disablement Process, plan health and social services for elderly persons and develop more cost-effective programs for preventing disability among them.", "corpus_id": 23480426, "score": 0 }, { "doc_id": "207536420", "title": "Risk Factors and Precipitants of Long-Term Disability in Community Mobility", "abstract": "BACKGROUND\nRelatively little is known about why older persons develop long-term disability in community mobility.\n\n\nOBJECTIVE\nTo identify the risk factors and precipitants for long-term disability in walking a quarter mile and driving a car.\n\n\nDESIGN\nProspective cohort study from March 1998 to December 2009.\n\n\nSETTING\nGreater New Haven, Connecticut.\n\n\nPARTICIPANTS\n641 persons, aged 70 years or older, who were active drivers or nondisabled in walking a quarter mile. Persons who were physically frail were oversampled.\n\n\nMEASUREMENTS\nCandidate risk factors were assessed every 18 months. Disability in community mobility and exposure to potential precipitants, including illnesses or injuries leading to hospitalization or restricted activity, were assessed every month. Disability that lasted 6 or more consecutive months was considered long-term.\n\n\nRESULTS\n318 (56.0%) and 269 (53.1%) participants developed long-term disability in walking and driving, respectively. Seven risk factors were independently associated with walking disability and 8 were associated with driving disability; the strongest associations for each outcome were found for older age and lower score on the Short Physical Performance Battery. The precipitants had a large effect on long-term disability, with multivariate hazard ratios for each outcome greater than 6.2 for hospitalization and greater than 2.4 for restricted activity. The largest differences in absolute risk were generally observed in participants with a specific risk factor who were subsequently hospitalized.\n\n\nLIMITATIONS\nThe observed associations may not be causal. The severity of precipitants was not assessed. The effect of the precipitants may have been underestimated because their exposure after the initial onset of disability was not evaluated.\n\n\nCONCLUSION\nLong-term disability in community mobility is common among older persons. Multiple risk factors, together with subsequent precipitants, greatly increase the likelihood of long-term mobility disability.\n\n\nPRIMARY FUNDING SOURCE\nNational Institute on Aging, National Institutes of Health.", "corpus_id": 207536420, "score": 0 }, { "doc_id": "8909720", "title": "Mortality risk associated with disability: a population-based record linkage study.", "abstract": "OBJECTIVES\nWe assessed the association between mortality and disability and quantified the effect of disability-associated risk factors.\n\n\nMETHODS\nWe linked data from cross-sectional health surveys in the Netherlands to the population registry to create a large data set comprising baseline covariates and an indicator of death. We used Cox regression models to estimate the hazard ratio of disability on mortality.\n\n\nRESULTS\nAmong men, the unadjusted hazard ratio for activities of daily living, mobility, or mild disability defined by the Organization for Economic Co-operation and Development at age 55 years was 7.85 (95% confidence interval [CI] = 4.36, 14.13), 5.21 (95% CI = 3.19, 8.51), and 1.87 (95% CI = 1.58, 2.22), respectively. People with disability in activities of daily living and mobility had a 10-year shorter life expectancy than nondisabled people had, of which 6 years could be explained by differences in lifestyle, sociodemographics, and major chronic diseases.\n\n\nCONCLUSIONS\nDisabled people face a higher mortality risk than nondisabled people do. Although the difference can be explained by diseases and other risk factors for those with mild disability, we cannot rule out that more severe disabilities have an independent effect on mortality.", "corpus_id": 8909720, "score": 1 }, { "doc_id": "25518549", "title": "Predictors of mortality in men and women aged 90 and older: a nine-year follow-up study in the Vitality 90+ study.", "abstract": "BACKGROUND\ninformation about the predictors of mortality among the oldest-old is limited. Also possible gender differences are poorly known.\n\n\nOBJECTIVE\nto examine the predictors of mortality among individuals aged 90 and older, focusing on differences between men and women. We also analysed gender differences in survival at different levels of mobility and activities in daily living (ADL).\n\n\nDESIGN\nthis 9-year follow-up study is part of the Vitality 90+ study, a population-based study of people aged 90 and older.\n\n\nSUBJECTS\nall inhabitants aged 90 and older in the area of Tampere, Finland were contacted, irrespective of health or dwelling place. The study population consisted of 171 men and 717 women.\n\n\nMETHODS\ndata were collected with a mailed questionnaire asking questions concerning ADL and mobility, self-rated health, chronic conditions and socio-economic factors. The participation rate was 79%. Cox regression enter models were used for the analysis.\n\n\nRESULTS\nolder age, male gender, disability in ADL and mobility, poor self-rated health and institutionalisation increased the risk of mortality in the total study group. In age-adjusted Cox regression models, ADL and mobility were stronger predictors in men than in women (gender interactions, P < 0.001). Among those who were partly but not totally dependent in ADL or mobility women survived longer than men.\n\n\nCONCLUSION\nthe same health indicators that are important at younger old age also predict mortality in the oldest-old. Disability increases the likelihood of death more in men than women. At a very old age, women survive longer with moderate disability than do men.", "corpus_id": 25518549, "score": 1 }, { "doc_id": "205085958", "title": "Gender differences in trajectories of health limitations and subsequent mortality. A study based on the German Socioeconomic Panel 1995-2001 with a mortality follow-up 2002-2005.", "abstract": "OBJECTIVES\nAlthough research on health limitations has investigated gender differences in health and mortality, gender differentials in individual-level trajectories have been studied less frequently. Moreover, there are no studies on the relationship between course types and subsequent mortality. We investigate course types, explore confounding by socioeconomic and demographic correlates, and pose the question of whether the gender gap in morbidity results from differences in the onset of, and/or survival with, health limitations.\n\n\nMETHODS\nUsing the German Socioeconomic Panel, we identify individual trajectories of health limitations and use multinomial logistic regressions to explore confounding and the relationship with mortality.\n\n\nRESULTS\nThe frequency of stable trajectories without limitations is lower among women because they tend to experience courses that involve extended periods of limitations and deteriorating health. Women also experience more frequently improvement after deterioration. The female mortality advantage is particularly large after health deterioration.\n\n\nDISCUSSION\nHealth limitations do not make men and women more equal in the face of death. Our results are consistent with earlier studies showing that mortality selection and differences in chronic conditions may explain the gender gap in health and mortality. We extend previous research showing that the female health disadvantage is largely the result of their mortality advantage.", "corpus_id": 205085958, "score": 0 }, { "doc_id": "584298", "title": "Ability to Walk 1/4 Mile Predicts Subsequent Disability, Mortality, and Health Care Costs", "abstract": "ABSTRACTBackgroundMobility, such as walking 1/4 mile, is a valuable but underutilized health indicator among older adults. For mobility to be successfully integrated into clinical practice and health policy, an easily assessed marker that predicts subsequent health outcomes is required.ObjectiveTo determine the association between mobility, defined as self-reported ability to walk 1/4 mile, and mortality, functional decline, and health care utilization and costs during the subsequent year.DesignAnalysis of longitudinal data from the 2003–2004 Medicare Current Beneficiary Survey, a nationally representative sample of Medicare beneficiaries.ParticipantsParticipants comprised 5895 community-dwelling adults aged 65 years or older enrolled in Medicare.Main MeasuresMobility (self-reported ability to walk 1/4 mile), mortality, incident difficulty with activities of daily living (ADLs), total annual health care costs, and hospitalization rates.Key ResultsAmong older adults, 28% reported difficulty and 17% inability to walk 1/4 mile at baseline. Compared to those without difficulty and adjusting for demographics, socioeconomic status, chronic conditions, and health behaviors, mortality was greater in those with difficulty [AOR (95% CI): 1.57 (1.10-2.24)] and inability [AOR (CI): 2.73 (1.79-4.15)]. New functional disability also occurred more frequently as self-reported ability to walk 1/4 mile declined (subsequent incident disability among those with no difficulty, difficulty, or inability to walk 1/4 mile at baseline was 11%, 29%, and 47% for instrumental ADLs, and 4%, 14%, and 23% for basic ADLs). Total annual health care costs were $2773 higher (95% CI $1443-4102) in persons with difficulty and $3919 higher (CI $1948-5890) in those who were unable. For each 100 persons, older adults reporting difficulty walking 1/4 mile at baseline experienced an additional 14 hospitalizations (95% CI 8-20), and those who were unable experienced an additional 22 hospitalizations (CI 14-30) during the follow-up period, compared to persons without walking difficulty.ConclusionsMobility disability, a simple self-report measure, is a powerful predictor of future health, function, and utilization independent of usual health and demographic indicators. Mobility disability may be used to target high-risk patients for care management and preventive interventions.", "corpus_id": 584298, "score": 1 }, { "doc_id": "3468253", "title": "Disability and all-cause mortality in the older population: evidence from the English Longitudinal Study of Ageing", "abstract": "Despite the vast body of literature studying disability and mortality, evidence to support their association is scarce. This work investigates the role of disability in explaining all‐cause mortality among individuals aged 50+ who participated in the English Longitudinal Study of Aging. The aim is to explain the gender paradox in health and mortality by analysing whether the association of disability with mortality differs between women and men. Disability was conceived following the International Classification of Functioning, Disability and Health (ICF), proposed by the WHO, that conceptualizes disability as a combination of three components: impairment, activity limitation and participation restriction. Latent variable models were used to identify domain-specific factors and general disability. The association of the latter with mortality up to 10 years after enrolment was estimated using discrete-time survival analysis. Our work confirms the validity of the ICF framework and finds that disability is strongly associated with mortality, with a time-varying effect among men, and a smaller constant effect for women. Adjusting for demographic, socioeconomic and behavioural factors attenuated the association for both sexes, but overall the effects remained high and significant. These findings confirm the existence of gender paradox by showing that, when affected by disability, women survive longer than men, although if men survive the first years they appear to become more resilient to disability. Sensitivity analyses suggested that the gender paradox cannot be solely explained by gender-specific health conditions: there must be other mechanisms acting within the pathway between disability and mortality that need to be explored.", "corpus_id": 3468253, "score": 1 }, { "doc_id": "23241689", "title": "Country of birth, instrumental activities of daily living, self-rated health and mortality: a Swedish population-based survey of people aged 55-74.", "abstract": "There is scant knowledge of the effects of country of birth on the health of individuals in the years prior to and after retirement. The aim of this study was to consider country of birth in relation to health status, instrumental activities of daily living (IADL) and all-cause mortality when adjusted for socioeconomic status (SES). Cross-sectional data were collected between 1986 and 1991 on 8959 individuals between the ages of 55 and 74. Self-reported data were analysed using a logistic regression model while the mortality data were analysed by means of a proportional hazard model. In the present study, immigrants from Southern Europe, Eastern Europe and Finland carried significantly increased risks of poor health even after adjustment for SES. Southern Europeans, refugees from Developing countries and Finns exhibited an increased risk of impaired IADL compared to Swedes, even after adjustment for SES. In conclusion, country of birth was associated with poor health status and impaired IADL. This association remained after adjustment for SES. In accordance with pre-study expectations, mortality was predicted by impaired IADL and male gender. Country of birth was not associated with all-cause mortality.", "corpus_id": 23241689, "score": 1 }, { "doc_id": "11520397", "title": "High-level activities of daily living and disease-specific mortality during a 12-year follow-up of an octogenarian population", "abstract": "Background Little is known about the relationship between disease-specific mortality and high-level activities of daily living in the elderly. We examined whether mortality is associated with high-level activities of daily living in an octogenarian population. Methods We conducted a population-based cross-sectional and prospective cohort study in 693 older persons aged 80 years and living in Japan’s Fukuoka Prefecture. We then evaluated the association between 12-year disease-specific mortality and high-level functional capacity as measured by the Tokyo Metropolitan Institute of Gerontology Index of Competence, which is a standardized multidimensional 13-item instrument; items 1 through 5 are classified as instrumental self-maintenance activity, items 6 through 9 as intellectual activity, items 10 through 13 as social roles activity, and all 13 items together yield total functional capacity. Results By the 12-year follow-up of the 693 participants, 413 had died, 242 survived, and 38 were unable to be located. Of the 413 who died, 105 died of cardiovascular disease, 73 of respiratory tract disease, 71 of cancer, and 39 of senility. Of the other 125 deaths, 59 were due to other diseases, and the cause of death for 66 participants is not known. The hazard ratio (HR) for all-cause mortality, adjusted for confounding factors with multivariate Cox analyses, fell by 6% (HR 0.937, 95% confidence interval [CI] 0.899–0.978, P = 0.003) with each one-point increase in participants’ scores on the Tokyo Metropolitan Institute of Gerontology Index of total functional capacity. With one-point increases in instrumental self-maintenance activity and in intellectual activity, the HRs for all-cause mortality decreased by 14% (HR 0.856, 95% CI 0.787–0.930, P = 0.000) and 12% (HR 0.884, 95% CI 0.794–0.983, P = 0.023), respectively. Respiratory mortality with HR adjustment fell by 11% (HR 0.887, 95% CI 0.804–0.978, P = 0.016) and 24% (HR 0.760, 95% CI 0.627–0.922, P = 0.005) with one-point increases in the scores of total functional capacity and instrumental self-maintenance activity, respectively. Similarly, mortality due to senility fell by 16% (HR 0.838, 95% CI 0.743–0.946, P = 0.004), 29% (HR 0.707, 95% CI 0.564–0.886, P = 0.003), and 29% (HR 0.710, 95% CI 0.522–0.966, P = 0.029) with one-point increases in the scores of total functional capacity, instrumental self-maintenance activity, and intellectual activity, respectively. Conclusion These findings suggest that high-level activities of daily living may be an independent predictor of mortality due to all causes, respiratory disease and senility in older persons.", "corpus_id": 11520397, "score": 1 }, { "doc_id": "24762971", "title": "Dementia and physical disability as competing risks for mortality in a community-based sample of the elderly Japanese.", "abstract": "To examine whether an excess mortality due to dementia is independent of coexisting physical disability, a probability-sample of the non-institutionalized elderly (n = 3,308) living in Sendai City, Japan was followed between 1988 and 1991. Of those, 128 were diagnosed as dementia in 1988 by psychiatrists, using Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised as a diagnostic standard. Information on the ability to perform activities of daily living (ADL) was collected by self-report of the study subjects in 1988 baseline survey. The survival status was investigated three years later. The risks of dementia and co-existing ADL disability for mortality was examined by Cox proportional hazard models. The results indicated that the relation between dementia and mortality was two-fold, depending upon the physical functions. Dementia increased the risk for mortality among those without ADL disability, but it did not so among those with ADL disability, rather ADL function was a stronger predictor for mortality among the latter individuals. Prevention and treatment of physical disability would be important for improving the survival of the demented people.", "corpus_id": 24762971, "score": 0 }, { "doc_id": "5557039", "title": "STUDIES OF ILLNESS IN THE AGED. THE INDEX OF ADL: A STANDARDIZED MEASURE OF BIOLOGICAL AND PSYCHOSOCIAL FUNCTION.", "abstract": "The Index of ADL was developed to study results of treatment and prognosis in the elderly and chronically ill. Grades of the Index summarize over-all performance in bathing, dressing, going to toilet, transferring, continence, and feeding. More than 2,000 evaluations of 1,001 individuals demonstrated use of the Index as a survey instrument, as an objective guide to the course of chronic illness, as a tool for studying the aging process, and as an aid in rehabilitation teaching. Of theoretical interest is the observation that the order of recovery of Index functions in disabled patients is remarkably similar to the order of development of primary functions in children. This parallelism, and similarity to the behavior of primitive peoples, suggests that the Index is based on primary biological and psychosocial function, reflecting the adequacy of organized neurological and locomotor response.", "corpus_id": 5557039, "score": 0 }, { "doc_id": "73136607", "title": "Assessment of Older People: Self-Maintaining and Instrumental Activities of Daily Living", "abstract": "THE use of formal devices for assessing function is becoming standard in agencies serving the elderly. In the Gerontological Society's recent contract study on functional assessment (Howell, 1968), a large assortment of rating scales, checklists, and other techniques in use in applied settings was easily assembled. The present state of the trade seems to be one in which each investigator or practitioner feels an inner compusion to make his own scale and to cry that other existent scales cannot possibly fit his own setting. The authors join this company in presenting two scales first standardized on their own population (Lawton, 1969). They take some comfort, however, in the fact that one scale, the Physical Self-Maintenance Scale (PSMS), is largely a scale developed and used by other investigators (Lowenthal, 1964), which was adapted for use in our own institution. The second of the scales, the Instrumental Activities of Daily Living Scale (IADL), taps a level of functioning heretofore inadequately represented in attempts to assess everyday functional competence. Both of the scales have been tested further for their usefulness in a variety of types of institutions and other facilities serving community-resident older people. Before describing in detail the behavior measured by these two scales, we shall briefly describe the schema of competence into which these behaviors fit (Lawton, 1969). Human behavior is viewed as varying in the degree of complexity required for functioning in a variety of tasks. The lowest level is called life maintenance, followed by the successively more complex levels of func-", "corpus_id": 73136607, "score": 0 }, { "doc_id": "43391762", "title": "A hierarchical model of domains of disablement in the elderly: a longitudinal approach", "abstract": "Purpose : the aims of this paper are to verify that a hierarchical relationship exists between the concepts of Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL) and mobility and to use this hierarchical model to describe the evolution of disability. Methods : 3751 elderly community dwellers were followed-up 3 and 5 years after baseline interview. A hierarchic disability scale was computed by summing up the number of domains (ADL, IADL, mobility) in which a subject was dependent. Coefficients of scalability and reproducibility of the scale were computed. The hierarchic scale was used to describe transitions between states at each follow-up. Results : the hierarchical model fitted 99.3% of the subjects at baseline. At each follow-up most transitions were towards contiguous grades of disability in survivors, whatever their age. There was a significant trend towards increasing disability. Death rates were higher in subjects aged 75 and over, whatever their disability level. The patterns of evolution differed according to gender. Conclusions : the cumulative disability scale can be used to describe the evolution of disability with time in elderly community dwellers.", "corpus_id": 43391762, "score": 1 }, { "doc_id": "39873777", "title": "A hierarchical categorisation of tasks in mobility disability", "abstract": "Purpose. In the field of long-term care, disability usually refers to difficulties in instrumental activities of daily living (IADL) or basic activities of daily living (BADL); this term may also refer to difficulties in mobility for those more interested in preventive intervention or general health promotion. The aims of this study were to (1) categorise a complete set of mobility tasks according to a revealed hierarchy, and (2) examine the relationship between this mobility hierarchy and IADL/BADL disabilities. Methods. We categorised nine mobility tasks according to appearance order in self-reported difficulties data obtained from a Taiwanese national database of community-dwelling elders aged over 65. We also performed correlation tests to explore the relationships of these mobility tasks with six tasks each of IADL and BADL. Results. The results revealed a three-level hierarchy of mobility disability: (1) mild disability indicated by difficulties in four mobility tasks, which correlated with difficulty in one IADL task; (2) moderate disability indicated by difficulties in three mobility tasks, which correlated with difficulties in most IADL tasks; and (3) severe disability indicated by difficulties in two mobility tasks, which correlated with difficulties in all BADL tasks. The same hierarchy was observed for males and females. Conclusions. There is a clear hierarchical structure of mobility disability that correlates differently with IADL and BADL disabilities. These results suggest that different mobility tasks should be included in disability assessments to suit specific purposes.", "corpus_id": 39873777, "score": 0 }, { "doc_id": "25099203", "title": "Longitudinal study of physical ability in the oldest-old.", "abstract": "Based on 1984 data from the Longitudinal Study on Aging, one-third of White persons aged 80 or older living in the community (N = 1,791) were defined as having no difficulty in walking 1/4 of a mile, in lifting 10 pounds, in climbing 10 steps without resting, or in stooping, crouching or kneeling. Physical ability was associated with lower risk of death over two years mean follow-up; Relative odds (RO) = .4 (95 percent confidence interval = .4, .6) and in survivors, lower utilization of hospitals RO = .4 (CI = .3, .7), physicians RO = .6 (CI = .5, .8) and nursing homes RO = .3 (CI = .2, .5) compared with those having difficulty on any of the four functional measures included in the definition of physical ability. Fifty percent of the women and 42 percent of the men physically able at the time of the baseline survey in 1984 remained physically able at follow-up. Continued physical ability in this group was associated with never having had cardiovascular disease RO = 2.1, (CI = 1.2, 3.7), never having had arthritic complaints RO = 1.9 (CI = 1.2, 2.7), a body mass index less than the 75th percentile RO = 1.8 (CI = 1.2, 2.9), younger age (for each decade of age, RO = 2.0 (CI = 1.1, 3.6), and higher level of education (greater than 13 years versus 0-6 years) RO = 2.4 (CI = 1.2, 4.7). These correlates include factors amenable to preventive measures and highlight the need to consider the heterogeneity of the oldest-old in formulating programs aimed at prevention and postponement of disability.", "corpus_id": 25099203, "score": 0 }, { "doc_id": "4875680", "title": "Disability transitions in the oldest old in the general population. The Leiden 85-plus study", "abstract": "Transitions between disability states in older people occur frequently. This study investigated predictors of disability transitions in the oldest old and was performed in the Leiden 85-plus study, a population-based prospective cohort study among 597 participants aged 85 years. At baseline (age 85 years), data on sociodemographic characteristics and chronic diseases were obtained. Disabilities in basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were measured annually for 5 years with the Groningen Activities Restriction Scale (GARS). Mortality data were obtained. A statistical multi-state model was used to assess the risks of transitions between no disabilities, IADL disability, BADL disability, and death. At baseline, 299 participants (50.0 %) were disabled in IADL only, and 155 participants (26.0 %) were disabled in both BADL and IADL. During 5-year follow-up, 374 participants (62.6 %) made >1 transition between disability states, mostly deterioration in disability. Males had a lower risk of deterioration [hazard ratio (HR), 0.75 (95 % CI, 0.58–0.96)] compared to females. No gender differences were observed for improvement [HR, 0.64 (95 % CI, 0.37–1.11)]. Participants with depressive symptoms were less likely to improve [HR, 0.50 (95 % CI, 0.28–0.87)]. Participants with depressive symptoms [HR, 1.46 (95 % CI, 1.12–1.91)], >1 chronic disease [HR, 1.60 (95 % CI, 1.27–2.01)], and with cognitive impairment [HR, 1.60 (95 % CI, 1.20–2.13)] had the highest risk of deteriorating. Disability is a dynamic process in the oldest old. Deterioration is more common than improvement. Older men are less likely to deteriorate than women. The presence of depressive symptoms, chronic disease, and cognitive impairment predicts deterioration.", "corpus_id": 4875680, "score": 1 }, { "doc_id": "16720460", "title": "Men: good health and high mortality. Sex differences in health and aging", "abstract": "This review examines sex differences in health and survival, with a focus on the Nordic countries. There is a remarkable discrepancy between the health and survival of the sexes: men are physically stronger and have fewer disabilities, but have substantially higher mortality at all ages compared with women: the so-called male-female health-survival paradox. A number of proposed explanations for this paradox are rooted in biological, social, and psychological interpretations. It is likely to be due to multiple causes that include fundamental biological differences between the sexes such as genetic factors, immune system responses, hormones, and disease patterns. Behavioral differences such as risk-taking and reluctance to seek and comply with medical treatment may also play a role. Another consideration is that part of the difference may be due to methodological challenges, such as selective non-participation and under-reporting of health problems, and delayed seeking of treatment by men. The Nordic countries provide a unique opportunity for such studies, as they have good-quality data in their national health registers, which cover the whole population, and a long tradition of high participation rates in surveys.", "corpus_id": 16720460, "score": 0 }, { "doc_id": "9181473", "title": "Predictors of 10-year mortality in a population of community-dwelling Brazilian elderly: the Bambuí Cohort Study of Aging.", "abstract": "We used data on 1,399 participants aged 60 and over from the Bambuí Cohort Study of Aging to examine predictors of mortality in a socioeconomically disadvantaged population. From 1997 to 2007, 599 participants died and 6.2% were lost to follow-up, leading to 12,415 person-years (pyrs) of observation. The death rate was 48.3 per 1,000 pyrs. Age (adjusted hazard ratio [HR] = 1.40), male gender (HR = 1.80), never married (HR = 1.78) or a widow (HR = 1.26), poor self-rated health (HR = 1.31), inability to perform four or more activities of daily living (HR = 3.29), number of cardiovascular risk factors (HR = 1.51 for two and HR = 1.91 for three or more), Trypanosoma cruzi infection (HR = 1.27), and number of medications (HR = 1.06) were each significantly (p < 0.05) and independently associated with mortality. The Mini-Mental State Examination score showed a protective effect (HR = 0.96). Except T. cruzi infection, other predictors of mortality were highly consistent with those found in more affluent elderly populations.", "corpus_id": 9181473, "score": 0 }, { "doc_id": "37868777", "title": "Dependence in Activities of Daily Living and Cognitive Impairment Strongly Predicted Mortality in Older Urban Residents in Brazil: A 2‐Year Follow‐Up", "abstract": "To identify a set of predictors of mortality among residents in the community, before any physical, biochemical, or image examination is performed, that could be collected on a routine standardized basis, to help the clinician define a patient follow‐up strategy and the health planner make decisions regarding the care of older people.", "corpus_id": 37868777, "score": 0 }, { "doc_id": "11666984", "title": "Cohort profile: the Bambui (Brazil) Cohort Study of Ageing.", "abstract": "Ageing of the population is the most important demographic change facing many countries around the world. The speed of demographic ageing in Latin American and the Caribbean, however, will be unprecedented in comparison with Western European and North American countries. This demographic change will generate populations with large numbers of elderly who at some time in their lives have been exposed to infectious diseases. Infections may affect ageing in different ways. Most important postulated mechanisms include enhanced inflammation, pathogen-dependent tissue destruction or accelerated cellular ageing through increased turnover. Most epidemiological studies of ageing have, understandably, focused on non-communicable diseases and related conditions. To our knowledge, no previous population-based cohort study had examined the consequences of the double burden of non-communicable diseases and a parasitic chronic infection in old age. Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic in Latin American countries, with about 8 million people infected. As a consequence of immigration from endemic countries, Chagas disease is an emerging issue in North America and Europe, and an example in the era of globalization of how infectious diseases extend beyond endemic areas. Chagas disease is related to poor socio-economic circumstances in early life. In endemic areas, the main source of infection is a bloodsucking triatomine insect that colonizes poor households. Most individuals in these areas acquire the infection at <20 years of age, and 30% develop chronic chagasic cardiomyopathy. The ageing of the population, together with a cohort effect observed in endemic areas where the household insect transmission has been interrupted, will lead to increases in the number of older adults who are already infected by T. cruzi. The main objective of the Bambui Cohort Study of Ageing is to examine the separate and joint effects of chronic T. cruzi infection and non-communicable diseases on health outcomes in old age.", "corpus_id": 11666984, "score": 0 }, { "doc_id": "4961646", "title": "Mortality risk attributable to smoking, hypertension and diabetes among English and Brazilian older adults (The ELSA and Bambui cohort ageing studies)", "abstract": "Background: The main aim of this study was to quantify and compare 6-year mortality risk attributable to smoking, hypertension and diabetes among English and Brazilian older adults. This study represents a rare opportunity to approach the subject in two different social and economic contexts. Methods: Data from the data from the English Longitudinal Study of Ageing (ELSA) and the Bambuí Cohort Study of Ageing (Brazil) were used. Deaths in both cohorts were identified through mortality registers. Risk factors considered in this study were baseline smoking, hypertension and diabetes mellitus. Both age–sex adjusted hazard ratios and population attributable risks (PAR) of all-cause mortality and their 95% confidence intervals for the association between risk factors and mortality were estimated using Cox proportional hazards models. Results: Participants were 3205 English and 1382 Brazilians aged 60 years and over. First, Brazilians showed much higher absolute risk of mortality than English and this finding was consistent in all age, independently of sex. Second, as a rule, hazard ratios for mortality to smoking, hypertension and diabetes showed more similarities than differences between these two populations. Third, there was strong difference among English and Brazilians on attributable deaths to hypertension. Conclusions: The findings indicate that, despite of being in more recent transitions, the attributable deaths to one or more risk factors was twofold among Brazilians relative to the English. These findings call attention for the challenge imposed to health systems to prevent and treat non-communicable diseases, particularly in populations with low socioeconomic level.", "corpus_id": 4961646, "score": 0 }, { "doc_id": "29272734", "title": "Mobility in older adults: a comprehensive framework.", "abstract": "Mobility is fundamental to active aging and is intimately linked to health status and quality of life. Although there is widespread acceptance regarding the importance of mobility in older adults, there have been few attempts to comprehensively portray mobility, and research has to a large extent been discipline specific. In this article, a new theoretical framework for mobility is presented with the goals of raising awareness of the complexity of factors that influence mobility and stimulating new integrative and interdisciplinary research ideas. Mobility is broadly defined as the ability to move oneself (e.g., by walking, by using assistive devices, or by using transportation) within community environments that expand from one's home, to the neighborhood, and to regions beyond. The concept of mobility is portrayed through 5 fundamental categories of determinants (cognitive, psychosocial, physical, environmental, and financial), with gender, culture, and biography (personal life history) conceptualized as critical cross-cutting influences. Each category of determinants consists of an increasing number of factors, demonstrating greater complexity, as the mobility environment expands farther from the home. The framework illustrates how mobility impairments can lead to limitations in accessing different life-spaces and stresses the associations among determinants that influence mobility. By bridging disciplines and representing mobility in an inclusive manner, the model suggests that research needs to be more interdisciplinary and current mobility findings should be interpreted more comprehensively, and new more complex strategies should be developed to address mobility concerns.", "corpus_id": 29272734, "score": 0 }, { "doc_id": "12441350", "title": "2011 Compendium of Physical Activities: a second update of codes and MET values.", "abstract": "PURPOSE\nThe Compendium of Physical Activities was developed to enhance the comparability of results across studies using self-report physical activity (PA) and is used to quantify the energy cost of a wide variety of PA. We provide the second update of the Compendium, called the 2011 Compendium.\n\n\nMETHODS\nThe 2011 Compendium retains the previous coding scheme to identify the major category headings and specific PA by their rate of energy expenditure in MET. Modifications in the 2011 Compendium include cataloging measured MET values and their source references, when available; addition of new codes and specific activities; an update of the Compendium tracking guide that links information in the 1993, 2000, and 2011 compendia versions; and the creation of a Web site to facilitate easy access and downloading of Compendium documents. Measured MET values were obtained from a systematic search of databases using defined key words.\n\n\nRESULTS\nThe 2011 Compendium contains 821 codes for specific activities. Two hundred seventeen new codes were added, 68% (561/821) of which have measured MET values. Approximately half (317/604) of the codes from the 2000 Compendium were modified to improve the definitions and/or to consolidate specific activities and to update estimated MET values where measured values did not exist. Updated MET values accounted for 73% of all code changes.\n\n\nCONCLUSIONS\nThe Compendium is used globally to quantify the energy cost of PA in adults for surveillance activities, research studies, and, in clinical settings, to write PA recommendations and to assess energy expenditure in individuals. The 2011 Compendium is an update of a system for quantifying the energy cost of adult human PA and is a living document that is moving in the direction of being 100% evidence based.", "corpus_id": 12441350, "score": 0 }, { "doc_id": "62781177", "title": "Energy expenditure through physical activity in a population of community-dwelling Brazilian elderly: cross-sectional evidences from the Bambuí Cohort Study of Aging.", "abstract": "The aim of this study was to estimate physical activity energy expenditure among older adults. The study comprised 1,585 residents in Bambuí, Minas Gerais State, Brazil, aged > 60 years (91% of the town's total elderly), and examined the frequency and duration of 23 types of physical activity among them. Median energy expenditure was 975 MET.min/week (1,195.8 among men and 803.1 among women), declining significantly with age in both sexes. The prevalence of sedentary lifestyles (< 450 MET.min/week) was 31.2%. Unhurried walking accounted for about 1/3 of total energy expenditure. Multivariate analysis based on ordinal logistic regression showed inverse associations between energy expenditure and age and hospitalizations in both sexes. Among men, inverse associations were observed with smoking, number of chronic diseases and number of medical appointments. These results emphasize the need for effective strategies to increase physical activity in older elderly, and underscore the high prevalence of walking in this group.", "corpus_id": 62781177, "score": 0 }, { "doc_id": "5646194", "title": "Physical function and self-rated health status as predictors of mortality: results from longitudinal analysis in the ilSIRENTE study", "abstract": "BackgroundPhysical function measures have been shown to predict negative health-related events in older persons, including mortality. These markers of functioning may interact with the self-rated health (SRH) in the prediction of events. Aim of the present study is to compare the predictive value for mortality of measures of physical function and SRH status, and test their possible interactions.MethodsData are from 335 older persons aged ≥ 80 years (mean age 85.6 years) enrolled in the \"Invecchiamento e Longevità nel Sirente\" (ilSIRENTE) study. The predictive values for mortality of 4-meter walk test, Short Physical Performance Battery (SPPB), hand grip strength, Activities of Daily Living (ADL) scale, Instrumental ADL (IADL) scale, and a SRH scale were compared using proportional hazard models. Kaplan-Meier survival curves for mortality and Receiver Operating Characteristic (ROC) curve analyses were also computed to estimate the predictive value of the independent variables of interest for mortality (alone and in combination).ResultsDuring the 24-month follow-up (mean 1.8 years), 71 (21.2%) events occurred in the study sample. All the tested variables were able to significantly predict mortality. No significant interaction was reported between physical function measures and SRH. The SPPB score was the strongest predictor of overall mortality after adjustment for potential confounders (per SD increase; HR 0.64; 95%CI 0.48–0.86). A similar predictive value was showed by the SRH (per SD increase; HR 0.76; 95%CI 0.59–0.97). The chair stand test was the SPPB subtask showing the highest prognostic value.ConclusionAll the tested measures are able to predict mortality with different extents, but strongest results were obtained from the SPPB and the SRH. The chair stand test may be as useful as the complete SPPB in estimating the mortality risk.", "corpus_id": 5646194, "score": 0 }, { "doc_id": "39911240", "title": "[Life expectancy with functional disability in elderly persons in São Paulo, Brazil].", "abstract": "OBJECTIVE\nFor persons 60 years of age or older living in the city of São Paulo, Brazil, in the year 2000 to estimate four characteristics: (1) life expectancy free of functional disability, (2) life expectancy with functional disability, (3) life expectancy with functional disability but without dependence, and (4) life expectancy with functional disability and dependence.\n\n\nMETHODS\nThe estimates of the four characteristics were calculated by means of a life table constructed based on the method proposed by Sullivan. The basic data used for the calculations were the elderly population estimated for the city of São Paulo as of mid-2000, obtained from the demographic censuses of 1991 and 2000, and deaths in the elderly population, obtained from the State Data Analysis System Foundation (Fundação Sistema Estadual de Análise de Dados, or SEADE) of the state of São Paulo. The prevalences of functional disability and of functional dependence were calculated based on data concerning activities of daily living collected in the city of São Paulo as part of a project called Health, Well-being, and Aging in Latin America and the Caribbean (the \"SABE project\"). The activities of daily living considered were: dressing, eating, bathing, using the bathroom, lying down on the bed and getting up from it, and walking across a room. Functional disability was defined as difficulty in performing one or more of the activities of daily living. Dependence was defined as the need for help in performing at least one of the activities of daily living.\n\n\nRESULTS\nIn 2000, 60-year-old men from the city of São Paulo could expect to live, on average, 17.6 years, of which 14.6 years (83%) would be free of functional disability. Women of the same age could expect to live 22.2 years, of which 16.4 years (74%) would be free of functional disability. Men would have a functional disability and be dependent on others for 1.6 years (9%), while the comparable period for women would be 2.5 years (11%).\n\n\nCONCLUSIONS\nDespite their longer life expectancy, the women faced more years with functional disability. The number of years with functional disability and dependence was also higher for the women. Public policies should take into account the differing needs of elderly women and of elderly men as well as other specific characteristics of this older population.", "corpus_id": 39911240, "score": 0 }, { "doc_id": "9100814", "title": "Disability in activities of daily living: patterns of change and a hierarchy of disability.", "abstract": "OBJECTIVES\nThis paper examines longitudinal data over 6 years to evaluate incidence rates of disability and the pattern of dependency in activities of daily living.\n\n\nMETHODS\nThe Longitudinal Study of Aging (n = 5151) was used to evaluate incidence of disability in activities of daily living; biennial interview data from 1984 through 1990 were used. The median age to disability onset for individual activities was estimated from survival analysis. A prevalent ordering of incident disability was identified from patterns of disability onset within individuals.\n\n\nRESULTS\nThe progression of incident disability among the elderly supported by longitudinal data, based on both the ordering of median ages to disability onset and patterns of incident disability, was as follows: walking, bathing, transferring, dressing, toileting, feeding. Gender differences were found in disability incidence rates.\n\n\nCONCLUSIONS\nThis study provides a mathematical picture of physical functioning as people age. These findings, based on longitudinal data, indicate a different hierarchical structure of disability than found in previous reports using cross-sectional data. Furthermore, the study documents gender differences in incident impairment, which indicate that although women outlive men, they spend more time in a disabled state.", "corpus_id": 9100814, "score": 0 }, { "doc_id": "30708114", "title": "Explaining the Effect of Gender on Functional Transitions in Older Persons", "abstract": "Background: Women live longer but experience greater disability than men. The reasons for this gender difference in disability are not well understood. Objective: Our objectives were to determine if the higher prevalence of disability in women is due to greater incidence of disability, longer duration of disability, or both, and to identify factors that potentially explain these gender differences. Methods: 754 community-living persons aged 70 and older who were non-disabled (required no personal assistance) in four essential activities of daily living (ADLs) were assessed monthly for disability for up to 6 years. A multi-state extension of the proportional hazards model was used to determine the effects of gender on transitions between states of no disability, mild disability, severe disability, and death, and to evaluate potential mediators of these effects. Results: Women were more likely to make the transition from no disability to mild disability and less likely to make the transitions from mild to no disability and from both mild and severe disability to death. The gender difference in the transitions between no disability and mild disability was largely explained by differences in gait speed and physical activity, but gender difference in transitions to death persisted despite adjustment for multiple potential mediators. Conclusion: The higher prevalence of disability in women versus men is due to a combination of higher incidence and longer duration, resulting from lower rates of recovery and mortality among disabled women.", "corpus_id": 30708114, "score": 0 } ]

{ "doc_id": "37134762", "title": "Superoxide is the major reactive oxygen species regulating autophagy", "abstract": "Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O2•−) and hydrogen peroxide (H2O2). However, the relative functions of O2•− and H2O2 in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors, and exogenous H2O2. We found that O2•− was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O2•− and H2O2. Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O2•− levels but increased H2O2 levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O2•− and H2O2 levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O2•− levels, lowered H2O2 levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H2O2 induced autophagy and increased intracellular O2•− but failed to increase intracellular H2O2. Taken together, these findings indicate that O2•− is the major ROS-regulating autophagy.", "corpus_id": 37134762 }

[ { "doc_id": "32867238", "title": "Ascorbic Acid Inhibits Lysosomal Autophagy of Ferritin *", "abstract": "Ascorbic acid retards ferritin degradation in K562 erythroleukemia cells leading to an increase in the availability of cellular iron (Bridges, K. R., and Hoffman, K. E. (1986) J. Biol. Chern. 261,14273-14277). To explore the mechanism of this effect, the influence of ascorbate on subcellular ferritin distribution was examined. Cellular ferritin was pulse-labeled with “Fe for 2 h, after which the cells were hypotonically lysed and fractionated on an 8% Percoll density gradient. Immediately after the labeling, all of the ferritin was in the cytoplasmic fractions at the top of the gradient. When the labeling was followed by a 24-h period of growth, a portion of the ferritin shifted to the lysosome-associated fractions at the bottom of the gradient, consistent with lysosomal autophagy of cytoplasmic ferritin. When ascorbate was added to the culture medium during the 24-h incubation, the magnitude of the shift was reduced. This process was also examined by size-fractionation of the contents of labeled cells using a Sepharose CL-GB column. Immediately after labeling, ferritin emerged from the column in two peaks, indicating the existence of both ferritin monomer and aggregates within the cytoplasm. After a 24-h period of growth, the monomer peak disappeared, while a new ferritin peak coincident with lysosomes emerged again, indicative of lysosomal autophagy of ferritin. In cells cultured with ascorbate for 24-h, there was a marked attenuation of the shift of ferritin to the lysosomal fractions. The monomer peak disappeared, as in the controls, but there was instead, an accumulation of ferritin as cytoplasmic aggregates. The total ferritin content of the ascorbate-treated cells was increased by 4-fold over that of the control. These experiments indicate that ascorbate blocks the degradation of cytoplasmic ferritin by reducing lysosomal autophagy of the protein. The access to the cell of the potentially toxic iron stored within the ferritin molecule is thereby increased.", "corpus_id": 32867238, "score": 0 }, { "doc_id": "34957843", "title": "The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy.", "abstract": "Using confocal microscopy, onset of the mitochondrial permeability transition (MPT) in individual mitochondria within living cells can be visualized by the redistribution of the cytosolic fluorophore, calcein, into mitochondria. Simultaneously, mitochondria release membrane potential-indicating fluorophores like tetramethylrhodamine methylester. The MPT occurs in several forms of necrotic cell death, including oxidative stress, pH-dependent ischemia/reperfusion injury and Ca2+ ionophore toxicity. Cyclosporin A (CsA) and trifluoperazine block the MPT in these models and prevent cell killing, showing that the MPT is a causative factor in necrotic cell death. During oxidative injury induced by t-butylhydroperoxide, onset of the MPT is preceded by pyridine nucleotide oxidation, mitochondrial generation of reactive oxygen species, and an increase of mitochondrial free Ca2+, all changes that promote the MPT. During tissue ischemia, acidosis develops. Because of acidotic pH, anoxic cell death is substantially delayed. However, when pH is restored to normal after reperfusion (reoxygenation at pH 7.4), cell death occurs rapidly (pH paradox). This killing is caused by pH-dependent onset of the MPT, which is blocked by reperfusion at acidotic pH or with CsA. In isolated mitochondria, toxicants causing Reye's syndrome, such as salicylate and valproate, induce the MPT. Similarly, salicylate induces a CsA-sensitive MPT and killing of cultured hepatocytes. These in vitro findings suggest that the MPT is the pathophysiological mechanism underlying Reye's syndrome in vivo. Kroemer and coworkers proposed that the MPT is a critical event in the progression of apoptotic cell death. Using confocal microscopy, the MPT can be directly documented during tumor necrosis factor-alpha induced apoptosis in hepatocytes. CsA blocks this MPT and prevents apoptosis. The MPT does not occur uniformly during apoptosis. Initially, a small proportion of mitochondria undergo the MPT, which increases to nearly 100% over 1-3 h. A technique based on fluorescence resonance energy transfer can selectively reveal mitochondrial depolarization. After nutrient deprivation, a small fraction of mitochondria spontaneously depolarize and enter an acidic lysosomal compartment, suggesting that the MPT precedes the normal process of mitochondrial autophagy. A model is proposed in which onset of the MPT to increasing numbers of mitochondria within a cell leads progressively to autophagy, apoptosis and necrotic cell death.", "corpus_id": 34957843, "score": 0 }, { "doc_id": "18075784", "title": "Loss of cardiolipin and mitochondria during programmed neuronal death: evidence of a role for lipid peroxidation and autophagy", "abstract": "Cardiolipin, a lipid of the mitochondrial inner membrane, is lost from many types of cells during apoptotic death. Here we show that the cardiolipin content of nerve growth factor (NGF)-deprived rat sympathetic neurons undergoing apoptotic death in cell culture decreased before extensive loss of mitochondria from the cells. By 18-24 h after NGF deprivation, many neurons did not stain with the cardiolipin-specific dye, Nonyl Acridine Orange, suggesting complete loss of cardiolipin. Gas chromatography confirmed the decline of cardiolipin content in NGF-deprived neurons. Electron microscopy and immunoblots for the mitochondrial-specific protein, heat shock protein 60 (HSP60), revealed that there was only a slight decrease in mitochondrial mass at this time. Cardiolipin loss after NGF deprivation was concurrent with increased production of mitochondrial-derived reactive oxygen species [Kirkland, R.A., Franklin, J.L., 2001. J. Neurosci. 21, 1949-1963] and increased lipid peroxidation. Compounds having antioxidant effects blocked peroxidation, loss of cardiolipin, and the decrease of mitochondrial mass in NGF-deprived neurons. These compounds also blocked an increase in the number of lysosomes and autophagosomes in NGF-deprived cells. The findings reported here show that the important mitochondrial inner membrane lipid, cardiolipin, is lost from mitochondria during neuronal apoptosis and that this loss occurs before significant loss of mitochondria from cells. They suggest that the loss of cardiolipin is mediated by free radical oxygen.", "corpus_id": 18075784, "score": 0 }, { "doc_id": "20703928", "title": "Dopamine induces autophagic cell death and α‐synuclein increase in human neuroblastoma SH‐SY5Y cells", "abstract": "Free cytoplasmic dopamine may be involved in the genesis of neuronal degeneration in Parkinson's disease and other such diseases. We used SH‐SY5Y human neuroblastoma cells to study the effect of dopamine on cell death, activation of stress‐induced pathways, and expression of α‐synuclein, the characteristic protein accumulated in Lewy bodies. We show that 100 and 500 μM dopamine causes a 40% and 60% decrease of viability, respectively, and triggers autophagy after 24 hr of exposure, characterized by the presence of numerous cytoplasmic vacuoles with inclusions. Dopamine causes mitochondrial aggregation in adherent cells prior to the loss of functionality. Plasma membrane and nucleus also maintain their integrity. Cell viability is protected by the dopamine transporter blocker nomifensine and the antioxidants N‐acetylcysteine and ascorbic acid. Dopamine activates the stress‐response kinases, SAPK/JNK and p38, but not ERK/MAPK or MEK, and increases α‐synuclein expression. Both cell viability and the increase in α‐synuclein expression are prevented by antioxidants; by the specific inhibitors of p38 and SAPK/JNK, SB203580 and SP600125, respectively; and by the inhibitor of autophagy 3‐methyladenine. This indicates that oxidative stress, stress‐activated kinases, and factors involved in autophagy up‐regulate α‐synuclein content. The results show that nonapoptotic death pathways are triggered by dopamine, leading to autophagy. These findings should be taken into account in the search for strategies to protect dopaminergic neurons from degeneration. © 2003 Wiley‐Liss, Inc.", "corpus_id": 20703928, "score": 1 }, { "doc_id": "38920632", "title": "Oxidative stress and autophagy.", "abstract": "Organisms respond to oxidative injury by orchestrating a stress response to prevent further damage. An increase in the intracellular levels of antioxidant agents, and at the same time the removal of already damaged components, are both part of the oxidative stress response. Lysosomes have been classically considered one of the main targets of the reactive oxygen species. In fact, the destabilization of the lysosomal membrane during oxidizing conditions promotes the leakage of the enzymes contained in these organelles and contributes to cellular damage. However, recent evidence supports a protective role of the lysosomal system, which can eliminate altered intracellular components through autophagy, at least in the first stages of oxidative injury. Consequently, activation of the main intracellular proteolytic systems, the ubiquitin/proteasome, and also the lysosomal/autophagic system occurs during the oxidative stress response. The opposing roles for the lysosomal system under oxidizing conditions are discussed in this review.", "corpus_id": 38920632, "score": 0 }, { "doc_id": "28539097", "title": "Lipid oxidation and autophagy in yeast.", "abstract": "Autophagy, a process involved in the degradation and the recycling of long-lived proteins and organelles to survive nitrogen starvation, is generally non-selective. However, recent data suggest that selective forms of autophagy exist, that are able to specifically target several organelles, including mitochondria. Conversely, mitochondrial alterations could trigger autophagy. Such a selective form of autophagy might be involved in the elimination of damaged mitochondria. We reported previously that, mitochondria were early targets of rapamycin-induced autophagy. Here we report that rapamycin-induced autophagy is accompanied by the early production of reactive oxygen species and by the early oxidation of mitochondrial lipid. Inhibition of these oxidative effects by resveratrol largely impaired autophagy of both cytosolic proteins and mitochondria, and delayed subsequent cell death. These results support a role of mitochondrial oxidation events in the activation of autophagy.", "corpus_id": 28539097, "score": 0 }, { "doc_id": "36971351", "title": "Protective effects of vacuolar H+-ATPase c on hydrogen peroxide-induced cell death in C6 glioma cells", "abstract": "We have isolated a gene, the c subunit (ATP6L) of vacuolar H(+)-ATPase, involved in oxidative stress response. In this study, we examined the role of ATP6L and its molecular mechanisms in glial cell death induced by H(2)O(2). Expression of the ATP6L gene was increased by H(2)O(2) treatment in C6 glial cells. ATP6L siRNA-transfected C6 cells treated with H(2)O(2) showed a significant decrease in viability. ATP6L siRNA-transfected cells that were pretreated with MEK1/2 inhibitor completely recovered cell viability. Pretreatment of the transfected cells with zVAD-fmk, a pan-specific caspase inhibitor, did not result in the recovery of cell viability, as determined by a H(2)O(2)-induced cytotoxicity assay. The ultrastructural morphology of the transfected cells as seen by the use of transmission electron microscopy showed numerous cytoplasmic autophagic vacuoles with double membrane. These results suggest that ATP6L has a protective role against H(2)O(2)-induced cytotoxicity via an inhibition of the Erk1/2 signaling pathway, leading to inhibition of autophagic cell death.", "corpus_id": 36971351, "score": 1 }, { "doc_id": "18451340", "title": "Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells.", "abstract": "Malignant gliomas are resistant to various proapoptotic therapies, such as radiotherapy and conventional chemotherapy. In this study, we show that selenite is preferentially cytotoxic to various human glioma cells over normal astrocytes via autophagic cell death. Overexpression of Akt, survivin, XIAP, Bcl-2, or Bcl-xL failed to block selenite-induced cell death, suggesting that selenite treatment may offer a potential therapeutic strategy against malignant gliomas with apoptotic defects. Before selenite-induced cell death in glioma cells, disruption of the mitochondrial cristae, loss of mitochondrial membrane potential, and subsequent entrapment of disorganized mitochondria within autophagosomes or autophagolysosomes along with degradation of mitochondrial proteins were noted, showing that selenite induces autophagy in which mitochondria serve as the main target. At the early phase of selenite treatment, high levels of superoxide anion were generated and overexpression of copper/zinc superoxide dismutase or manganese superoxide dismutase, but not catalase, significantly blocked selenite-induced mitochondrial damage and subsequent autophagic cell death. Furthermore, treatment with diquat, a superoxide generator, induced autophagic cell death in glioma cells. Taken together, our study clearly shows that superoxide anion generated by selenite triggers mitochondrial damage and subsequent mitophagy, leading to irreversible cell death in glioma cells.", "corpus_id": 18451340, "score": 1 }, { "doc_id": "36135601", "title": "Apoptosis and Autophagy in Photoreceptors Exposed to Oxidative Stress", "abstract": "Studies on human and animal models of retinal dystrophy have suggested that apoptosis may be the common pathway of photoreceptor cell death. Autophagy, the major cellular degradation process in animal cells, is important in normal development and tissue remodeling, as well as under pathological conditions. Previously we provided evidence that genes, whose products are involved in apoptosis and autophagy, may be co-expressed in photoreceptors undergoing degeneration. Here, we investigated autophagy in oxidative stress-mediated cell death in photoreceptors, analyzing the light-damage mouse model and 661W photoreceptor cells challenged with H2O2. In the in vivo model, we demonstrated a time-dependent increase in the number of TUNEL-positive cells, concomitant with the formation of autophagosomes. In vitro, oxidative stress increased mRNA levels of apoptotic and autophagic marker genes. H2O2 treatment resulted in the accumulation of TUNEL-positive cells, the majority of which contain autophagosomes. To determine whether autophagy and apoptosis might precede each other or co-occur, we performed inhibitor studies. The autophagy inhibitor 3-methyladenine (3-MA), silencing RNA (siRNA) against two genes whose products are required for autophagy (autophagy-related (ATG) gene 5 and beclin 1), as well as the pan-caspase-3 inhibitor, zVAD-fmk, were both found to partially block cell death. Blocking autophagy also significantly decreased caspase-3 activity, whereas blocking apoptosis increased the formation of autophagosomes. The survival effects of 3-MA and zVAD-fmk were not additive; rather treatment with both inhibitors lead to increased cell death by necrosis. In summary, the study first suggests that autophagy participates in photoreceptor cell death possibly by initiating apoptosis. Second, it confirms that cells that normally die by apoptosis will execute cell death by necrosis if the normal pathway is blocked. And third, these results argue that the up-stream regulators of autophagy need to be identified as potential therapeutic targets in photoreceptor degeneration.", "corpus_id": 36135601, "score": 0 }, { "doc_id": "38674775", "title": "Degradation of Oxidized Proteins by Autophagy during Oxidative Stress in Arabidopsis1[W][OA]", "abstract": "Upon encountering oxidative stress, proteins are oxidized extensively by highly reactive and toxic reactive oxidative species, and these damaged, oxidized proteins need to be degraded rapidly and effectively. There are two major proteolytic systems for bulk degradation in eukaryotes, the proteasome and vacuolar autophagy. In mammalian cells, the 20S proteasome and a specific type of vacuolar autophagy, chaperone-mediated autophagy, are involved in the degradation of oxidized proteins in mild oxidative stress. However, little is known about how cells remove oxidized proteins when under severe oxidative stress. Using two macroautophagy markers, monodansylcadaverine and green fluorescent protein-AtATG8e, we here show that application of hydrogen peroxide or the reactive oxidative species inducer methyl viologen can induce macroautophagy in Arabidopsis (Arabidopsis thaliana) plants. Macroautophagy-defective RNAi-AtATG18a transgenic plants are more sensitive to methyl viologen treatment than wild-type plants and accumulate a higher level of oxidized proteins due to a lower degradation rate. In the presence of a vacuolar H+-ATPase inhibitor, concanamycin A, oxidized proteins were detected in the vacuole of wild-type root cells but not RNAi-AtATG18a root cells. Together, our results indicate that autophagy is involved in degrading oxidized proteins under oxidative stress conditions in Arabidopsis.", "corpus_id": 38674775, "score": 0 }, { "doc_id": "6475016", "title": "Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species", "abstract": "Autophagy is a self-digestion process important for cell survival during starvation. It has also been described as a form of programmed cell death. Mitochondria are important regulators of autophagy-induced cell death and damaged mitochondria are often degraded by autophagosomes. Inhibition of the mitochondrial electron transport chain (mETC) induces cell death through generating reactive oxygen species (ROS). The role of mETC inhibitors in autophagy-induced cell death is unknown. Herein, we determined that inhibitors of complex I (rotenone) and complex II (TTFA) induce cell death and autophagy in the transformed cell line HEK 293, and in cancer cell lines U87 and HeLa. Blocking the expression of autophagic genes (beclin 1 and ATG5) by siRNAs or using the autophagy inhibitor 3-methyladenine (3-MA) decreased cell death that was induced by rotenone or TTFA. Rotenone and TTFA induce ROS production, and the ROS scavenger tiron decreased autophagy and cell death induced by rotenone and TTFA. Overexpression of manganese-superoxide dismutase (SOD2) in HeLa cells decreased autophagy and cell death induced by rotenone and TTFA. Furthermore, blocking SOD2 expression by siRNA in HeLa cells increased ROS generation, autophagy and cell death induced by rotenone and TTFA. Rotenone- and TTFA-induced ROS generation was not affected by 3-MA, or by beclin 1 and ATG5 siRNAs. By contrast, treatment of non-transformed primary mouse astrocytes with rotenone or TTFA failed to significantly increase levels of ROS or autophagy. These results indicate that targeting mETC complex I and II selectively induces autophagic cell death through a ROS-mediated mechanism.", "corpus_id": 6475016, "score": 1 }, { "doc_id": "7640899", "title": "Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells", "abstract": "Autophagy is a self-digestion process that degrades intracellular structures in response to stresses leading to cell survival. When autophagy is prolonged, this could lead to cell death. Generation of reactive oxygen species (ROS) through oxidative stress causes cell death. The role of autophagy in oxidative stress-induced cell death is unknown. In this study, we report that two ROS-generating agents, hydrogen peroxide (H2O2) and 2-methoxyestradiol (2-ME), induced autophagy in the transformed cell line HEK293 and the cancer cell lines U87 and HeLa. Blocking this autophagy response using inhibitor 3-methyladenine or small interfering RNAs against autophagy genes, beclin-1, atg-5 and atg-7 inhibited H2O2 or 2-ME-induced cell death. H2O2 and 2-ME also induced apoptosis but blocking apoptosis using the caspase inhibitor zVAD-fmk (benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone) failed to inhibit autophagy and cell death suggesting that autophagy-induced cell death occurred independent of apoptosis. Blocking ROS production induced by H2O2 or 2-ME through overexpression of manganese-superoxide dismutase or using ROS scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid-disodium salt decreased autophagy and cell death. Blocking autophagy did not affect H2O2- or 2-ME-induced ROS generation, suggesting that ROS generation occurs upstream of autophagy. In contrast, H2O2 or 2-ME failed to significantly increase autophagy in mouse astrocytes. Taken together, ROS induced autophagic cell death in transformed and cancer cells but failed to induce autophagic cell death in non-transformed cells.", "corpus_id": 7640899, "score": 1 }, { "doc_id": "22100039", "title": "Hyperthermia in combination with oxidative stress induces autophagic cell death in HT‐29 colon cancer cells", "abstract": "The purpose of this study was to evaluate the mechanism of ROS‐induced hyperthermic cell death in a colon cancer cell line. HT‐29 colon cancer cells were exposed to heat (43 °C) in the presence of tert‐butyl hydroperoxide (t‐BOOH). t‐BOOH combined with hyperthermia significantly decreased cell viability as compared with t‐BOOH or hyperthermia alone. This decrease in cell numbers was associated with retardation in the S phase transit and not through apoptosis. Cell death was noted to be accompanied by specific features characteristic of autophagy: the presence of cytoplasmic autophagic vacuoles; autophagosome membrane association of microtubule‐associated protein light chain 3; accumulation of acidic vesicular organelles; and increased incorporation of MDC in the autophagosome. Thermal sensitization through modulation of cellular ROS may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality.", "corpus_id": 22100039, "score": 0 }, { "doc_id": "196584778", "title": "The reduced catalase expression in TrkA-induced cells leads to autophagic cell death via ROS accumulation", "abstract": "TrkA receptor activation is a pivotal process for neuronal cell differentiation and survival. However, its overactivation or removal of its ligand NGF tends to cause the cell death. Recently, we demonstrated that TrkA overexpression induces cell death via apoptosis. In this study we also show that the TrkA-mediated cell death is associated with autophagy. TrkA-induced cells revealed an increase of GFP-LC3 punctate formation, development of acidic vesicular organelles (AVO) and formation of autophagosomes, which were eventually blocked by the addition of some autophagy inhibitors such as 3-methyladenine, ammonium chloride or wortmannin. In addition, although expression of autophagy-related proteins such as LC3-II or Beclin-1 was subtly altered during the TrkA-mediated cell death, depletion of ATG5 or Beclin-1 substantially decreased cell death in TrkA-expressing cells. In particular, reactive oxygen species (ROS) were dramatically accumulated in TrkA-induced cells, and the high accumulation of ROS was released by treatment of autophagy inhibitors. Furthermore, addition of an antioxidant N-acetylcysteine promoted the survival of TrkA-expressing cells and suppressed AVO production in cells. We also showed that this ROS accumulation was closely associated with reduction of catalase expression. Taken together, TrkA overexpression causes ROS accumulation via reduced catalase expression, ultimately leading to autophagic cell death.", "corpus_id": 196584778, "score": 0 }, { "doc_id": "11058364", "title": "Compensatory activation of ERK1/2 in Atg5-deficient mouse embryo fibroblasts suppresses oxidative stress-induced cell death", "abstract": "Despite of the increasing evidence that oxidative stress may induce non-apoptotic cell death or autophagic cell death, the mechanism of this process is unclear. Here, we report a role and a down-stream molecular event of Atg5 during oxidative stress-induced cell death. Compared to wild type (WT) cells, Atg5-deficient mouse embryo fibroblasts (Atg5-/- MEFs) and Atg5 knockdown HT22 neuronal cells were more resistant to cell death induced by H2O2. On the contrary, Atg5-/- MEFs were as sensitive to tumor necrosis factor (TNF)-α and cycloheximide as WT cells, and were more sensitive to cell death triggered by amino acid-deprivation than WT MEFs. Treatment with H2O2 induced the recruitment of a GFP-LC3 fusion protein and conversion of LC3 I to LC3 II, correlated with the extent of autophagosome formation in WT cells, but much less in Atg5-deficient cells. Among stress kinases, ERK1/2 was markedly activated in Atg5-/- MEFs and Atg5 knockdown HT22 and SH-SY5Y neuronal cells. The inhibition of ERK1/2 by MEK1 inhibitor (PD98059) or dominant negative ERK2 enhanced the susceptibility of Atg5-/- MEFs to H2O2-induced cell death. Further, reconstitution of Atg5 sensitized Atg5-/- MEFs to H2O2 and suppressed the activation of ERK1/2. These results suggest that the inhibitory effect of Atg5 deficiency on cell death is attributable by the compensatory activation of ERK1/2 in Atg5-/- MEFs during oxidative stress-induced cell death.", "corpus_id": 11058364, "score": 0 }, { "doc_id": "33239486", "title": "Reactive oxygen species and nitric oxide regulate mitochondria-dependent apoptosis and autophagy in evodiamine-treated human cervix carcinoma HeLa cells", "abstract": "The redox environment of the cell is currently thought to be extremely important to control either apoptosis or autophagy. This study reported that reactive oxygen species (ROS) and nitric oxide (NO) generations were induced by evodiamine time-dependently; while they acted in synergy to trigger mitochondria-dependent apoptosis by induction of mitochondrial membrane permeabilization (MMP) through increasing the Bax/Bcl-2 or Bcl-xL ratio. Autophagy was also stimulated by evodiamine, as demonstrated by the positive autophagosome-specific dye monodansylcadaverine (MDC) staining as well as the expressions of autophagy-related proteins, Beclin 1 and LC3. Pre-treatment with 3-MA, the specific inhibitor for autophagy, dose-dependently decreased cell viability, indicating a survival function of autophagy. Importantly, autophagy was found to be promoted or inhibited by ROS/NO in response to the severity of oxidative stress. These findings could help shed light on the complex regulation of intracellular redox status on the balance of autophagy and apoptosis in anti-cancer therapies.", "corpus_id": 33239486, "score": 0 }, { "doc_id": "40500365", "title": "Autophagy in cell death: an innocent convict?", "abstract": "The visualization of autophagosomes in dying cells has led to the belief that autophagy is a nonapoptotic form of programmed cell death. This concept has now been evaluated using cells and organisms deficient in autophagy genes. Most evidence indicates that, at least in cells with intact apoptotic machinery, autophagy is primarily a pro-survival rather than a pro-death mechanism. This review summarizes the evidence linking autophagy to cell survival and cell death, the complex interplay between autophagy and apoptosis pathways, and the role of autophagy-dependent survival and death pathways in clinical diseases.", "corpus_id": 40500365, "score": 0 }, { "doc_id": "3126469", "title": "Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3", "abstract": "Hypoxia (lack of oxygen) is a physiological stress often associated with solid tumors. Hypoxia correlates with poor prognosis since hypoxic regions within tumors are considered apoptosis-resistant. Autophagy (cellular “self digestion”) has been associated with hypoxia during cardiac ischemia and metabolic stress as a survival mechanism. However, although autophagy is best characterized as a survival response, it can also function as a mechanism of programmed cell death. Our results show that autophagic cell death is induced by hypoxia in cancer cells with intact apoptotic machinery. We have analyzed two glioma cell lines (U87, U373), two breast cancer cell lines (MDA-MB-231, ZR75) and one embryonic cell line (HEK293) for cell death response in hypoxia (", "corpus_id": 3126469, "score": 0 }, { "doc_id": "12816678", "title": "How to Interpret LC3 Immunoblotting", "abstract": "Microtubule-associated protein light chain 3 (LC3) is now widely used to monitor autophagy. One approach is to detect LC3 conversion (LC3-I to LC3-II) by immunoblot analysis because the amount of LC3-II is clearly correlated with the number of autophagosomes. However, LC3-II itself is degraded by autophagy, making interpretation of the results of LC3 immunoblotting problematic. Furthermore, the amount of LC3 at a certain time point does not indicate autophagic flux, and therefore, it is important to measure the amount of LC3-II delivered to lysosomes by comparing LC3-II levels in the presence and absence of lysosomal protease inhibitors. Another problem with this method is that LC3-II tends to be much more sensitive to be detected by immunoblotting than LC3-I. Accordingly, simple comparison of LC3-I and LC3-II, or summation of LC3-I and LC3-II for ratio determinations, may not be appropriate, and rather, the amount of LC3-II can be compared between samples.", "corpus_id": 12816678, "score": 0 }, { "doc_id": "40449248", "title": "Oxidative stress and apoptosis: impact on cancer therapy.", "abstract": "It is well established that some chemotherapeutic agents and radiation therapy generate reactive oxygen species (ROS) in patients during cancer therapy. Free radicals, particularly ROS have been proposed as common mediators for apoptosis. Recent studies have demonstrated that the mode of cell death depends on the severity of the oxidative damage. This review will address some of the current paradigms of oxidative stress, and antioxidants on apoptosis, and discuss the potential mechanisms by which oxidants can regulate apoptotic pathways. It will also review new developments in eliminating cancer cells by selectively inducing apoptosis.", "corpus_id": 40449248, "score": 0 }, { "doc_id": "45438817", "title": "Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment.", "abstract": "Reactive oxygen species (ROS) have been identified as signaling molecules in various pathways regulating both cell survival and cell death. Autophagy, a self-digestion process that degrades intracellular structures in response to stress, such as nutrient starvation, is also involved in both cell survival and cell death. Alterations in both ROS and autophagy regulation contribute to cancer initiation and progression, and both are targets for developing therapies to induce cell death selectively in cancer cells. Many stimuli that induce ROS generation also induce autophagy, including nutrient starvation, mitochondrial toxins, hypoxia, and oxidative stress. Some of these stimuli are under clinical investigation as cancer treatments, such as 2-methoxyestrodial and arsenic trioxide. Recently, it was demonstrated that ROS can induce autophagy through several distinct mechanisms involving Atg4, catalase, and the mitochondrial electron transport chain (mETC). This leads to both cell-survival and cell-death responses and could be selective toward cancer cells. In this review, we give an overview of the roles ROS and autophagy play in cell survival and cell death, and their importance to cancer. Furthermore, we describe how autophagy is mediated by ROS and the implications of this regulation to cancer treatments.", "corpus_id": 45438817, "score": 0 }, { "doc_id": "4318344", "title": "Autophagy fights disease through cellular self-digestion", "abstract": "Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.", "corpus_id": 4318344, "score": 0 }, { "doc_id": "11386093", "title": "2-Methoxyestradiol-induced apoptosis in human leukemia cells proceeds through a reactive oxygen species and Akt-dependent process", "abstract": "The effects of 2-Methoxyestradiol (2ME)-induced apoptosis was examined in human leukemia cells (U937 and Jurkat) in relation to mitochondrial injury, oxidative damage, and perturbations in signaling pathways. 2ME induced apoptosis in these cells in a dose-dependent manner associated with release of mitochondrial proteins (cytochrome c, AIF), generation of reactive oxygen species (ROS), downregulation of Mcl-1 and XIAP, and inactivation (dephosphorylation) of Akt accompanied by activation of JNK. In these cells, enforced activation of Akt by a constitutively active myristolated Akt construct prevented 2ME-mediated mitochondrial injury, XIAP and Mcl-1 downregulation, JNK activation, and apoptosis, but not ROS generation. Conversely, 2ME lethality was potentiated by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Furthermore, in U937 cells, the hydrogen peroxide scavenger catalase and a superoxide dismutase (SOD) mimetic, TBAP, blocked these events, as well as Akt inactivation. Interruption of the JNK pathway by pharmacologic or genetic (e.g. siRNA) means attenuated 2ME-induced mitochondrial injury, XIAP and Mcl-1 downregulation, and apoptosis. Collectively, these findings suggest a hierarchical model of 2ME-related apoptosis induction in human leukemia cells in which 2ME-induced oxidative injury represents a primary event resulting in Akt inactivation, leading, in turn, to JNK activation, and culminating in XIAP and Mcl-1 downregulation, mitochondrial injury, and apoptosis. They also suggest that in human leukemia cells, the Akt pathway plays a critical role in mediating the response to oxidative stress induced by 2ME.", "corpus_id": 11386093, "score": 0 }, { "doc_id": "29770930", "title": "Detection of catalase in rat heart mitochondria.", "abstract": "The presence of heme-containing catalase in rat heart mitochondria (20 +/- 5 units/mg) was demonstrated by biochemical and immunocytochemical analysis. Intact rat heart mitochondria efficiently consumed exogenously added H2O2. The rate of H2O2 consumption was not influenced by succinate, glutamate/malate, or N-ethylmaleimide but was significantly inhibited by cyanide. Hydrogen peroxide decomposition by mitochondria yielded molecular oxygen in a 2:1 stoichiometry, consistent with a catalytic mechanism. Mitochondrial fractionation studies and quantitative electron microscopic immunocytochemistry revealed that most catalase was matrix-associated. Electrophoretic analysis and Western blotting of the mitochondrial matrix fraction indicated the presence of a protein with similar electrophoretic mobility to bovine and rat liver catalase and immunoreactive to anti-catalase antibody. Myocardial tissue has a lower catalase-specific activity and a greater mitochondrial H2O2 production/g of tissue than most organs. Thus catalase, representing 0.025% of heart mitochondrial protein, is important for detoxifying mitochondrial derived H2O2 and represents a key antioxidant defense mechanism for myocardial tissue.", "corpus_id": 29770930, "score": 0 } ]

{ "doc_id": "16600184", "title": "Isolated Intracranial Rosai-Dorfman Disease", "abstract": "Background. Rosai-Dorfman disease (RDD) is a benign histiocytic proliferative disorder of unknown etiology. This rare condition commonly causes massive cervical lymphadenopathy. Intracranial RDD without any nodal involvement is extremely rare. Case Report. A young Bangladeshi male complained of bilateral complete blindness with left sided deafness for about three years. There was no lymphadenopathy. MRI and CT scan of brain suggested an inflammatory/neoplastic (?meningioma) lesion located at left parasellar region which extended frontally to encircle both optic nerves and also to left prepontine area. Histopathologically the lesion was diagnosed as RDD. The patient was treated with steroid and significant clinical improvement observed. Conclusion. The prognosis of intracranial RDD is not poor. It can be treated with surgery with or without corticosteroids, chemotherapy, and so forth. But as the condition is extremely rare and often misdiagnosed, the clinician, radiologist, and histopathologist should have a suspicion in their mind about the possibility of RDD.", "corpus_id": 16600184 }

[ { "doc_id": "45488972", "title": "Intracranial Rosai-Dorfman disease with relapsing spinal lesions.", "abstract": "et al: Treatment of children with B-cell non-Hodgkin's lymphoma in developing countries: The experience of a single center in Brazil. et al: Laboratory strategies for efficient handling of paraffin-embedded tissues for molecular detection of clonality in non-Hodgkin lymphomas. et al: VH gene sequences from primary central nervous system lymphomas indicate derivation from highly mutated germinal center B cell with ongoing mutational activity. 6. Camilleri-Broë t S, Martin A, Moreau A, et al: Primary central nervous system lymphomas in 72 immunocompetent patients: Pathological findings and clinical correlations: Groupe Ouest Est d'E ´ tude des Leucé mies et Autres Mala-dies du Sang (GOELAMS). Am J Clin Pathol 110:607-612, 1998 7. Montesinos-Rongen M, Kü ppers R, Schlü ter D, et al: Primary central nervous system lymphomas are derived from germinal-center B cells and show a preferential usage of the V4-34 gene segment. et al: AIDS primary central nervous system lymphoma: Molecular analysis of the expressed VH genes and possible implications for lymphomagenesis. A, et al: The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the disease and is consistent with histogenetic derivation from germinal center-related B cells. 11. Camilleri-Broë t S, Criniere E, Broë t P, et al: A uniform activated B-cell like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: Analysis of 83 cases. A 50-year-old man developed a left lateral occipital tingling sensation , left-sided intermittent diplopia, and numbness over the left lip and cheek. Magnetic resonance imaging (MRI) demonstrated multiple extra-axial dural-based lesions (Fig 1A-1D, yellow arrows). The largest lesions were located at the left frontal convexity and both temporal regions and exhibited homogenous isointense signal intensity to gray matter on T1-and T2-weighted images, subtle hyperin-tensity on the fluid-attenuated inversion recovery images, and avid contrast uptake. Diffusion-weighted images, apparent diffusion coefficient values, and the exponential diffusion coefficient were all isoin-tense to gray matter. Perilesional brain edema (Fig 1B, blue asterisk) and mass effect were also evident. An enhancing dural tail was present (Fig 1D, blue arrow), with no evidence of hyperostosis, calcification, or hemorrhage. Bilateral petroclival lesions that exhibited the same signal behavior were also present, with extension into the prepontine cistern and compression of the corresponding cavernous sinuses and trigeminal nerves at the Meckel's caves (Figs 1A-1C). The smaller lesions appeared as a plaque-like enhancing focal meningeal thickening with no mass effect, edema, or hyperostosis. They were not dis-cernable …", "corpus_id": 45488972, "score": 1 }, { "doc_id": "22941930", "title": "Rosai-Dorfman Disease Isolated to the Central Nervous System: A Report of 11 Cases", "abstract": "Sinus histocytosis with massive lymphadenopathy, also known as Rosai-Dorfman Disease (RDD), is an idiopathic histiocytic proliferation affecting lymph nodes. Although extranodal involvement has been reported in diverse sites, central nervous system (CNS) manifestation, particularly in the absence of nodal disease is uncommon. We report 11 cases of RDD primary to the CNS without evidence of other sites of involvement. The cases included 7 males and 4 females ranging in age from 22 to 63 years (mean: 41 y). The patients presented with headaches, seizures, numbness, or paraplegia. Eight cases involved the cranial cavity and three cases, the spinal canal. Lesions were most often extra-axial and dura based. Only one presented in the CNS parenchyma. Histologically, the lesions consisted of variable numbers of pale-staining histocytes with emperipolesis often overshadowed by extensive lymphoplasmacytic infiltrates and fibrosis in the background. Special stains for organisms were negative. By immunohistochemical analysis, the characteristic histiocytes were positive for S100 protein and CD68 and negative for CD1a. Treatment consisted of surgical biopsy or excision. Follow-up, available for 10 cases with intervals ranging from 5 days to 42 months (mean: 15 mo), disclosed one patient dying of operative complications 5 days after biopsy and nine patients with no evidence of disease progression RDD should be considered in the differential diagnosis of inflammatory lesions of the CNS. Our study suggests that this entity may have been misdiagnosed in the past as plasma cell granuloma or inflammatory pseudotumor.", "corpus_id": 22941930, "score": 1 }, { "doc_id": "31133415", "title": "Isolated intracranial Rosai Dorfman disease.", "abstract": "Rosai Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a benign histiocytic proliferative disorder mainly affecting the lymph nodes. Although several cases of extra-nodal involvement have been reported previously, central nervous system involvement, particularly in the absence of nodal disease is extremely rare. We report a case of isolated intracranial RDD occurring in a relatively elder patient, which was shown by histological examination to have a dura-based involvement.", "corpus_id": 31133415, "score": 0 }, { "doc_id": "10390622", "title": "Isolated intracranial Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy).", "abstract": "SUMMARY\nRosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) rarely affects the intracranial region without involvement of other sites. We report the case of a 68-year-old woman with isolated Rosai-Dorfman disease of the frontal dura. She presented with a new onset seizure. Initial MR imaging showed subtle mild change in the left frontal region. During the ensuing 8 months, a dural mass made its symptomatic and definite MR imaging appearance in the same region. No extracranial lesion was present.", "corpus_id": 10390622, "score": 1 }, { "doc_id": "26582426", "title": "Isolated intracranial Rosai-Dorfman disease mimicking meningioma in a child: a case report and review of the literature.", "abstract": "We report the first case of extensive involvement of isolated intracranial Rosai-Dorfman's disease (RDD) in a child. Our case is unique because it presents with involvement of the middle cranial fossa, cavernous sinus, pituitary gland, orbit, ethmoid and sphenoid sinuses. Previous cases of intracranial RDD in children have reported separate involvement of cavernous sinus, suprasellar region, and frontal and petroclival regions. Involvement of the pituitary gland has so far not been reported. A 14-year-old male presented with a medical history of loss of vision, raised erythrocyte sedimentation rate (ESR), and abnormal prolactin and cortisol levels. Radiologically the diagnosis was meningioma. The histopathological diagnosis was RDD with emperipolesis and S-100 positivity. RDD is a histiocytic proliferation of unknown aetiology, which commonly affects lymph nodes. Uncommonly it involves the extranodal sites and rarely the central nervous system (CNS). 80 cases of RDD involving CNS have been reported in the literature, and only 5 were in children. Although the definitive diagnosis of RDD disease is based on the histopathology report, it should be included in the differentials of a lesion mimicking meningioma especially in children.", "corpus_id": 26582426, "score": 1 }, { "doc_id": "36429541", "title": "Multiple involvement of the central nervous system in Rosai-Dorfman disease.", "abstract": "Rosai-Dorfman disease is a rare, benign, idiopathic histio-proliferative disorder. Only 5% of cases involve the central nervous system. We describe a 10-year-old girl with pain in her lower limbs and back. Spinal magnetic resonance imaging revealed an intradural extramedullary lesion at T9-T10. We decided on surgical treatment. An anatomic/pathologic examination revealed histiocytic-like cells and extensive fibrosis. Immunohistochemistry revealed positivity for CD68 protein and negativity for CD1a protein. Craniospinal magnetic resonance imaging demonstrated an extra-axial lesion in the right frontal region, a small nodule in the left middle cerebellar peduncle, and another small lesion in the right ventral pons. We performed a complete removal of the frontal lesion. The histologic examination produced results compatible with Rosai-Dorfman disease. Most lesions in intracranial Rosai-Dorfman disease mimic meningioma. The definitive diagnosis relies on pathologic and immunohistochemical characteristics. Surgical removal is generally regarded as the treatment of choice. Disease progression after surgical resection is uncommon. Surgical treatment is not recommended until clear disease progression is detected, or focal disease causes neurologic compression. This disease must be included in the differential diagnosis of lesions that mimic meningioma.", "corpus_id": 36429541, "score": 1 }, { "doc_id": "26140578", "title": "Solitary Intracranial Rosai-Dorfman Disease: Case Report and Literature Review", "abstract": "Rosai-Dorfman disease is a well-established autoimmune histioproliferative disorder, and solitary central nervous system involvement is rare. A 35-year-old man presented with headache and transient blurred vision of 4 months' duration and weakness of the left extremities for 1 month. He had left temporal hemianopsia, a right nasal visual field defect of the upper medial quadrant and decreased muscle strength of the left extremities. Magnetic resonance imaging (MRI) showed a contrast-enhancing tentorium-based lesion in the right trigone, intruding into the right lateral ventricle. The lesion was totally resected. Rosai-Dorfman disease was confirmed pathologically by an inflammatory infiltrate in the absence of an infectious agent, emperipolesis and positive S100 staining. From a review of the literature on Rosai-Dorfman disease in the central nervous system it is concluded that follow-up MRI should be performed in order to detect possible recurrence and that this rare entity should be considered in the differential diagnosis of intracranial lesions.", "corpus_id": 26140578, "score": 0 }, { "doc_id": "897276", "title": "Rosai dorfman disease of the orbit", "abstract": "ObjectiveTo report the clinico-histopathologic features, management and outcome of Rosai-Dorfman disease of the orbit.DesignNon-comparative case series.ResultsRosai-Dorfman disease of the orbit constituted 0.09% of all ocular specimens received at our Institute, presenting with a firm rubbery mass causing proptosis; bilateral in 4 (57%) cases. The median age at presentation was 13 years (range 5–65); median duration of symptoms was 6 (range 3–15) years. Lymphadenopathy was noted in 4 (57%); extranodal involvement in 3 (43%). After biopsy, 3 cases were treated with systemic corticosteroids, 2 cases developed local recurrence that responded to systemic corticosteroid therapy. Polymorphous population of lymphocytes, plasma cells, and characteristic S-100-positive histiocytes showing emperipolesis were pathognomonic histologic features.ConclusionRosai-Dorfman disease of the orbit, although rare, should be considered in young individuals with chronic proptosis with rubbery masses. Excision and corticosteroid therapy provide a favorable outcome.", "corpus_id": 897276, "score": 0 }, { "doc_id": "39970387", "title": "Regression of intracranial rosai-dorfman disease following corticosteroid therapy. Case report.", "abstract": "Rosai-Dorfman disease (RDD) is an idiopathic histioproliferative disorder usually presenting with massive, painless lymphadenopathy. Extranodal involvement has been reported including at least 50 cases affecting the central nervous system (CNS). The treatment of CNS RDD as reported in the literature has primarily involved a surgical technique. The authors report on the case of a 53-year-old man presenting with multiple skull base lesions mimicking meningiomas. The patient suffered visual deterioration and underwent a right orbitopterional craniotomy as well as optic nerve decompression. Histopathological analysis revealed histiocytic cells and emperipolesis consistent with RDD. Following surgery, corticosteroid agents were administered, leading to marked resolution of both the remaining surgically untreated lesions and the balance of the patient's symptoms. This report represents the first case of the resolution of intracranial RDD following corticosteroid therapy. Corticosteroid agents should be considered an effective option in the treatment of CNS RDD.", "corpus_id": 39970387, "score": 0 }, { "doc_id": "23199854", "title": "Sinus Histiocytosis With Massive Lymphadenopathy Involving the Orbit: Reversal of Compressive Optic Neuropathy After Chemotherapy", "abstract": "A 38-year-old woman from Antigua had compressive optic neuropathy of the right eye caused by orbital involvement with sinus histiocytosis. There was also nasal sinus involvement and massive cervical lymphadenopathy resulting in radiographic compression of the airway and carotid sheath. Because of the compressive optic neuropathy and threat to the airway and carotid perfusion, the patient underwent a 6-month chemotherapeutic regimen of cyclophosphamide, vincristine, and prednisone. After chemotherapy, the visual dysfunction resolved in correlation with diminution of the orbital mass, and marked regression of the cervical lymphadenopathy. This case demonstrates the potential efficacy of chemotherapy in the treatment of compressive optic neuropathy in cases of orbital sinus histiocytosis with massive lymphadenopathy.", "corpus_id": 23199854, "score": 0 }, { "doc_id": "9470180", "title": "Rosai–Dorfman Disease. Extranodal Sinus Histiocytosis in Three Co-existing Sites. A Case Report", "abstract": "A 73-year-old woman presented with mild anterior uveitis, ipsilateral optic neuropathy, and ipsilateral skin nodules. A compressive mass at the level of the orbital apex and sphenoid wing was found on cranial magnetic resonance imaging. Biopsy of the skin nodules revealed histopathologic evidence of sinus histiocytosis with massive lymphadenopathy, or Rosai–Dorfman disease (RDD). Systemic investigations failed to show any massive lymphadenopathy, making this a case of extranodal RDD. This is a salient case in that it proposes three simultaneous and separate sites of involvement by extranodal RDD. It also exemplifies that RDD should be a suspect diagnosis even in the absence of lymphadenopathy.", "corpus_id": 9470180, "score": 1 }, { "doc_id": "8835647", "title": "Subconjunctival Masses Associated With Central Nervous System Rosai–Dorfman Disease", "abstract": "Purpose: To describe a case of subconjunctival masses with multiple intracranial masses diagnosed as Rosai-Dorfman disease by biopsy. Methods: Case report. Results: A 25-year-old white man presented with bilateral subconjunctival masses, left optic nerve pallor, and posterior segment changes suggestive of regressed choroidal disease. Systemic evaluation was instituted including blood testing, neuroimaging, brain biopsy, and biopsy of the left subconjunctival mass. Pathologic analysis of the brain and subconjunctival mass biopsies revealed Rosai-Dorfman disease. Conclusions: The authors present a case of extensive extranodal involvement of Rosai-Dorfman of the eye and the central nervous system.", "corpus_id": 8835647, "score": 0 }, { "doc_id": "16769681", "title": "Sinus histiocytosis with massive lymphadenopathy--isolated suprasellar involvement.", "abstract": "An unusual case of an isolated histioproliferative lesion arising from the suprasellar region is described. The presence of lymphophagocytosis suggested that this represented an extranodal intracranial form of sinus histiocytosis with massive lymphadenopathy.", "corpus_id": 16769681, "score": 0 }, { "doc_id": "23081400", "title": "Rosai Dorfman disease: Case with extensive dural involvement and cerebrospinal fluid pleocytosis", "abstract": "We report a young adult man who presented with chronic raised intracranial tension features and unusually progressive bilateral visual and hearing impairment of 18 months duration. MR imaging showed extensive dural involvement and contiguous orbital and spinal disease. Cerebrospinal fluid demonstrated persistent high lymphocytic pleocytosis. Dural biopsy obtained from posterior cervical approach with C1 arch excision and meningeal biopsy revealed features of classical of Rosai-Dorfman disease. Histiocytes were strongly positive for CD-68 and S-100 proteins. The illness relentlessly progressed with patient developing total deafness and near total blindness at last follow-up.", "corpus_id": 23081400, "score": 0 }, { "doc_id": "25512534", "title": "Rosai-Dorfman disease associated with neurosensorial hearing loss in two siblings.", "abstract": "Rosai-Dorfman disease (RDD) is an uncommon pathologic condition of unknown ethiology with an idiopathic proliferation of the hystiocytes. It is generally presented with massive bilateral hypertrophy of the cervical lymph nodes. But other lymph nodes may also be involved. Approximately, 30% of these patients have extra nodal mass or lesion with different signs or symptoms depending on localization. We present two male siblings with Rosai-Dorfman disease who have classical cervical lymphadenopathy associated with progressive neurosensorial hearing loss and dural-based intracranial lesions.", "corpus_id": 25512534, "score": 0 }, { "doc_id": "26054034", "title": "Otolaryngologic manifestations of Rosai-Dorfman Disease.", "abstract": "PURPOSE\nTo describe an unusual head and neck occurrence of Rosai-Dorfman Disease (RDD) and to review the otolaryngologic manifestations of this rare entity.\n\n\nMETHODS\nA case presentation with review of the literature describing Rosai-Dorfman Disease and its head and neck involvement.\n\n\nSETTING\nA tertiary care, urban children's hospital.\n\n\nRESULTS\nThis is the first description, to the best of our knowledge, of RDD [Sinus Histiocytosis with Massive Lymphadenopathy (SHML)] involving bilateral external auditory canals and middle ear in a 12 year old patient previously diagnosed with 'asthma' and hearing loss. This patient also had extensive involvement of the tracheobronchial tree. Representative clinical, radiographic and histological findings are presented. Its etiology, diagnosis and management are also reviewed.\n\n\nCONCLUSION\nThis is the first reported case of middle ear and external auditory canal involvement of RDD in a patient with hearing loss and associated tracheobronchial lesions. RDD, although rare, may be considered in the differential diagnosis of unusual histiocytic lesions of the external auditory canal, especially with findings of similar or comparable lesions involving the respiratory tract. Confirmation is with identification of emperipolesis and appropriate immunohistochemical staining (S-100 positive, CD-68 positive and CD-1a negative). Intervention is recommended in cases where there is increased risk of mortality, as in severe obstruction of the tracheobronchial tree. Otherwise, since these lesions are self-limiting, the patients can be observed closely.", "corpus_id": 26054034, "score": 0 } ]

{ "doc_id": "29236662", "title": "Charge-dependent secretion of an intrinsically disordered protein via the autotransporter pathway", "abstract": "Significance Bacterial autotransporter proteins contain a large segment that is transported from the periplasm (the space between the inner and outer membranes) to the extracellular milieu. Because the periplasm lacks ATP, the energy required for the transport reaction is thought to be derived from the folding of this segment following its secretion. Contrary to the prevailing view, we found that a heterologous polypeptide that cannot fold was secreted efficiently when it was fused to an autotransporter. Reducing the negative charge of this polypeptide, however, strongly impaired secretion. Our results identify net charge as a potentially important factor that drives autotransporter secretion. Autotransporters are a large class of virulence proteins produced by Gram-negative bacteria. They contain an N-terminal extracellular (“passenger”) domain that folds into a β-helical structure and a C-terminal β-barrel (“β”) domain that anchors the protein to the outer membrane. Because the periplasm lacks ATP, the source of energy that drives passenger domain secretion is unknown. The prevailing model postulates that vectorial folding of the β-helix in the extracellular space facilitates unidirectional secretion of the passenger domain. In this study we used a chimeric protein composed of the 675-residue receptor-binding domain (RD) of the Bordetella pertussis adenylate cyclase toxin CyaA fused to the C terminus of the Escherichia coli O157:H7 autotransporter EspP to test this hypothesis. The RD is a highly acidic, repetitive polypeptide that is intrinsically disordered in the absence of calcium. Surprisingly, we found that the RD moiety was efficiently secreted when it remained in an unfolded conformation. Furthermore, we found that neutralizing or reversing the charge of acidic amino acid clusters stalled translocation in the vicinity of the altered residues. These results challenge the vectorial folding model and, together with the finding that naturally occurring passenger domains are predominantly acidic, provide evidence that a net negative charge plays a significant role in driving the translocation reaction.", "corpus_id": 29236662 }

[ { "doc_id": "19562964", "title": "From self sufficiency to dependence: mechanisms and factors important for autotransporter biogenesis", "abstract": "Autotransporters are a superfamily of proteins that use the type V secretion pathway for their delivery to the surface of Gram-negative bacteria. At first glance, autotransporters look to contain all the functional elements required to promote their own secretion: an amino-terminal signal peptide to mediate translocation across the inner membrane, a central passenger domain that is the secreted functional moiety, and a channel-forming carboxyl terminus that facilitates passenger domain translocation across the outer membrane. However, recent discoveries of common structural themes, translocation intermediates and accessory interactions have challenged the perceived simplicity of autotransporter secretion. Here, we discuss how these studies have led to an improved understanding of the mechanisms responsible for autotransporter biogenesis.", "corpus_id": 19562964, "score": 0 }, { "doc_id": "31652774", "title": "Pertactin beta-helix folding mechanism suggests common themes for the secretion and folding of autotransporter proteins.", "abstract": "Many virulence factors secreted from pathogenic Gram-negative bacteria are autotransporter proteins. The final step of autotransporter secretion is C --> N-terminal threading of the passenger domain through the outer membrane (OM), mediated by a cotranslated C-terminal porin domain. The native structure is formed only after this final secretion step, which requires neither ATP nor a proton gradient. Sequence analysis reveals that, despite size, sequence, and functional diversity among autotransporter passenger domains, >97% are predicted to form parallel beta-helices, indicating this structural topology may be important for secretion. We report the folding behavior of pertactin, an autotransporter passenger domain from Bordetella pertussis. The pertactin beta-helix folds reversibly in isolation, but folding is much slower than expected based on size and native-state topology. Surprisingly, pertactin is not prone to aggregation during folding, even though folding is extremely slow. Interestingly, equilibrium denaturation results in the formation of a partially folded structure, a stable core comprising the C-terminal half of the protein. Examination of the pertactin crystal structure does not reveal any obvious reason for the enhanced stability of the C terminus. In vivo, slow folding would prevent premature folding of the passenger domain in the periplasm, before OM secretion. Moreover, the extra stability of the C-terminal rungs of the beta-helix might serve as a template for the formation of native protein during OM secretion; hence, vectorial folding of the beta-helix could contribute to the energy-independent translocation mechanism. Coupled with the sequence analysis, the results presented here suggest a general mechanism for autotransporter secretion.", "corpus_id": 31652774, "score": 0 }, { "doc_id": "10221869", "title": "Autotransporter structure reveals intra-barrel cleavage followed by conformational changes", "abstract": "Autotransporters are virulence factors produced by Gram-negative bacteria. They consist of two domains, an N-terminal 'passenger' domain and a C-terminal β-domain. β-domains form β-barrel structures in the outer membrane while passenger domains are translocated into the extracellular space. In some autotransporters, the two domains are separated by proteolytic cleavage. Using X-ray crystallography, we solved the 2.7-Å structure of the post-cleavage state of the β-domain of EspP, an autotransporter produced by Escherichia coli strain O157:H7. The structure consists of a 12-stranded β-barrel with the passenger domain–β-domain cleavage junction located inside the barrel pore, approximately midway between the extracellular and periplasmic surfaces of the outer membrane. The structure reveals an unprecedented intra-barrel cleavage mechanism and suggests that two conformational changes occur in the β-domain after cleavage, one conferring increased stability on the β-domain and another restricting access to the barrel pore.", "corpus_id": 10221869, "score": 0 }, { "doc_id": "205245963", "title": "Interaction of an autotransporter passenger domain with BamA during its translocation across the bacterial outer membrane", "abstract": "Autotransporters are a superfamily of virulence factors produced by Gram-negative bacteria consisting of a large N-terminal extracellular domain (“passenger domain”) and a C-terminal β barrel domain (“β domain”). The mechanism by which the passenger domain is translocated across the outer membrane (OM) is unknown. Here we show that the insertion of a small linker into the passenger domain of the Escherichia coli O157:H7 autotransporter EspP effectively creates a translocation intermediate by transiently stalling translocation near the site of the insertion. Using a site-specific photocrosslinking approach, we found that residues adjacent to the stall point interact with BamA, a component of a heterooligomeric complex (Bam complex) that catalyzes OM protein assembly, and that residues closer to the EspP N terminus interact with the periplasmic chaperones SurA and Skp. The EspP–BamA interaction was short-lived and could be detected only when passenger domain translocation was stalled. These results support a model in which molecular chaperones prevent misfolding of the passenger domain before its secretion and the Bam complex catalyzes both the integration of the β domain into the OM and the translocation of the passenger domain across the OM in a C- to N-terminal direction.", "corpus_id": 205245963, "score": 1 }, { "doc_id": "20036874", "title": "Sequential and spatially restricted interactions of assembly factors with an autotransporter β domain", "abstract": "Autotransporters are bacterial virulence factors that consist of an N-terminal extracellular (“passenger”) domain and a C-terminal β barrel domain (“β domain”) that resides in the outer membrane. Here we used an in vivo site-specific photocrosslinking approach to gain insight into the mechanism by which the β domain is integrated into the outer membrane and the relationship between β domain assembly and passenger domain secretion. We found that periplasmic chaperones and specific components of the β barrel assembly machinery (Bam) complex interact with the β domain of the Escherichia coli O157:H7 autotransporter extracellular serine protease P (EspP) in a temporally and spatially regulated fashion. Although the chaperone Skp initially interacted with the entire β domain, BamA, BamB, and BamD subsequently interacted with discrete β domain regions. BamB and BamD remained bound to the β domain longer than BamA and therefore appeared to function at a later stage of assembly. Interestingly, we obtained evidence that the completion of β domain assembly is regulated by an intrinsic checkpoint mechanism that requires the completion of passenger domain secretion. In addition to leading to a detailed model of autotransporter biogenesis, our results suggest that the lipoprotein components of the Bam complex play a direct role in the membrane integration of β barrel proteins.", "corpus_id": 20036874, "score": 0 }, { "doc_id": "9847060", "title": "The Bam (Omp85) complex is involved in secretion of the autotransporter haemoglobin protease.", "abstract": "Autotransporters are large virulence factors secreted by Gram-negative bacteria. They are synthesized with a C-terminal domain that forms a beta-barrel pore in the outer membrane implicated in translocation of the upstream 'passenger' domain across the outer membrane. However, recent structural data suggest that the diameter of the beta-barrel pore is not sufficient to allow the passage of partly folded structures observed for several autotransporters. Here, we have used a stalled translocation intermediate of the autotransporter Hbp to identify components involved in insertion and translocation of the protein across the outer membrane. At this intermediate stage the beta-domain was not inserted and folded as an integral beta-barrel in the outer membrane whereas part of the passenger was surface exposed. The intermediate was copurified with the periplasmic chaperone SurA and subunits of the Bam (Omp85) complex that catalyse the insertion and assembly of outer-membrane proteins. The data suggest a critical role for this general machinery in the translocation of autotransporters across the outer membrane.", "corpus_id": 9847060, "score": 0 }, { "doc_id": "38646651", "title": "Role of a Highly Conserved Bacterial Protein in Outer Membrane Protein Assembly", "abstract": "After transport across the cytoplasmic membrane, bacterial outer membrane proteins are assembled into the outer membrane. Meningococcal Omp85 is a highly conserved protein in Gram-negative bacteria, and its homolog Toc75 is a component of the chloroplast protein-import machinery. Omp85 appeared to be essential for viability, and unassembled forms of various outer membrane proteins accumulated upon Omp85 depletion. Immunofluorescence microscopy revealed decreased surface exposure of outer membrane proteins, which was particularly apparent at the cell-division planes. Thus, Omp85 is likely to play a role in outer membrane protein assembly.", "corpus_id": 38646651, "score": 0 }, { "doc_id": "52861584", "title": "Reconstitution of Outer Membrane Protein Assembly from Purified Components", "abstract": "Bring Out the β-Barrel The assembly of β-barrel membrane proteins, which are found in the outer membrane of Gram-negative bacteria and in the mitochondria and chloroplasts of eukaryotes, is poorly understood. Now Hagan et al. (p. 890, published online 8 April; see the Perspective by Stroud et al.) describe the development of a reconstituted system that recapitulates the process of assembly of β-barrel membrane proteins by the Escherichia coli Bam complex. The assembly of a protein substrate required the purified five-protein Bam complex and several subcomplexes and a chaperone, but did not require an external input of energy. Assembly of a β-barrel membrane protein in a cell-free system does not require added energy. β-barrel membrane proteins in Gram-negative bacteria, mitochondria, and chloroplasts are assembled by highly conserved multi-protein complexes. The mechanism by which these molecular machines fold and insert their substrates is poorly understood. It has not been possible to dissect the folding and insertion pathway because the process has not been reproduced in a biochemical system. We purified the components that fold and insert Escherichia coli outer membrane proteins and reconstituted β-barrel protein assembly in proteoliposomes using the enzymatic activity of a protein substrate to report on its folding state. The assembly of this protein occurred without an energy source but required a soluble chaperone in addition to the multi-protein assembly complex.", "corpus_id": 52861584, "score": 0 }, { "doc_id": "24650962", "title": "Protein secretion in gram-negative bacteria via the autotransporter pathway.", "abstract": "Autotransporters are a large and diverse superfamily of proteins produced by pathogenic gram-negative bacteria that are composed of an N-terminal passenger domain, which typically harbors a virulence function, and a C-terminal beta domain. It has long been known that the beta domain anchors the protein to the outer membrane and facilitates transport of the passenger domain into the extracellular space. Despite the apparent simplicity of the autotransporter pathway, several aspects of autotransporter biogenesis remain poorly understood, most notably the mechanism by which the passenger domain is translocated across the outer membrane. Here we review recent evidence that the enormous sequence diversity of both passenger and beta domains belies a remarkable conservation of structure. We also discuss insights into each stage of autotransporter biogenesis that have emerged from recent structural, biochemical, and imaging studies.", "corpus_id": 24650962, "score": 0 }, { "doc_id": "85646598", "title": "Vectorial Transport and Folding of an Autotransporter Virulence Protein During Outer Membrane Secretion", "abstract": "Many virulence factors secreted from pathogenic Gram-negative bacteria are autotransporter proteins. The final step of autotransporter secretion is passage across the outer membrane (OM), mediated by a cotranslated C-terminal porin domain. Sequence analysis reveals that, despite size, sequence, and functional diversity, >97% of autotransporter passenger domains are predicted to form parallel β-helices, suggesting this structure is important for secretion. We report the folding behavior of pertactin, an autotransporter passenger domain from Bordetella pertussis. Despite slow but reversible folding in vitro, the β-helix is not prone to aggregation. Interestingly, equilibrium denaturation results in formation of a partially folded structure, with a stable core comprising the C-terminal half of pertactin. Examination of the crystal structure does not reveal any obvious reason for the enhanced stability of the C-terminus. Crystallographic data of the partially folded state shows native like structure for the C-terminus. Interestingly, the C-terminus forms a dimer with a non-native interface with a relatively low KD ∼ 0.3 μM. In vivo, slow folding would prevent premature folding in the periplasm, before OM secretion. Moreover, the extra stability of the C-terminal rungs might serve as a template for the β-helix formation during secretion; hence, vectorial folding of the β-helix could contribute to the energy-independent translocation. We show here that the C-terminus is the first part of the pertactin passenger domain reaching the OM, and that the C-terminus can adopt a stable structure outside the cell, prior to the completion of OM secretion. Coupled with the sequence analysis, these results suggest a general mechanism for autotransporter secretion. The combination of this data, including the lack of pertactin aggregation, could lead to new insights into the formation and prevention of protein aggregation in vivo.", "corpus_id": 85646598, "score": 0 }, { "doc_id": "25569", "title": "Gene structure and extracellular secretion of Neisseria gonorrhoeae IgA protease", "abstract": "Several human bacterial pathogens, including the Gram-negative diplococcus Neisseria gonorrhoeae, produce extracellular proteases that are specific for human immunoglobulin IgA1, (refs 1, 2). Immunoglobulin A (IgA) proteases have been studied extensively and the genes of some species cloned in Escherichia coli3–7, but their role in pathogenesis remains unclear8. Recently we derived a DNA fragment of 5 kilobases (kb) from N. gonorrhoeae MS 11 directing extracellular active enzyme in E. coli4. Although the mature enzyme of strain MS 11 was shown to have a relative molecular mass of 106,000 (Mr 106K) in gels4 , the DNA sequence of this cloned fragment reveals a single gene coding for a 169K precursor of IgA protease. The precursor contains three functional domains, the amino-terminal leader which is assumed to initiate the inner membrane transport of the precursor, the protease, and a carboxyl-terminal 'helper' domain apparently required for extracellular secretion (excretion). Based on the structural features of the precursor, we propose a model in which the helper serves as a pore for excretion of the protease domain through the outer membrane. IgA protease acquires an active conformation as its extracellular transport proceeds and is released as a proform from the membrane-bound helper by autoproteolysis. The soluble proform further matures into the 106 K IgA protease and a small stable α-protein.", "corpus_id": 25569, "score": 0 }, { "doc_id": "22898404", "title": "Efficient secretion of a folded protein domain by a monomeric bacterial autotransporter", "abstract": "Bacterial autotransporters are proteins that contain a small C‐terminal ‘β domain’ that facilitates translocation of a large N‐terminal ‘passenger domain’ across the outer membrane (OM) by an unknown mechanism. Here we used EspP, an autotransporter produced by Escherichia coli 0157:H7, as a model protein to gain insight into the transport reaction. Initially we found that the passenger domain of a truncated version of EspP (EspPΔ1‐851) was translocated efficiently across the OM. Blue Native polyacrylamide gel electrophoresis, analytical ultracentrifugation and other biochemical methods showed that EspPΔ1‐851 behaves as a compact monomer and strongly suggest that the channel formed by the β domain is too narrow to accommodate folded polypeptides. Surprisingly, we found that a folded protein domain fused to the N‐terminus of EspPΔ1‐851 was efficiently translocated across the OM. Further analysis revealed that the passenger domain of wild‐type EspP also folds at least partially in the periplasm. To reconcile these data, we propose that the EspP β domain functions primarily to target and anchor the protein and that an external factor transports the passenger domain across the OM.", "corpus_id": 22898404, "score": 1 }, { "doc_id": "6894877", "title": "Limited tolerance towards folded elements during secretion of the autotransporter Hbp", "abstract": "Many virulence factors secreted by pathogenic Gram‐negative bacteria belong to the autotransporter (AT) family. ATs consist of a passenger domain, which is the actual secreted moiety, and a β‐domain that facilitates the transfer of the passenger domain across the outer membrane. Here, we analysed folding and translocation of the AT passenger, using Escherichia coli haemoglobin protease (Hbp) as a model protein. Dual cysteine mutagenesis, instigated by the unique crystal structure of the Hbp passenger, resulted in intramolecular disulphide bond formation dependent on the periplasmic enzyme DsbA. A small loop tied off by a disulphide bond did not interfere with secretion of Hbp. In contrast, a bond between different domains of the Hbp passenger completely blocked secretion resulting in degradation by the periplasmic protease DegP. In the absence of DegP, a translocation intermediate accumulated in the outer membrane. A similar jammed intermediate was formed upon insertion of a calmodulin folding moiety into Hbp. The data suggest that Hbp can fold in the periplasm but must retain a certain degree of flexibility and/or modest width to allow translocation across the outer membrane.", "corpus_id": 6894877, "score": 1 }, { "doc_id": "29948303", "title": "Incorporation of a polypeptide segment into the β‐domain pore during the assembly of a bacterial autotransporter", "abstract": "Bacterial autotransporters consist of an N‐terminal ‘passenger domain’ that is transported into the extracellular space by an unknown mechanism and a C‐terminal ‘β‐domain’ that forms a β‐barrel in the outer membrane. Recent studies have revealed that fully assembled autotransporters have an unusual architecture in which a small passenger domain segment traverses the pore formed by the β‐domain. It is unclear, however, whether this configuration forms prior to passenger domain translocation or results from the translocation of the passenger domain through the β‐domain pore. By examining the accessibility of tobacco etch virus protease sites and single‐cysteine residues in the passenger domain of the Escherichia coli O157:H7 autotransporter EspP at different stages of protein biogenesis, we identified a novel pre‐translocation intermediate whose topology resembles that of the fully assembled protein. This intermediate was isolated in the periplasm in cell fractionation experiments. The data strongly suggest that the EspP β‐domain and an embedded polypeptide segment are integrated into the outer membrane as a single pre‐formed unit. The data also provide indirect evidence that at least some outer membrane proteins acquire considerable tertiary structure prior to their membrane integration.", "corpus_id": 29948303, "score": 0 }, { "doc_id": "3742835", "title": "Secretion of a bacterial virulence factor is driven by the folding of a C-terminal segment", "abstract": "Autotransporters are bacterial virulence factors consisting of an N-terminal “passenger domain” that is secreted in a C- to-N-terminal direction and a C-terminal “β domain” that resides in the outer membrane (OM). Although passenger domain secretion does not appear to use ATP, the energy source for this reaction is unknown. Here, we show that efficient secretion of the passenger domain of the Escherichia coli O157:H7 autotransporter EspP requires the stable folding of a C-terminal ≈17-kDa passenger domain segment. We found that mutations that perturb the folding of this segment do not affect its translocation across the OM but impair the secretion of the remainder of the passenger domain. Interestingly, an examination of kinetic folding mutants strongly suggested that the ≈17-kDa segment folds in the extracellular space. By mutagenizing the ≈17-kDa segment, we also fortuitously isolated a unique translocation intermediate. Analysis of this intermediate suggests that a heterooligomer that facilitates the membrane integration of OM proteins (the Bam complex) also promotes the surface exposure of the ≈17-kDa segment. Our results provide direct evidence that protein folding can drive translocation and help to clarify the mechanism of autotransporter secretion.", "corpus_id": 3742835, "score": 1 }, { "doc_id": "7672148", "title": "Autotransporter β-domains have a specific function in protein secretion beyond outer-membrane targeting.", "abstract": "Autotransporters (ATs) of Gram-negative bacteria contain an N-proximal passenger domain that is transported to the extracellular milieu and a C-terminal β-domain that inserts into the outer membrane (OM) in a β-barrel conformation. This β-domain facilitates translocation of the passenger domain across the OM and has long been considered to be the translocation pore. However, available crystal structures of β-domains show that the β-barrel pore is too narrow for the observed transport of folded elements within the passenger domains. ATs have recently been shown to interact with the β-barrel assembly machinery. These findings questioned a direct involvement of the β-domain in passenger translocation and suggested that it may only target the passenger to the β-barrel assembly machinery pore. To address the function of the β-domain in more detail, we have replaced the β-domain of the Escherichia coli AT hemoglobin protease by β-domains originating from other OM proteins. Furthermore, we have modified the diameter of the β-domain pore. The mutant proteins were analyzed for their capacity to insert into the OM and for surface display of the passenger. Our results show that efficient passenger secretion requires a specific β-domain that not only functions as a targeting device but also is directly involved in the translocation of the passenger to the cell surface.", "corpus_id": 7672148, "score": 0 }, { "doc_id": "1661386", "title": "Mechanistic link between β barrel assembly and the initiation of autotransporter secretion", "abstract": "Significance Most proteins that reside in the bacterial outer membrane are β sheets that fold into a unique cylindrical structure known as a “β barrel.” Here we describe significant insights into the function of the Bam complex, a protein machine that catalyzes the insertion of β barrel proteins into the membrane by an unknown mechanism. By analyzing the assembly of autotransporters, a specialized family of outer membrane proteins, we found that the function of the Bam complex can be divided into an initial substrate binding stage and a subsequent insertion stage that is surprisingly sensitive to structural distortions in client proteins. Autotransporters are bacterial virulence factors that contain an N-terminal extracellular (“passenger”) domain and a C-terminal β barrel (“β”) domain that anchors the protein to the outer membrane. The β domain is required for passenger domain secretion, but its exact role in autotransporter biogenesis is unclear. Here we describe insights into the function of the β domain that emerged from an analysis of mutations in the Escherichia coli O157:H7 autotransporter EspP. We found that the G1066A and G1081D mutations slightly distort the structure of the β domain and delay the initiation of passenger domain translocation. Site-specific photocrosslinking experiments revealed that the mutations slow the insertion of the β domain into the outer membrane, but do not delay the binding of the β domain to the factor that mediates the insertion reaction (the Bam complex). Our results demonstrate that the β domain does not simply target the passenger domain to the outer membrane, but promotes translocation when it reaches a specific stage of assembly. Furthermore, our results provide evidence that the Bam complex catalyzes the membrane integration of β barrel proteins in a multistep process that can be perturbed by minor structural defects in client proteins.", "corpus_id": 1661386, "score": 0 }, { "doc_id": "35443090", "title": "Selective extracellular release of cholera toxin B subunit by Escherichia coli: dissection of Neisseria Iga beta‐mediated outer membrane transport.", "abstract": "The C‐terminal domain (Iga beta) of the Neisseria IgA protease precursor is involved in the transport of covalently attached proteins across the outer membrane of Gram‐negative bacteria. We investigated outer membrane transport in Escherichia coli using fusion proteins consisting of an N‐terminal signal sequence for inner membrane transport, the Vibrio cholerae toxin B subunit (CtxB) as a passenger and Iga beta. The process probably involves two distinct steps: (i) integration of Iga beta into the outer membrane and (ii) translocation of the passenger across the membrane. The outer membrane integrated part of Iga beta is the C‐terminal 30 kDa core, which serves as a translocator for both the passenger and the linking region situated between the passenger and Iga beta core. The completeness of the translocation is demonstrated by the extracellular release of the passenger protein owing to the action of the E. coli outer membrane OmpT protease. Translocation of the CtxB moiety occurs efficiently under conditions preventing intramolecular disulphide bond formation. In contrast, if disulphide bond formation in the periplasm proceeds, then translocation halts after the export of the linking region. In this situation transmembrane intermediates are generated which give rise to characteristic fragments resulting from rapid proteolytic degradation of the periplasmically trapped portion. Based on the identification of translocation intermediates we propose that the polypeptide chain of the passenger passes in a linear fashion across the bacterial outer membrane.", "corpus_id": 35443090, "score": 0 }, { "doc_id": "5132032", "title": "ATP-independent control of autotransporter virulence protein transport via the folding properties of the secreted protein.", "abstract": "Autotransporter (AT) proteins are the largest class of extracellular virulence proteins secreted from Gram-negative bacteria. The mechanism by which AT proteins cross the bacterial outer membrane (OM), in the absence of ATP or another external energy source, is unknown. Here we demonstrate a linear correlation between localized regions of stability (ΔG(folding)) in the mature virulence protein (the AT \"passenger\") and OM secretion efficiency. Destabilizing the C-terminal β-helical domain of a passenger reduced secretion efficiency. In contrast, destabilizing the globular N-terminal domain of a passenger produced a linearly correlated increase in secretion efficiency. Thus, C-terminal passenger stability facilitates OM secretion, whereas N-terminal stability hinders it. The contributions of regional passenger stability to OM secretion demonstrate a crucial role for the passenger itself in directing its secretion, suggesting a novel type of ATP-independent, folding-driven transporter.", "corpus_id": 5132032, "score": 0 }, { "doc_id": "16402980", "title": "Energetics of Protein Transport across Biological Membranes A Study of the Thylakoid ΔpH-Dependent/cpTat Pathway", "abstract": "Among the pathways for protein translocation across biological membranes, the DeltapH-dependent/Tat system is unusual in its sole reliance upon the transmembrane pH gradient to drive protein transport. The free energy cost of protein translocation via the chloro-plast DeltapH-dependent/Tat pathway was measured by conducting in vitro transport assays with isolated thylakoids while concurrently monitoring energetic parameters. These experiments revealed a substrate-specific energetic barrier to cpTat-mediated transport as well as direct utilization of protons from the gradient, consistent with a H+/protein antiporter mechanism. The magnitude of proton flux was assayed by four independent approaches and averaged 7.9 x 10(4) protons released from the gradient per transported protein. This corresponds to a DeltaG transport of 6.9 x 10(5) kJ.mol protein translocated(-1), representing the utilization of an energetic equivalent of 10(4) molecules of ATP. At this cost, we estimate that the DeltapH-dependent/cpTat pathway utilizes approximately 3% of the total energy output of the chloroplast.", "corpus_id": 16402980, "score": 0 }, { "doc_id": "11672648", "title": "Precursor protein translocation by the Escherichia coli translocase is directed by the protonmotive force.", "abstract": "The SecY/E protein of Escherichia coli was coreconstituted with the proton pump bacteriorhodopsin and cytochrome c oxidase yielding proteoliposomes capable of sustaining a protonmotive force (delta p) of defined polarity and composition. Proteoliposomes support the ATP‐ and SecA‐dependent translocation of proOmpA which is stimulated by a delta p, inside acid and positive. delta p of opposite polarity, inside alkaline and negative, suppresses translocation while SecA‐mediated ATP hydrolysis continues unabated. delta psi and delta pH are equally effective in promoting or inhibiting translocation. Membrane‐spanning translocation intermediates move backwards in the presence of a reversed delta p. These results support a model [Schiebel, E., Driessen, A.J.M., Hartl, F.‐U. and Wickner, W. (1991) Cell, 64, 927–939] in which the delta p defines the direction of translocation after ATP hydrolysis has released proOmpA from its association with SecA. The polarity effect of the delta p challenges models involving delta p‐dependent membrane destabilization and provides further evidence for a role of the delta p as driving force in precursor protein translocation.", "corpus_id": 11672648, "score": 0 }, { "doc_id": "30460903", "title": "Energetic cost of protein import across the envelope membranes of chloroplasts", "abstract": "Chloroplasts are the organelles of green plants in which light energy is transduced into chemical energy, forming ATP and reduced carbon compounds upon which all life depends. The expenditure of this energy is one of the central issues of cellular metabolism. Chloroplasts contain ∼3,000 proteins, among which less than 100 are typically encoded in the plastid genome. The rest are encoded in the nuclear genome, synthesized in the cytosol, and posttranslationally imported into the organelle in an energy-dependent process. We report here a measurement of the amount of ATP hydrolyzed to import a protein across the chloroplast envelope membranes—only the second complete accounting of the cost in Gibbs free energy of protein transport to be undertaken. Using two different precursors prepared by three distinct techniques, we show that the import of a precursor protein into chloroplasts is accompanied by the hydrolysis of ∼650 ATP molecules. This translates to a ΔGprotein transport of some 27,300 kJ/mol protein imported. We estimate that protein import across the plastid envelope membranes consumes ∼0.6% of the total light-saturated energy output of the organelle.", "corpus_id": 30460903, "score": 0 }, { "doc_id": "39174489", "title": "Protein folding--what's the question?", "abstract": "The folding reactions of many small, globular proteins exhibit two-state kinetics, in which the folded and unfolded states interconvert readily without observable intermediates. Typically, the free energy difference, delta G, between the native and denatured states of such a protein is quite small, lying in the range of approximately -5 to -15 kcal/mol. We point out that, under these circumstances, a population of native-like molecules will persist, even in the presence of mutations sufficiently destabilizing to change the sign of delta G. Therefore, it is not energy per se that determines conformation. A corollary to this argument is that specificity--not stability--would be the more informative focus in future folding studies.", "corpus_id": 39174489, "score": 0 }, { "doc_id": "36767188", "title": "Secretion of cyclolysin, the calmodulin‐sensitive adenylate cyclase‐haemolysin bifunctional protein of Bordetella pertussis.", "abstract": "The calmodulin‐sensitive adenylate cyclase of Bordetella pertussis, a 45 kd secreted protein, is synthesized as a 1706 amino acid precursor. We have shown that this precursor is a bifunctional protein, carrying both adenylate cyclase and haemolytic activities. The 1250 carboxy‐terminal amino acids of the precursor showed 25% similarity with Escherichia coli alpha‐haemolysin (HlyA) and 22% similarity with Pasteurella haemolytica leucotoxin. Three open reading frames were identified downstream from the cyaA gene: cyaB, cyaD and cyaE, coding for polypeptides of 712, 440 and 474 amino acid residues, respectively. As for E. coli alpha‐haemolysin, secretion of B.pertussis adenylate cyclase and haemolysin requires the expression of additional genes. The gene products of cyaB and cyaD are highly similar to HlyB and HlyD, known to be necessary for the transport of HlyA across the cell envelope and for its release into the external medium. Complementation and functional studies indicate that the B.pertussis adenylate cyclase‐haemolysin bifunctional protein is secreted by a mechanism similar to that described for E.coli alpha‐haemolysin, requiring, in addition to the cyaB and cyaD gene products, the presence of a third gene product specified by the cyaE gene.", "corpus_id": 36767188, "score": 0 }, { "doc_id": "20410702", "title": "Interaction of Calcium with Bordetella pertussis Adenylate Cyclase Toxin", "abstract": "The adenylate cyclase (CyaA) secreted by Bordetella pertussis is a toxin that is able to enter eukaryotic cells and cause a dramatic increase in cAMP level. In addition, the toxin also exhibits an intrinsic hemolytic activity that is independent from the ATP cycling catalytic activity of the toxin. Both the cytotoxic and hemolytic activities are calcium-dependent. In this work, we have analyzed the calcium interacting properties of CyaA. We have shown that CyaA exposed to CaCl2 could retain membrane binding capability and hemolytic activity when it was further assayed in the presence of an excess of EGTA. Determination of the calcium content of CyaA exposed first to calcium and subsequently to EGTA indicated that some (3, 4, 5) calcium ions remained bound to the protein, suggesting the existence of Ca binding sites of high affinity. Binding of Ca to these sites might be necessary for both the membrane binding capability and the hemolytic activity of the toxin. In addition, CyaA possesses a large number (about 45) of low affinity (K = 0.5-0.8 mM) Ca binding sites that are located in the C terminus of the toxin, between amino acids 1007 and 1706. This region mainly consists of about 45 repeated sequences of the type GGXGXDXLX (where X represents any amino acid) that are characteristic of the RTX (Repeat in ToXin) bacterial protein family. Our data suggest that each one can bind one calcium ion. Circular dichroism spectroscopy analysis showed that calcium binding to the low affinity sites induces a large conformational change of CyaA, as revealed by an important increase in the content of α-helical structures. This conformational change might be directly involved in the Ca-dependent translocation of the catalytic domain of CyaA through the plasma membrane of target cells.", "corpus_id": 20410702, "score": 0 }, { "doc_id": "30987097", "title": "Calcium-induced folding and stabilization of the intrinsically disordered RTX domain of the CyaA toxin.", "abstract": "The adenylate cyclase toxin (CyaA) is one of the major virulence factors of Bordetella pertussis, the causative agent of whooping cough. Its C-terminal region, the receptor-binding domain (RD), contains ∼40 calcium-binding Repeat in ToXin (RTX) motifs, which are characteristic of many virulence factors of pathogenic bacteria. We previously showed that RD is intrinsically disordered in the absence of calcium and acquires its functional three-dimensional structure upon calcium binding. To gain further insight into the physicochemical properties of RD, we characterized its calcium-induced conformational and stability changes by combining spectroscopic approaches. We show that RD, in the absence of calcium, adopts premolten globule conformations, due in part to the strong internal electrostatic repulsions between the negative charges of the aspartate-rich polypeptide sequence. Accordingly, sodium is able to screen these electrostatic repulsions, allowing a partial compaction of the polypeptide, whereas calcium triggers a strong compaction as well as the acquisition of secondary and tertiary structures in a highly cooperative manner. The differential sensitivity of the calcium-loaded state to guanidinium- and urea-induced denaturations provides further evidence that electrostatic interactions play a critical role in the folding and stability of RD. These results provide new insights into the folding/function relationship of the RTX motifs.", "corpus_id": 30987097, "score": 1 }, { "doc_id": "18068406", "title": "Intrinsically unstructured proteins and their functions", "abstract": "Many gene sequences in eukaryotic genomes encode entire proteins or large segments of proteins that lack a well-structured three-dimensional fold. Disordered regions can be highly conserved between species in both composition and sequence and, contrary to the traditional view that protein function equates with a stable three-dimensional structure, disordered regions are often functional, in ways that we are only beginning to discover. Many disordered segments fold on binding to their biological targets (coupled folding and binding), whereas others constitute flexible linkers that have a role in the assembly of macromolecular arrays.", "corpus_id": 18068406, "score": 0 }, { "doc_id": "19493530", "title": "RTX Calcium Binding Motifs Are Intrinsically Disordered in the Absence of Calcium", "abstract": "The Repeat in Toxin (RTX) motif is a tandemly repeated calcium-binding nonapeptide sequence present in proteins that are secreted by the type I secretion system (T1SS) of Gram-negative bacteria. Here, we have characterized the structural and hydrodynamic properties of the RTX Repeat Domain (RD) of the CyaA toxin from Bordetella pertussis. This 701-amino acid long domain contains about 40 RTX motifs. We showed that, in the absence of calcium, RD was natively disordered, weakly stable, and highly hydrated. Calcium binding induced compaction and dehydration of RD, along with the formation of stable secondary and tertiary structures. The calcium-induced conformational switch between unfolded conformations of apo-RD and stable structures of holo-RD is likely to be a key property for the biological function of the CyaA toxin: in the low calcium environment of the bacterial cytosol, the intrinsically disordered character of the protein may facilitate its secretion through the secretion machinery. In the extracellular medium, calcium binding can then trigger the folding of the polypeptide into its functional state. The intrinsic disorder of RTX-containing proteins in the absence of calcium may thus be directly involved in the efficient secretion of proteins through T1SS.", "corpus_id": 19493530, "score": 1 }, { "doc_id": "23695246", "title": "Three‐dimensional structure of the alkaline protease of Pseudomonas aeruginosa: a two‐domain protein with a calcium binding parallel beta roll motif.", "abstract": "The three‐dimensional structure of the alkaline protease of Pseudomonas aeruginosa, a zinc metalloprotease, has been solved to a resolution of 1.64 A by multiple isomorphous replacement and non‐crystallographic symmetry averaging between different crystal forms. The molecule is elongated with overall dimensions of 90 × 35 × 25 A; it has two distinct structural domains. The N‐terminal domain is the proteolytic domain; it has an overall tertiary fold and active site zinc ligation similar to that of astacin, a metalloprotease isolated from a European freshwater crayfish. The C‐terminal domain consists of a 21‐strand beta sandwich. Within this domain is a novel ‘parallel beta roll’ structure in which successive beta strands are wound in a right‐handed spiral, and in which Ca2+ ions are bound within the turns between strands by a repeated GGXGXD sequence motif, a motif that is found in a diverse group of proteins secreted by Gram‐negative bacteria.", "corpus_id": 23695246, "score": 0 }, { "doc_id": "45989965", "title": "Identification by in vitro complementation of regions required for cell‐invasive activity of Bordetella pertussis adenylate cyclase toxin", "abstract": "The adenylate cyclase toxin (CyaA) of Bordetella pertussis is a 1706‐residue protein composed of an amino‐terminal adenylate cyclase (AC) domain linked to a 1300‐residue channel‐forming RTX (repeats in toxin) haemolysin. The toxin delivers its AC domain into a variety of eukaryotic cells and impairs cellular functions by catalysing unregulated synthesis of cAMP from intracellular ATP. We have examined toxin activities of a set of deletion derivatives of CyaA. The results indicate that CyaA does not have a dedicated target cell‐binding domain and that structural integrity and co‐operation of all domains, as well as the post‐translational fatty acylation mediated by an accessory protein CyaC, are all essential for target cell association and toxin activity of CyaA. When tested individually, all toxin derivatives were inactive and impaired in the tight association with the target cell surface. However, pairs of constructs with non‐overlapping deletions complemented each other in vitro and exhibited a partially restored cytotoxic activity. This suggests that at least a part of the active toxin may act in the form of dimers or higher oligomers. The complementation analysis revealed that the last 217 residues of CyaA, containing the unprocessed secretion signal, form an autonomous domain essential for toxin activity, and that the region from residue 624 to 780 may be directly involved in delivery of the AC toxin into cells.", "corpus_id": 45989965, "score": 0 }, { "doc_id": "26692486", "title": "Characterization of the C‐terminal domain essential for toxic activity of adenylate cyclase toxin", "abstract": "Adenylate cyclase toxin (CyaA) of Bordetella pertussis belongs to the RTX family of toxins. These toxins are characterized by a series of glycine‐ and aspartate‐rich nonapeptide repeats located at the C‐terminal half of the toxin molecules. For activity, RTX toxins require Ca2+, which is bound through the repeat region. Here, we identified a stretch of 15 amino acids (block A) that is located C‐terminally to the repeat region and is essential for the toxic activity of CyaA. Block A is required for the insertion of CyaA into the plasma membranes of host cells. Mixing of a short polypeptide composed of block A and eight Ca2+ binding repeats with a mutant of CyaA lacking block A restores toxic activity fully. This in vitro interpolypeptide complementation is achieved only when block A is present together with the Ca2+ binding repeats on the same polypeptide. Neither a short polypeptide composed of block A only nor a polypeptide consisting of eight Ca2+ binding repeats, or a mixture of these two polypeptides, complement toxic activity. It is suggested that functional complementation occurs because of binding between the Ca2+ binding repeats of the short C‐terminal polypeptide and the Ca2+ binding repeats of the CyaA mutant lacking block A.", "corpus_id": 26692486, "score": 0 }, { "doc_id": "11790062", "title": "Cleavage of a bacterial autotransporter by an evolutionarily convergent autocatalytic mechanism", "abstract": "Bacterial autotransporters are comprised of an N‐terminal ‘passenger domain’ and a C‐terminal β barrel (‘β domain’) that facilitates transport of the passenger domain across the outer membrane. Following translocation, the passenger domains of some autotransporters are cleaved by an unknown mechanism. Here we show that the passenger domain of the Escherichia coli O157:H7 autotransporter EspP is released in a novel autoproteolytic reaction. After purification, the uncleaved EspP precursor underwent proteolytic processing in vitro. An analysis of protein topology together with mutational studies strongly suggested that the reaction occurs inside the β barrel and revealed that two conserved residues, an aspartate within the β domain (Asp1120) and an asparagine (Asn1023) at the P1 position of the cleavage junction, are essential for passenger domain cleavage. Interestingly, these residues were also essential for the proteolytic processing of two distantly related autotransporters. The data strongly suggest that Asp1120 and Asn1023 form an unusual catalytic dyad that mediates self‐cleavage through the cyclization of the asparagine. Remarkably, a very similar mechanism has been proposed for the maturation of eukaryotic viral capsids.", "corpus_id": 11790062, "score": 0 }, { "doc_id": "45028621", "title": "Calcium-induced folding of a beta roll motif requires C-terminal entropic stabilization.", "abstract": "Beta roll motifs are associated with several proteins secreted by the type 1 secretion system (T1SS). Located just upstream of the C-terminal T1SS secretion signal, they are believed to act as calcium-induced switches that prevent folding before secretion. Bordetella pertussis adenylate cyclase (CyaA) toxin has five blocks of beta roll motifs (or repeats-in-toxin motifs) separated by linkers. The block V motif on its own has been reported to be non-responsive to calcium. Only when the N- and C-terminal linkers, or flanking groups, were fused did the motif bind calcium and fold. In an effort to understand the requirements for beta roll folding, we have truncated the N- and C-terminal flanks at several locations to determine the minimal essential sequences. Calcium-responsive beta roll folding occurred even in the absence of the natural N-terminal flank. The natural C-terminal flank could not be truncated without decreased calcium affinity and only partially truncated before losing calcium-responsiveness. Globular protein fusion at the C-terminus likewise enabled calcium-induced folding but fusions solely at the N-terminus failed. This demonstrates that calcium-induced folding is an inherent property of the beta roll motif rather than the flanking groups. Given the disparate nature of the observed functional flanking groups, C-terminal fusions appear to confer calcium-responsiveness to the beta roll motif via a non-specific mechanism, suggesting that entropic stabilization of the unstructured C-terminus can enable beta roll folding. Increased calcium affinity was observed when the natural C-terminal flank was used to enable calcium-induced folding, pointing to its cooperative participation in beta roll formation. This work indicates that a general principle of C-terminal entropic stabilization can enable stimulus-responsive repeat protein folding, while the C-terminal flank has a specific role in tuning calcium-responsive beta roll formation. These observations are in stark contrast to what has been reported for other repeat proteins.", "corpus_id": 45028621, "score": 0 }, { "doc_id": "12497300", "title": "Protein structure prediction on the Web: a case study using the Phyre server", "abstract": "Determining the structure and function of a novel protein is a cornerstone of many aspects of modern biology. Over the past decades, a number of computational tools for structure prediction have been developed. It is critical that the biological community is aware of such tools and is able to interpret their results in an informed way. This protocol provides a guide to interpreting the output of structure prediction servers in general and one such tool in particular, the protein homology/analogy recognition engine (Phyre). New profile–profile matching algorithms have improved structure prediction considerably in recent years. Although the performance of Phyre is typical of many structure prediction systems using such algorithms, all these systems can reliably detect up to twice as many remote homologies as standard sequence-profile searching. Phyre is widely used by the biological community, with >150 submissions per day, and provides a simple interface to results. Phyre takes 30 min to predict the structure of a 250-residue protein.", "corpus_id": 12497300, "score": 0 }, { "doc_id": "36707543", "title": "Adenylate cyclase toxin from Bordetella pertussis. Identification and purification of the holotoxin molecule.", "abstract": "Bordetella pertussis adenylate cyclase (AC) toxin is a calmodulin-activated adenylate cyclase enzyme which has the capacity to enter eukaryotic target cells and catalyze the conversion of endogenous ATP into cyclic AMP. In this work, the AC holotoxin molecule is identified and isolated. It is a single polypeptide of apparent 216 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Monoclonal antibodies which immunoprecipitate AC activity from extracts of wild type B. pertussis (BP338) react with this 216-kDa band on Western blots, and it is absent from a transposon Tn5 mutant (BP348) specifically lacking AC toxin. Isolation of the 216-kDa protein to greater than 85% purity by hydrophobic chromatography, preparative sucrose gradient centrifugation, and affinity chromatography using either calmodulin-Sepharose or monoclonal antibody coupled to Sepharose 4B yields stepwise increases in AC toxin potency, to a maximum of 88.3 mumol of cAMP/mg of target cell protein/mg of toxin. Electroelution of the 216-kDa band following sodium dodecyl sulfate-polyacrylamide gel electrophoresis yields a preparation with both AC enzyme and toxin activities. These data indicate that this protein represents the AC holotoxin molecule.", "corpus_id": 36707543, "score": 0 }, { "doc_id": "25329367", "title": "Oligomerization is involved in pore formation by Bordetella adenylate cyclase toxin", "abstract": "The Bordetella adenylate cyclase‐hemolysin (CyaA, ACT, or AC‐Hly) is a multifunctional toxin. Simultaneously with promoting calcium ion entry, CyaA delivers into host cells an adenylate cyclase enzyme (AC) and permeabilizes cell membrane by forming small cation‐selective pores. Indirect evidence suggested that these two activities were accomplished by different membraneinserted CyaA conformers, one acting as an AC‐delivering monomer and the other as an uncharacterized poreforming oligomer. We tested this model by directly detecting toxin oligomers in cell membrane and by assessing oligomerization of specific mutants with altered poreforming properties. CyaA oligomers were revealed in sheep erythrocyte membranes by immunogold labeling and directly demonstrated by pulldown of membraneinserted CyaA together with biotinylated CyaAAC‐ toxoid. Membrane oligomers of CyaAcould also be resolved by nondenaturing electrophoresis of mild detergent extracts of erythrocytes. Furthermore, CyaA mutants exhibiting enhanced (E581K) or reduced (E570K+E581P) specific hemolytic and pore‐forming activity were found to exhibit also a correspondingly enhanced or reduced propensity to form oligomers in erythrocyte membranes. On the other hand, processed CyaA, with the AC domain cleaved off by erythrocyte proteases, was detected only in a monomeric form excluded from the oligomers of unprocessed CyaA. These results provide the first direct evidence that oligomerization is involved in formation of CyaApores in target membranes and that translocation of the AC domain across cell membrane may be accomplished by monomelic CyaA.—Vojtova‐Vodolanova, J., Basler, M., Osicka, R., Knapp, O., Maier, E., Cerny, J., Benada, O., Benz, R., Sebo, P. Oligomerization is involved in pore formation by Bordetella adenylate cyclase toxin. FASEB J. 23, 2831–2843 (2009). www.fasebj.org", "corpus_id": 25329367, "score": 0 }, { "doc_id": "31224099", "title": "The Periplasmic Folding of a Cysteineless Autotransporter Passenger Domain Interferes with Its Outer Membrane Translocation", "abstract": "ABSTRACT Autotransporters are single polypeptides consisting of an outer membrane translocation domain mediating the translocation of a passenger domain. The periplasmic folding state of the passenger domain is controversial. By comparisons of passenger domains differing in their folding properties, our results suggest that periplasmic folding of passenger domains interferes with translocation.", "corpus_id": 31224099, "score": 0 }, { "doc_id": "23020265", "title": "A Bioinformatic Strategy for the Detection, Classification and Analysis of Bacterial Autotransporters", "abstract": "Autotransporters are secreted proteins that are assembled into the outer membrane of bacterial cells. The passenger domains of autotransporters are crucial for bacterial pathogenesis, with some remaining attached to the bacterial surface while others are released by proteolysis. An enigma remains as to whether autotransporters should be considered a class of secretion system, or simply a class of substrate with peculiar requirements for their secretion. We sought to establish a sensitive search protocol that could identify and characterize diverse autotransporters from bacterial genome sequence data. The new sequence analysis pipeline identified more than 1500 autotransporter sequences from diverse bacteria, including numerous species of Chlamydiales and Fusobacteria as well as all classes of Proteobacteria. Interrogation of the proteins revealed that there are numerous classes of passenger domains beyond the known proteases, adhesins and esterases. In addition the barrel-domain-a characteristic feature of autotransporters-was found to be composed from seven conserved sequence segments that can be arranged in multiple ways in the tertiary structure of the assembled autotransporter. One of these conserved motifs overlays the targeting information required for autotransporters to reach the outer membrane. Another conserved and diagnostic motif maps to the linker region between the passenger domain and barrel-domain, indicating it as an important feature in the assembly of autotransporters.", "corpus_id": 23020265, "score": 0 }, { "doc_id": "82260122", "title": "Protein structure and function", "abstract": "1. From Sequence to Structure 2. From Structure to Function 3. Control of Protein Function 4. From Sequence to Function: Case Studies in Structural and Functional Genomics 5. Structure Determination", "corpus_id": 82260122, "score": 0 }, { "doc_id": "25561432", "title": "Salt bridge stability in monomeric proteins.", "abstract": "Here, we present the results of continuum electrostatic calculations on a dataset of 222 non-equivalent salt bridges derived from 36 non-homologous high-resolution monomeric protein crystal structures. Most of the salt bridges in our dataset are stabilizing, regardless of whether they are buried or exposed, isolated or networked, hydrogen bonded or non-hydrogen bonded. One-third of the salt bridges in our dataset are buried in the protein core, with the remainder exposed to the solvent. The difference in the dielectric properties of water versus the hydrophobic protein interior cost buried salt bridges large desolvation penalties. However, the electrostatic interactions both between the salt-bridging side-chains, and between the salt bridges and charges in their protein surroundings, are also stronger in the interior, due to the absence of solvent screening. Even large desolvation penalties for burying salt bridges are frequently more than compensated for, primarily by the electrostatic interactions between the salt-bridging side-chains. In networked salt bridges both types of electrostatic interactions, those between the salt-bridging side-chains, and those between the salt bridge and its protein environment, are of similar magnitudes. In particular, a major finding of this work is that salt bridge geometry is a critical factor in determining salt bridge stability. Salt bridges with favorable geometrical positioning of the interacting side-chain charged groups are likely to be stabilizing anywhere in the protein structure. We further find that most of the salt bridges are formed between residues that are relatively near each other in the sequence.", "corpus_id": 25561432, "score": 0 }, { "doc_id": "9992070", "title": "Inactivation of Haemophilus influenzae Lipopolysaccharide Biosynthesis Genes Interferes with Outer Membrane Localization of the Hap Autotransporter", "abstract": "ABSTRACT Nontypeable Haemophilus influenzae is a major cause of localized respiratory tract disease and initiates infection by colonizing the nasopharynx. Colonization requires adherence to host epithelial cells, which is mediated by surface proteins such as the Hap adhesin. In this study, we identified a relationship between Hap levels in the outer membrane and lipopolysaccharide (LPS) biosynthesis enzymes. We found that mutation of the rfaF, pgmB, lgtC, kfiC, orfE, rfbP, lsgB, or lsgD genes, which are involved in the synthesis of the LPS oligosaccharide core in H. influenzae strain Rd/HapS243A, resulted in loss of Hap in the bacterial outer membrane and a decrease in hap transcript levels. In contrast, the same mutations had no effect on outer membrane localization of H. influenzae P5 or IgA1 protease or levels of p5 or iga1 transcripts, suggesting a Hap-specific effect. Elimination of the HtrA periplasmic protease resulted in a return of Hap to the outer membrane and restoration of hap transcript levels. Consistently, in lgtC phase-off bacteria, Hap was absent from the outer membrane, and hap transcript levels were reduced. Hap localization and hap transcript levels were not related to LPS size but to the functions of the LPS biosynthesis enzymes themselves. We speculate that the lack of certain LPS biosynthesis enzymes causes Hap to mislocalize and accumulate in the periplasm, where it is degraded by HtrA. This degradation then leads to a decrease in hap transcript levels. Together, these data highlight a novel interplay between Hap and LPS biosynthesis that can influence H. influenzae interactions with the host.", "corpus_id": 9992070, "score": 0 }, { "doc_id": "5933780", "title": "Absence of O antigen suppresses Shigella flexneri IcsA autochaperone region mutations.", "abstract": "The Shigella flexneri IcsA (VirG) protein is a polarly distributed autotransporter protein. IcsA functions as a virulence factor by interacting with the host actin regulatory protein N-WASP, which in turn activates the Arp2/3 complex, initiating actin polymerization. Formation of F-actin comet tails allows bacterial cell-to-cell spreading. Although various accessory proteins such as periplasmic chaperones and the β-barrel assembly machine (BAM) complex have been shown to be involved in the export of IcsA, the IcsA translocation mechanism remains to be fully elucidated. A putative autochaperone (AC) region (amino acids 634-735) located at the C-terminal end of the IcsA passenger domain, which forms part of the self-associating autotransporter (SAAT) domain, has been suggested to be required for IcsA biogenesis, as well as for N-WASP recruitment, based on mutagenesis studies. IcsA(i) proteins with linker insertion mutations within the AC region have a significant reduction in production and are defective in N-WASP recruitment when expressed in smooth LPS (S-LPS) S. flexneri. In this study, we have found that the LPS O antigen plays a role in IcsA(i) production based on the use of an rmlD (rfbD) mutant having rough LPS (R-LPS) and a novel assay in which O antigen is depleted using tunicamycin treatment and then regenerated. In addition, we have identified a new N-WASP binding/interaction site within the IcsA AC region.", "corpus_id": 5933780, "score": 0 }, { "doc_id": "44636559", "title": "On the physical basis for the cis‐positive rule describing protein orientation in biological membranes", "abstract": "The topology of hydrophobic intramembrane proteins is characterized by a statistical asymmetry in the distribution of positively‐charged residues on the two sides of the membrane, the ‘inside‐ or cis‐positive rule’. A mechanism is proposed involving only neutral residue transfer. For a tightly bound polypeptide adsorbed on the membrane and not at equilibrium, the pK values of the ionic residues related to dissociation of the proton into the aqueous phase bulk are increased because of interaction with the negative charges at the membrane surface. The pK shift would selectively neutralize aspartate and glutamate residues, favoring their translocation across the membrane, while stabilizing the impermeant positively charged state of lysine and arginine residues.", "corpus_id": 44636559, "score": 0 }, { "doc_id": "4335057", "title": "Structural and energetic basis of folded protein transport by the FimD usher", "abstract": "Type 1 pili, produced by uropathogenic Escherichia coli, are multisubunit fibres crucial in recognition of and adhesion to host tissues. During pilus biogenesis, subunits are recruited to an outer membrane assembly platform, the FimD usher, which catalyses their polymerization and mediates pilus secretion. The recent determination of the crystal structure of an initiation complex provided insight into the initiation step of pilus biogenesis resulting in pore activation, but very little is known about the elongation steps that follow. Here, to address this question, we determine the structure of an elongation complex in which the tip complex assembly composed of FimC, FimF, FimG and FimH passes through FimD. This structure demonstrates the conformational changes required to prevent backsliding of the nascent pilus through the FimD pore and also reveals unexpected properties of the usher pore. We show that the circular binding interface between the pore lumen and the folded substrate participates in transport by defining a low-energy pathway along which the nascent pilus polymer is guided during secretion.", "corpus_id": 4335057, "score": 0 }, { "doc_id": "23141355", "title": "Discovery of an archetypal protein transport system in bacterial outer membranes", "abstract": "Bacteria have mechanisms to export proteins for diverse purposes, including colonization of hosts and pathogenesis. A small number of archetypal bacterial secretion machines have been found in several groups of bacteria and mediate a fundamentally distinct secretion process. Perhaps erroneously, proteins called 'autotransporters' have long been thought to be one of these protein secretion systems. Mounting evidence suggests that autotransporters might be substrates to be secreted, not an autonomous transporter system. We have discovered a new translocation and assembly module (TAM) that promotes efficient secretion of autotransporters in proteobacteria. Functional analysis of the TAM in Citrobacter rodentium, Salmonella enterica and Escherichia coli showed that it consists of an Omp85-family protein, TamA, in the outer membrane and TamB in the inner membrane of diverse bacterial species. The discovery of the TAM provides a new target for the development of therapies to inhibit colonization by bacterial pathogens.", "corpus_id": 23141355, "score": 0 }, { "doc_id": "7392543", "title": "Size and Conformation Limits to Secretion of Disulfide-bonded Loops in Autotransporter Proteins*", "abstract": "Background: There is a general paucity of cysteine residues within the passenger domains of autotransporter proteins. Results: Distantly spaced cysteines forming disulfide-bonded loops or those enclosing structural elements are secretion-incompetent. Conclusion: Only closely spaced cysteine pairs are compatible with the autotransporter pathway. Significance: Secretion of folded peptides by the autotransporter pathway is limited; hence autotransporters lack large disulfide-bonded loops to remain secretion-competent. Autotransporters are a superfamily of virulence factors typified by a channel-forming C terminus that facilitates translocation of the functional N-terminal passenger domain across the outer membrane of Gram-negative bacteria. This final step in the secretion of autotransporters requires a translocation-competent conformation for the passenger domain that differs markedly from the structure of the fully folded secreted protein. The nature of the translocation-competent conformation remains controversial, in particular whether the passenger domain can adopt secondary structural motifs, such as disulfide-bonded segments, while maintaining a secretion-competent state. Here, we used the endogenous and closely spaced cysteine residues of the plasmid-encoded toxin (Pet) from enteroaggregative Escherichia coli to investigate the effect of disulfide bond-induced folding on translocation of an autotransporter passenger domain. We reveal that rigid structural elements within disulfide-bonded segments are resistant to autotransporter-mediated secretion. We define the size limit of disulfide-bonded segments tolerated by the autotransporter system demonstrating that, when present, cysteine pairs are intrinsically closely spaced to prevent congestion of the translocator pore by large disulfide-bonded regions. These latter data strongly support the hairpin mode of autotransporter biogenesis.", "corpus_id": 7392543, "score": 0 }, { "doc_id": "206210876", "title": "Estimating the size of the active translocation pore of an autotransporter.", "abstract": "Autotransporters (ATs) are large virulence factors secreted by Gram-negative bacteria. The passenger domain, carrying the virulence functions, is transported across the bacterial outer membrane in a step that is facilitated by a C-terminal β-domain. This domain folds into a β-barrel with a central aqueous pore of ∼1 nm inner diameter according to crystal structures. However, these static dimensions are not compatible with the observed secretion of passengers that may contain natural short-spaced disulfide bonds or artificially fused folded elements. Here, we have systematically analyzed the dimensions of the active AT passenger translocator by inserting peptides of different length and structural complexity in the passenger of the AT hemoglobin protease. The peptides were introduced in a short loop protruding from the main structure and flanked by two single cysteines. Our results show that the attained secondary structure may be more critical for secretion than the length of peptide inserted. Furthermore, the data suggest that, during passenger translocation, at least four extended polypeptides or an extended polypeptide and an α-helix are accommodated in the translocator, indicating that the diameter of the active translocation pore is up to 1.7 nm. If the β-domain functions as the translocator, it must be forced into an expanded conformation during passenger translocation.", "corpus_id": 206210876, "score": 0 }, { "doc_id": "32149237", "title": "Tightly regulated tac promoter vectors useful for the expression of unfused and fused proteins in Escherichia coli.", "abstract": "A series of new plasmid expression vectors (the pTrc series) has been constructed for the regulated expression of genes in Escherichia coli. Based on pKK233-2 [Amann and Brosius, Gene 40 (1985) 183-190], the vectors carry a strong hybrid trp/lac promoter, the lacZ ribosome-binding site (RBS), the multiple cloning site of pUC18 and the rrnB transcription terminators. With the aid of synthetic oligodeoxynucleotides, the multiple cloning site has been inserted behind an NcoI site in three reading frames. Thus, the vectors are equally useful for the expression of proteins in their authentic, non-fused form (by using the NcoI site) and for the expression of fusion proteins (by choosing any of the cloning sites in the correct translational frame). To ensure complete repression of the hybrid trp/lac promoter during construction and growth in any host strain, the lacIq allele of the lac repressor gene was added to some of the vectors. The complete vector nucleotide sequence and examples of heterologous gene expression (human coagulation factor XIIIa and human placental anticoagulant protein PP4) with the new vectors are presented.", "corpus_id": 32149237, "score": 0 }, { "doc_id": "15246619", "title": "The E. coli Signal Recognition Particle Is Required for the Insertion of a Subset of Inner Membrane Proteins", "abstract": "E. coli homologs of the signal recognition particle (SRP) and its receptor are essential for viability, but their role in protein export is unclear. To elucidate their function, we devised a genome-wide screen to identify genes that encode SRP substrates. Inhibition of the SRP pathway sharply blocked the membrane insertion of several polytopic inner membrane proteins (IMPs) that were predicted to be SRP substrates, but had a smaller effect on the insertion of other IMPs and no significant effect on preprotein translocation. Our results suggest that whereas most E. coli preproteins and some IMPs can utilize SRP-independent targeting pathways effectively, the structural features of a subset of IMPs have required the conservation of an SRP-based targeting machinery.", "corpus_id": 15246619, "score": 0 }, { "doc_id": "16509924", "title": "SignalP 4.0: discriminating signal peptides from transmembrane regions", "abstract": "We benchmarked SignalP 4.0 against SignalP 3.0 and ten other signal peptide prediction algorithms (Fig. 1). We compared prediction performance using the Matthews correlation coefficient16, for which each sequence was counted as a true or false positive or negative. To test SignalP 4.0 performance, we did not use data that had been used in training the networks or selecting the optimal architecture, and the test data did not contain homologs to the training and optimization data (Supplementary Methods). The test set for SignalP 3.0 was also independent of the training set because we removed sequences used to construct SignalP 3.0 and their homologs from the benchmark data. For other algorithms more recent than SignalP 3.0, the benchmark data may include data used to train the methods, possibly leading to slight overestimations of their performance. Our results show that SignalP 4.0 was the best signal-peptide predictor for all three organism types (Fig. 1). This comes at a price, however, because SignalP 4.0 was not in all cases as good as SignalP 3.0 according to cleavage-site sensitivity or signal-peptide correlation when there are no transmembrane proteins present (Supplementary Results). An ideal method would have the best SignalP 4.0: discriminating signal peptides from transmembrane regions", "corpus_id": 16509924, "score": 0 } ]

{ "doc_id": "1346453", "title": "Signal Transducer and Activator of Transcription 6 Is Essential in the Induction of Contact Hypersensitivity", "abstract": "Contact hypersensitivity (CHS) is thought to be mainly associated with the activation of T helper type 1 (Th1) cells. However, there is also evidence that Th2 cells or Th2 cytokines play a role in the development of CHS. To analyze the functional contribution of Th2 cytokines interleukin (IL)-4 and IL-13, signal transducer and activator of transcription 6 (STAT6)-deficient (STAT6−/−) and wild-type (wt) control C57BL/6 mice were contact sensitized with 5% 2,4,6-trinitrochlorobenzene (TNCB), 0.5% 2,4-dinitrofluorobenzene, or 5% 4-ethoxyl methylene-2-phenyl-2-oxazolin-5-one, and any skin reactions were examined. Ear swelling was significantly reduced with a delayed peak response in STAT6−/− mice compared with wt mice. A histological analysis revealed that the infiltration of both eosinophils and neutrophils in the skin challenged after 24 h in STAT6−/− mice decreased substantially compared with that in wt mice. The expression of Th2 cytokines (IL-4, IL-5) in TNCB-challenged skin tissues and the supernatants from T cells stimulated by 2,4,6-trinitrobenzene sulfonate–modified spleen cells, as well as the immunoglobulin (Ig)E and IgG1 response after challenge, were also profoundly reduced in STAT6−/− mice, whereas the expression of interferon γ was the same in STAT6−/− and wt mice after challenge. Furthermore, adoptive transfer experiments revealed that STAT6−/− mice induced CHS after injection of lymph node cells obtained from sensitized wt mice. Our data suggest that the STAT6 signal plays a critical role in the induction phase of CHS.", "corpus_id": 1346453 }

[ { "doc_id": "35339768", "title": "Interleukin-4 is a critical cytokine in contact sensitivity.", "abstract": "This study demonstrates an essential role for interleukin-4 (IL-4) in the delayed hypersensitivity reaction, as illustrated by contact sensitivity (CS) to trinitrochlorobenzene (TNCB). Injection of mice with monoclonal antibody to IL-4, but not with control antibody, reduced CS after active immunization by 75%, as judged by ear swelling. The histological alterations of CS were also reduced. IL-4 was essential to the effector stage, as inhibition of its production or action blocked the passive transfer of CS. In particular, treatment of immune lymph node cells with antisense oligonucleotide to IL-4 inhibited the systemic transfer of CS. Transfer was also inhibited by monoclonal antibody to IL-4 given to the recipient. The present results indicate that IL-4 is an essential cytokine at the effector stage of the CS reaction.", "corpus_id": 35339768, "score": 1 }, { "doc_id": "25763756", "title": "Role of IL‐4 in delayed type hypersensitivity", "abstract": "IL‐4 plays a key role in the contact sensitivity skin reaction. This has several implications. First, the view that contact sensitivity (CS) is only mediated by cells with a Th1 profile of cytokine secretion needs modification, in the light of the essential role of IL‐4 at the effector stage. Second, the concept of a single cell involved in the systemic transfer of CS is no longer tenable, as it is known that both αβ and γδ cells are required. Studies with the cell lines (which contain both αβ and a few γδ cells) suggest that this double requirement may involve the action of IL‐4 on γδ cells, which bear receptors for IL‐4. Finally, the view that T cell lines only transfer CS when injected locally, but not when injected intravenously (systemic transfer), is correct but incomplete, as T cell lines actually give systemic transfer of CS, providing the cell line or the recipient is treated with IL‐4.", "corpus_id": 25763756, "score": 1 }, { "doc_id": "25324605", "title": "Diminished Contact Hypersensitivity Response in IL‐4 Deficient Mice at a Late Phase of the Elicitation Reaction", "abstract": "Contact hypersensitivity (CHS) is thought to depend on the activation of T cells of Th1 and/or Tc1 type. The role of Th2/Tc2 cells in the contact allergic reaction is not clear. The aim of this study was to analyse the functional contribution of Th2/Tc2 cells in CHS using the interleukin‐4 (IL‐4) deficient mouse model. Interleukin‐4 deficient (IL4T) and control (wt) mice were sensitized by epicutaneous application of 2,4‐dinitrofluorobenzene. The ear swelling response measured 24 h after challenge was similar in IL4T and control mice. However, from 48 h onwards, ear swelling values were significantly reduced in IL4T mice. The stimulatory capacity of freshly isolated as well as 3‐day cultured epidermal cells, prepared from IL4T and wt mice, for allogeneic T cells in a primary and secondary response, was comparable. The reduced number of T cell receptor (TCR) γδ+ cells observed in epidermal sheets prepared from IL4T mice was not responsible for the decreased ear swelling response in IL4T mice, because the use of TCR δ deficient mice lacking TCR γδ+ cells revealed a down‐regulatory role of this cell population in the CHS response. The data indicate that the effector stage of the CHS response can be subdivided into two phases. The first phase proceeds efficiently in IL‐4 deficient mice indicating the dependence on Th1/Tc1 cells, while the second phase does not develop in mice lacking IL‐4, suggesting the possibility that Th2/Tc2 cells intensify the reaction.", "corpus_id": 25324605, "score": 0 }, { "doc_id": "12985786", "title": "Interleukin 10 but not interleukin 4 is a natural suppressant of cutaneous inflammatory responses", "abstract": "We have examined the role of endogenously produced interleukin (IL) 4 and IL-10 in the regulation of inflammatory and immune reactions in the skin. In these experiments, irritant and contact hypersensitivity (CH) responses were elicited in mice with targeted disruptions of the IL-4 (IL-4T) or IL-10 (IL-10T) gene. Our study showed that IL-4T and wild- type (wt) mice exhibited equivalent responses to the irritant croton oil. In contrast, the response of IL-10T mice challenged with croton oil was abnormally increased. When IL-10T mice were exposed to a higher dose of irritant, irreversible tissue damage occurred. By comparison, any treatment of wt mice with croton oil resulted in far less tissue damage and resolution of inflammation. Neutralizing antibody studies demonstrated that the necrosis that occurred in IL-10T mice was due to the overproduction of tumor necrosis factor. The anti-tumor necrosis factor antibody treatment of IL-10T mice did not significantly reduce the edema or the influx of inflammatory cells, suggesting that these changes were due to the uncontrolled production of other proinflammatory cytokines. T cell-dependent immune responses were also evaluated using the contact sensitizer oxazolone. The response of IL-4T mice did not differ from wt mice. In contrast, IL-10T mice mounted an exaggerated CH response, increased in both magnitude and duration as compared with wt mice. Based on these studies, we have concluded that IL-10, but not IL-4, is a natural suppressant of irritant responses and of CH, and it limits immunopathologic damage in the skin.", "corpus_id": 12985786, "score": 1 }, { "doc_id": "22223209", "title": "Inhibition of allergic contact dermatitis to DNCB but not to oxazolone in interleukin-4-deficient mice.", "abstract": "The role of interleukin-4 as a regulator of immune responses in the skin is investigated with regard to the outcome of contact hypersensitivity reaction in interleukin-4-deficient BALB/C mice. In previous studies conflicting results were obtained concerning the role of interleukin-4 in contact hypersensitivity reactions supporting either a proinflammatory or rather an inhibitory function of this cytokine. Interleukin-4 deficient BALB/C mice sensitized to 2,4-dinitrochlorobenzene showed after challenge a significant reduction in magnitude and duration of the contact hypersensitivity response in comparison with wild-type mice. This attenuation was accompanied by a significant reduction of edema and cellular infiltrates in the dermis and a lacking induction of IL-10 mRNA expression in skin. Also, adoptive transfer experiments revealed that BALB/C mice failed to exhibit contact hypersensitivity after injection of lymph node cells obtained from sensitized interleukin-4 deficient mice. To examine further the role of the contact allergen used to induce the contact hypersensitivity response, mice were also sensitized and challenged with Oxazolone. Here a similar magnitude and duration of contact hypersensitivity in both the interleukin-4 deficient mice and BALB/C control mice was observed. This indicates that the contact hypersensitivity response to 2,4-dinitrochlorobenzene and Oxazolone may partly evolve on different pathways being dependent and independent of interleukin-4. Our results clearly show that the complete loss of endogenous interleukin-4 expression in BALB/C mice is associated with an impaired manifestation of contact hypersensitivity response to 2,4-dinitrochlorobenzene, implying an important proinflammatory function of this cytokine.", "corpus_id": 22223209, "score": 1 }, { "doc_id": "4340375", "title": "Essential role of Stat6 in IL-4 signalling", "abstract": "INTERLEUKIN-4(IL-4) is a pleiotropic lymphokine which plays an important role in the immune system1. IL-4 activates two distinct signalling pathways through tyrosine phosphorylation of Stat6, a signal transducer and activator of transcription, and of a 170K protein called 4PS2–7. To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting. We report here that in the mutant mice, expression of CD23 and major histocompatibility complex (MHC) class II in resting B cells was not enhanced in response to IL-4. IL-4-induced B-cell proliferation costimulated by anti-IgM antibody was abolished. The T-cell proliferative response was also notably reduced. Furthermore, production of Th2 cytokines from T cells as well as IgE and IgGl responses after nematode infection were profoundly reduced. These findings agreed with those obtained in IL-4-deficient mice8,9 or using antibodies to IL-410 and the IL-4 receptor11. We conclude that Stat6 plays a central role in exerting IL-4-mediated biological responses.", "corpus_id": 4340375, "score": 1 }, { "doc_id": "43553700", "title": "Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice.", "abstract": "IL-13 shares many biologic responses with IL-4. In contrast to well-characterized IL-4 signaling pathways, which utilize STAT6 and 4PS/IRS2, IL-13 signaling pathways are poorly understood. Recent studies performed with STAT6-deficient mice have demonstrated that STAT6 plays an essential role in IL-4 signaling. In this study, the functions of peritoneal macrophages of STAT6-deficient mice in response to IL-13 were analyzed. In STAT6-deficient mice, neither morphologic changes nor augmentation of MHC class II expression in response to IL-13 was observed. In addition, IL-13 did not decrease the nitric oxide production by activated macrophages. Taken together, these results suggest that the macrophage functions in response to IL-13 were impaired in STAT6-deficient mice, indicating that IL-13 and IL-4 share the signaling pathway via STAT6.", "corpus_id": 43553700, "score": 1 }, { "doc_id": "35603116", "title": "Blockade of costimulatory molecules B7‐1 (CD80) and B7‐2 (CD86) down‐regulates induction of contact sensitivity by haptenated epidermal cells", "abstract": "The hapten, trinitrobenzene sulphonic acid, induced weak B7‐1 (CD80) and moderate B7‐2 (CD86) expression on Langerhans cells and mRNA expression of both molecules in organ‐cultured murine skin. The intradermal injection of hapten‐treated epidermal cells induced hapten‐specific contact sensitivity in synergic mice. Cells of the keratinocyte cell line, Pam 212, or epidermal cells treated with a mixture of anti‐Ia/thy 1·2/γδ antibody plus complement, did not show any sensitizing ability. When hapten‐treated epidermal cells were injected into mice after incubation with anti‐B7‐2 (CD86) or B7‐1 (CD80) antibody the resultant contact sensitivity reaction was decreased to less than 50% of the control reaction, a reduction which was similar to that seen with the anti‐ICAM‐1 and anti‐LFA‐1 antibody‐induced inhibition of contact sensitivity. Anti‐B7‐1 (CD80) or anti‐B7‐2 (CD86) antibody also inhibited hapten‐specific lymphocyte proliferation or the allogenic mixed lymphocyte and epidermal cell reaction in vitro, although the inhibitory effect of anti‐B7‐1 antibody was not as significant as that of anti‐B7‐2 antibody. These results indicate that costimulatory signals induced by a hapten on epidermal Langerhans cells play an important role in the induction of hapten‐specific contact sensitivity in mice.", "corpus_id": 35603116, "score": 0 }, { "doc_id": "31795313", "title": "Functional CD86 (B7-2/B70) on cultured human Langerhans cells.", "abstract": "CD86 (B70/B7-2) has recently been identified as an alternative CD28/CTLA-4 ligand on activated B cells. CD86 has also been demonstrated as possibly serving as a primary costimulatory molecule in the initial immune response. Since the human Langerhans cell is one of the most potent antigen-presenting cells, we examined whether CD86 expression and function are found on organ-cultured skin, freshly isolated Langerhans cells, and cultured Langerhans cells in normal human epidermis. Immunohistochemical study in situ revealed that CD86 was expressed on dendritic cells with CD1a antigen in organ-cultured but not fresh skin. Fluorescence-activated cell sorter analysis revealed that no staining for either CD80 or CD86 was observed in freshly isolated Langerhans cells but that both CD80 and CD86 were expressed on cultured Langerhans cells. The actual expression of CD86 on cultured Langerhans cells was further confirmed by the detection of 70-kDa glycoprotein on Western blot analysis. Analysis of polymerase chain reaction demonstrated that both CD80 and CD86 were specifically amplified from purified cultured and freshly isolated Langerhans cells but not from Langerhans cell-depleted epidermal cells, indicating that both CD80 and CD86 genes were expressed by Langerhans cells. The functional importance of CD86 on Langerhans cells was confirmed by the allogeneic CD4 T cell proliferative responses with enriched Langerhans cells. A monoclonal antibody against CD86 caused 81% inhibition in contrast with 29% inhibition produced by anti-CD80 monoclonal antibody. This inhibitory effect was enhanced to 85.3% inhibition when a combination of anti-CD86 and anti-CD80 was administered. These results indicate that CD86 is predominantly expressed on the surface of cultured Langerhans cells and may transduce a primordial costimulatory signal in the interaction of Langerhans cells and T cells.", "corpus_id": 31795313, "score": 0 }, { "doc_id": "31727629", "title": "Initiation of delayed-type hypersensitivity by low doses of monoclonal IgE antibody. Mediation by serotonin and inhibition by histamine.", "abstract": "Elicitation of delayed-type hypersensitivity (DTH) responses by DTH effector T cells requires a prior phase of DTH initiation. This consists of an immediate hypersensitivity-like response mediated by Ag-specific DTH-initiating factors that are analogous to IgE antibodies in that they sensitize tissue mast cells for release of the vasoactive amine serotonin (5-HT). Experiments were conducted to determine whether IgE mAb injected i.v., or 5-HT injected locally, could initiate DTH. It was found that small doses of IgE (1 microgram/mouse), or of 5-HT (50 to 500 ng locally), which mediated small immediate responses, were optimal for DTH initiation. Even lower doses of IgE (10 ng/mouse), or of 5-HT (5 ng locally), which did not mediate macroscopically measurable immediate responses, were capable of DTH initiation. Higher doses of IgE (10 to 100 micrograms/mouse), which mediated large immediate responses, were not able to initiate DTH. A similar dose response for DTH initiation was found with IgG1 mAb, which is another mast cell-sensitizing isotype of Ig. The inability of high doses of IgE or IgG1 to mediate DTH initiation was probably caused by local release of large inhibitory amounts of histamine, because systemic treatment with the histamine-2 receptor antagonist cimetidine allowed high doses of IgE to initiate DTH. Thus, IgE and IgG1 antibodies could initiate DTH via release of small amounts of 5-HT, but simultaneous release of large amounts of histamine were inhibitory, probably via an effect on histamine-2 receptors of recruited T cells. We concluded the following: 1) IgE or IgG1 antibodies can initiate DTH; 2) DTH initiation need not be associated with macroscopically detectable early responses; 3) mast cell release of 5-HT acts positively whereas release of histamine acts negatively in murine DTH; 4) Ag-specific factors are not the only mechanism of DTH initiation.", "corpus_id": 31727629, "score": 0 }, { "doc_id": "14847180", "title": "T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: interferon gamma-producing (Tc1) effector CD8+ T cells and interleukin (Il) 4/Il-10-producing (Th2) negative regulatory CD4+ T cells", "abstract": "Contact hypersensitivity (CHS) is a T cell-mediated response to hapten sensitization of the epidermis. The roles of CD4+ and CD8+ T cells in CHS have remained unclear, however, as studies to define either subset as the T cells mediating CHS have provided conflicting results. The goal of this study was to correlate the in vivo function of CD4+ and CD8+ T cells in CHS with the cytokines produced by each T cell population. Antibody-mediated depletion of CD4+ T cells before sensitization of BALB/c mice with 2,4-dinitrofluorobenzene (DNFB) or oxazolone (Ox) resulted in increased and prolonged CHS responses, indicating CD4+ T cells as negative regulators of the response. Depletion of CD8+ T cells resulted in low or abrogated responses, indicating CD8+ T cells as the effector cells in CHS. Sensitization with DNFB or Ox induced lymph node cell populations of CD8+ T cells producing interferon (IFN)-gamma and no interleukin (Il) 4 or Il-10, and CD4+ T cells producing Il-4 and Il-10 and no or little detectable IFN-gamma. The polarized patterns of cytokine production were stimulated by culture of hapten-primed lymph node cells either on anti- T cell receptor antibody-coated wells or with semipurified Langerhans cells isolated from hapten-sensitized mice. Stimulation of cytokine production during culture of hapten-primed CD4+ or CD8+ T cells with Langerhans cells was hapten specific and restricted to class II or class I major histocompatibility complex, respectively. The induction of the CD4+ and CD8+ T cells producing the polarized patterns of cytokines was not restricted to BALB/c mice, as cells from Ox sensitized C57B1/6 and B10.D2 mice produced the same patterns. Collectively, these results expose the induction of two polarized and functionally opposing populations of T cells by hapten sensitization to induce CHS: IFN-gamma-producing effector CD8+ T cells and Il-4/Il-10- producing CD4+ T cells that negatively regulate the response.", "corpus_id": 14847180, "score": 0 }, { "doc_id": "8841851", "title": "Low zone tolerance to contact allergens in mice: a functional role for CD8+ T helper type 2 cells", "abstract": "Normal skin is permeable to low molecular hydrophobic substances, including allergenic chemicals. Whereas such foreign matter appears to enter the skin naturally, it rarely induces contact hypersensitivity. This suggests that immunological tolerance would be the normal state of affairs. In search of a suitable model, we painted picryl chloride or oxazolone once or repeatedly on normal skin of BALB/c or C57B1/6 mice and found subsensitizing doses to be tolerogenic. The most effective doses in inducing tolerance were doses between those at the point of inflection from no responses to threshold sensitivity. But even doses three orders of magnitude lower than these suppressed subsequent sensitization if applied repeatedly. C57B1/6 mice (low responders) were consistently easier to make tolerant than BALB/c mice (high responders). The tolerant state established by a single painting was found to be fully developed at 48 h after initiation and long-lasting (>14 d). It could be adoptively transferred by intravenous injection of total spleen cells (SC), lymph node cells (LNC), or purified T cells and shown to be hapten specific. Pretreatment with cyclophosphamide (Cy) prevented tolerization. The T cells capable of transferring suppressive activity were found to be generated irrespective of the dose applied. On day 2 after painting, tolerance could be transferred with LNC from both tolerant and sensitized animals. On day 5, however, only cells from tolerant donors transferred tolerance. But by action of Cy, suppression was shown to be part of every sensitization, although masked. Production of hapten-specific antibodies was suppressed as well. Through depletion by monoclonal antibody in vitro the T suppressor cells were shown to belong to the murine CD8+ subset (Lyt2+). Upon restimulation in vitro by haptenized and irradiated normal SC, LNC from tolerant donors produced predominantly interleukin (IL)-4, IL-5, and IL-10. In contrast, LNC from sensitized donors produced preferentially IL-2 and interferon-gamma. Thus we demonstrate that painting subsensitizing doses of contact sensitizers on normal murine skin generates CD8+ Th2-like cells that give rise to hapten- specific tolerance. The model may have broader significance and apply to other species, including humans.", "corpus_id": 8841851, "score": 0 }, { "doc_id": "9832166", "title": "Cultured epidermal Langerhans cells activate effector T cells for contact sensitivity.", "abstract": "To investigate whether Langerhans cells are capable of inducing contact sensitivity effector T cells, we incubated purified T cells from naive mice with syngeneic cultured trinitrophenyl-modified Langerhans cells for 4-5 d. The cells were then expanded in interleukin-2 and fresh medium for another 6-9 d and injected intravenously into naive syngeneic recipient mice. After the ears of recipient mice were painted with 1% trinitrochlorobenzene, we observed an ear-swelling response peaking at 24-48 h. The ear-swelling response was hapten specific. CD8- but not CD4-depleted T cells mediated strong contact sensitivity. Systemic adoptive transfer into nude mice also lead to a hapten-specific delayed ear-swelling response. However, this response was less protracted than in euthymic animals, suggesting the participation of the recipient (non-immunized) T cells in the ear-swelling response of the euthymic mice. Lymphokine analysis of in vitro primed and restimulated T cells revealed predominant production of interleukin-2 but little or no interleukin-4. These in vitro primed cells therefore resemble type 1 or inflammatory T helper cell clones.", "corpus_id": 9832166, "score": 0 }, { "doc_id": "8283304", "title": "Th2 cells mediate IL-4-dependent local tissue inflammation.", "abstract": "We investigated whether polyclonal murine Th1 and Th2 cells obtained after short term culture in vitro were capable of mediating tissue inflammation in vivo. Th cells were pulsed with mAb to the TCR/CD3 complex and injected into the footpads or ears of naive syngeneic recipient mice. Th1 induced delayed swelling that peaked at 24 to 48 h and lasted > or = 5 days. Th2-induced swelling peaked at 6 h and lasted < or = 48 h. Similar responses were also observed in athymic nude mice. Lesions with both Th1 and Th2 cells contained a predominant neutrophilic infiltrate at 6 h, and mainly mononuclear cells at 48 h. The inflammatory response with Th2 was blocked by cyclosporin A, by mAb to IL-4 or by soluble rIL-4R. The requirement for IL-4 was early and transient. Four alloreactive short term Th2 clones induced swelling in allogeneic recipients. mAb- and IL-4-dependent swelling responses were also observed with two long term Th2 clones. Our results demonstrate that Th2 cells mediate IL-4-dependent tissue inflammation, and strengthen the concept that Th2 cells play an important role in some T cell-dependent immune reactions and, possibly, in allergic disorders such as atopic dermatitis and allergic asthma.", "corpus_id": 8283304, "score": 0 }, { "doc_id": "22269039", "title": "IL-4 inhibits the synthesis of IFN-gamma and induces the synthesis of IgE in human mixed lymphocyte cultures.", "abstract": "The T cell-derived lymphokine IL-4 is essential for the induction of IgE synthesis by human lymphocytes. The IgE-inducing effect of IL-4 is antagonized by IFN-gamma. The secretion of IFN-gamma is vigorously triggered in MLC. Thus, IL-4-stimulated MLC represent a suitable model to characterize the functional antagonism between IL-4 and IFN-gamma. In this report, we show that rIL-4 consistently induced IgE synthesis when added to human primary MLC. IL-4-dependent IgE production required cognate T/B cell recognition, because it was inhibited by antibodies to CD3 and MHC class II (HlA-DR) Ag. A neutralizing anti-IFN-gamma mAb dramatically enhanced IL-4-dependent IgE synthesis by MLC, indicating that endogenous IFN-gamma is a major inhibitor of IgE production. More importantly, addition of rIL-4 markedly inhibited the release of IFN-gamma in supernatants of MLC and Con A-activated PBMC. The decrease in IFN-gamma protein was accompanied by a decreased expression of IFN-gamma mRNA transcripts. The downregulation of IFN-gamma by IL-4 is likely to play an important role in the IL-4-dependent induction of IgE synthesis.", "corpus_id": 22269039, "score": 0 }, { "doc_id": "28898419", "title": "The cellular infiltrate in contact hypersensitivity to picryl chloride in the mouse.", "abstract": "In the present work, the contact hypersensitivity skin test reaction to picryl chloride in CBA mice was examined. The test was performed by applying the contact allergen to the ear skin and making a series of histological analyses up to 24 hours after challenge. An increment in ear thickness, measured with an engineer's micrometer 24 hours after challenge, was obvious in a group of sensitized mice when compared with a nonsensitized control group, and the difference was found to be highly significant. One hour after challenge, mononuclear cells appeared in the dermis, increasing in numbers during the following 12 hours. At this time, neutrophil granulocytes were the dominant cells in the infiltrate and remained so up to 24 hours after challenge. On the basis of the experiments performed here we conclude that measuring of the ear swelling with a micrometer 24 hours after challenge is a useful and reliable test of contact sensitivity in the mouse.", "corpus_id": 28898419, "score": 0 }, { "doc_id": "43858338", "title": "Pharmacologic modulation of picryl chloride-induced contact dermatitis in the mouse.", "abstract": "A biphasic response of ear swelling was observed 2 h and 24 h after application of the antigen to picryl chloride-sensitized Balb/c mice. A platelet-activating factor (PAF) antagonist, BN 52063, or the anti-inflammatory drug, betamethasone, applied topically or injected subcutaneously, inhibited in a dose-dependent fashion the antigen-induced increase in ear thickness observed after 24 h. In addition, BN 52063 and betamethasone presented a synergistic effect when administered in vivo simultaneously and subcutaneously. Indomethacin administered subcutaneously at the time of the antigen challenge significantly potentiated the early swelling phase and inhibited the late one. In contrast, the inhibitors of histamine and serotonin, ketotifen and methysergide, respectively, modulated mostly the early, and to a lower extent the late phase when administered at the time of antigen challenge. In contrast, none of these drugs inhibited the late phase reaction when administered 4 h after the antigen. A significant eosinophil and mononuclear-cell ear infiltrate was observed following topical application of the antigen, a phenomenon that was markedly reduced by either BN 52063 or betamethasone. These results demonstrate the effectiveness of PAF antagonists, either alone or in association with glucocorticosteroids, in experimental CD, the modulation of the infiltration of eosinophils and mononuclear cells possibly explaining part of the inhibitory action of these drugs.", "corpus_id": 43858338, "score": 0 }, { "doc_id": "6147187", "title": "Signal Transducer and Activator of Transcription Factor 6 (Stat6)-deficient Mice Are Protected from Antigen-induced Airway Hyperresponsiveness and Mucus Production", "abstract": "The pleiotropic cytokine interleukin 4 (IL-4) has been shown to regulate many processes thought to be important in the allergic diathesis. To determine the mechanism(s) by which IL-4 mediates allergic airway responses to inhaled allergens, we compared the effects of antigen sensitization and challenge on the development of allergic airway responses in mice in which the gene for the signal transducer and activator of transcription factor 6 (Stat6) was disrupted to those of their wild-type littermates. Strikingly, Stat6-deficient mice failed to develop airway hyperresponsiveness (AHR), which was observed in their wild-type littermates after allergen provocation. Moreover, antigen-induced increases in mucus-containing cells were found to be completely Stat6 dependent. Consistent with the lack of Th2 cytokine responses in Stat6-deficient mice, no ovalbumin-specific immunoglobulin (Ig)E was detected in their serum. In contrast, Stat6 signaling only partially mediated antigen-induced eosinophilia with no role in vascular adhesion molecule 1 expression. These results indicate that Stat6 signal transduction is critical in the development of allergen-induced AHR and that agents that specifically inhibit this pathway may provide a novel strategy for the treatment of allergic disorders.", "corpus_id": 6147187, "score": 0 }, { "doc_id": "38944336", "title": "STAT6 deficiency in a mouse model of allergen‐induced airways inflammation abolishes eosinophilia but induces infiltration of CD8+ T cells", "abstract": "The TH2‐type cytokines have been reported to contribute to the asthmatic response. STAT6 has an essential role in IL‐4 signalling and in production of TH2 cytokines from T cells and is involved in IgE and IgG1 responses after nematode infections, indicating that STAT6 has an important role in allergic diseases.", "corpus_id": 38944336, "score": 0 }, { "doc_id": "20690919", "title": "The late phase of the immediate wheal and flare skin reaction. Its dependence upon IgE antibodies.", "abstract": "IgE antibodies are usually thought to induce only immediate skin reactions. We have shown that the intradermal injection of a number of different allergens can produce a prolonged inflammatory reaction after the immediate wheal and flare in most sensitive subjects. This late inflammatory response occurs 6-12 h after challenge and is characterized by diffuse edema, erythema, pruritus, and heat. Both immediate and late responses can also be seen after passive sensitization of skin sites in nonatopic subjects. That IgE is involved in inducing the reaction was shown by the abolition of both immediate and late responses by passive transfer tests in the following experiments: (a) heating atopic serum at 56degreesC for 4 h, (b) removing IgE from the atopic serum by a solid phase anti-IgE immunoabsorbent, and (c) competitively inhibiting the binding of IgE antibodies to cells by an IgE myeloma protein. In addition, both responses were induced by affinity chromatography-purified IgE antibody, followed by antigenic challenge. Very similar lesions could also be induced by intradermal injection of Compound 48/80, thus suggesting a central role in the reaction for the mast cell or basophil. Histologically, the late phase is characterized by edema and a mixed cellular infiltration, predominantly lymphocytic but also containing eosinophils, neutrophils and basophils. Direct immunofluorescent staining did not show deposition of immunoglobulins or complement components, except IgM in 2 of 15 and C3 in 1 of 15 patients. This finding indicates that the late phase does not depend on the deposition of immune complexes. The results of the study suggest that IgE-allergen interaction on the surfaces of mast cells or on infiltrating basophils causes both immediate and late cutaneous responses.", "corpus_id": 20690919, "score": 0 }, { "doc_id": "38780682", "title": "Identification of histamine releasing factor(s) in the late phase of cutaneous IgE-mediated reactions.", "abstract": "We have shown that fluids collected from antigen-challenged skin blisters during the late phase reaction cause the release of substantial amounts of histamine (means = 42%, n = 14) from human basophils in vitro. Control fluids collected either during the immediate phase or from an unchallenged blister released less than or equal to 10% histamine from both basophils and lung mast cells. Late phase blister fluids induced low levels of histamine release from human lung cells (means = 11%, n = 4) that were slightly but not significantly greater than levels induced by control blister fluids. The characteristics of basophil release were similar to IgE-mediated stimuli in dose dependence, calcium and temperature requirements, and kinetics. The IgE dependence of the late phase blister fluid was demonstrated by desensitization of the basophils to anti-IgE, which obviated the response to anti-IgE and blister fluid but did not affect a non-IgE-mediated stimulus. Removal of the cell surface IgE with lactic acid also abolished the response to both anti-IgE and late phase blister fluid. Incubation of the \"stripped\" cells with serum containing IgE myeloma restored the response to anti-IgE but failed to affect response to late phase blister fluid. The characteristics of release obtained with this factor closely resemble those of an IgE-dependent histamine releasing factor from cultured macrophages previously described by our group.", "corpus_id": 38780682, "score": 0 }, { "doc_id": "1299314", "title": "Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha", "abstract": "Using granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 we have established dendritic cell (DC) lines from blood mononuclear cells that maintain the antigen capturing and processing capacity characteristic of immature dendritic cells in vivo. These cells have typical dendritic morphology, express high levels of major histocompatibility complex (MHC) class I and class II molecules, CD1, Fc gamma RII, CD40, B7, CD44, and ICAM-1, and lack CD14. Cultured DCs are highly stimulatory in mixed leukocyte reaction (MLR) and are also capable of triggering cord blood naive T cells. Most strikingly, these DCs are as efficient as antigen-specific B cells in presenting tetanus toxoid (TT) to specific T cell clones. Their efficiency of antigen presentation can be further enhanced by specific antibodies via FcR- mediated antigen uptake. Incubation of these cultured DCs with tumor necrosis factor alpha (TNF-alpha) or soluble CD40 ligand (CD40L) for 24 h results in an increased surface expression of MHC class I and class II molecules, B7, and ICAM-1 and in the appearance of the CD44 exon 9 splice variant (CD44-v9); by contrast, Fc gamma RII is markedly and sometimes completely downregulated. The functional consequences of the short contact with TNF-alpha are in increased T cell stimulatory capacity in MLR, but a 10-fold decrease in presentation of soluble TT and a 100-fold decrease in presentation of TT-immunoglobulin G complexes.", "corpus_id": 1299314, "score": 0 }, { "doc_id": "25974594", "title": "Differentiation of human dendritic cells from monocytes in vitro", "abstract": "Since either macrophages (Mϕ) or dendritic cells (DC) differentiate from monocytes (MO) depending on culture conditions, we investigated the relationship of the DC and Mϕ differentiation pathways. Culturing MO‐enriched blood mononuclear cells with Mϕ colony‐stimulating factor (M‐CSF) or with granulocyte/Mϕ (GM)‐CSF induced Mϕ with a different morphology and CD14/CD1a expression. In contrast, in cultures with GM‐CSF and interleukin (IL)‐4, cells rapidly became nonadherent and acquired DC morphology, ultrastructure, CD1a expression, and most DC markers; they lost membrane CD14 and CD64 and capacity of phagocytosis, displayed less CD68 than Mϕ, but retained nonspecific esterase activity. These DC directly developed from MO without proliferation inasmuch as only day 0 FACS‐sorted MO, but not small CD14− cells, differentiated into DC when cultured with GM‐CSF and IL‐4, or to Mϕ with M‐CSF. While overall cell numbers declined, DC numbers plateaued from culture day 2 onwards, indicating that most had differentiasted by then. This differentiation was radioresistant and occurred without [3H]thymidine incorporation. Commitment to differentiate into DC with GM‐CSF and IL‐4 was irreversible by day 2, since discontinuing IL‐4 at this point did not revert cells to Mϕ. Alternatively, cells rapidly converted to DC when IL‐4 was added from day 2 to cultures initiated with GM‐CSF only. If cultures were initiated with M‐CSF and switched to GM‐CSF and IL‐4 after 2 or 5 days, about half of the cells still converted to DC. Thus, the capacity of MO and even of Mϕ to differentiate into DC was conserved for at least this period. The increased capacity to stimulate the mixed leukocyte reaction correlated with the relative number of CD1a− cells at any time and under each condition tested, a confirmation that these cells functionally qualify as DC. Thus, MO and even Mϕ can be directed to differentiate into DC depending on the cytokine microenvironment.", "corpus_id": 25974594, "score": 0 }, { "doc_id": "37544763", "title": "The ikaros gene is required for the development of all lymphoid lineages", "abstract": "The Ikaros gene encodes a family of early hematopoietic- and lymphocyte-restricted transcription factors. Mice homozygous for a germline mutation in the Ikaros DNA-binding domain lack not only T and B lymphocytes and natural killer cells but also their earliest defined progenitors. In contrast, the erythroid and myeloid lineages were intact in these mutant mice. We propose that Ikaros promotes differentiation of pluripotential hematopoietic stem cell(s) into the lymphocyte pathways. In the absence of a functional Ikaros gene, these stem cells are exclusively diverted into the erythroid and myeloid lineages.", "corpus_id": 37544763, "score": 0 } ]

{ "doc_id": "3407836", "title": "A simple and rapid method for preparing the whole section of starchy seed to investigate the morphology and distribution of starch in different regions of seed", "abstract": "BackgroundStorage starch in starchy seed influences the seed weight and texture, and determines its applications in food and nonfood industries. Starch granules from different plant sources have significantly different shapes and sizes, and even more the difference exists in the different regions of the same tissue. Therefore, it is very important to in situ investigate the morphology and distribution of starch in the whole seed. However, a simple and rapid method is deficient to prepare the whole section of starchy seed for investigating the morphology and distribution of starch in the whole seeds for a large number of samples.ResultsA simple and rapid method was established to prepare the whole section of starchy seed, especially for floury seed, in this study. The whole seeds of translucent and chalky rice, vitreous and floury maize, and normal barley and wheat were sectioned successfully using the newly established method. The iodine-stained section clearly exhibited the shapes and size of starch granules in different regions of seed. The starch granules with different morphologies and iodine-staining colors existed regionally in the seeds of high-amylose rice and maize. The sections of lotus and kidney bean seeds also showed the feasibility of this method for starchy non-cereal seeds.ConclusionThe simple and rapid method was proven effective for preparing the whole sections of starchy seeds. The whole section of seed could be used to investigate the morphology and distribution of starch granules in different regions of the whole seed. The method was especially suitable for large sample numbers to investigate the starch morphology in short time.", "corpus_id": 3407836 }

[ { "doc_id": "2099321", "title": "Starch synthesis in the cereal endosperm.", "abstract": "The pathway of starch synthesis in the cereal endosperm is unique, and requires enzyme isoforms that are not present in other cereal tissues or non-cereal plants. Recent information on the functions of individual enzyme isoforms has provided insight into how the linear chains and branch linkages in cereal starch are synthesized and distributed. Genetic analyses have led to the formulation of models for the roles of de-branching enzymes in cereal starch production, and reveal pleiotropic effects that suggest that certain enzymes may be physically associated. For the first time, tools for global analyses of starch biosynthesis are available for cereal crops, and are heralded by the draft sequence of the rice genome.", "corpus_id": 2099321, "score": 0 }, { "doc_id": "85627079", "title": "Physico‐chemical properties of starches from Indian kidney bean (Phaseolus vulgaris) cultivars", "abstract": "Summary \n \nStarches isolated from four Kidney bean cultivars (French Yellow, Contender, Master Bean, Local Red) grown in temperate climate were studied for their physico-chemical, morphological, thermal, pasting, textural and retrogradation properties. Physico-chemical properties such as composition, amylose content, water absorption capacity, swelling power, syneresis, freeze–thaw stability and light transmittance showed significant differences among starches. Amylose content (36.4–41.7%) showed strong correlations with peak, trough, breakdown, final and setback viscosity, gel hardness, gumminess and chewiness. The starch granule morphology of these starches showed considerable variation when studied by scanning electron microscopy. Starch granules were observed to be round, irregular or elliptical with smooth surfaces. Master Bean starch granules were larger than those of other kidney bean starches. Pasting and textural properties of French Yellow starches were found to be higher than other kidney bean starches. Local Red starches showed the highest gelatinisation transition temperatures, whereas Master Bean starches showed the lowest transition temperatures.", "corpus_id": 85627079, "score": 0 }, { "doc_id": "5591408", "title": "Structural and physicochemical properties of lotus seed starch treated with ultra-high pressure.", "abstract": "Aqueous lotus seed starch suspensions (15%, w/w) were subjected to ultra-high pressure treatment (UHP, 100-600 MPa) for 30 min. The effects of UHP treatment on the structural and physicochemical properties of starch were investigated. The SEM and laser diffraction particle size analysis revealed that UHP treatment affected the shape and size distribution of starch granules. The morphological structure of starch was completely destroyed at 600 MPa, indicating complete gelatinization. Analysis of HPSEC-MALLS-RI suggested that the dispersity index of UHP-treated starch were decreased from 1.28 to 1.11. According to XRD analyses, UHP treatment converted native starch (C-type) into a B-type pattern. The swelling power and solubility presented a significant decrease at 85 and 95 °C, but opposite trends were found at 55-75 °C. The DSC results indicated a reduction in gelatinization temperatures and enthalpy with increasing pressure treatment. The RVA viscograms revealed that UHP-treated starch showed a decreased breakdown and setback viscosity, reflecting lower retrogradation tendency compared to native starch.", "corpus_id": 5591408, "score": 0 }, { "doc_id": "21614268", "title": "A rapid, direct observation method to isolate mutants with defects in starch grain morphology in rice.", "abstract": "Starch forms transparent grains, referred to as starch grains (SGs), in amyloplasts. Despite the simple glucose polymer composition of starch, SGs exhibit different morphologies depending on plant species, especially in the endosperm of the Poaceae family. This study reports a novel method for preparing thin sections of endosperm without chemical fixation or resin embedding that allowed us to visualize subcellular SGs clearly. Using this method, we observed the SG morphologies of >5,000 mutagenized rice seeds and were able to isolate mutants in which SGs were morphologically altered. In five mutants, named ssg (substandard starch grain), increased numbers of small SGs (ssg1-ssg3), enlarged SGs (ssg4) and abnormal interior structures of SGs (ssg5) were observed. Amylopectin chain length distribution analysis and identification of the mutated gene suggested a possible allelic relationship between ssg1, ssg2, ssg3 and the previously isolated amylose-extender (ae) mutants, while ssg4 and ssg5 seemed to be novel mutants. Compared with conventional observation methods, the methods developed here are more effective for obtaining fine images of subcellular SGs and are suitable for the observation of a large number of samples.", "corpus_id": 21614268, "score": 1 }, { "doc_id": "12806300", "title": "Maize endosperm-specific transcription factors O2 and PBF network the regulation of protein and starch synthesis", "abstract": "Significance Nutritional quality and yield are equally important considerations in crop breeding, although they sometimes appear at odds. In this work we made the discovery that these traits are linked through regulation by two transcription factors. Mutations that affect the expression of these transcription factors can improve the nutritional quality of the seed but also can reduce kernel yield and hardness. Therefore future corn-breeding programs should silence zein genes directly, not by blocking transcription factors. The maize endosperm-specific transcription factors opaque2 (O2) and prolamine-box binding factor (PBF) regulate storage protein zein genes. We show that they also control starch synthesis. The starch content in the PbfRNAi and o2 mutants was reduced by ∼5% and 11%, respectively, compared with normal genotypes. In the double-mutant PbfRNAi;o2, starch was decreased by 25%. Transcriptome analysis reveals that >1,000 genes were affected in each of the two mutants and in the double mutant; these genes were mainly enriched in sugar and protein metabolism. Pyruvate orthophosphate dikinase 1 and 2 (PPDKs) and starch synthase III (SSIII) are critical components in the starch biosynthetic enzyme complex. The expression of PPDK1, PPDK2, and SSIII and their protein levels are further reduced in the double mutants as compared with the single mutants. When the promoters of these genes were analyzed, we found a prolamine box and an O2 box that can be additively transactivated by PBF and O2. Starch synthase IIa (SSIIa, encoding another starch synthase for amylopectin) and starch branching enzyme 1 (SBEI, encoding one of the two main starch branching enzymes) are not directly regulated by PBF and O2, but their protein levels are significantly decreased in the o2 mutant and are further decreased in the double mutant, indicating that o2 and PbfRNAi may affect the levels of some other transcription factor(s) or mRNA regulatory factor(s) that in turn would affect the transcript and protein levels of SSIIa and SBEI. These findings show that three important traits—nutritional quality, calories, and yield—are linked through the same transcription factors.", "corpus_id": 12806300, "score": 0 }, { "doc_id": "97650664", "title": "Anthology of Starch Granule Morphology by Scanning Electron Microscopy", "abstract": "Scanning electron micrographs of the granules of 54 starches obtained from a wide variety of plant sources, consisting of roots and tubers, grains, maize, peas and beans, fruits and nuts, and small granule starches, are presented as a comparative study of their sizes and morphologies. All micrographs are presented at a magnification of 1500X with the addition of micrographs of 600X for the very large granules and micrographs of 10,000X for the very small granules.", "corpus_id": 97650664, "score": 0 }, { "doc_id": "96197689", "title": "Characteristics of the different corn types and their grain fractions: physicochemical, thermal, morphological, and rheological properties of starches", "abstract": "Abstract Pop corn, dent corn and baby corn (dent type) grains were fractionated into different fractions on the basis of their size. The starches were separated from these fractions and evaluated for physicochemical, morphological, thermal and rheological properties. Significant difference was observed in various properties among different fractions of dent corn and pop corn. Mean granule diameter of the starches separated from different fractions ranged between 6.33 and 13.64 μm. The shape of starch granules varied from oval to polyhedral. Baby corn starch showed the presence of oval shape granules whereas polyhedral shape granules were observed in starches from other corn types. Amylose content of starches from different corn types ranged between 15.3% and 25.1%. Baby corn starch showed lowest swelling power, solubility, amylose content and mean granule diameter. The transition temperatures ( T o , T p and T c ) and enthalpy of gelatinization (Δ H gel ) of starches were determined using differential scanning calorimetry. T o , T p , T c and Δ H gel varied from 66.3 to 69.3, 71.5 to 73.1, 76.5 to 78 °C and 8.9 to 10.9 J/g, respectively. Baby corn starch showed lowest T o , T p , Δ H gel and PHI. The values of these parameters were highest for both the fractions of dent corn and large grain fraction of pop corn starch. The rheological properties of the starches from different fractions of pop corn and dent corn measured using a dynamic rheometer, showed significant variation in the peak G ′ , G ″ and peak tan δ values. Pop corn large grain fraction showed highest values for peak G ′ , G ″ and breakdown in G ′ , whereas pop corn small grain fraction showed lower values of these parameters. The turbidity of the gelatinized aqueous starch pastes from all the corn types increased with increase in storage period. Baby corn starch showed the lowest and pop corn large grain fraction showed highest retrogradation values during storage.", "corpus_id": 96197689, "score": 0 }, { "doc_id": "84294953", "title": "Comparison of physicochemical properties of starches from seed and rhizome of lotus", "abstract": "Abstract Lotus seed and rhizome starches have been used as functional foods in east Asia for thousands of years. In this paper, starches were isolated from lotus seed and rhizome, and their physicochemical properties were compared. Seed starches were small oval granules, rhizome starches had small oval granules and large elongated granules. Seed starches showed significantly higher amylose content and gelatinization temperature and lower swelling power than rhizome starches. Seed starches exhibited an A-type X-ray diffraction pattern with higher crystalline degree, while rhizome starches showed a C-type pattern which changed from C- to A-type with gradually increasing crystalline degree during acid hydrolysis. The degree of order in starch external region was higher in rhizome than in seed. The external region structure of rhizome starches became more ordered during acid hydrolysis. Rhizome starches had higher rate of acid hydrolysis and lower rate of porcine pancreatic α-amylase hydrolysis than seed starches.", "corpus_id": 84294953, "score": 0 }, { "doc_id": "22188626", "title": "Comparison of starch granule development and physicochemical properties of starches in wheat pericarp and endosperm.", "abstract": "BACKGROUND\nThe objectives of this study were: (i) to characterize structural development of starch granule in pericarp and endosperm during wheat caryopsis growth; (ii) to compare physicochemical properties of starches in pericarp and endosperm; (iii) to further discover the relationships between pericarp starches and endosperm starches. Wheat pericarp and endosperm at different development stages were observed by light microscopy and scanning electron microscopy, respectively. Structural properties of starches were determined using X-ray power diffraction and (13) C solid nuclear magnetic resonance.\n\n\nRESULTS\nPericarp starch granules (PSG) accumulated in amyloplasts and chloroplasts, and showed a typical accumulation peak at 5 days after fertilization (DAF), and then gradually decomposed during 5-22 DAF. PSG in the abdominal region showed a higher rate of decomposition compared to the dorsal region of pericarp. Endosperm starch granules (ESG) accumulated in amyloplasts, and occurred in endosperm cells at 5 DAF, then rapidly enriched the endosperm cells until 22 DAF. Compared with ESG, PSG were compound granules of irregular shape and small size distribution. The results also suggested lower amylose content and V-type single-helix content and higher proportions of double helices for PSG compared to ESG.\n\n\nCONCLUSION\nBased on the structural development of PSG and ESG, we speculated that the saccharides resulting from decomposition of PSG, on one hand, enabled the pericarp to survive before maturity of wheat caryopsis and, on the other hand, provided extra nutrition for the growth of ESG.", "corpus_id": 22188626, "score": 0 }, { "doc_id": "85424701", "title": "Development of Small Starch Granule in Barley Endosperm", "abstract": "The structural characteristics and physicochemical properties of barley starch differ with granule size, which are important in final product applications of barley flours. A barley (Hordeum vulgare L.) cultivar, Yangsimai 3, was used to investigate the development of small starch granule in endosperm under electron microscope to provide references to barley breeding. Large starch granules were formed and developed at the early stage of endosperm development. Large amyloplasts with large starch granules were divided and increased in number through binary fission. One large amyloplast had only 1 large starch granule. Small starch granules could be formed and develop at the middle and late stage of endosperm development. Endosperm cells had large amyloplasts that exhibited protrusion, and some of the protrusions contained small starch granules. Small amyloplasts with small starch granules formed new small amyloplasts to produce small starch granules by the way of protruding their envelopes. Many small starch granules were formed and developed in 1 small amyloplast. The amyloplast envelope began to degrade and release starch granules into cell matrix when amyloplast was full of starch granules. These results showed that small amyloplasts came from the protrusion of amyloplast envelopes. Many small starch granules, which were compound starch granules, were formed and developed in 1 small amyloplast.", "corpus_id": 85424701, "score": 0 }, { "doc_id": "31868993", "title": "Physicochemical properties and development of wheat large and small starch granules during endosperm development", "abstract": "Wheat mature seeds have large, lenticular A-type starch granules, and small, spherical B-type and irregular C-type starch granules. During endosperm development, large amyloplasts came from proplastid, divided and increased in number through binary fission from 4 to 12 days after flowering (DAF). Large starch granules formed and developed in the large amyloplast. One large amyloplast had only one large starch granule. Small amyloplasts came from the protrusion of large amyloplast envelope, divided and increased in number through envelope protrusion after 12 DAF. B-type starch granules formed and developed in small amyloplast from 12 to 18 DAF, C-type starch granules formed and developed in small amyloplast after 18 DAF. Many B- and C-type starch granules might form and develop in one small amyloplast. The amyloplast envelopes were asynchronously degraded and starch granules released into cell matrix when amyloplasts were full of starch granules. Apparent amylose contents of large starch granules were higher than that of small starch granules, and increased with endosperm development. The swelling powers and crystallinity of large starch granule were lower than that of small starch granules, and decreased with endosperm development. Small starch granules displayed broader gelatinization temperature ranges than did large starch granules.", "corpus_id": 31868993, "score": 0 }, { "doc_id": "22281195", "title": "Structural variability between starch granules in wild type and in ae high-amylose mutant maize kernels.", "abstract": "Starch granule structure within wild-type and ae high-amylose mutant maize kernels has been mapped in situ using light, electron and atomic force microscopy, and both Raman and infra-red spectroscopy. The population of wild-type starch granules is found to be homogenous. The ae mutant granule population is heterogeneous. Heterogeneity in chemical and physical structure is observed within individual granules, between granules within cells, and spatially within the kernel. The highest level of heterogeneity is observed in the region where starch is first deposited during kernel development. Light microscopy demonstrates structural diversity through use of potassium iodide/iodine staining and polarised microscopy. Electron and atomic force microscopy, and infra-red and Raman spectroscopy defined the nature of the structural changes within granules. The methodology provides novel information on the changes in starch structure resulting from kernel development.", "corpus_id": 22281195, "score": 1 }, { "doc_id": "39759446", "title": "Heterogeneous structure and spatial distribution in endosperm of high-amylose rice starch granules with different morphologies.", "abstract": "Starch granules from high-amylose cereal mutants or transgenic lines usually have different morphologies. It is not clear whether the structure and spatial distribution of starch granules with different morphologies in endosperm is homogeneous or heterogeneous. In the present study, the structure and spatial distribution in endosperm of morphologically different starch granules from high-amylose transgenic rice line (TRS) were investigated. The TRS endosperm had individual, aggregate, elongated, and interior hollow starch granules. The individual and interior hollow granules had the lowest and the highest amylose content and gelatinization resistance, respectively, among the four types of granules. The individual granules were mainly distributed in the middle of the endosperm; the aggregate granules in the starchy endosperm cells between the subaleurone layer and the middle of the endosperm; the elongated granules in the peripheral starchy endosperm cells adjacent to the subaleurone layer; and the interior hollow granules in the subaleurone layer cells.", "corpus_id": 39759446, "score": 1 }, { "doc_id": "45949883", "title": "Formation of elongated starch granules in high-amylose maize", "abstract": "GEMS-0067 maize starch contains up to 32% elongated starch granules, much higher than amyloseextender (ae) single-mutant maize starch (7%) and normal (non-mutant) maize starch (0%). These elongated granules are highly resistant to enzymatic hydrolysis at 95–100 C, which function as resistant starch. The structure and formation of these elongated starch granules, however, were not known. In this study, light, confocal laser-scanning, scanning electron, and transmission electron microscopy were used to reveal the structure and formation of these elongated starch granules. The transmission electron micrographs showed fusion through amylose interaction between adjacent small granules in the amyloplast at the early stage of granule development. A mechanistic model for the formation of elongated starch granules is proposed.", "corpus_id": 45949883, "score": 0 }, { "doc_id": "5107307", "title": "Different structures of heterogeneous starch granules from high-amylose rice.", "abstract": "High-amylose cereal starches usually have heterogeneous starch granules in morphological structure. In the present study, the polygonal, aggregate, elongated, and hollow starch granules were separated from different regions of the kernels of high-amylose rice, and their structures were investigated. The results showed that the polygonal starch granules had low amylose content and high short branch-chain and branching degree of amylopectin, and exhibited A-type crystallinity. The aggregate starch granules had high long branch-chain of amylopectin, relative crystallinity, and double helix content, and exhibited C-type crystallinity. The elongated starch granules had high amylose content and low branching degree of amylopectin and relative crystallinity, and exhibited C-type crystallinity. The hollow starch granules had very high amylose content, proportion of amorphous conformation, and amylose-lipid complex, and very low branch-chain of amylopectin, branching degree of amylopectin, and double helix content, and exhibited no crystallinity. The different structures of heterogeneous starch granules from high-amylose rice resulted in significantly different thermal properties.", "corpus_id": 5107307, "score": 0 }, { "doc_id": "88877350", "title": "Application of whole sections of mature cereal seeds to visualize the morphology of endosperm cell and starch and the distribution of storage protein.", "abstract": "The morphology of endosperm cell and starch and the distribution of storage protein affect the kernel weight and endosperm quality of cereal crops, and are of interest for crop breeders. They are significantly different in different regions of endosperm. Therefore, it is very important for in situ investigation of the morphology of endosperm cell and starch and the distribution of storage protein in mature cereal seed. In the present study, we reported a method for preparing the whole section of mature rice, maize, and wheat seeds. The section could be easily stained with fluorescent brightener 28, iodine solution, and coomassie brilliant blue R250 to exhibit the cell wall, starch, and storage protein. The observation of whole section of seed showed that the morphology of endosperm cell and starch and the distribution of storage protein were significantly different in different regions of endosperm of rice, maize, and wheat seed. The method could in situ investigate the morphology of endosperm cell and starch and the distribution of storage protein in not only mature cereal seed but also developing, germinated, and gelatinized cereal seed. This study was very useful for investigation of cereal seed development and utilization.", "corpus_id": 88877350, "score": 1 }, { "doc_id": "84723325", "title": "Chemical Composition and Microstructure of Two Naked Waxy Barleys", "abstract": "Abstract Two naked waxy barley cultivars, Bz 489-30 and Prowashonupana were analysed in order to study the chemical composition and the microstructure. Prowashonupana contained more protein, fat and ash, and less starch than Bz 489-30. The content of mixed-linked β-glucan was almost three times higher in Prowashonupana (14·9%) than in Bz 489-30 (5·6%), but extractability at 40 °C was much lower. Microscopy studies showed that kernels and endosperm cells of Prowashonupana were irregular, and that cell walls were thicker with a higher content of mixed-linked β-glucan than in Bz 489-30. In both barleys the sub-aleurone layer contained black starch granules, indicating a higher amylose content in this structure compared to the rest of the kernel. Starch was isolated from both barleys using two different procedures and analysed for amylose content. The amylose content was higher, while volume % of A-granules was lower and mean diameter of A-granules was smaller in starch isolated from Prowashonupana than from Bz 489-30. Both composition and yield of starch were however influenced by the isolation procedure used. The procedure which gave higher starch yield resulted in a higher amylose content, probably because of greater recovery of starch from outer parts of the kernel with a higher amylose content.", "corpus_id": 84723325, "score": 0 }, { "doc_id": "84861869", "title": "Endosperm and aleurone cell structure in barley and wheat as studied by optical and Raman microscopy", "abstract": "Abstract Grain ultrastructure is of utmost importance when designing grain processing procedures in the food industry. In this study, wheat and barley grain components were localised using optical and Raman microscopy. The optical microscopic analyses were performed using several selective stains to localise β-glucan, protein and starch or autofluorescence to image the ferulic acid and other fluorescing substances. Alternatively, Raman microscopy was applied to localise the grain components without any need for preceding staining or other sample pretreatment. Both methods provided consistent information on the grain structures, illustrating the distribution of polysaccharides, aromatics and protein in endosperm and aleurone layers. In aleurone layers of both barley and wheat, a distinct difference between the anticlinal and periclinal cell walls was observed. The anticlinal cell walls were enriched with aromatic substances which were present in remarkably lower concentrations in the inner periclinal cell walls but for barley, an even higher concentration in the outer periclinal cell wall was observed. In addition, Raman spectroscopy illustrated the detailed distribution of substances across the aleurone cell walls: β-glucan was adjacent to proteins and it was deficient in the middle lamella whereas arabinoxylan was enriched in the outer cell wall layers and middle lamella.", "corpus_id": 84861869, "score": 0 }, { "doc_id": "86336264", "title": "In situ Raman microscopy of starch granule structures in wild type and ae mutant maize kernels", "abstract": "A method developed for in situ imaging of starch granule structure in dry seeds has been applied to compare the starch granule structures found in wild type and ae mutant maize kernels. In the isogenic ae mutant the activity of the starch branching enzyme IIb is inhibited, which gives rise to a high amylose starch. The granule structures in the wild type samples have been found to be homogeneous, whereas those in the ae mutant are grossly heterogeneous within individual granules, between granules within individual cells, and between cells across the endosperm. The level of heterogeneity observed in situ appears to be more marked than that previously reported for studies on isolated ae mutant starches. Iodine/potassium iodide staining and polarised light microscopy have been used together with Raman microscopy, which has allowed high-resolution mapping of the composition and physical state of the structures within the granules, to probe the origins of the heterogeneity of the starch structures. Although the mutation inhibits the activity of the branching enzyme within the granules, and both the composition and level of crystallinity within and between granules is variable, the major origin of the heterogeneity of the granule architecture appears to result from significant changes in the assembly and packaging of the crystalline structures within the granule. It is suggested that this arises due to the mutation of the starch branching enzyme introducing defects into the self-assembly of the crystalline structure, resulting in an accumulation of defects and increased randomisation of the granule structure.", "corpus_id": 86336264, "score": 1 }, { "doc_id": "54520635", "title": "Chalk5 encodes a vacuolar H+-translocating pyrophosphatase influencing grain chalkiness in rice", "abstract": "Grain chalkiness is a highly undesirable quality trait in the marketing and consumption of rice grain. However, the molecular basis of this trait is poorly understood. Here we show that a major quantitative trait locus (QTL), Chalk5, influences grain chalkiness, which also affects head rice yield and many other quality traits. Chalk5 encodes a vacuolar H+-translocating pyrophosphatase (V-PPase) with inorganic pyrophosphate (PPi) hydrolysis and H+-translocation activity. Elevated expression of Chalk5 increases the chalkiness of the endosperm, putatively by disturbing the pH homeostasis of the endomembrane trafficking system in developing seeds, which affects the biogenesis of protein bodies and is coupled with a great increase in small vesicle-like structures, thus forming air spaces among endosperm storage substances and resulting in chalky grain. Our results indicate that two consensus nucleotide polymorphisms in the Chalk5 promoter in rice varieties might partly account for the differences in Chalk5 mRNA levels that contribute to natural variation in grain chalkiness.", "corpus_id": 54520635, "score": 0 }, { "doc_id": "15555438", "title": "Chalky part differs in chemical composition from translucent part of japonica rice grains as revealed by a notched‐belly mutant with white‐belly", "abstract": "Abstract BACKGROUND Chalkiness has a deleterious influence on rice appearance and milling quality. We identified a notched‐belly mutant with a high percentage of white‐belly, and thereby developed a novel comparison system that can minimize the influence of genetic background and growing conditions. Using this mutant, we examined the differences in chemical composition between chalky and translucent endosperm, with the aim of exploring relations between occurrence of chalkiness and accumulation of starch, protein and minerals. RESULTS Comparisons showed a significant effect of chalkiness on chemical components in the endosperm. In general, occurrence of chalkiness resulted in higher total starch concentration and lower concentrations of the majority of the amino acids measured. Chalkiness also had a positive effect on the concentrations of As, Ba, Cd, Cr, Mn, Na, Sr and V, but was negatively correlated with those of B, Ca, Cu, Fe and Ni. By contrast, no significant chalkiness effect on P, phytic acid‐P, K, Mg or Zn was observed. In addition, substantial influence of the embryo on endosperm composition was detected, with the embryo showing a negative effect on total protein, amino acids such as Arg, His, Leu, Lys, Phe and Tyr, and all the 17 minerals measured, excluding Ca, Cu, P and Sr. CONCLUSION An inverse relation between starch and protein as well as amino acids was found with respect to chalkiness occurrence. Phytic acid and its colocalized elements K and Mg were not affected by chalkiness. The embryo exerted a marked influence on chemical components of the endosperm, in particular minerals, suggesting the necessity of examining the role of the embryo in chalkiness formation. © 2016 The Authors. Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.", "corpus_id": 15555438, "score": 0 }, { "doc_id": "6505782", "title": "Formation of semi-compound C-type starch granule in high-amylose rice developed by antisense RNA inhibition of starch-branching enzyme.", "abstract": "Cereal starch granules with high-amylose and resistant starch (RS) always show irregular morphology and special crystalline structure, but their formation during grain development is not yet clear. In our previous studies, we had generated a transgenic rice line (TRS) enriched with amylose and RS, which contained semi-compound starch showing a C-type crystalline structure. In this study, the formation of semi-compound C-type starch granule during TRS endosperm development was carefully investigated with light, scanning electron, and transmission electron microscopes and X-ray powder diffraction. The results showed that the TRS starch subgranules, each with a central hilum, were individually initiated in amyloplast and showed an A-type crystal at the early stage of starch granule development, which was similar to that in its wild type. However, with the endosperm development, the amylose content in TRS endosperm starch increased and the B-type starch crystal was deposited in the periphery of subgranules; then, the adjacent subgranules fused together and finally formed a continuous outer layer band surrounding the entire circumference of the starch granule. Accordingly, a mechanistic model for the formation of semi-compound C-type starch granules is proposed.", "corpus_id": 6505782, "score": 0 }, { "doc_id": "86800878", "title": "The effect of high temperature on kernel dimensions and the type and occurrence of kernel damage in rice", "abstract": "Rice (Oryza sativa L. cv. Calrose) growing at 27/22\"C was either transferred to day/night temperatures ranging from 24/19 to 39/34\"C 7days after heading and held at these temperatures until maturity, or transferred to a temperature of 36/31°C for 8 day periods at regular intervals commencing from heading. Kernel dimensions were measured directly and the types of kernel damage at maturity were characterized by direct viewing under the light microscope of intact and sectioned kernels, or by scanning electron microscopy of the exposed surface of kernels cut transversely with a razor blade. Kernel thickness was reduced most by high temperature treatments commencing 12 days after heading, but other kernel dimensions (length and width) were most sensitive to high temperature earlier in development. Sterility and pathenocarpy were most evident when temperature treatments commenced at heading (approximately 2 days before anthesis) and were greatest at the highest temperature (39/34\"C). Abortive and opaque kernels were most evident when the high temperature commenced 4 days after heading and were also most numerous at the highest temperature tested. From observations on the morphology of the kernels it appears that temperatures above 27/22\"C can interfere with the early stages of cell division and development in the endosaerm. Chalky endosperm tissue occurred in several forms depending on both the temperature level and the timing of the temperature treatment. White-core kernels were only evident at a temperature of 27/2Z°C. White-back kernels were most numerous at 36/31°C and when the high temperature treatment commenced 16 days after heading. Milky-white kernels were found in all but the lowest temperature treatment (24/1g0C), with a peak at 36/31°C and this type of damage was most evident when the high temperature treatment commenced 12 days after heading. Differences in endosperm cellular morphology were observed between the different types of damage, and in accord with other published data the chalky appearance was associated with the development of numerous air spaces between loosely packed starch granules and a change in light refraction.", "corpus_id": 86800878, "score": 0 }, { "doc_id": "84188775", "title": "Endosperm Structure of White-Belly and White-Core Rice Grains Shown by Scanning Electron Microscopy", "abstract": "Abstract: White-belly and white-core are the major two types of grain chalkiness in japonica rice. This study aims to compare the morphological features of white-belly and white-core using a scanning electron microcope (SEM). A japonica rice cultivar Wuyujing3 and its mutants were used as materials. Nearly 1000 SEM images were observed, and 12 representative photos were selected. SEM images showed contrasting differences between white-belly and white-core in endosperm microstructure including the shape of endosperm cell, the size distribution of starch granules, and the amount of protein bodies. White-belly and white-core also varied markedly in morphological features of the cracked compound starch granules. Our findings should help to advance our understanding of the multi-faceted nature of grain chalkiness from the perspective of starch and protein accumulation, and should be of value for future work on rice grain chalkiness.", "corpus_id": 84188775, "score": 0 }, { "doc_id": "27171667", "title": "Comprehensive Expression Profiling of Rice Grain Filling-Related Genes under High Temperature Using DNA Microarray[OA]", "abstract": "To elucidate the effect of high temperature on grain-filling metabolism, developing rice (Oryza sativa) ‘Nipponbare’ caryopses were exposed to high temperature (33°C/28°C) or control temperature (25°C/20°C) during the milky stage. Comprehensive gene screening by a 22-K DNA microarray and differential hybridization, followed by expression analysis by semiquantitative reverse transcription-PCR, revealed that several starch synthesis-related genes, such as granule-bound starch synthase I (GBSSI) and branching enzymes, especially BEIIb, and a cytosolic pyruvate orthophosphate dikinase gene were down-regulated by high temperature, whereas those for starch-consuming α-amylases and heat shock proteins were up-regulated. Biochemical analyses of starch showed that the high temperature-ripened grains contained decreased levels of amylose and long chain-enriched amylopectin, which might be attributed to the repressed expression of GBSSI and BEIIb, respectively. SDS-PAGE and immunoblot analysis of storage proteins revealed decreased accumulation of 13-kD prolamin, which is consistent with the diminished expression of prolamin genes under elevated temperature. Ripening under high temperature resulted in the occurrence of grains with various degrees of chalky appearance and decreased weight. Among them, severely chalky grains contained amylopectin enriched particularly with long chains compared to slightly chalky grains, suggesting that such alterations of amylopectin structure might be involved in grain chalkiness. However, among high temperature-tolerant and sensitive cultivars, alterations of neither amylopectin chain-length distribution nor amylose content were correlated to the degree of grain chalkiness, but rather seemed to be correlated to grain weight decrease, implying different underlying mechanisms for the varietal difference in grain chalkiness. The possible metabolic pathways affected by high temperature and their relevance to grain chalkiness are discussed.", "corpus_id": 27171667, "score": 0 }, { "doc_id": "83107401", "title": "Endosperm and starch granule morphology in wild cereal relatives", "abstract": "Australia's native grass species contain a diverse array of wild cereal relatives which are adapted to a broader range of environmental conditions than current commercial cereals and may contain novel alleles which have utility in commercial production systems. Characterizing the available variation in endosperm morphology is one of the first steps towards in planta manipulation of endosperm by either the introgression of novel alleles or bioengineering cereal starch and protein. The endosperm of 19 crop wild relatives (CWR) was examined using scanning electron microscopy (SEM). Mature caryopses were fixed, dehydrated, critical-point dried and then snap fractured transversely through the grain. Wild relatives exhibited similar types of starch granules to that of their respective cultivated species, though in general the wild species retained a greater proportion of the endosperm cell wall at maturity. The two species examined with no closely related cultivated species exhibited a rice-like endosperm. Wild sorghum relatives exhibited an abundance of endosperm variations described as variations in starch granule size, shape and surface morphology, and the distribution of protein bodies. This is particularly important because the grain of Sorghum bicolor has inherently low starch and protein digestibility. These variations within the wild relatives of commercial cereals may provide novel sources of genetic diversity for future grain improvement programmes.", "corpus_id": 83107401, "score": 0 }, { "doc_id": "26461791", "title": "Physicochemical properties and starch digestibility of whole grain sorghums, millet, quinoa and amaranth flours, as affected by starch and non-starch constituents.", "abstract": "Minor grains such as sorghum, millet, quinoa and amaranth can be alternatives to wheat and corn as ingredients for whole grain and gluten-free products. In this study, influences of starch structures and other grain constituents on physicochemical properties and starch digestibility of whole flours made from these grains were investigated. Starches were classified into two groups according to their amylopectin branch chain-length: (i) quinoa, amaranth, wheat (shorter chains); and (ii) sorghum, millet, corn (longer chains). Such amylopectin features and amylose content contributed to the differences in thermal and pasting properties as well as starch digestibility of the flours. Non-starch constituents had additional impacts; proteins delayed starch gelatinization and pasting, especially in sorghum flours, and high levels of soluble fibre retarded starch retrogradation in wheat, quinoa and amaranth flours. Enzymatic hydrolysis of starch was restricted by the presence of associated protein matrix and enzyme inhibitors, but accelerated by endogenous amylolytic enzymes.", "corpus_id": 26461791, "score": 0 }, { "doc_id": "83892785", "title": "Amylolysis of large and small granules of native triticale, wheat and corn starches using a mixture of α-amylase and glucoamylase", "abstract": "Abstract Starch granules from different sources differ in their morphology and structure, resulting in diverse amylolysis, which is closely related to bioconversion efficiency of starch to fermentable sugars during ethanol production. In this study, large and small granules were fractionated from native triticale, wheat and corn starches using a centrifugal sedimentation protocol and were hydrolyzed by a granular starch hydrolyzing enzyme at sub-gelatinization temperatures. Native triticale starches had bimodal granule size distribution with highest sizes of 14.9–15.9, 19.1–20.2, and 7.2 μm in diameter for overall, large and small granules, respectively, when compared to those of wheat and corn starches. The large granules in triticale starches contributed higher proportion of the total granules either by number (36–45%) or by weight (93–95%) than did those of wheat and corn starches. Surface pores and internal channels viewed by SEM and CLSM were more visible in large granules than in small granules of triticale, wheat, and corn starches, but corn starch generally displayed more pores and channels than triticale and wheat starches. Large granules contained significantly higher apparent amylose content and higher relative crystallinity than did small granules (23.0–28.5% vs. 12.4–21.0% and 24.9–26.8% vs. 20.8–24.4%, respectively) in all starches. Small granules were hydrolyzed significantly faster than did large granules initially (DH 9.3–18.0%, 24.7–40.3%, 17.7% higher in small granules than in large counterparts of triticale, wheat, and corn starches, respectively, at 55 °C for 1 h), however slowed down in later stage of hydrolysis. The final DH of large and small granules were similar in triticale (82.3–84.5%) and corn (80.8–83.4%) starches except wheat starches (90.8–95.1% in large and 79.6–86.2% in small granules) at 72 h hydrolysis. SEM and CLSM further revealed that the hydrolysis pattern differed between large and small starch granules and among starches, indicating diverse structure of large and small granules existed at macro, micro, and nano levels within and between species and cultivars. The study may be beneficial for precise control of liquefaction and saccharification in simultaneous hydrolysis and fermentation process of ethanol production.", "corpus_id": 83892785, "score": 0 }, { "doc_id": "85090603", "title": "The susceptibility of large and small granules of waxy, normal and high-amylose genotypes of barley and corn starches toward amylolysis at sub-gelatinization temperatures", "abstract": "Abstract Starches from waxy (CDC Candle), normal (CDC McGwire) and high-amylose (SH 99250) genotypes of hull-less barley were isolated and fractionated into large and small granules. The unfractionated and fractionated barley starches were then characterized toward their composition, morphology and structure, and compared with commercial corn starches of similar genotypes. The effect of starch properties on degree of hydrolysis (DH) at 55 °C for 1 h followed by at 30 °C for 72 h using granular starch hydrolyzing enzymes (mixture of α-amylase and glucoamylase) was also evaluated. Morphological changes of starches before and after hydrolysis were visualized by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). The proportion (% weight) of small granules in high-amylose (HA) genotypes of barley (46.5%) and corn (32.4%) starches were higher than in the waxy (WX) and normal (NM) genotypes. Apparent amylose (AM) content of corn genotypes ranged from 1 to 1.1% (WX), 21 to 26% (NM), and 66 to 70% (HA). Whereas, the corresponding ranges for barley genotypes were 4–6% (WX), 17–24% (NM), and 35–40% (HA). HA corn starch exhibited a mixed ‘A + V’-type X-ray pattern, whereas the other genotypes of corn and barley starches exhibited an ‘A’-type X-ray pattern. The relative crystallinity (RC) of the genotypes of corn and barley starches followed the order: WX > NM > HA. The AM content and RC of small granules in corn and barley starches were lower than in large granules. Regardless of genotypes and starch sources, smaller granules had a higher gelatinization temperature range (15.5–42.8 °C) and a lower enthalpy of gelatinization (9.7–21.2 J/g) than those of larger granules (11.1–41.9 °C and 13.4–23.9 J/g, respectively). Compared to large granules, the small granules were initially hydrolyzed to a greater extent (18% higher). However after 72 h, hydrolysis was 10% higher in the large granules. SEM and CLSM images revealed that the distribution of surface pores and internal channels varied between genotypes of corn and barley starches. Although small variations exist between the NM corn and NM barley starches with respect to their proximate composition and amylose content, the observed large variations in the extent of amylolysis at the initial stages of hydrolysis is indicative that the molecular architecture and granule porosity influence amylolysis.", "corpus_id": 85090603, "score": 0 }, { "doc_id": "93302764", "title": "Comparative structure of starches from high-amylose maize inbred lines and their hybrids", "abstract": "Abstract High-amylose maize starch is of interest because of its health benefits and industrial uses. Hybrid maize is widely grown for the practical and economical value of heterosis. However, starch structure of high-amylose hybrid maize has seldom been reported compared with that of high-amylose inbred maize. In this study, structure of starches from high-amylose maize inbred lines and their hybrids was investigated and compared. Starch granule became smaller in size and more spherical, oval or elongated in shape with increasing amylose content. Hybrid maize starch had lower amylose content and long branch-chain of amylopectin and higher short branch-chain and branching degree of amylopectin than inbred maize starch. Inbred maize starch had B-type crystalline structure with low relative crystallinity, but hybrid maize starch had CB-type crystalline structure and high relative crystallinity. Hybrid maize starch had lower degree of order at a short-range scale on the edge of starch granule than inbred maize starch. Hybrid maize starch had higher double helix content and lower amorphous starch than inbred maize starch. Hybrid maize starch had higher peak intensity and longer Bragg spacing of lamellar structure than inbred maize starch. Hybrid maize starch had lower gelatinization temperature and higher gelatinization enthalpy and swelling power than inbred maize starch. The different structural properties of starches had significant correlation.", "corpus_id": 93302764, "score": 0 }, { "doc_id": "7568292", "title": "Cotyledon cells of Vigna mungo seedlings use at least two distinct autophagic machineries for degradation of starch granules and cellular components", "abstract": "α-Amylase is expressed in cotyledons of germinated Vigna mungo seeds and is responsible for the degradation of starch that is stored in the starch granule (SG). Immunocytochemical analysis of the cotyledon cells with anti–α-amylase antibody showed that α-amylase is transported to protein storage vacuole (PSV) and lytic vacuole (LV), which is converted from PSV by hydrolysis of storage proteins. To observe the insertion/degradation processes of SG into/in the inside of vacuoles, ultrastructural analyses of the cotyledon cells were conducted. The results revealed that SG is inserted into LV through autophagic function of LV and subsequently degraded by vacuolar α-amylase. The autophagy for SG was structurally similar to micropexophagy detected in yeast cells. In addition to the autophagic process for SG, autophagosome-mediated autophagy for cytoplasm and mitochondria was detected in the cotyledon cells. When the embryo axes were removed from seeds and the detached cotyledons were incubated, the autophagosome-mediated autophagy was observed, but the autophagic process for the degradation of SG was not detected, suggesting that these two autophagic processes were mediated by different cellular mechanisms. The two distinct autophagic processes were thought to be involved in the breakdown of SG and cell components in the cells of germinated cotyledon.", "corpus_id": 7568292, "score": 0 }, { "doc_id": "46373038", "title": "Effect of cooking methods on selected physicochemical and nutritional properties of barlotto bean, chickpea, faba bean, and white kidney bean", "abstract": "The effects of atmospheric pressure cooking (APC) and high-pressure cooking (HPC) on the physicochemical and nutritional properties of barlotto bean, chickpea, faba bean, and white kidney bean were investigated. The hardness of the legumes cooked by APC or HPC were not statistically different (P > 0.05). APC resulted in higher percentage of seed coat splits than HPC. Both cooking methods decreased Hunter “L” value significantly (P < 0.05). The “a” and “b” values of dark-colored seeds decreased after cooking, while these values tended to increase for the light-colored seeds. The total amounts of solid lost from legume seeds were higher after HPC compared with APC. Rapidly digestible starch (RDS) percentages increased considerably after both cooking methods. High pressure cooked legumes resulted in higher levels of resistant starch (RS) but lower levels of slowly digestible starch (SDS) than the atmospheric pressure cooked legumes.", "corpus_id": 46373038, "score": 0 }, { "doc_id": "83955086", "title": "Physicochemical properties of high-amylose rice starches during kernel development", "abstract": "In this paper, endosperm starches were isolated from a high-amylose transgenic rice line (TRS) and its wild type rice Teqing (TQ) kernels at different developmental stages. TQ and TRS starches showed similar amylose contents and shapes at early developmental stage, then the amylose content increased with kernel development. The rate of increase in amylose content was much faster in TRS starches than that in TQ starches. TRS starches showed heterogenous granules at the middle and late developmental stages. TQ starch crystallinity remained A-type, but TRS starch crystallinity changed from A- to C- via CA-type. TRS starches showed higher gelatinization temperatures, lower gelatinization enthalpies, lower swelling powers, and lower hydrolysis rates at middle and late developmental stages compared with TQ starches. The amylose content had a significantly negative correlation with crystallinity, gelatinization enthalpy, swelling power, enzyme digestibility, and acid hydrolysis.", "corpus_id": 83955086, "score": 0 } ]

{ "doc_id": "44690610", "title": "Spatio-temporal Prior Shape Constraint for Level Set Segmentation", "abstract": "This paper exposes a novel formulation of prior shape constraint incorporation for the level set segmentation of objects from corrupted images. Applicable to variational frameworks, the proposed scheme consists in weighting the prior shape constraint by a function of time and space to overcome local minima issues of the energy functional. Pose parameters which make the prior shape constraint invariant from global transformations are estimated by the downhill simplex algorithm, which is more tractable and robust than the traditional gradient descent. The proposed scheme is simple, easy to implement and can be generalized to any variational approach incorporating a single prior shape. Results illustrated with different kinds of images demonstrate the efficiency of the method.", "corpus_id": 44690610 }

[ { "doc_id": "9209299", "title": "Boundary Finding with Parametrically Deformable Models", "abstract": "Segmentation using boundary finding is enhanced both by considering the boundary as a whole and by using model-based global shape information. The authors apply flexible constraints, in the form of a probabilistic deformable model, to the problem of segmenting natural 2-D objects whose diversity and irregularity of shape make them poorly represented in terms of fixed features or form. The parametric model is based on the elliptic Fourier decomposition of the boundary. Probability distributions on the parameters of the representation bias the model to a particular overall shape while allowing for deformations. Boundary finding is formulated as an optimization problem using a maximum a posteriori objective function. Results of the method applied to real and synthetic images are presented, including an evaluation of the dependence of the method on prior information and image quality. >", "corpus_id": 9209299, "score": 0 }, { "doc_id": "125385001", "title": "Statistical shape influence in geodesic active contours", "abstract": "A novel method of incorporating shape information into the image segmentation process is presented. We introduce a representation for deformable shapes and define a probability distribution over the variances of a set of training shapes. The segmentation process embeds an initial curve as the zero level set of a higher dimensional surface, and evolves the surface such that the zero level set converges on the boundary of the object to be segmented. At each step of the surface evolution, we estimate the maximum a posteriori (MAP) position and shape of the object in the image, based on the prior shape information and the image information. We then evolve the surface globally, towards the MAP estimate, and locally, based on image gradients and curvature. Results are demonstrated on synthetic data and medical imagery, in 2D and 3D.", "corpus_id": 125385001, "score": 1 }, { "doc_id": "7911344", "title": "Using Prior Shapes in Geometric Active Contours in a Variational Framework", "abstract": "In this paper, we report an active contour algorithm that is capable of using prior shapes. The energy functional of the contour is modified so that the energy depends on the image gradient as well as the prior shape. The model provides the segmentation and the transformation that maps the segmented contour to the prior shape. The active contour is able to find boundaries that are similar in shape to the prior, even when the entire boundary is not visible in the image (i.e., when the boundary has gaps). A level set formulation of the active contour is presented. The existence of the solution to the energy minimization is also established.We also report experimental results of the use of this contour on 2d synthetic images, ultrasound images and fMRI images. Classical active contours cannot be used in many of these images.", "corpus_id": 7911344, "score": 0 }, { "doc_id": "6972902", "title": "Diffusion Snakes: Introducing Statistical Shape Knowledge into the Mumford-Shah Functional", "abstract": "We present a modification of the Mumford-Shah functional and its cartoon limit which facilitates the incorporation of a statistical prior on the shape of the segmenting contour. By minimizing a single energy functional, we obtain a segmentation process which maximizes both the grey value homogeneity in the separated regions and the similarity of the contour with respect to a set of training shapes. We propose a closed-form, parameter-free solution for incorporating invariance with respect to similarity transformations in the variational framework. We show segmentation results on artificial and real-world images with and without prior shape information. In the cases of noise, occlusion or strongly cluttered background the shape prior significantly improves segmentation. Finally we compare our results to those obtained by a level set implementation of geodesic active contours.", "corpus_id": 6972902, "score": 1 }, { "doc_id": "897936", "title": "Shape Priors for Level Set Representations", "abstract": "Level Set Representations, the pioneering framework introduced by Osher and Sethian [14] is the most common choice for the implementation of variational frameworks in Computer Vision since it is implicit, intrinsic, parameter and topology free. However, many Computer vision applications refer to entities with physical meanings that follow a shape form with a certain degree of variability. In this paper, we propose a novel energetic form to introduce shape constraints to level set representations. This formulation exploits all advantages of these representations resulting on a very elegant approach that can deal with a large number of parametric as well as continuous transformations. Furthermore, it can be combined with existing well known level set-based segmentation approaches leading to paradigms that can deal with noisy, occluded and missing or physically corrupted data. Encouraging experimental results are obtained using synthetic and real images.", "corpus_id": 897936, "score": 0 }, { "doc_id": "6428775", "title": "Level set based shape prior segmentation", "abstract": "We propose a level set based variational approach that incorporates shape priors into Chan-Vese's model for the shape prior segmentation problem. In our model, besides the level set function for segmentation, as in Cremers' work, we introduce another labelling level set function to indicate the regions on which the prior shape should be compared. Our model can segment an object, whose shape is similar to the given prior shape, from a background where there are several objects. Moreover, we provide a proof for a fast solution principle, which was mentioned by F. Gibou et al., and similar to the one proposed in [B. Song et al., (2002)], for minimizing Chan-Vese's segmentation model without length term. We extend the principle to the minimization of our prescribed functionals.", "corpus_id": 6428775, "score": 1 }, { "doc_id": "10695770", "title": "Towards Recognition-Based Variational Segmentation Using Shape Priors and Dynamic Labeling", "abstract": "We propose a novel variational approach based on a level set formulation of the Mumford-Shah functional and shape priors. We extend the functional by a labeling function which indicates image regions in which the shape prior is enforced. By minimizing the proposed functional with respect to both the level set function and the labeling function, the algorithm selects image regions where it is favorable to enforce the shape prior. By this, the approach permits to segment multiple independent objects in an image, and to discriminate familiar objects from unfamiliar ones by means of the labeling function. Numerical results demonstrate the performance of our approach.", "corpus_id": 10695770, "score": 1 }, { "doc_id": "10276646", "title": "A Pseudo-distance for Shape Priors in Level Set Segmentation", "abstract": "We study the question of integrating prior shape knowledge into level set based segmentation methods. In particular, we investigate dissimilarity measures for shapes encoded by the signed distance function. We consider extensions and improvements of existing measures. As a result, we propose a novel dissimilarity measure which constitutes a pseudo-distance. Compared to alternative approaches, this measure is symmetric and not biased toward small area. Based on this pseudo-distance, we propose a shape prior for level set segmentation methods which is pose invariant. In numerical experiments, we demonstrate that the resulting prior permits the segmentation of corrupted versions of a familiar object which is independent of the pose of the object. Moreover, we demonstrate the advantage of the symmetric formulation of the dissimilarity measure when segmenting corrupted images of known objects which consist of multiple components.", "corpus_id": 10276646, "score": 0 }, { "doc_id": "1369652", "title": "Kernel Density Estimation and Intrinsic Alignment for Knowledge-Driven Segmentation: Teaching Level Sets to Walk", "abstract": "We address the problem of image segmentation with statistical shape priors in the context of the level set framework. Our paper makes two contributions: Firstly, we propose a novel multi-modal statistical shape prior which allows to encode multiple fairly distinct training shapes. This prior is based on an extension of classical kernel density estimators to the level set domain. Secondly, we propose an intrinsic registration of the evolving level set function which induces an invariance of the proposed shape energy with respect to translation. We demonstrate the advantages of this multi-modal shape prior applied to the segmentation and tracking of a partially occluded walking person.", "corpus_id": 1369652, "score": 0 }, { "doc_id": "35034127", "title": "Model-based curve evolution technique for image segmentation", "abstract": "We propose a model-based curve evolution technique for segmentation of images containing known object types. In particular, motivated by the work of Leventon et al. (2000), we derive a parametric model for an implicit representation of the segmenting curve by applying principal component analysis to a collection of signed distance representations of the training data, The parameters of this representation are then calculated to minimize an objective function for segmentation. We found the resulting algorithm to be computationally efficient, able to handle multidimensional data, robust to noise and initial contour placements, while at the same time, avoiding the need for point correspondences during the training phase of the algorithm. We demonstrate this technique by applying it to two medical applications.", "corpus_id": 35034127, "score": 1 }, { "doc_id": "205007680", "title": "Fronts propagating with curvature dependent speed: algorithms based on Hamilton-Jacobi formulations. Final report", "abstract": "New numerical algorithms are devised (PSC algorithms) for following fronts propagating with curvature-dependent speed. The speed may be an arbitrary function of curvature, and the front can also be passively advected by an underlying flow. These algorithms approximate the equations of motion, which resemble Hamilton-Jacobi equations with parabolic right-hand-sides, by using techniques from the hyperbolic conservation laws. Non-oscillatory schemes of various orders of accuracy are used to solve the equations, providing methods that accurately capture the formation of sharp gradients and cusps in the moving fronts. The algorithms handle topological merging and breaking naturally, work in any number of space dimensions, and do not require that the moving surface be written as a function. The methods can be used also for more general Hamilton-Jacobi-type problems. The algorithms are demonstrated by computing the solution to a variety of surface motion problems.", "corpus_id": 205007680, "score": 0 }, { "doc_id": "15315786", "title": "DIGITAL BUILDING MAP REFINEMENT FROM KNOWLEDGE-DRIVEN ACTIVE CONTOURS AND VERY HIGH RESOLUTION OPTICAL IMAGERY", "abstract": "We propose a novel approach for digital building map refinement based on the use of knowledge-driven active contours and very high resolution panchromatic optical imagery. This methodology is designed to finely match each building symbolized in an urban Geographical Information System (GIS) database onto its counterpart representation in remote sensing data. This method is GIS mapdriven: GIS data globally registered to the image allows to initialize an active contour near the target building in the image to achieve subsequent refinement. Moreover the digital map provides valuable shape information about the object in the image we aim at matching. This geometric and specific prior knowledge is embedded as a shape constraint into the active contour and enables to overcome urban artifacts issues. Besides, we propose to embed a coarse Digital Surface Model (DSM) as well as a spatio-temporal shape prior constraint within the active contour model. Experimental results carried out over Beijing city area and illustrated in this paper show how these latter contributions improve the robustness and speed of the map refinement process. Map refinement addressed in this paper is becoming an essential issue for urban planning, telecommunications, automobile navigation, crisis and pollution management, which all rely on up-to-date and precise digital maps of a city.", "corpus_id": 15315786, "score": 0 }, { "doc_id": "122055904", "title": "On the incorporation of shape priors into geometric active contours", "abstract": "A novel model for boundary determination that incorporates prior shape information into geometric active contours is presented. The basic idea of this model is to minimize the energy functional depending on the information of the image gradient and the shape of interest, so that the boundary of the object can be captured either by higher magnitude of the image gradient or by the prior knowledge of its shape. The level set form of the proposed model is also provided. We present our experimental results on some synthetic images, functional MR brain images, and ultrasound images for which the existing active contour methods are not applicable. The existence of the solution to the proposed minimization problem is also discussed.", "corpus_id": 122055904, "score": 0 }, { "doc_id": "2208295", "title": "A Simplex Method for Function Minimization", "abstract": "A method is described for the minimization of a function of n variables, which depends on the comparison of function values at the (n 41) vertices of a general simplex, followed by the replacement of the vertex with the highest value by another point. The simplex adapts itself to the local landscape, and contracts on to the final minimum. The method is shown to be effective and computationally compact. A procedure is given for the estimation of the Hessian matrix in the neighbourhood of the minimum, needed in statistical estimation problems.", "corpus_id": 2208295, "score": 0 }, { "doc_id": "206631161", "title": "Matching Distance Functions: A Shape-to-Area Variational Approach for Global-to-Local Registration", "abstract": "This paper deals with the matching of geometric shapes. Our primary contribution is the use of a simple, robust, rich and efficient way to represent shapes, the level set representations according to singed distance transforms. Based on these representations we propose a variational framework for global as well as local shape registration that can be extended to deal with structures of higher dimension. The optimization criterion is invariant to rotation, translation and scale and combines efficiently a global motion model with local pixel-wise deformations. Promising results are obtained on examples showing small and large global deformations as well as arbitrary topological changes.", "corpus_id": 206631161, "score": 0 } ]

{ "doc_id": "15956244", "title": "Exposure to Community Violence, Psychopathology, and Personality Traits in Russian Youth", "abstract": "Previous research with the US inner-city youth demonstrated the hazardous effects of community violence exposure. It remains unclear, however, whether these findings are generalizable to other cultures and populations. Furthermore, the role of factors influencing the processing of traumatic events such as personality has not been investigated. Two groups of Russian adolescents (community youth (N = 546) and male delinquents (N = 352)) completed questionnaires assessing their exposure to community violence, conduct problems, internalizing psychopathology and personality. The study demonstrates that the relationships between exposure to violence and psychopathology are similar across different populations within the same culture (community youth and juvenile delinquents), suggesting similar mechanisms behind this phenomenon. The patterns of these relationships were also similar for boys and girls, suggesting similarities in the mechanisms across gender. Hence, the effects of community violence exposure are generalizable to other cultures outside the US. The associations between personality traits and specific types of behaviors also tend to be similar across different populations. Higher levels of novelty seeking were related to more severe problem behaviors and to higher levels of witnessing and victimization, whereas higher levels of harm avoidance were related to higher levels of depression and posttraumatic stress.", "corpus_id": 15956244 }

[ { "doc_id": "10730041", "title": "Emotional impact of children's exposure to community violence: a preliminary study.", "abstract": "OBJECTIVE\nTo use multiple methods and measures to investigate preliminarily the emotional impact of children's exposure to community violence.\n\n\nMETHOD\nThirty-seven schoolchildren between the ages of 7 and 12 years were categorized into groups with \"high\" or \"low\" frequency of exposure.\n\n\nRESULTS\nDiffering levels of exposure to community violence did not appear to have an impact on DSM-III-R diagnoses. Exposure to high levels of community violence was not related to internalizing behavior and disorders, but rather was associated with externalizing behavior.\n\n\nCONCLUSIONS\nThere appears to be an adverse relationship between high levels of exposure to community violence and emotional and conduct problems. Vicarious learning serves as an explanatory construct for these findings.", "corpus_id": 10730041, "score": 0 }, { "doc_id": "28388141", "title": "The prevalence and consequences of exposure to violence among African-American youth.", "abstract": "The objective of this study was to examine the relationship between chronic exposure to community violence and post-traumatic stress disorder (PTSD) symptoms in a nonrandom sample (N = 221) of low-income African-American youth between 7 and 18 years old. Results showed males were more likely than females to be victims of and witnesses to violent acts; there were no other significant sociodemographic differences in the degree of exposure to violence. PTSD symptom reporting was moderately high for this sample of youth; 54 youth (27.1%) met all three of the diagnostic criteria considered. Regression analyses revealed that being victimized and witnessing violence were significantly related to the reporting of PTSD symptoms. These symptoms were more extreme among victimized females and victimized youth who had no primary males living with them in the household (i.e., fathers and/or brothers). Exposure to violence among youth is clearly significant to their reporting of PTSD symptomatology, yet the clinical implications of this relationship remain largely unexplored.", "corpus_id": 28388141, "score": 0 }, { "doc_id": "26234063", "title": "Life threat and posttraumatic stress in school-age children.", "abstract": "One hundred fifty-nine children (14.5% of the student body) were sampled after a fatal sniper attack on their elementary school playground. Systematic self-reports of posttraumatic stress disorder (PTSD) symptoms were obtained by use of a child PTSD Reaction Index. Analysis of variance revealed significant differences by exposure but not by sex, ethnicity, or age. Additional analyses were conducted of individual item response, overall severity of PTSD reaction, symptom grouping, and previous life events. The results provide strong evidence that acute PTSD symptoms occur in school-age children with a notable correlation between proximity to the violence and type and number of PTSD symptoms. Sampling at approximately one month after the trauma provided adequate delineation among exposure groups. The symptom profile of highly exposed children lends validity to the diagnosis of acute PTSD in childhood.", "corpus_id": 26234063, "score": 0 }, { "doc_id": "27555322", "title": "Violent events reported by normal urban school-aged children: characteristics and depression correlates.", "abstract": "OBJECTIVE\nThis paper reports data on the prevalence of morbid thoughts of death or injury and the experiences of violence for a sample of 6 to 12 year old urban school children and examines the relationship of these thoughts and experiences to the child's emotional health.\n\n\nMETHOD\nFifty-seven of the sample of 223 children who attended the same inner-city school described violent events occurring to themselves, a relative or friend. All children were interviewed and assessed on the Children's Depression Rating Scale-Revised (CDRS-R).\n\n\nRESULTS\nSignificantly higher CDRS-R sum scores, indicating the presence of suspected depression or of clinical concern, were recorded for the 57 children reporting experiences with violence. As well, the subgroup of 57 children were significantly more distressed by specific symptoms of low self-esteem, weeping, and worries about death or injury.\n\n\nCONCLUSIONS\nFinding so many children reporting violent events occurring in their homes and community and that these children's experiences of violence were associated with emotional disturbances such as depression, dysphoric mood, low self-esteem, and excessive fears and worries about death or injury suggests the need for routine examination of the history of exposure to violence in the evaluation of inner-city children.", "corpus_id": 27555322, "score": 0 }, { "doc_id": "25682689", "title": "The NIMH community violence project: I. Children as victims of and witnesses to violence.", "abstract": "The 1980s witnessed an extraordinary increase in community violence in most major cities across the United States. In 1990 the homicide rate in Boston increased by 45% over the previous year; in Denver, by 29%; in Chicago, Dallas, and New Orleans, by more than 20%; in Los Angeles, by 16%; in New York, by 11%. In Washington, DC, which has the highest per capita homicide rate in the country, the 1990 murder rate set an all time record in the District's history (Escobar 1991). Across the country, 1 out of 5 teenage and young adult deaths was gun related in 1988 - the first year in which firearm death rates for both Black and White teenagers exceeded the total for all natural causes of death combined. Also in 1988, the firearm homicide rate for young Black males increased by 35%, and Black male teens were 11 times more likely than their White counterparts to be killed by guns (Christofel 1990).", "corpus_id": 25682689, "score": 0 }, { "doc_id": "20989508", "title": "No safe haven: a study of violence exposure in an urban community.", "abstract": "OBJECTIVE\nTo examine levels of violence exposure and reports of feeling unsafe in relation to psychological and behavioral characteristics for a general population sample of youths from an urban setting.\n\n\nMETHOD\nA comprehensive survey of high-risk behaviors, attitudes, indicators of adaptive behavior, and daily involvements was administered to a sample of 2,248 students in the 6th, 8th, and 10th grades in an urban public school system.\n\n\nRESULTS\nMore than 40% of the youths surveyed reported exposure to a shooting or stabbing in the past year, and 74% reported feeling unsafe in one or more common environmental contexts. Multiple regression analyses indicated significant relationships between violence exposure/feeling unsafe and a set of indicators of psychological and behavioral adaptation and expressed attitudes.\n\n\nCONCLUSIONS\nThese results attest to the picture of violence as a common fact of inner-city life and to the demand that is placed on urban youths to accommodate in their psychological development to chronic threat and lack of safety.", "corpus_id": 20989508, "score": 1 }, { "doc_id": "11428566", "title": "No safe haven. II: The effects of violence exposure on urban youth.", "abstract": "OBJECTIVES\nTo examine the moderating effects of gender, grade level, and ethnicity on the associations between violence exposure and adolescents' internalizing symptoms and externalizing behavior and to explore whether such relationships persist over time.\n\n\nMETHOD\nA survey of adolescents' exposure to violence, internalizing symptoms, and externalizing behavior was administered to 2 cross-sectional samples of 6th, 8th, and 10th graders (N = 2,748 in 1994 and 2,600 in 1996) in an urban school system. Approximately 1,100 adolescents participated in both surveys and served as the longitudinal sample.\n\n\nRESULTS\nStructural equation models indicated that violence exposure was closely associated with both externalizing behavior (r = 0.74-0.79) and internalizing symptoms (r = 0.36-0.38). The strength of association was similar across gender and ethnic groups. However, violence exposure was more closely related with internalizing symptoms for younger adolescents than their older counterparts. The longitudinal analysis suggested that exposure to violence reported at time 1 was related to adolescents' internalizing symptoms and externalizing behavior 2 years later.\n\n\nCONCLUSIONS\nThese results document high levels of violence exposure for urban youths and indicate links to a range of psychiatric symptoms and indicators of poor adjustment. Such findings carry implications for direct clinical work with young people, as well as for program development and public policy.", "corpus_id": 11428566, "score": 1 }, { "doc_id": "28660040", "title": "Traumatic Stress and Children", "abstract": "����� News reports, official statistics, and research data indicate that relatively large numbers of inner-city children are exposed to violence on a regular basis. Furthermore, the exposure occurs in such a manner that it and its pernicious effects are often subtle and underestimated. While child victims of violence elicit considerable concern, and rightfully so, many more children witness extreme acts of violence, often perpetrated against family and friends. This direct observation of the violent assault of another person, referred to as \"co-victimization\" by Shakoor1, is frequently accompanied by immersion in a violent milieu in which the child is in constant danger if, in fact, never actuaUy victimized. Such exposure to violence has serious consequences for the child's mental health, often resulting in post-traumatic stress disorder (PTSD) symptoms similar to those resulting from direct victimization. In the absence of understanding the symptoms and the circumstances under which they occur, the child's dysfunctional behavior, which often includes poor achievement and acting out, maybe misinterpreted, inaccurately diagnosed, and inappropriately treated. This paper discusses black youths' exposure to violence, the traumatic", "corpus_id": 28660040, "score": 0 }, { "doc_id": "906009", "title": "The role of exposure to community violence and developmental problems among inner-city youth.", "abstract": "While research has well documented that urban youth are exposed to increasing rates of community violence, little is known about what increases risk for violence exposure, what protects children from exposure to violence, and what factors reduce the most negative outcomes associated with witnessing violence. This study expands on current research by evaluating the relations between exposure to violence, family relationship characteristics and parenting practices, and aggression and depression symptoms. Data were drawn from a sample of 245 African-American and Latino boys and their caregivers from economically disadvantaged inner-city neighborhoods in Chicago. Rates of exposure could not be predicted from family relationship and parenting characteristics, although there was a trend for discipline to be related. Exposure to community violence was related to increases in aggressive behavior and depression over a 1-year period even after controlling for previous status. Future studies should continue to evaluate the role of exposure to violence on the development of youth among different neighborhoods and communities. Implications for intervention and policy are discussed.", "corpus_id": 906009, "score": 1 }, { "doc_id": "35775855", "title": "Witnessed community violence and antisocial behavior in high-risk, urban boys.", "abstract": "Examined the longitudinal relation between children's self-report of witnessing community violence, family environment, and parent report of child antisocial behavior in a sample of 6- to 10-year-old urban American boys (N = 97) at familial risk for antisocial behavior. Boys reported high rates of lifetime exposure to community violence. Boys' reports of witnessing community violence were significantly positively related to changes over 15 months in child antisocial behavior, even after controlling for the possible effects of 3 aspects of parent-child interactions shown previously to be related to problematic child behavior. Furthermore, family environment, particularly the degree to which parents engaged in conflict with their sons, moderated the effect of witnessed violence on changes in antisocial behavior. In families with low conflict, higher levels of witnessed violence predicted increases in antisocial behavior over time. In contrast, in families with relatively high levels of parent-child conflict, high-witnessed violence had no additional influence on antisocial outcome. This is the first prospective longitudinal study to document an association between witnessed community violence and changes in antisocial behavior in young, urban boys at familial risk for antisocial behavior.", "corpus_id": 35775855, "score": 0 }, { "doc_id": "24456761", "title": "Adolescents' exposure to violence and associated symptoms of psychological trauma.", "abstract": "OBJECTIVE\nTo examine the extent to which adolescents are exposed to various types of violence as either victims or witnesses, and the association of such exposure with trauma symptoms; specifically, the hypotheses that exposure to violence will have a positive and significant association with depression, anger, anxiety, dissociation, posttraumatic stress, and total trauma symptoms.\n\n\nDESIGN AND SETTING\nThe study employed a survey design using an anonymous self-report questionnaire administered to students (grades 9 through 12) in six public high schools during the 1992-1993 school year.\n\n\nPARTICIPANTS\nSixty-eight percent of the students attending the participating schools during the survey participated in the study (N = 3735). Ages ranged from 14 to 19 years; 52% were female; and 35% were African American, 33% white, and 23% Hispanic.\n\n\nRESULTS\nAll hypotheses were supported. Multiple regression analyses of the total sample revealed that violence exposure variables (and to a lesser extent, demographic variables) explained a significant portion of variance in all trauma symptom scores, including depression (R2 = .31), anger (R2 = .30), dissociation (R2 = .23), posttraumatic stress (R2 = .31), and total trauma (R2 = .37).\n\n\nCONCLUSIONS\nA significant and consistent association was demonstrated linking violence exposure to trauma symptoms within a diverse sample of high school students. Our findings give evidence of the need to identify and provide trauma-related services for adolescents who have been exposed to violence.", "corpus_id": 24456761, "score": 0 }, { "doc_id": "35491593", "title": "Trauma, Drugs and Violence Among Juvenile Offenders", "abstract": "Abstract Trauma typically occurs when one experiences a situation where life has been threatened or lost. If the trauma is not resolved, negative residual effects may result in alcohol and drug use, involvement in violent activities as well as the development of mental health problems such as posttraumatic stress disorder (PTSD). Findings from a National Institute on Drug Abuse-funded study examining the link between trauma, drug use and violence among youth are presented. Results from interviews with 414 juveniles remanded to the Office of Children and Family Services (formerly New York State Division For Youth) for assault, sexual assault, robbery or homicide, document the trauma experienced by these youth, as well as how it correlated with their drug usage and participation in violent, illegal activities. Discussion of these findings, their implications for understanding and intervening, and recommendations for future research are highlighted.", "corpus_id": 35491593, "score": 0 }, { "doc_id": "34643083", "title": "What children can tell us about living in danger.", "abstract": "Developmental challenges faced by children growing up in situations of chronic danger linked to community violence and communal conflict are reviewed. The concept of post-traumatic stress disorder is expanded to include situations of chronic and on-going traumatic stress associated with dangerous environments--war zones and inner city neighborhoods plagued by violence and crime. Of particular importance is the impact of chronic stress and danger on the child's world view, the child's social map, and the child's moral development. On the basis of field work in 5 war zones, the article points to the importance of adult-led \"processing\" of the young child's experience to his or her psychological coping and moral development. Some of the contradictions operating in such environments are explored--for example, that \"fanatical\" ideology may provide short-term support for adults and children but also may serve to prolong communal conflict, impede the necessary processing of experience, and increase vulnerability in the long run.", "corpus_id": 34643083, "score": 0 }, { "doc_id": "40562027", "title": "Violence exposure and mental health of adolescents in small towns: an exploratory study.", "abstract": "This study explores the impact of violence exposure on the mental health of the adolescents in a rural small town. A structured questionnaire was used to survey 347 adolescents. Violence experienced and witnessed by the adolescents at school, in the neighbourhood, and at home was measured. Mental health was represented by the psychiatric symptoms, depression level, and self-esteem. The level of violence perpetrated by the adolescents was also explored. Results of the multiple regression analysis show that adolescents who have been exposed to more violence, either as a victim or as a witness, report more psychiatric symptoms, higher levels of depression, and more problems of self-esteem. Being a witness of violence also contributes significantly to the variance of violence committed by the adolescents. The implications of the findings to violence prevention are discussed in the conclusion.", "corpus_id": 40562027, "score": 0 }, { "doc_id": "11832089", "title": "Violence exposure, posttraumatic stress, and personality in juvenile delinquents.", "abstract": "OBJECTIVE\nTo assess posttraumatic stress and its relationship to comorbid psychopathology, violence exposure, and personality traits in Russian male juvenile delinquents.\n\n\nMETHOD\nPosttraumatic stress and comorbid psychopathology were assessed by a semistructured psychiatric interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) in 370 delinquent youths during winter-spring of 1999. In addition, violence exposure, personality, and psychopathology were assessed by self-reports.\n\n\nRESULTS\nMost delinquents reported some degree of posttraumatic stress: 156 subjects (42%) fulfilled partial criteria and 87 (25%) fulfilled full DSM-IV criteria for posttraumatic stress disorder (PTSD). Violence-related experiences (witnessing and victimization) were the most common types of trauma. Higher levels of posttraumatic stress were accompanied by higher rates of comorbid psychopathology, with the most striking differences occurring between the groups with full versus partial PTSD criteria. Violence exposure was related to temperamental behavior activation (novelty seeking), whereas PTSD symptom scores were predominantly related to behavior inhibition and poor coping (high harm avoidance and low self-directedness).\n\n\nCONCLUSIONS\nSimilar to findings from American samples, Russian juvenile delinquents represent a severely traumatized population, mainly due to high levels of violence exposure. Those with full PTSD are the most severely traumatized and have highest rates of psychopathology, as compared to those with no or partial PTSD, and they require the most clinical attention and rehabilitation. Both exposure to violence and levels of posttraumatic stress are related to personality traits, which influence degree of exposure and individual perception of stress. The latter should be considered in individualized approaches to rehabilitation.", "corpus_id": 11832089, "score": 1 }, { "doc_id": "22860426", "title": "Posttraumatic stress disorder in incarcerated juvenile delinquents.", "abstract": "OBJECTIVE\nTo assess the prevalence of posttraumatic stress disorder (PTSD) in severely delinquent subjects and to measure associated personality characteristics.\n\n\nMETHOD\nEighty-five incarcerated boys (mean age 16.6, SD = 1.2) with mostly violent offenses were studied. The sample was representative of the California Youth Authority population. They received a standard psychiatric screen, a semistructured interview for PTSD, and self-report questionnaires measuring personality traits and defenses. A nonclinical sex- and age-matched group was used for comparing psychometrics.\n\n\nRESULTS\nSubjects suffered from PTSD at higher rates than other adolescent community samples and at higher rates than those found in county probation camps. Thirty-two percent fulfilled criteria for PTSD, 20% partial criteria. One half of the subjects described the witnessing of interpersonal violence as the traumatizing event. Psychometric results converged in the predicted way: Subjects with PTSD showed elevated distress, anxiety, depression, and lowered restraint, impulse control, and suppression of aggression; they had high levels of immature defenses such as projection, somatization, conversion, dissociation, and withdrawal.\n\n\nCONCLUSIONS\nPTSD occurs at high rates in delinquents, and this finding has implications for management and treatment. Personality characteristics that might put individuals at risk for the development of PTSD were identified.", "corpus_id": 22860426, "score": 1 }, { "doc_id": "20111309", "title": "Adolescent psychopathology as a function of informant and risk status.", "abstract": "Adolescents selected for delinquency risk in a community study, their parents, and teachers completed versions of the Child Behavior Checklist, with the raw scores representing the adolescents' level of psychopathology. All three informants rated high risk adolescents as showing higher levels of delinquency as well as other forms of psychopathology, particularly anxiety, aggression, social problems, thought problems, and, to a slightly less consistent extent, withdrawn behavior. In addition, compared with parents and adolescents, teachers rated psychopathology in African-American adolescents higher than that in Anglo-American adolescents. The results are analyzed using knowledge drawn from social and child psychiatry.", "corpus_id": 20111309, "score": 0 }, { "doc_id": "23176884", "title": "Traumatic events and posttraumatic stress disorder in an urban population of young adults.", "abstract": "To ascertain the prevalence of posttraumatic stress disorder (PTSD) and risk factors associated with it, we studied a random sample of 1007 young adults from a large health maintenance organization in the Detroit, Mich, area. The lifetime prevalence of exposure to traumatic events was 39.1%. The rate of PTSD in those who were exposed was 23.6%, yielding a lifetime prevalence in the sample of 9.2%. Persons with PTSD were at increased risk for other psychiatric disorders; PTSD had stronger associations with anxiety and affective disorders than with substance abuse or dependence. Risk factors for exposure to traumatic events included low education, male sex, early conduct problems, extraversion, and family history of psychiatric disorder or substance problems. Risk factors for PTSD following exposure included early separation from parents, neuroticism, preexisting anxiety or depression, and family history of anxiety. Life-style differences associated with differential exposure to situations that have a high risk for traumatic events and personal predispositions to the PTSD effects of traumatic events might be responsible for a substantial part of PTSD in this population.", "corpus_id": 23176884, "score": 0 }, { "doc_id": "30376389", "title": "Epidemiology of trauma: frequency and impact of different potentially traumatic events on different demographic groups.", "abstract": "The frequency and impact of 10 potentially traumatic events were examined in a sample of 1,000 adults. Drawn from four southeastern cities, the sample was half Black, half White, half male, half female, and evenly divided among younger, middle-aged, and older adults. Over their lifetimes, 69% of the sample experienced at least one of the events, as did 21% in the past year alone. The 10 events varied in importance, with tragic death occurring most often, sexual assault yielding the highest rate of posttraumatic stress disorder (PTSD), and motor vehicle crash presenting the most adverse combination of frequency and impact. Numerous differences were observed in the epidemiology of these events across demographic groups. Lifetime exposure was higher among Whites and men than among Blacks and women; past-year exposure was highest among younger adults. When impact was analyzed as a continuous variable (perceived stress), Black men appeared to be most vulnerable to the effects of events, but young people showed the highest rates of PTSD.", "corpus_id": 30376389, "score": 0 }, { "doc_id": "22304420", "title": "Post-traumatic stress disorder in the community: an epidemiological study.", "abstract": "Post-traumatic stress disorder (PTSD) was studied in the Piedmont region of North Carolina. Among 2985 subjects, the lifetime and six month prevalence figures for PTSD were 1.30 and 0.44% respectively. In comparison to non-PTSD subjects, those with PTSD had significantly greater job instability, family history of psychiatric illness, parental poverty, child abuse, and separation or divorce of parents prior to age 10. PTSD was associated with greater psychiatric comorbidity and attempted suicide, increased frequency of bronchial asthma, hypertension, peptic ulcer and with impaired social support. Differences were noted between chronic and acute PTSD on a number of measures, with chronic PTSD being accompanied by more frequent social phobia, reduced social support and greater avoidance symptoms.", "corpus_id": 22304420, "score": 0 }, { "doc_id": "43602983", "title": "Traumas and posttraumatic stress disorder in a community population of older adolescents.", "abstract": "OBJECTIVE\nThe prevalence of DSM-III-R traumas and posttraumatic stress disorder (PTSD) and their impact on psychosocial functioning were examined in a community population of older adolescents.\n\n\nMETHODS\nSubjects were 384 adolescents participating in an ongoing longitudinal study. When subjects were aged 18 years, the NIMH Diagnostic Interview Schedule, Version IIIR, was used to identify lifetime traumatic events and diagnoses of PTSD, major depression, phobias, and substance dependence. Behavioral, emotional, and academic functioning in later adolescence was evaluated through self-report measures and school records.\n\n\nRESULTS\nMore than two fifths of adolescents experienced at least one DSM-III-R trauma by age 18 years; PTSD developed in 14.5% of these affected youths or 6.3% of the total sample. Youths with PTSD demonstrated widespread impairment at age 18, including more overall behavioral-emotional problems, interpersonal problems, academic failure, suicidal behavior, and health problems, as well as an increased risk for additional disorders. An equally striking finding was that youths who experienced traumas but did not develop PTSD also showed deficits in many of these areas when compared with their peers who had not experienced traumas.\n\n\nCONCLUSIONS\nThe substantial risk faced by youths in community settings for experiencing traumas and PTSD, along with associated impairments in later adolescence, underscores the need for programs of prompt intervention.", "corpus_id": 43602983, "score": 0 }, { "doc_id": "45760573", "title": "The role of social and cognitive processes in children's adjustment to community violence.", "abstract": "This study examined associations of community violence exposure and psychological well-being among 99 8-12 year old children (M = 10.7 years) using home interviews with mothers and children. Both moderators and mediators of the links between violence exposure and well-being were tested. After demographics and concurrent life stressors were controlled for violence exposure was significantly associated with intrusive thinking, anxiety, and depression. Regression analyses indicated that intrusive thinking partially mediated associated between violence exposure and internalizing symptoms. Planned comparisons revealed that violence exposure had the strongest effect on well-being among children with low social support or high levels of social strains. Furthermore, children with high levels of intrusive thinking were most likely to show heightened internalizing symptoms when they had inadequate social support.", "corpus_id": 45760573, "score": 0 }, { "doc_id": "143511525", "title": "Validation of the tridimensional personality questionnaire in a sample of male drug users", "abstract": "Abstract One hundred seventy-three male drug using volunteers for drug-related studies completed the Cloninger Tridimensional Personality Questionnaire (TPQ), with most of these S s also completing the Eysenck Personality Questionnaire, the Eysenck I.7, the Buss-Durkee Hostility Inventory, the Symptom Check List 90, the Elliott-Huizinga Lifetime Criminality Measure, the Diagnostic Interview Schedule for DSM-III, and the Personality Disorders Questionnaire. TPQ novelty seeking was correlated with impulsivity, aggression, and criminality, TPQ harm avoidance was correlated with introversion, neuroticism, low venturesomeness, and high psychological distress, while TPQ reward dependence was correlated with extraversion, low psychoticism, and empathy. With the possible exception of novelty seeking, the TPQ scales did not, as predicted by Cloninger, correlate with specific personality disorders or alcohol and drug abuse. The rationale for the construction of the TPQ scales was generally not supported in the present sample.", "corpus_id": 143511525, "score": 0 }, { "doc_id": "34704631", "title": "Behaviour/emotional problems in male juvenile delinquents and controls in Russia: the role of personality traits", "abstract": "Recent studies based on the psychobiological theory of personality by Cloninger postulate a relationship between certain personality traits and various psychopathological manifestations. To test this theory, we administered the Temperament and Character Inventory and the Youth Self‐Report to 188 male delinquents from a juvenile correction centre in Northern Russia, and to 111 age‐matched male controls recruited from among schoolchildren. As assumed by previous studies, psychological symptoms were primarily positively correlated with harm avoidance and negatively correlated with self‐directedness. At the same time, the higher levels of aggressive and delinquent behaviour were positively correlated with novelty‐seeking and negatively correlated with co‐operativeness. The possible mechanisms underlying these findings are discussed.", "corpus_id": 34704631, "score": 1 }, { "doc_id": "145433499", "title": "Does violence beget violence? A critical examination of the literature.", "abstract": "Critically examines the \"violence breeds violence\" hypothesis broadly defined. Organized into seven sections, the literature review includes (a) the abuse breeds abuse hypothesis; (b) reports of small numbers of violent/homicidal offenders; (c) studies examining the relationship of abuse and neglect to delinquency, (d) to violent behavior, and (e) to aggressive behavior in infants and young children; (f) abuse, withdrawal, and self-destructive behavior; and (g) studies of the impact of witnessing or observing violent behavior. A detailed discussion of methodological considerations and shortcomings precedes the review. The author concludes that existing knowledge of the long-term consequences of abusive home environments is limited and suggests that conclusions about the strength of the cycle of violence be tempered by the dearth of convincing empirical evidence. Recommendations are made for further research. VioLit summary: OBJECTIVE: The aim of this study by Widom was to provide a comprehensive and critical assessment of the \"violence breeds violence\" hypothesis by examining the empirical literature found in the fields of psychology, sociology, criminology, psychiatry, social work and nursing. METHODOLOGY: The author conducted a non-experimental exploratory study, evaluating literature collected from computerized searches of psychological and educational abstracts, as well as from the national database on child abuse, through the year 1985. FINDINGS/DISCUSSION: The author began with an examination of methodologies employed in studies in the field of violence, and concluded that the many methodological problems that are evident hamper current research. The definition and criteria for child abuse and neglect vary widely, making research less replicable and therefore less reliable. The retrospective nature of the data makes its accuracy questionable, due to possible recall problems. Sampling techniques are often weak, using populations chosen for convenience rather than for representativeness. Many studies are ex post facto in nature, so prediction power is not strong. Most also rely on correlations, so that the issue of causality cannot be addressed. Abused and neglected children are usually treated as one group, which may hide important distinctions between the two. There is generally a lack of control groups in most studies, with no consideration of statistical base rates. The outcome variables usually include general delinquency, rather than violent criminal behavior. Finally, few of the studies examine the long-term effects of childhood abuse and neglect upon behavior in adulthood. The author broke down the \"cycle of violence\" hypothesis into a number of constituent parts. The first hypothesis found within the broader area is that \"abuse breeds abuse.\" According to this belief, adults who were abused as children will be more likely to abuse their own children. The sparse empirical evidence for this hypothesis is hampered by an over-dependence upon retrospective and self-report data, as well as little use of control groups. Despite this, it seems that if abused as children adults are more likely to be abusers. However, most abusive parents were not victims of abuse as children. A second type of evidence for the \"cycle of violence\" hypothesis is the use of case studies of violent or homicidal offenders in clinical settings. Studies have found a history of abuse in the backgrounds of these people. However, the studies use no control groups, do not control for confounding factors and rely upon small numbers of subjects who report retrospectively about prior abuse. In order to examine the consequences of abuse and neglect in a larger and more controlled context, other researchers have examined the relationship between abuse or neglect and delinquency. In studies using a prospective design, fewer than 20% of abused or neglected children later exhibit delinquency. In retrospective studies, the rates of abuse in the backgrounds of delinquents range from 8% to 26%. Other studies examine the relationship between abuse or neglect and violent behavior, using either delinquent or patient groups for samples. Studies using juvenile delinquency find support for a relationship between abuse in childhood and later violent behavior, with violent boys being more likely to have experienced or witnessed abuse than non-violent boys. A smaller number of studies examine groups of patients, and conclude that violent patients are more likely to have been abused as children. These studies provide tentative support for the \"cycle of violence\" hypothesis, although some contradictory results do exist. In developmental psychology research examining the relationship between abuse, neglect and aggressive behavior in young children, much research has been in the form of experimental laboratory studies. In general, these studies suggest that abused children will exhibit more aggression and problem behavior than those without such victimization experiences. Other studies have examined the notion that abuse in childhood results not only in external aggression, but also to internal aggression, withdrawal and self-destructive behavior. Findings suggest that childhood abuse can lead to self-abuse and ultimately to suicidal tendencies. Many studies have examined the consequences of observing violence between parents or on television. Studies of children observing marital violence have found modest but consistent relationships between witnessing family aggression as a child and marital violence in the next generation. Among children witnessing family violence, 16% to 17% report marital violence in their own later relationships. Exposure to violence on television has been found to increase aggression, both immediately after viewing and in the long-term, as well as to lead to emotional insensitivity to violence and to a distorted perception of real-life violence. The author concluded that despite the many studies in the field of family violence, researchers still do not know much about the consequences of an abusive family environment. It was suggested that the magnitude of the problem is hard to ascertain because of methodological flaws in many of the studies, as well as a simplistic conceptualization of the relationship between child abuse and violence. AUTHOR'S RECOMMENDATIONS: The author suggested a number of approaches to improve research in the area of violence. Included in these were the need to distinguish between abuse and neglect, and to include control variables such as measures of social desirability, number of children in the household and income level. More discriminating analyses, with protective factors such as personal attributes, environmental context, biological predisposition and positive events that could mediate the negative effects of violence should also be included, in order to understand why many children do not suffer the adverse effects of abuse and neglect. The author also cited the need for more sophisticated methodologies, and for a recognition of the shortcomings of previous work. EVALUATION: The author clearly and concisely presents a thorough review of the literature, as well as an important discussion of methodological problems and excellent suggestions for future research. This paper provides a valuable piece of critical evaluation for the study of the relationship between childhood abuse and violence. (CSPV Abstract - Copyright © 1992-2007 by the Center for the Study and Prevention of Violence, Institute of Behavioral Science, Regents of the University of Colorado) N1 - Call Number: F-26, AB-26 KW - 1980s KW - Intergenerational Transmission of Child Abuse KW - Intergenerational Transmission of Violence KW - Domestic Violence Effects KW - Domestic Violence Causes KW - Domestic Violence Offender KW - Domestic Violence Victim KW - Long-Term Effects KW - Child Abuse Effects KW - Child Abuse Victim KW - Child Abuse Offender KW - Child Abuse Causes KW - Child Physical Abuse Causes KW - Child Physical Abuse Effects KW - Child Physical Abuse Offender KW - Child Physical Abuse Victim KW - Child Victim KW - Childhood Experience KW - Childhood Victimization KW - Victim Turned Offender KW - Adult Parent KW - Adult Offender KW - Adult Violence KW - Child Victim KW - Parent Offender KW - Literature Review Language: en", "corpus_id": 145433499, "score": 0 }, { "doc_id": "39268821", "title": "Assessment of Exposure to Political Violence and Other Potentially Traumatizing Events. A Critical Review", "abstract": "This paper focuses on the common use of internal-consistency reliability, test-retest, and interrater correlations based on counts of events, events sampling, and factor-analytic techniques in assessment of exposure to political violence and other potentially traumatizing events. The author attributes the continued use of these strategies to a tendency among researchers to identify items from conventional events lists as effect indicators. Through a discussion of four alternative measurement models, the rationale is provided for the proposition that exposure to political violence and similar constructs should be treated as composite variables with causal indicators, rather than as latent variables with effect indicators.", "corpus_id": 39268821, "score": 0 }, { "doc_id": "25581406", "title": "Post-traumatic stress reactions in children after the 1988 Armenian earthquake.", "abstract": "One and a half years after the devastating earthquake in Armenia in 1988, 231 children from three cities at increasing distances from the epicentre were randomly screened in their schools to determine the frequency and severity of post-traumatic stress reactions, using the Children's Post-traumatic Stress Disorder Reaction Index (CPTSD-RI). A systematic clinical assessment of PTSD based on DSM-III-R criteria was also conducted on approximately half of this sample. A high CPTSD-RI score was strongly correlated with a clinical diagnosis of PTSD. A strong positive correlation was found between proximity to the epicentre and overall severity of post-traumatic stress reaction, as well as severity of core component symptoms of PTSD. High rates of chronic, severe post-traumatic stress reactions were found among children in the two most damaged cities, Spitak and Gumri. Analyses controlling for exposure revealed that girls reported more persistent fears than boys. These findings indicate that after catastrophic natural disaster, post-traumatic reactions in children may reach epidemic proportions, remain high for a prolonged period, and jeopardise the well-being of the child population of a large region. Systematic screening of children for PTSD can provide critical information for a rational public mental health programme after such a disaster.", "corpus_id": 25581406, "score": 0 }, { "doc_id": "40145105", "title": "An inventory for measuring depression.", "abstract": "The difficulties inherent in obtaining consistent and adequate diagnoses for the purposes of research and therapy have been pointed out by a number of authors. Pasamanick12in a recent article viewed the low interclinician agreement on diagnosis as an indictment of the present state of psychiatry and called for \"the development of objective, measurable and verifiable criteria of classification based not on personal or parochial considerations, but on behavioral and other objectively measurable manifestations.\" Attempts by other investigators to subject clinical observations and judgments to objective measurement have resulted in a wide variety of psychiatric rating scales.4,15These have been well summarized in a review article by Lorr11on \"Rating Scales and Check Lists for the Evaluation of Psychopathology.\" In the area of psychological testing, a variety of paper-and-pencil tests have been devised for the purpose of measuring specific", "corpus_id": 40145105, "score": 0 }, { "doc_id": "40012240", "title": "A systematic method for clinical description and classification of personality variants. A proposal.", "abstract": "A systematic method for clinical description and classification of both normal and abnormal personality variants is proposed based on a general biosocial theory of personality. Three dimensions of personality are defined in terms of the basic stimulus-response characteristics of novelty seeking, harm avoidance, and reward dependence. The possible underlying genetic and neuroanatomical bases of observed variation in these dimensions are reviewed and considered in relation to adaptive responses to environmental challenge. The functional interaction of these dimensions leads to integrated patterns of differential response to novelty, punishment, and reward. The possible tridimensional combinations of extreme (high or low) variants on these basic stimulus-response characteristics correspond closely to traditional descriptions of personality disorders. This reconciles dimensional and categorical approaches to personality description. It also implies that the underlying structure of normal adaptive traits is the same as that of maladaptive personality traits, except for schizotypal and paranoid disorders.", "corpus_id": 40012240, "score": 0 }, { "doc_id": "8763111", "title": "Temperament and novelty seeking in adolescent substance use: convergence of dimensions of temperament with constructs from Cloninger's theory.", "abstract": "This study investigated the convergence of temperament dimensions with constructs from C. R. Cloninger's (1987a) theory using data from a sample of 949 adolescents (M age = 13.6 years). Substantial convergence was found, and both types of constructs were related in predicted ways to self-regulation variables and adolescent substance use. Structural modeling procedures tested a mediational model for substance use; results showed mediation through self-control, academic competence, negative life events, and deviant peer affiliations. Interactions indicated that substance use could be predicted from a balance of systems for good control and poor control. Poor self-control was present for dimensions implicated in both externalizing and internalizing disorders. Results are discussed with reference to self-regulation models of substance use and the comorbidity of substance abuse and mental disorder.", "corpus_id": 8763111, "score": 0 }, { "doc_id": "13118304", "title": "Reliability and Validity of the Japanese Version of the Temperament and Character Inventory", "abstract": "The Temperament and Character Inventory was translated into Japanese, and, to confirm the psychometric properties of the inventory, three samples were recruited from a nonpatient population. In nonpatient population A (N = 555), the full version (240 items) of the inventory with dichotomous measuring, along with the General Health Questionnaire and the Social Desirability Scale, were distributed to the subjects. Factor analyses of the subscales showed that the factor structure of the inventory was consistent with Cloninger's theory. Correlations of the scale scores with the General Health Questionnaire and the Social Desirability Scale scores were almost negligible, indicating that the scale is resistant to the current psychopathology and response bias. In this and the other two university student samples (ns = 395 and 377), Cronbach coefficients α of the scale scores were substantially high except for the short version (125 items) of the inventory with dichotomous measures. The Japanese version of the inventory appears to have internal reliability and content and construct validity in a Japanese population.", "corpus_id": 13118304, "score": 0 }, { "doc_id": "45944448", "title": "Relationships between Tridimensional Personality Questionnaire Dimensions and DSM-III-R personality traits in Italian adolescents.", "abstract": "The predictions of Cloninger's neurobiologic learning model on the relationships between novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (P) and the traditional DSM-III-R personality disorders (PDs) were tested on a sample of 2,889 (1,475 males and 1,414 females) Italian high school students aged 16 to 18 years, using the Structured Clinical Interview for DSM-III-R Personality Disorders-self-report (SCID-II) and the Tridimensional Personality Questionnaire (TPQ). All relationships were in the predicted direction for antisocial, narcissistic, avoidant, and obsessive-compulsive PD alone, and at least two were in the predicted direction for schizoid, histrionic, borderline-explosive, dependent, and passive-aggressive PD. Eight of nine relationships were in the predicted direction for NS, but only seven of nine for HA and RD. This study provides substantial support for Cloninger's neurobiologic learning model as a useful tool to describe and classify personality variants and, because of the supposed neurochemical implications, to link personality traits to the underlying neurochemical and neuroanatomic substrate.", "corpus_id": 45944448, "score": 0 }, { "doc_id": "143504935", "title": "Unidimensional Versus Domain Representative Parceling of Questionnaire Items: An Empirical Example", "abstract": "Two alternative methods for parceling questionnaire items for use in confirmatory analyses are presented. The first method requires that parcels must (a) pass a minimum standard of reliability and (b) provide indications of unidimensionality to be retained for analysis. The second method requires that parcels be equally representative of the multiple aspects of a domain. The parcels may then serve as adequate indicators for the general construct. The latter method is consistent with the rationale underlying aggregation of measures, a procedure currently recommended for improving the psychometric properties of behavioral measures of personality. The two methods for parceling and a comparison are illustrated with an empirical example.", "corpus_id": 143504935, "score": 0 }, { "doc_id": "120166447", "title": "Alternative Ways of Assessing Model Fit", "abstract": "This article is concerned with measures of fit of a model. Two types of error involved in fitting a model are considered. The first is error of approximation which involves the fit of the model, with optimally chosen but unknown parameter values, to the population covariance matrix. The second is overall error which involves the fit of the model, with parameter values estimated from the sample, to the population covariance matrix. Measures of the two types of error are proposed and point and interval estimates of the measures are suggested. These measures take the number of parameters in the model into account in order to avoid penalizing parsimonious models. Practical difficulties associated with the usual tests of exact fit or a model are discussed and a test of “close fit” of a model is suggested.", "corpus_id": 120166447, "score": 0 }, { "doc_id": "24856241", "title": "Posttraumatic stress disorder in children: a review of the past 10 years.", "abstract": "OBJECTIVE\nTo review current knowledge about the clinical presentation, assessment, and treatment of posttraumatic stress disorder (PTSD) in children.\n\n\nMETHOD\nThe literature on PTSD in children is examined.\n\n\nRESULTS\nOver the past 10 years, PTSD has been described in children exposed to a variety of traumatic experiences. Little is known about the epidemiology of the disorder in children. Partial symptomatology and comorbidity are common. A variety of factors influence response to trauma and affect recovery. They include characteristics of the stressor and exposure to it; individual factors such as gender, age and developmental level, and psychiatric history; family characteristics; and cultural factors. Since the condition is likely to occur after disaster situations, much of the literature describes the child's response to disaster and interventions tend to include efforts within schools and/or communities. A number of clinical approaches have been used to treat the condition.\n\n\nCONCLUSIONS\nWhile assessment has been studied extensively, the longitudinal course of PTSD and treatment effectiveness have not been. Biological correlates of the condition also warrant greater attention.", "corpus_id": 24856241, "score": 0 }, { "doc_id": "10907698", "title": "Exposure to violence and presence of depression among low-income, African-American youth.", "abstract": "Distributional properties and correlates of the Children's Depression Inventory (CDI) were presented for a sample (n = 221) of low-income, African-American youths between 7 and 18 years of age. The results showed that younger children and those living in a household without their mother reported more depressive symptoms. Regression analyses revealed that victims of violence reported more depressive symptoms. However, chronic exposure to violence, in the form of witnessing violent acts, was not significantly related to depression. On further inspection, it was discovered that witnessing violence had a negative effect on depression. This finding, although somewhat unexpected, may be the result of some youths possessing a set of extraordinary coping mechanisms that help to insulate them from negative environmental experiences.", "corpus_id": 10907698, "score": 0 }, { "doc_id": "25323223", "title": "Youth exposure to violence: prevalence, risks, and consequences.", "abstract": "Recent empirical work on the distribution, determinants, and consequences of children and adolescents' witnessing of community violence are reviewed. Major findings across studies indicate that males, ethnic minorities, and urban residents are at increased risk for witnessing violence, and that higher rates of PTSD, depression, distress, aggression, and externalizing behavior disturbances are reported among those who witness violence. Degree of family conflict, domestic violence, and family support were demonstrated to modify the impact of exposure to violence. Research and policy recommendations are offered.", "corpus_id": 25323223, "score": 0 }, { "doc_id": "936537", "title": "Behavioral and physiological antecedents of inhibited and uninhibited behavior.", "abstract": "4-month-old infants were specifically selected for patterns of affective and motoric reactivity that were hypothesized to be associated with later inhibited and uninhibited behavior. Infants were classified as high on motor activity and negative affect, high on motor activity and positive affect, or low on motor activity and affect. Brain electrical activity was assessed in these infants at 9 months of age, and behavior toward novelty was observed at 14 months of age. Infants who were high on motor activity and negative affect exhibited greater right frontal EEG activation at 9 months of age and inhibited behavior at 14 months of age. Infants classified as high motor/high positive at 4 months of age exhibited uninhibited behavior at 14 months of age. No relations were found between frontal asymmetry at 9 months of age and inhibited behavior at 14 months of age. However, greater activation in both the left and right frontal hemispheres was associated with higher inhibition scores at 14 months of age. These findings are discussed in terms of the role that affective and physiological reactivity may play in the development of social behavior during toddlerhood.", "corpus_id": 936537, "score": 0 }, { "doc_id": "53999636", "title": "The role of frontal activation in the regulation and dysregulation of social behavior during the preschool years", "abstract": "We examined whether the interaction of resting frontal electroencephalogram (EEG) asymmetry and social behavior during peer play was related to the occurrence of maladaptive behavior in preschoolers. Two independent cohorts of children were observed interacting in same-age and -gender play quartets at 4 years of age. Each child was also seen individually for a psychophysiology session during which time measures of EEG activity were recorded. We found that highly sociable children who exhibited greater relative right frontal EEG asymmetry were more likely to exhibit externalizing problems than sociable children who exhibited greater relative left frontal EEG asymmetry. We also found that shy children who exhibited greater relative right frontal EEG asymmetry were more likely to exhibit internalizing problems than shy children who exhibited left frontal EEG asymmetry. These findings suggest that the pattern of frontal EEG asymmetry in combination with social behavioral style is a significant predictor of maladaptive behavior problems during the preschool period.", "corpus_id": 53999636, "score": 0 }, { "doc_id": "145802311", "title": "Emotion and Affective Style: Hemispheric Substrates", "abstract": "Research on cerebral asymmetry and the experience and expression of emotion is reviewed. The studies described use electrophysiological procedures to make inferences about patterns of regional cortical activation. Such procedures have sufficient temporal resolution to be used in the study of brief emotional experiences denoted by spontaneous facial expressions. In adults and infants, the experimental arousal of positive, approach-related emotions is associated with selective activation of the left frontal region, while arousal of negative, withdrawal-related emotions is associated with selective activation of the right frontal region. Individual differences in baseline measures of frontal asymmetry are associated with dispositional mood, affective reactivity, temperament, and immune function. These studies suggest that neural systems mediating approach- and withdrawal-related emotion and action are, in part, represented in the left and right frontal regions, respectively, and that individual differences in the activation levels of these systems are associated with a coherent nomological network of associations which constitute a person's affective style.", "corpus_id": 145802311, "score": 0 } ]

{ "doc_id": "89728145", "title": "The Challenge of Human Mesenchymal Stromal Cell Expansion: Current and Prospective Answers", "abstract": "In the field of cell therapy, allogenic human mesenchymal stromal cells (hMSCs) are often used in clinical trials, creating a demand for cell mass production using efficient dynamic bioreactor systems. As an advanced therapy medicinal product (ATMP), such cells should meet certain special requirements, including product specifications requiring a production process compatible with good manufacturing practice (GMP). The development of processes in which the cells are the product therefore remains a significant challenge. This chapter describes the requirements at different steps in the upstream and downstream phases of such dynamic processes. Potential solutions are presented and future prospects are discussed, including the selection of media and carriers for the strictly adherent growing cells, allowing efficient cell adhesion and detachment. Strategies for dynamic cultivation in bioreactors are described in detail for fixed‐bed and stirred‐tank reactors based on GMP requirements and the integration of process analytical technology (PAT). Following cell harvest, separation and purification, the formulation and storage of the product are also described. Finally, the chapter covers important cell quality characteristics necessary for the approval of ATMPs.", "corpus_id": 89728145 }

[ { "doc_id": "43457849", "title": "Regenerative Medicine - from Protocol to Patient", "abstract": "Generation and regeneration as an answer to disease are far from being a new idea. Philosophers, naturalists and scientists were intrigued by the marvels of regeneration seen in nature. By the middle of the nineties life scientists thought we were only a few years away from bioartifi cial organs grown in a Petri dish. However, by the dawn of the new millennium it became clear that the mechanistic approach dictated by tissue engineering so far, had neglected issues of vascularization. Processes of angiogenesis were central to homeostasis, bioassimilation and biointegration of tissue engineered constructs. Furthermore, the fi eld of tissue engineering had evolved into something vast, encompassing satellite technologies that were becoming separate science sectors. Advances in genetical engineering, stem cell biology, cloning, biomaterials and biomedical devices to name a few, would come to play a major role of their own – tissue engineering had become a part of a bigger whole. Regenerative medicine is the collective fi eld to shelter these technologies “... that seeks to develop functional cell, tissue, and organ substitutes to repair, replace or enhance biological function that has been lost due to congenital abnormalities, injury, disease, or aging”.", "corpus_id": 43457849, "score": 0 }, { "doc_id": "7728036", "title": "Clinical applications of mesenchymal stem cells", "abstract": "Mesenchymal stem cells (MSC) have generated a great amount of enthusiasm over the past decade as a novel therapeutic paradigm for a variety of diseases. Currently, MSC based clinical trials have been conducted for at least 12 kinds of pathological conditions, with many completed trials demonstrating the safety and efficacy. This review provides an overview of the recent clinical findings related to MSC therapeutic effects. Roles of MSCs in clinical trials conducted to treat graft-versus-host-disease (GVHD) and cardiovascular diseases are highlighted. Clinical application of MSC are mainly attributed to their important four biological properties- the ability to home to sites of inflammation following tissue injury when injected intravenously; to differentiate into various cell types; to secrete multiple bioactive molecules capable of stimulating recovery of injured cells and inhibiting inflammation and to perform immunomodulatory functions. Here, we will discuss these four properties. Moreover, the issues surrounding clinical grade MSCs and principles for MSC therapeutic approaches are also addressed on the transition of MSCs therapy from bench side to bedside.", "corpus_id": 7728036, "score": 0 }, { "doc_id": "27511857", "title": "Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial", "abstract": "BACKGROUND\nComplex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease.\n\n\nMETHODS\nWe did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (≥18 years) with Crohn's disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579.\n\n\nFINDINGS\n212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15·2%, 97·5% CI 0·2-30·3; p=0·024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15·8%, 0·5-31·2; p=0·021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine).\n\n\nINTERPRETATION\nCx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both.\n\n\nFUNDING\nTiGenix.", "corpus_id": 27511857, "score": 0 }, { "doc_id": "30359021", "title": "Maintenance of differentiation potential of human bone marrow mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene despite [corrected] extensive proliferation.", "abstract": "Human bone marrow mesenchymal stem cells (hMSC) represent a population of stem cells that are capable of differentiation into multiple lineages. However, these cells exhibit senescence-associated growth arrest and phenotypic changes during long-term in vitro culture. We have recently demonstrated that overexpression of human telomerase reverse transcriptase (hTERT) in hMSC reconstitutes telomerase activity and extends life span of the cells [Nat. Biotechnol. 20 (2002) 592]. In the present study, we have performed extensive characterization of three independent cell lines derived from the parental hMSC-TERT cell line based on different plating densities during expansion in culture: 1:2 (hMSC-TERT2), 1:4 (hMSC-TERT4), and 1:20 (hMSC-TERT20). The 3 cell lines exhibited differences in morphology and growth rates but they all maintained the characteristics of self-renewing stem cells and the ability to differentiate into multiple mesoderm-type cell lineages: osteoblasts, adipocytes, chondrocytes, and endothelial-like cells over a 3-year period in culture. Also, surface marker studies using flow cytometry showed a pattern similar to that known from normal hMSC. Thus, telomerization of hMSC by hTERT overexpression maintains the stem cell phenotype of hMSC and it may be a useful tool for obtaining enough number of cells with a stable phenotype for mechanistic studies of cell differentiation and for tissue engineering protocols.", "corpus_id": 30359021, "score": 0 }, { "doc_id": "2073028", "title": "Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells", "abstract": "Human bone marrow stromal cells (hMSCs) were stably transduced by a retroviral vector containing the gene for the catalytic subunit of human telomerase (hTERT). Transduced cells (hMSC-TERTs) had telomerase activity, and the mean telomere length was increased as compared with that of control cells. The transduced cells have now undergone more than 260 population doublings (PD) and continue to proliferate, whereas control cells underwent senescence-associated proliferation arrest after 26 PD. The cells maintained production of osteoblastic markers and differentiation potential during continuous subculturing, did not form tumors, and had a normal karyotype. When implanted subcutaneously in immunodeficient mice, the transduced cells formed more bone than did normal cells. These results suggest that ectopic expression of telomerase in hMSCs prevents senescence-associated impairment of osteoblast functions.", "corpus_id": 2073028, "score": 0 }, { "doc_id": "28099333", "title": "The translation of cell-based therapies: clinical landscape and manufacturing challenges.", "abstract": "Cell-based therapies have the potential to make a large contribution toward currently unmet patient need and thus effective manufacture of these products is essential. Many challenges must be overcome before this can become a reality and a better definition of the manufacturing requirements for cell-based products must be obtained. The aim of this study is to inform industry and academia of current cell-based therapy clinical development and to identify gaps in their manufacturing requirements. A total of 1342 active cell-based therapy clinical trials have been identified and characterized based on cell type, target indication and trial phase. Multiple technologies have been assessed for the manufacture of these cell types in order to facilitate product translation and future process development.", "corpus_id": 28099333, "score": 0 }, { "doc_id": "11844730", "title": "Large‐scale production of human mesenchymal stem cells for clinical applications", "abstract": "Human mesenchymal stem cells (hMSCs) have many potential applications in tissue engineering and regenerative medicine. Currently, hMSCs are generated through conventional static adherent cultures in the presence of fetal bovine serum (FBS) for clinical applications (e.g., multiple sclerosis). However, these methods are not appropriate to meet the expected future demand for quality‐assured hMSCs for human therapeutic use. Hence, it is imperative to develop an effective hMSC production system, which should be controllable, reproducible, and scalable. To this end, efforts have been made by several international research groups to develop (i) alternative media either by replacing FBS with human‐sourced supplements (such as human serum or platelet lysate) or by identifying defined serum‐free formulations consisting of key growth/attachment factors, and (ii) controlled bioreactor protocols. In this regard, we review here current hMSC production technologies and future perspectives toward efficient methods for the generation of clinically relevant numbers of hMSC therapeutics.", "corpus_id": 11844730, "score": 0 }, { "doc_id": "12149845", "title": "Application of human mesenchymal and pluripotent stem cell microcarrier cultures in cellular therapy: achievements and future direction.", "abstract": "Mesenchymal stem cells (MSCs) have recently made significant progress with multiple clinical trials targeting modulation of immune responses, regeneration of bone, cartilage, myocardia, and diseases like Metachromatic leukodystrophy and Hurler syndrome. On the other hand, the use of human embryonic and induced pluripotent stem cells (hPSCs) in clinical trials is rather limited mainly due to safety issues. Only two clinical trials, retinal pigment epithelial transplantation and treatment of spinal cord injury were reported. Cell doses per treatment can range between 50,000 and 6 billion cells. The current 2-dimensional tissue culture platform can be used when low cell doses are needed and it becomes impractical when doses above 50 million are needed. This demand for future cell therapy has reinvigorated interests in the use of the microcarrier platform for generating stem cells in a scalable 3-dimensional manner. Microcarriers developed for culturing adherent cell lines in suspension have been used mainly in vaccine production and research purposes. Since MSCs grow as monolayers similar to conventional adherent cell lines, adapting MSCs to a microcarrier based expansion platform has been progressing rapidly. On the other hand, establishing a robust microcarrier platform for hPSCs is more challenging as these cells grow in multilayer colonies on extracellular matrices and are more susceptible to shear stress. This review describes properties of commercially available microcarriers developed for cultivation of anchorage dependent cells and present current achievements for expansion and differentiation of stem cells. Key issues such as microcarrier properties and coatings, cell seeding conditions, medium development and improved bioprocess parameters needed for optimal stem cell systems are discussed.", "corpus_id": 12149845, "score": 0 }, { "doc_id": "74795765", "title": "Accreditation and regulations in cell therapy", "abstract": "Advances in stem cell biology and immunology raise hopes for new developments in regenerative medicine as well as cell‐based immune intervention, with potential applications in many medical disciplines. Emerging from the medical practices of organ, tissue and cell transplantations over several decades, the development of cellular therapies nowadays enter a new era in which the industry may take cell manufacturing activities away from academic facilities, using complex procedures for cell engineering and large‐scale production at centralized facilities. Recent changes in regulations push towards this historical transition; however, a pragmatic analysis of met and unmet clinical needs, as well as of specific procedural and organizational aspects that govern human cell procurement and processing suggest that a significant role will remain for academic facilities in the near future. Taking advantage of the large experience in the field of haematopoietic stem cell transplantation, we here review actual and potential consequences of regulatory changes in these medical practices, with a focus on the unique system for quality management that has been established in Europe and the United States of America to address specific risks associated with these therapeutic procedures.", "corpus_id": 74795765, "score": 0 }, { "doc_id": "87643239", "title": "Regulation for Gene and Cell Therapy Medicinal Products in Europe", "abstract": "An important step in the regulation of cell and gene therapy medicinal products, which are classified as advanced therapy medicinal products (ATMPs) in the European Union, has been made with Regulation 1394/2007/EC. By this regulation a new committee, the Committee for Advanced Therapies, has been established to ensure appropriate coverage of scientific and regulatory aspects of ATMPs. In addition, novel regulatory tools specific for ATMPs such as the classification, certification, and hospital exemption were introduced to support the development of this product class. By nature, ATMPs are a special class of medicinal products with characteristics different to conventional drugs and even other biologicals. Hence, regulatory requirements for manufacturing and clinical evaluation need to be tailored to the type and design of the ATMP, as well as to its manufacturing process and clinical indication. This chapter summarizes the general regulatory pathway for ATMPs as well as the currently applicable ATMP-specific procedures. In addition, the regulatory requirements regarding manufacturing, quality, and nonclinical and clinical testing for cell and gene therapy medicinal products are discussed. Important aspects of the environmental risk assessment, a provision for ATMPs containing genetically modified organisms, are also reviewed.", "corpus_id": 87643239, "score": 0 }, { "doc_id": "11462927", "title": "Good manufacturing practice and clinical-grade human embryonic stem cell lines.", "abstract": "Human embryonic stem cell (hESC) lines, after directed differentiation, hold the greatest potential for cell transplantation treatment in many severe diseases. Good manufacturing practice (GMP) quality, defined by both the European Medicines Agency and the Food and Drug Administration, is a requirement for clinical-grade cells, offering optimal defined quality and safety in cell transplantation. Using animal substance-free culture media, feeder cells or feeder-free matrix in derivation, passaging, expansion and cryopreservation procedures, immune reactions against animal proteins in the cells, and infection risk caused by animal microbes can be avoided. It is also possible to apply GMP to animal components if no better options are available. In recent production of GMP-quality hESC lines, feeder cells had been cultured in fetal bovine serum, and the medium supplemented with an animal protein containing a serum replacement component. Using embryos cultured in a GMP laboratory, isolating the inner cell mass mechanically, deriving lines on human feeder cells originally cultured in xeno-free medium in a GMP laboratory, and using xeno-free media for derivation and culture of hESC lines themselves, GMP-quality xeno-free hESC lines could be established today. Human serum is a xeno-free component available today, but many chemically defined media are under development.", "corpus_id": 11462927, "score": 0 }, { "doc_id": "32381227", "title": "Ex vivo expanded mesenchymal stromal cell minimal quality requirements for clinical application.", "abstract": "Mesenchymal stromal cells (MSCs), as advanced therapy products, must satisfy all the requirements for human use of medicinal products, aiming to maintain the quality and safety of the cells. The MSC manufacturing process for clinical use should comply with the principles of Good Manufacturing Practice (GMP). This ensures that cell preparations are produced and controlled, from the collection and manipulation of raw materials, through the processing of intermediate products, to the quality controls, storage, labeling and packaging, and release. The objective of this document is to provide the minimal quality requirements for the MSC production and its delivery for clinical use, so that the safety of the final cell therapy product will not be compromised. For this purpose, the document evaluates the most important steps of GMP-compliant MSC production: the isolation and expansion process; the validation phase of the process, including all quality controls for the characterization, functionality, potency, and safety of MSCs; and the quality control at the batch release to guarantee the safety of patient infusion.", "corpus_id": 32381227, "score": 0 }, { "doc_id": "22430511", "title": "Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.", "abstract": "The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.", "corpus_id": 22430511, "score": 0 }, { "doc_id": "24978699", "title": "Standardization of Good Manufacturing Practice-compliant production of bone marrow-derived human mesenchymal stromal cells for immunotherapeutic applications.", "abstract": "BACKGROUND AIMS\nHuman mesenchymal stem or stromal cells (MSCs) represent a potential resource not only for regenerative medicine but also for immunomodulatory cell therapies. The application of different MSC culture protocols has significantly hampered the comparability of experimental and clinical data from different laboratories and has posed a major obstacle for multicenter clinical trials. Manufacturing of cell products for clinical application in the European Community must be conducted in compliance with Good Manufacturing Practice and requires a manufacturing license. In Germany, the Paul-Ehrlich-Institut as the Federal Authority for Vaccines and Biomedicines is critically involved in the approval process.\n\n\nMETHODS\nThis report summarizes a consensus meeting between researchers, clinicians and regulatory experts on standard quality requirements for MSC production.\n\n\nRESULTS\nThe strategy for quality control testing depends on the product's cell composition, the manufacturing process and the indication and target patient population. Important quality criteria in this sense are, among others, the immunophenotype of the cells, composition of the culture medium and the risk for malignant transformation, as well as aging and the immunosuppressive potential of the manufactured MSCs.\n\n\nCONCLUSIONS\nThis position paper intends to provide relevant information to interested parties regarding these criteria to foster the development of scientifically valid and harmonized quality standards and to support approval of MSC-based investigational medicinal products.", "corpus_id": 24978699, "score": 0 }, { "doc_id": "12755494", "title": "Process control in cell culture technology using dielectric spectroscopy.", "abstract": "In the biopharmaceutical industry, mammalian and insect cells as well as plant cell cultures are gaining worldwide importance to produce biopharmaceuticals and as products themselves, for example in stem cell therapy. These highly sophisticated cell-based production processes need to be monitored and controlled to guarantee product quality and to satisfy GMP requirements. With the process analytical technology (PAT) initiative, requirements regarding process monitoring and control have changed and real-time in-line monitoring tools are now recommended. Dielectric spectroscopy (DS) can serve as a tool to satisfy some PAT requirements. DS has been used in the medical field for quite some time and it may allow real-time process monitoring of biological cell culture parameters. DS has the potential to enable process optimization, automation, cost reduction, and a more consistent product quality. Dielectric spectroscopy is reviewed here as a tool to monitor biochemical processes. Commercially available dielectric sensing systems are discussed. The potential of this technology is demonstrated through examples of current and potential future applications in research and industry for mammalian and insect cell culture.", "corpus_id": 12755494, "score": 0 }, { "doc_id": "45909413", "title": "Mass Production of Mesenchymal Stem Cells — Impact of Bioreactor Design and Flow Conditions on Proliferation and Differentiation", "abstract": "Stem cells have enormous potential in health and medical research due to their ability to differentiate into specialized cells and to self-renew. Applications can be seen in cell-based therapies, e.g. for the treatment of Parkinson's disease, type I diabetes, arthritis, burn victims, and cardiovascular diseases, as well as in tissue engineering of artificial organs, development and testing of drugs, and in vitro toxicity tests [1-9].", "corpus_id": 45909413, "score": 1 }, { "doc_id": "5084658", "title": "Media formulation options and manufacturing process controls to safeguard against introduction of animal origin contaminants in animal cell culture", "abstract": "Technical limitations and evolution of therapeuticapplications for cell culture-derived products haveaccelerated elimination of animal-derived constituentsto minimize inadvertent introduction of adventitiousviral or prion agents. Practical considerationsdemand adequate emphasis both on design of theserum-free/protein-free culture environment and onnutrient media manufacturing process controls. Protein components may be acceptable, given adequateattention to synthetic process, sourcing (e.g.,geographic location and endemicity, species andtissue/organ) and validated treatment method. Variousoptions exist for re-engineering of traditionalserum-free formulations (containing insulin,transferrin and other protein factors) withnon-protein substitutes. Caution must also beexercised with sourcing of non-protein additives,particularly amino acids and lipids, to avoidintroducing adventitious contaminants. Simpleguidelines facilitate adaptation, cryopreservation andrecovery of many cell types within a protein-freeculture environment. Scrupulous maintenance offacility and equipment and monitoring of processwater, air handling systems and technical personnelare required to ensure that approved raw materials arecorrectly formulated and dispensed. Validatedsanitization processes provide additional assuranceagainst cross-contamination from previous batches ina multi-use facility.", "corpus_id": 5084658, "score": 0 }, { "doc_id": "17325792", "title": "Ex Vivo Expansion of Human Mesenchymal Stem Cells in Defined Serum-Free Media", "abstract": "Human mesenchymal stem cells (hMSCs) are presently being evaluated for their therapeutic potential in clinical studies to treat various diseases, disorders, and injuries. To date, early-phase studies have indicated that the use of both autologous and allogeneic hMSCs appear to be safe; however, efficacy has not been demonstrated in recent late-stage clinical trials. Optimized cell bioprocessing protocols may enhance the efficacy as well as safety of hMSC therapeutics. Classical media used for generating hMSCs are typically supplemented with ill-defined supplements such as fetal bovine serum (FBS) or human-sourced alternatives. Ideally, culture media are desired to have well-defined serum-free formulations that support the efficient production of hMSCs while maintaining their therapeutic and differentiation capacity. Towards this objective, we review here current cell culture media for hMSCs and discuss medium development strategies.", "corpus_id": 17325792, "score": 0 }, { "doc_id": "24895745", "title": "Development of a serum‐free system to expand dental‐derived stem cells: PDLSCs and SHEDs", "abstract": "Recently, extracted teeth have been identified as a viable source of stem cells for tissue regenerative approaches. Current expansion of these cells requires incorporation of animal sera; yet, a fundamental issue underlying cell cultivation methods for cell therapy regards concerns in using animal sera. In this study, we investigated the development of a chemically defined, serum‐free media (K‐M) for the expansion of human periodontal ligament stem cells (PDLSCs) and human stem cells from exfoliated deciduous teeth (SHEDs). Proliferation assays were performed comparing cells in serum‐containing media (FBS‐M) with cells cultured in four different serum‐free medium and these demonstrated that in these medium, the cell proliferation of both cell types was significantly less than the proliferation of cells in FBS‐M. Additional proliferation assays were performed using pre‐coated fibronectin (FN) tissue culture plates and of the four serum‐free medium, only K‐M enabled PDLSCs and SHEDs to proliferate at higher rates than cells cultured in FBS‐M. Next, alkaline phosphatase activity showed that PDLSCs and SHEDs exhibited similar osteogenic potential whether cultured in K‐M or FBS‐M, and, additionally, cells retained their multipotency in K‐M as seen by expression of chondrogenic and adipogenic genes, and positive Von Kossa, Alcian blue, and Oil Red O staining. Finally, differential expression of 84 stem cell associated genes revealed that for most genes, PDLSCs and SHEDs did not differ in their expression regardless of whether cultured in K‐M or FBS‐M. Taken together, the data suggest that K‐M can support the expansion of PDLSCs and SHEDs and maintenance of their multipotency. J. Cell. Physiol. 226: 66–73, 2010. © 2010 Wiley‐Liss, Inc.", "corpus_id": 24895745, "score": 0 }, { "doc_id": "36899378", "title": "A defined medium and substrate for expansion of human mesenchymal stromal cell progenitors that enriches for osteo- and chondrogenic precursors.", "abstract": "Human mesenchymal stromal cells (hMSCs) have generated significant interest due to their potential use in clinical applications. hMSCs are present at low frequency in vivo, but after isolation can be expanded considerably, generating clinically useful numbers of cells. In this study, we demonstrate the use of a defined embryonic stem cell expansion medium, mTeSR (Stem Cell Technologies), for the expansion of bone-marrow-derived hMSCs. The hMSCs grow at comparable rates, demonstrate tri-lineage differentiation potential, and show similar surface marker profiles (CD29(+), CD44(+), CD49a(+), CD73(+), CD90(+), CD105(+), CD146(+), CD166(+), CD34(-), and CD45(-)) in both the fetal bovine serum (FBS)-supplemented medium and mTeSR. However, expression of early differentiation transcription factors runt-related transcription factor 2, sex-determining region Y box 9, and peroxisome proliferator-activated receptor gamma changed significantly. Both runt-related transcription factor 2 and sex-determining region Y box 9 were upregulated, whereas peroxisome proliferator-activated receptor gamma was downregulated in mTeSR compared with FBS. Although osteogenic and chondrogenic differentiation was comparable in cells grown in mTeSR compared to FBS, adipogenic differentiation was significantly decreased in mTeSR-expanded cells, both in terms of gene expression and absolute numbers of adipocytes. The removal of the FBS from the medium and the provision of a defined medium with disclosed composition make mTeSR a superior study platform for hMSC biology in a controlled environment. Further, this provides a key step toward generating a clinical-grade medium for expansion of hMSCs for clinical applications that rely on osteo- and chondroinduction of MSCs, such as bone repair and cartilage generation.", "corpus_id": 36899378, "score": 0 }, { "doc_id": "44817630", "title": "Growth factor-defined culture medium for human mesenchymal stem cells.", "abstract": "Human bone marrow-derived mesenchymal stem cells (hMSCs) are potential cellular sources of therapeutic stem cells as they have the ability to proliferate and differentiate into a wide array of mesenchymal cell types such as osteoblasts, chondroblasts and adipocytes. hMSCs have been used clinically to treat patients with graft vs. host disease, osteogenesis imperfect, or alveolar cleft, suggesting that transplantation of hMSCs is comparatively safe as a stem cell-based therapy. However, conventional culture medium for hMSCs contains fetal bovine serum (FBS). In the present study, we developed a growth factor-defined, serum-free medium for culturing hMSCs. Under these conditions, TGF-beta1 promoted proliferation of hMSCs. The expanded hMSC population expressed the human pluripotency markers SSEA-3, -4, NANOG, OCT3/4 and SOX2. Furthermore, double positive cells for SSEA-3 and a mesenchymal cell marker, CD105, were detected in the population. The potential to differentiate into osteoblasts and adipocytes was confirmed. This work provides a useful tool to understand the basic biological properties of hMSCs in culture.", "corpus_id": 44817630, "score": 0 }, { "doc_id": "6779727", "title": "Defined serum- and xeno-free cryopreservation of mesenchymal stem cells", "abstract": "Mesenchymal stem cells (MSCs) have vast potential in cell therapy, and are experimentally used in the clinic. Therefore, it is critical to find a serum- and xeno-free cryopreservation method. The aim of this study was to compare two serum- and xeno-free cryoprotectants for MSCs. Adipose tissue MSCs (Ad-MSCs) and bone marrow MSCs (BM-MSCs) were cryopreserved in two cryoprotectants: the defined serum- and xeno-free STEM-CELLBANKER™ (CB) and 10 % dimethyl sulfoxide (DMSO) in a xeno-free serum replacement cell culture medium and compared to non-cryopreserved MSCs. MSCs cryopreserved in CB or DMSO had similar morphology and surface marker expression compared to their respective non-cryopreserved MSC. Ad-MSCs and BM-MSC in both cryoprotectant media exhibited reduced mean fluorescence intensity (MFI) for CD105, BM-MSCs for CD73 and Ad-MSC increased MFI for HLA class I compared to non-cryopreserved MSCs. Population doubling time of CB cryopreserved and non-cryopreserved Ad-MSCs was similar (38.1 ± 13.6 and 36.8 ± 12.1 h), but somewhat higher when cryopreserved in DMSO (42.2 ± 10.8 h). BM-MSCs had higher population doubling time (CB 47.7 ± 11.4 and DMSO 62.3 ± 32.9 h respectively, p < 0.05) compared to Ad-MSCs. The viability of Ad-MSCs was significantly higher after cryopreservation in CB compared to DMSO (90.4 ± 4.5 % vs. 79.9 ± 3.8 % respectively). Ad-MSCs and BM-MSCs retained their mesodermal differentiation potential when cryopreserved in both cryoprotectants. The characteristics of Ad-MSCs post-thawing are better preserved by CB than by DMSO in serum- and xeno-free medium. Furthermore, Ad-MSCs and BM-MSCs are differently affected by the cryoprotectants, which may have implications for cell therapy.", "corpus_id": 6779727, "score": 0 }, { "doc_id": "7719558", "title": "Serum‐free media for the production of human mesenchymal stromal cells: a review", "abstract": "The regenerative potential of mesenchymal stromal cells (MSC) holds great promise in using them for treatment of a wide range of debilitating diseases. Several types of culture media and systems have been used for large‐scale expansion of MSCs in vitro; however, the majority of them rely heavily on using foetal bovine serum (FBS)‐supplement for optimal cell proliferation. FBS‐based cultures pose the potential threat of spread of transmissible spongiform encephalopathy and bovine spongiform encephalopathy to MSCs and then to their recipients. A recent trend in cell culture is to change from serum‐use to serum‐free media (SFM). In this context, the current review focuses specifically on employment of various SFM for MSCs and discusses existences of various options with which to substitute FBS. In addition, we analyse MSC population growth kinetic patterns using various SFM for large‐scale production of MSCs.", "corpus_id": 7719558, "score": 0 }, { "doc_id": "382831", "title": "Serum-free cell culture: the serum-free media interactive online database.", "abstract": "Fetal bovine serum (FBS) is a ubiquitously used essential supplement in cell culture media. However, there are serious scientific and ethical concerns about the use of FBS regarding its harvest and production. During the last three decades, FBS could be substituted by other supplements or by the use of defined chemical components in serum-free cell culture. A number of serum-free medium formulations have been described for mammalian and insect cell lines as well as for primary cultures. However, the switch to serum-free media still demands a time-consuming literature survey and a manufacturer search for appropriate medium formulations, respectively. Here we present the second collection of commercially available serum-free media in an updated, freely accessible interactive online database. Searches for serum-free media and continuous cell lines already adapted to serum-free culture can be performed according to various criteria. These include the degree of chemical definition, e.g. serum-free (SF), animal-derived component free (ADCF) or chemically defined (CD), and the type of medium, e.g. basal media, medium supplements, or full replacement media. In order to specify the cell lines that are adapted to serum-free media, search terms like species, organ, tissue, cell type and disease can be used. All commercially available serum-free media and adapted cell lines currently available from major distributors (e.g. ATCC, ECACC and DMSZ) are included in the database. Despite an extensive search for serum-free media and adapted cell lines, detailed information from certain companies and suppliers is still lacking and is specifically highlighted. It is intended to create a platform for the interactive exchange of information and experience by experts in the field in order to continuously improve and extend the serum-free online database. The database is accessible at http://www.goodcellculture.com/", "corpus_id": 382831, "score": 0 }, { "doc_id": "53346907", "title": "Mesenchymal Stem Cells and Their Cell Surface Receptors", "abstract": "Daily increasing evidence indicates that stem cells can be found in nearly every tissue. Mesenchymal stem cells (MSCs) are adult stem cells, which reside in the bone marrow and other mesenchymal tissues. MSCs can be expanded to large numbers and can be driven into diverse mesenchymal cell lineages, including chondrocytes. Therefore, MSCs have attracted the attention of the biomedical community as very promising tools for repair of joint tissues, such as articular cartilage. This review will outline the MSC surface receptors and will focus on receptors that deliver important signals for chondrogenic differentiation of MSCs. Finally, the role of receptors in the progression of cartilage degeneration disorders, such as osteoarthritis (OA), will be discussed.", "corpus_id": 53346907, "score": 0 }, { "doc_id": "17896498", "title": "Control of stem cell fate by physical interactions with the extracellular matrix.", "abstract": "A diverse array of environmental factors contributes to the overall control of stem cell activity. In particular, new data continue to mount on the influence of the extracellular matrix (ECM) on stem cell fate through physical interactions with cells, such as the control of cell geometry, ECM geometry/topography at the nanoscale, ECM mechanical properties, and the transmission of mechanical or other biophysical factors to the cell. Here, we review some of the physical processes by which cues from the ECM can influence stem cell fate, with particular relevance to the use of stem cells in tissue engineering and regenerative medicine.", "corpus_id": 17896498, "score": 0 }, { "doc_id": "526188", "title": "Advances in cell culture: anchorage dependence", "abstract": "Anchorage-dependent cells are of great interest for various biotechnological applications. (i) They represent a formidable production means of viruses for vaccination purposes at very large scales (in 1000–6000 l reactors) using microcarriers, and in the last decade many more novel viral vaccines have been developed using this production technology. (ii) With the advent of stem cells and their use/potential use in clinics for cell therapy and regenerative medicine purposes, the development of novel culture devices and technologies for adherent cells has accelerated greatly with a view to the large-scale expansion of these cells. Presently, the really scalable systems—microcarrier/microcarrier-clump cultures using stirred-tank reactors—for the expansion of stem cells are still in their infancy. Only laboratory scale reactors of maximally 2.5 l working volume have been evaluated because thorough knowledge and basic understanding of critical issues with respect to cell expansion while retaining pluripotency and differentiation potential, and the impact of the culture environment on stem cell fate, etc., are still lacking and require further studies. This article gives an overview on critical issues common to all cell culture systems for adherent cells as well as specifics for different types of stem cells in view of small- and large-scale cell expansion and production processes.", "corpus_id": 526188, "score": 0 }, { "doc_id": "6723063", "title": "Attachment, Growth, and Detachment of Human Mesenchymal Stem Cells in a Chemically Defined Medium", "abstract": "The manufacture of human mesenchymal stem cells (hMSCs) for clinical applications requires an appropriate growth surface and an optimized, preferably chemically defined medium (CDM) for expansion. We investigated a new protein/peptide-free CDM that supports the adhesion, growth, and detachment of an immortalized hMSC line (hMSC-TERT) as well as primary cells derived from bone marrow (bm-hMSCs) and adipose tissue (ad-hMSCs). We observed the rapid attachment and spreading of hMSC-TERT cells and ad-hMSCs in CDM concomitant with the expression of integrin and actin fibers. Cell spreading was promoted by coating the growth surface with collagen type IV and fibronectin. The growth of hMSC-TERT cells was similar in CDM and serum-containing medium whereas the lag phase of bm-hMSCs was prolonged in CDM. FGF-2 or surface coating with collagen type IV promoted the growth of bm-hMSCs, but laminin had no effect. All three cell types retained their trilineage differentiation capability in CDM and were detached by several enzymes (but not collagenase in the case of hMSC-TERT cells). The medium and coating did not affect detachment efficiency but influenced cell survival after detachment. CDM combined with cell-specific surface coatings and/or FGF-2 supplements is therefore as effective as serum-containing medium for the manufacture of different hMSC types.", "corpus_id": 6723063, "score": 1 }, { "doc_id": "544263", "title": "Expansion and Harvesting of hMSC-TERT", "abstract": "The expansion of human mesenchymal stem cells as suspension culture by means of spinner flasks and microcarriers, compared to the cultivation in tissue culture flasks, offers the advantage of reducing the requirements of large incubator capacities as well as reducing the handling effort during cultivation and harvesting. Nonporous microcarriers are preferable when the cells need to be kept in viable condition for further applications like tissue engineering or cell therapy. In this study, the qualification of Biosilon, Cytodex 1, Cytodex 3, RapidCell and P102-L for expansion of hMSC-TERT with an associated harvesting process using either trypsin, accutase, collagenase or a trypsin-accutase mixture was investigated. A subsequent adipogenic differentiation of harvested hMSC-TERT was performed in order to observe possible negative effects on their (adipogenic) differentiation potential as a result of the cultivation and harvesting method. The cultivated cells showed an average growth rate of 0.52 d-1. The cells cultivated on Biosilon, RapidCell and P102-L were harvested succesfully achieving high cell yield and vitalities near 100%. This was not the case for cells on Cytodex 1 and Cytodex 3. The trypsin-accutase mix was most effective. After spinner expansion and harvesting the cells were successfully differentiated to adipocytes.", "corpus_id": 544263, "score": 0 }, { "doc_id": "10535114", "title": "Good manufacturing practices production of mesenchymal stem/stromal cells.", "abstract": "Because of their multi/pluripotency and immunosuppressive properties mesenchymal stem/stromal cells (MSCs) are important tools for treating immune disorders and for tissue repair. The increasing use of MSCs has led to production processes that need to be in accordance with Good Manufacturing Practice (GMP). In cellular therapy, safety remains one of the main concerns and refers to donor validation, choice of starting material, processes, and the controls used, not only at the batch release level but also during the development of processes. The culture processes should be reproducible, robust, and efficient. Moreover, they should be adapted to closed systems that are easy to use. Implementing controls during the manufacturing of clinical-grade MSCs is essential. The controls should ensure microbiological safety but also avoid potential side effects linked to genomic instability driving transformation and senescence or decrease of cell functions (immunoregulation, differentiation potential). In this rapidly evolving field, a new approach to controls is needed.", "corpus_id": 10535114, "score": 0 }, { "doc_id": "31388542", "title": "Closed system isolation and scalable expansion of human placental mesenchymal stem cells", "abstract": "Mesenchymal stem cells (MSC) are emerging as a leading cellular therapy for a number of diseases. However, for such treatments to become available as a routine therapeutic option, efficient and cost‐effective means for industrial manufacture of MSC are required. At present, clinical grade MSC are manufactured through a process of manual cell culture in specialized cGMP facilities. This process is open, extremely labor intensive, costly, and impractical for anything more than a small number of patients. While it has been shown that MSC can be cultivated in stirred bioreactor systems using microcarriers, providing a route to process scale‐up, the degree of numerical expansion achieved has generally been limited. Furthermore, little attention has been given to the issue of primary cell isolation from complex tissues such as placenta. In this article we describe the initial development of a closed process for bulk isolation of MSC from human placenta, and subsequent cultivation on microcarriers in scalable single‐use bioreactor systems. Based on our initial data, we estimate that a single placenta may be sufficient to produce over 7,000 doses of therapeutic MSC using a large‐scale process. Biotechnol. Bioeng. 2012; 109:1817–1826. © 2012 Wiley Periodicals, Inc.", "corpus_id": 31388542, "score": 0 }, { "doc_id": "82199340", "title": "Bioprocessing of human mesenchymal stem/stromal cells for therapeutic use: Current technologies and challenges", "abstract": "Abstract The long-term outlook for regenerative medicine predicts an increased need for scalable cell expansion technologies that utilize non-animal derived materials and are compatible with the limited number of downstream processing steps required for cell-based therapies. As more stem cell therapeutics progress through clinical testing, current in vitro culture methods using planar vessels are proving cumbersome to scale. Therefore, alternative processes are under investigation. Many human mesenchymal stem/stromal cell (hMSC) bioreactor-based manufacturing processes, in particular, are complicated by the requirement to separate cells from microcarriers with high cell yield and viability whilst maintaining target phenotypic and functional characteristics. Here we review currently available technologies and ongoing development for the expansion of cellular therapeutics, with focus on allogeneic hMSCs and microcarrier-based processes. Upstream challenges include the interplay between the cell culture substrate and media formulation, sourcing of high quality animal-free reagents, and considerations for the use of microcarriers in stirred-tank systems. Complications in downstream processes include harvest approaches for separation of cells from microcarriers and volume reduction.", "corpus_id": 82199340, "score": 1 }, { "doc_id": "20179287", "title": "Stirred tank bioreactor culture combined with serum-/xenogeneic-free culture medium enables an efficient expansion of umbilical cord-derived mesenchymal stem/stromal cells.", "abstract": "Mesenchymal stem/stromal cells (MSC) are being widely explored as promising candidates for cell-based therapies. Among the different human MSC origins exploited, umbilical cord represents an attractive and readily available source of MSC that involves a non-invasive collection procedure. In order to achieve relevant cell numbers of human MSC for clinical applications, it is crucial to develop scalable culture systems that allow bioprocess control and monitoring, combined with the use of serum/xenogeneic (xeno)-free culture media. In the present study, we firstly established a spinner flask culture system combining gelatin-based Cultispher(®) S microcarriers and xeno-free culture medium for the expansion of umbilical cord matrix (UCM)-derived MSC. This system enabled the production of 2.4 (±1.1) x10(5) cells/mL (n = 4) after 5 days of culture, corresponding to a 5.3 (±1.6)-fold increase in cell number. The established protocol was then implemented in a stirred-tank bioreactor (800 mL working volume) (n = 3) yielding 115 million cells after 4 days. Upon expansion under stirred conditions, cells retained their differentiation ability and immunomodulatory potential. The development of a scalable microcarrier-based stirred culture system, using xeno-free culture medium that suits the intrinsic features of UCM-derived MSC represents an important step towards a GMP compliant large-scale production platform for these promising cell therapy candidates.", "corpus_id": 20179287, "score": 0 }, { "doc_id": "44239368", "title": "Production of oncolytic adenovirus and human mesenchymal stem cells in a single‐use, Vertical‐Wheel bioreactor system: Impact of bioreactor design on performance of microcarrier‐based cell culture processes", "abstract": "Anchorage‐dependent cell cultures are used for the production of viruses, viral vectors, and vaccines, as well as for various cell therapies and tissue engineering applications. Most of these applications currently rely on planar technologies for the generation of biological products. However, as new cell therapy product candidates move from clinical trials towards potential commercialization, planar platforms have proven to be inadequate to meet large‐scale manufacturing demand. Therefore, a new scalable platform for culturing anchorage‐dependent cells at high cell volumetric concentrations is urgently needed. One promising solution is to grow cells on microcarriers suspended in single‐use bioreactors. Toward this goal, a novel bioreactor system utilizing an innovative Vertical‐Wheel™ technology was evaluated for its potential to support scalable cell culture process development. Two anchorage‐dependent human cell types were used: human lung carcinoma cells (A549 cell line) and human bone marrow‐derived mesenchymal stem cells (hMSC). Key hydrodynamic parameters such as power input, mixing time, Kolmogorov length scale, and shear stress were estimated. The performance of Vertical‐Wheel bioreactors (PBS‐VW) was then evaluated for A549 cell growth and oncolytic adenovirus type 5 production as well as for hMSC expansion. Regarding the first cell model, higher cell growth and number of infectious viruses per cell were achieved when compared with stirred tank (ST) bioreactors. For the hMSC model, although higher percentages of proliferative cells could be reached in the PBS‐VW compared with ST bioreactors, no significant differences in the cell volumetric concentration and expansion factor were observed. Noteworthy, the hMSC population generated in the PBS‐VW showed a significantly lower percentage of apoptotic cells as well as reduced levels of HLA‐DR positive cells. Overall, these results showed that process transfer from ST bioreactor to PBS‐VW, and scale‐up was successfully carried out for two different microcarrier‐based cell cultures. Ultimately, the data herein generated demonstrate the potential of Vertical‐Wheel bioreactors as a new scalable biomanufacturing platform for microcarrier‐based cell cultures of complex biopharmaceuticals. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:1600–1612, 2015", "corpus_id": 44239368, "score": 0 }, { "doc_id": "6595895", "title": "Expansion of Human Mesenchymal Stem Cells in a Fixed-Bed Bioreactor System Based on Non-Porous Glass Carrier – Part B: Modeling and Scale-up of the System", "abstract": "Human mesenchymal stem cells (hMSC) are a promising cell source for the manufacturing of cell therapy or tissue-engineered implants. In part A of this publication a fixed-bed bioreactor system based on non-porous borosilicate glass spheres and procedures for the automated expansion of hMSC with high yield and vitality was introduced. Part B of this study deals with the modeling of the process in order to transfer the bioreactor system from the laboratory to the production scale. Relevant model parameters were obtained by fitting them to the experimental data of hMSC-TERT cultivations in scales up to 300 cm3. Scale-up calculations were carried out exemplarily for a target cell number of twenty billion cells.", "corpus_id": 6595895, "score": 0 }, { "doc_id": "82954076", "title": "Expansion of human mesenchymal stem cells in fibrous bed bioreactor", "abstract": "Abstract Expansion of human mesenchymal stem cells (hMSCs) in bioreactor while preserving their innate properties is important in translation of hMSC-based therapy to clinical applications. The present study investigates the feasibility of hMSC expansion in a 2.5 L CelliGen ® 310 Bioreactor packed with Fibra-Cel ® disks. After 9 days of expansion, a 9.2-fold increase in cell number with the population doubling (PD) time of 2.8 days (67.2 h) was achieved and that the specific glucose consumption and lactate production were measured to be 12.48 pmol/cell/day and 20.95 pmol/cell/day, respectively. hMSCs harvested from the bioreactor maintained their properties based on the analysis of phenotypic surface markers, colony forming unit-fibroblasts (CFU-F) number, and multilineage differentiation ability. The results demonstrate the feasibility and the potential of the fibrous bed bioreactor for large scale hMSC expansion.", "corpus_id": 82954076, "score": 0 }, { "doc_id": "55200159", "title": "hMSC Production in Disposable Bioreactors with Regards to GMP and PAT", "abstract": "Reactor concepts for human mesenchymal stem cell (hMSC) production are introduced. Thereby, special interest is laid on the realization of these concepts as disposables fulfilling the GMP and PAT requirements. The specialty of the hMSC production process is the cell itself being the product. This results in completely different process requirements compared to e.g. protein production in mammalian cells. Thus, great attention has to be given to the shear sensitivity of the cells. The cultivation and the harvest of the cells have to be very gentle to neither influence cell viability nor cell differentiability. Further, the production process should not cause any undesirable cell changes. For hMSC production, cell harvest is the main challenging process step. The reactor concepts should be suitable for hMSC production for clinical trials as ATMPs. Therefore, disposable systems are especially applicable. The review describes more detailed bone marrow-derived hMSC production in a disposable stirred tank reactor as promising reactor concept.", "corpus_id": 55200159, "score": 1 }, { "doc_id": "10310874", "title": "Optimising Human Mesenchymal Stem Cell Numbers for Clinical Application: A Literature Review", "abstract": "Adult mesenchymal stem cells (MSCs) are being investigated further for their use in stem cell therapies. However, as they are found in very low numbers in adult tissue, expansion in vitro is required to produce desired MSC numbers for clinical application. The need for effective cell-based therapies is increasing due to a rise in the ageing population, increasing the prevalence of musculoskeletal disorders. This review investigates how factors, age and gender of donor, as well as seeding density can affect MSC expansion. Age and gender of donor have received mixed results from studies, whereas seeding density studies have produced consistent results for numerous MSC sources, favouring lower seeding densities. Further research is required to reduce the risk of infection, loss of cell characterisation in cell culture, and making cell-based therapies more cost effective through creating rapid expansion of MSCs regardless of patient factors.", "corpus_id": 10310874, "score": 0 }, { "doc_id": "19661099", "title": "Expansion of human mesenchymal stem cells on microcarriers", "abstract": "The effects on human mesenchymal stem cell growth of choosing either of two spinner flask impeller geometries, two microcarrier concentrations and two cell concentrations (seeding densities) were investigated. Cytodex 3 microcarriers were not damaged when held at the minimum speed, NJS, for their suspension, using either impeller, nor was there any observable damage to the cells. The maximum cell density was achieved after 8–10 days of culture with up to a 20-fold expansion in terms of cells per microcarrier. An increase in microcarrier concentration or seeding density generally had a deleterious or neutral effect, as previously observed for human fibroblast cultures. The choice of impeller was significant, as was incorporation of a 1 day delay before agitation to allow initial attachment of cells. The best conditions for cell expansion on the microcarriers in the flasks were 3,000 microcarriers ml−1 (ca. 1 g dry weight l−1), a seeding density of 5 cells per microcarrier with a 1 day delay before agitation began at NJS (30 rpm), using a horizontally suspended flea impeller with an added vertical paddle. These findings were interpreted using Kolmogorov’s theory of isotropic turbulence.", "corpus_id": 19661099, "score": 0 }, { "doc_id": "24121312", "title": "A Microcarrier‐Based Cultivation System for Expansion of Primary Mesenchymal Stem Cells", "abstract": "Microcarrier cultures have been shown to allow extensive cell expansion of tissue engineering relevant cells, such as chondrocytes, while maintaining their phenotype. Our aim was to investigate the in vitro three‐dimensional expansion of porcine bone‐marrow‐derived primary mesenchymal stem cells (MSC) using commercially available Cytodex type 1, type 2, and type 3 microcarriers. In comparison, the Cytodex type 1 microcarriers showed the best results for adherence with over 80% adherent cells after 3 h of incubation, analyzed by the Poisson distribution. Different start cell densities ranging from 1 to 3 × 106 cells per 100 cm2 had only a minor influence on adhesion. The proliferation was examined on Cytodex type 1 microcarriers over a cultivation time of 28 days, which could reveal cell growth and proof of cells recolonizing freshly added microcarriers. Scanning electron microscopy displayed appropriate cell morphology and confirmed cell proliferation. After enzymatic harvest from microcarriers, the osteogenic and chondrogenic differentiation of these cells was induced and shown by relevant histochemistry, such as von Kossa and Alcian blue staining. Totaling the results, we have shown that the three‐dimensional expansion of MSC on microcarriers represents a beneficial alternative to the conventional two‐dimensional monolayer cultivation method.", "corpus_id": 24121312, "score": 0 }, { "doc_id": "206528662", "title": "Expansion of human mesenchymal stromal cells on microcarriers: growth and metabolism", "abstract": "Adult stem cells, or mesenchymal stromal cells (MSCs), are of great potential for cell therapy and tissue‐engineering applications. However, for therapeutic use, these cells need to be isolated from tissue or a biopsy and efficiently expanded, as they cannot be harvested in sufficient quantities from the body. In our opinion, efficient expansion of MSCs can be achieved in a microcarrier‐based cultivation system. This study selected a suitable microcarrier for human bone marrow‐derived stromal cells (HBMSCs), optimized cell‐seeding strategies by varying serum concentrations, and optimized dynamic expansion of the HBMSCs in a microcarrier‐based spinner flask cultivation system by applying various feeding regimes. Cytodex 1 microcarriers in combination with a low‐serum concentration (0–5%) in the medium resulted in the highest seeding efficiency for the HBMSCs. Subsequently, significant expansion of the HBMSCs on these carriers has been observed. The highest number of HBMSCs population doublings (4.8 doublings) was obtained by a combination of 50% medium refreshment combined with addition of 30% medium containing microcarriers every 3 days. Exponential cell growth was observed for at least 9 days after seeding, provided that sufficient nutrients (such as glucose) were present, metabolite concentrations (such as ammonia) were kept below growth‐inhibitory concentrations and adequate surface area was present for the cells. After dynamic expansion of the HBMSCs, the cells retained their differentiation potential and their cell surface markers, indicating that HBMSCs expansion on Cytodex 1 microcarriers did not alter the phenotypic properties of the cells. Copyright © 2009 John Wiley & Sons, Ltd.", "corpus_id": 206528662, "score": 0 }, { "doc_id": "8156203", "title": "Microcarrier-based Expansion Process for hMSCs with High Vitality and Undifferentiated Characteristics", "abstract": "For cell therapy, a high biomass of human mesenchymal stem cells (hMSCs) is required for clinical applications, such as in the form of encapsulated implants. An easy and reproducible microcarrier-based stirred tank reactor cultivation process for hMSCs in 1.68 L scale is described. To avoid medium changes, studies comparing high-glucose DMEM (DMEM-HG) with low-glucose EMEM were performed showing that high-glucose medium has positive effects on cell proliferation and that cell differentiability remains. Studies on the inoculation strategy and cell density, carrier concentration, volume, and stirrer speed were performed and resulted in a set of optimized parameters, inoculation strategy was found to be 45 minutes of static state and 2 minutes of stirring repeated in 4 cycles. The inoculation density was chosen to be 7×103 cells/cm2, and the carrier concentration of glass surface carrier was 25 g/L. For the described reactor system, a stirrer speed of 120 rpm for the inoculation process and a daily increase of 10 rpm up to 160 rpm were found to be suitable. Process reproducibility was shown by 3 repeated cultivations at the determined set of parameters allowing high biomass values of up to 7×108 cells per batch. With DMEM-HG, no limitation of glucose was found, and lactate and ammonia remained lower than critical inhibitory concentrations. Comparison of the static (T-flask) and dynamic cultures in the stirred tank reactor showed for both cases, that cells were of high vitality and both maintained differentiability. In both cases, encapsulation of the cells resulted in high bead vitality, a basic requirement for cell therapy application.", "corpus_id": 8156203, "score": 1 }, { "doc_id": "82832220", "title": "Biomanufacturing of human mesenchymal stem cells in cell therapy: Influence of microenvironment on scalable expansion in bioreactors", "abstract": "Abstract Human mesenchymal stem cells (hMSCs) are the primary candidate in cell therapy and have demonstrated significant potential in a wide range of diseases. The clinical translation of hMSC therapy requires robust and scalable expansion technology for the biomanufacturing of therapeutically competent cells. By nature, hMSCs are highly sensitive and responsive to the microenvironments and their therapeutic potency is significantly influenced by the culture conditions during expansion. Here, we discuss the emerging roles of microenvironments in regulating hMSC fate and the implication of regulating hMSC microenvironment to achieve scalable hMSC expansion in bioreactors.", "corpus_id": 82832220, "score": 0 }, { "doc_id": "22541747", "title": "OPTIMIZING CULTURE CONDITIONS FOR THE PRODUCTION OF ANIMAL CELLS IN MICROCARRIER CULTURE", "abstract": "Cytodex 1 microcarriers have been used for the successful culture of more than 80 different types of animal cells--including primary cells, normal diploid cell strains and established or transformed cell lines. culture volumes have ranged from a few milliliters for diagnostic studies to over several hundred liters for vaccine production. Experience with this wide variety of cell types and culture volumes has enabled the identification of several parameters critical for obtaining maximum cell yields from microcarrier cultures. The most vital stage for the successful microcarrier culture of many cell types was the initial stage of the culture cycle. To achieve high cell yields, it was necessary to use culture procedures which maximized plating efficiency and final cell yield could be further increased by ensuring that the inoculation cell density exceeded a critical viable cell/microcarrier ratio. Modifications of the standard microcarrier culture procedures included reducing initial culture volume, reducing the initial stirring speed and/or supplementing the medium during the early stages of the culture cycle. Control of pH, nutrient supply, and gas tension were all critical throughout the culture cycle. Results with low-serum and serum-free media indicate that the requirement for fetal calf serum in the microcarrier culture of Vero and MRC-5 cells can be reduced or even eliminated. Large scale microcarrier culture equipment should take into account the modified culture procedures which are often required to achieve the full potential of this culture method. The design of a new flexible culture system suitable for pilot and production scale cultures is presented. This system accomodates a wide variety of culture and production procedures and through a recirculation system permits: (a) \"in-line\" monitoring and control of culture parameters; (b) provides an efficient gas exchange capacity which obviates the need for fermenter headspace and sparging; and (c) allows for maximal utilization of medium components and rapid harvesting of medium or cell products.", "corpus_id": 22541747, "score": 0 }, { "doc_id": "97524469", "title": "Scale‐up of adipose tissue‐derived mesenchymal stem cell production in stirred single‐use bioreactors under low‐serum conditions", "abstract": "Suspension cultures, in which human mesenchymal stem cells are cultivated on microcarriers in scalable single‐use stirred bioreactor types, have been shown to be a promising alternative to planar flask cultures. However, stirred single‐use bioreactors were originally developed for production processes with robust, permanent cell lines. Human mesenchymal stem cells are adherent primary cells and thus expanding them in such bioreactor systems imposes more stringent requirements on bioreactor systems. For low‐serum conditions (5%) and different types of stirred single‐use bioreactors, a suspension criteria‐based approach for expanding human adipose tissue‐derived mesenchymal stem cells (hASCs) from milliliter to pilot scale was successfully developed. For process scale‐up, experimental and numerical investigations were performed to (i) predict optimum impeller speeds, (ii) determine the main engineering parameters (local shear stress, turbulent dissipation rate, Kolmogorov microscale), and (iii) verify suspension criteria NS1 and NS1u for rapid process transfer from 100 mL to 2 L and 35 L cultures. Using optimized medium‐microcarrier combinations as well as NS1 and NS1u as scale‐up factors, total hASC quantities between 3 × 107 (100 mL scale) and 1 × 1010 (35 L scale) were obtained. The cell quantities obtained are the highest reported to date for scalable single‐use bioreactors under low‐serum conditions.", "corpus_id": 97524469, "score": 0 }, { "doc_id": "98908492", "title": "Multiphase mixing characteristics in a microcarrier-based stirred tank bioreactor suitable for human mesenchymal stem cell expansion", "abstract": "Abstract Large-scale human mesenchymal stem cell expansion calls for a bioreaction system, that provides a sufficient growth surface. An alternative to static cultivations systems like cell factories are disposable stirred tank reactors. Here, microcarriers provide the required growth surface, but these make it difficult to achieve a complete homogenization in the bioreactor, while avoiding shear stress. To gain insight into this process, we investigated the impact of different power inputs (0.02–2.6 W m −3 ) on the mixing time (t m ). Whereas t m was inversely proportional to agitation in a one-phase-system, aeration resulted in a constant mixing time at 30–70 rpm. A high microcarrier concentration (30 g L −1 ) and low stirrer speed (30 rpm) in the liquid-solid system caused a 50-fold increase in t m and the formation of a discrete non-mixed upper zone. The effect of the microcarrier concentration on t m became negligible at higher stirrer speeds. In the three-phase system, microcarrier settling was prevented by aeration and a minimal specific power input of 0.6 W m −3 was sufficient for complete homogenization. We confirmed that a low power input during stem cell expansion leads to inhomogeneity, which has not been investigated in the three-phase system up to date.", "corpus_id": 98908492, "score": 0 }, { "doc_id": "38533545", "title": "Maximizing the ex vivo expansion of human mesenchymal stem cells using a microcarrier-based stirred culture system.", "abstract": "Bioreactor systems have been developed as alternatives to standard culture flasks due to their homogeneous nature, easiness of monitoring and increased cell production. Here we investigated the in vitro expansion of bone marrow (BM) mesenchymal stem cells (MSC) in spinner flasks, using gelatin microcarriers (Cultispher S) to support cell adhesion and proliferation. MSC expansion was performed using a low-serum containing medium (2% of fetal bovine serum, FBS). A strategy was defined for the maximization of cell expansion: microcarriers were pre-coated with FBS in order to increase cell seeding efficiency and an adequate feeding regime was established (25% medium exchange everyday). The maximum cell density, 4.2 x 10(5)cells/mL, was obtained at day 8, corresponding to a fold increase in total cell number of 8.4+/-0.8. Expanded MSC retained their differentiation potential into adipogenic and osteogenic lineages, as well as their clonogenic ability. Harvested cells expressed >90% of CD73, CD90 and CD105 markers. These results demonstrated that a microcarrier-based stirred culture system is adequate for human MSC expansion, using a low-serum containing medium, allowing the generation of significant cell numbers for potential applications in regenerative medicine.", "corpus_id": 38533545, "score": 0 }, { "doc_id": "3343824", "title": "The catalytic triad of serine peptidases", "abstract": "Abstract.The catalytic action of serine peptidases depends on the interplay of a nucleophile, a general base and an acid. In the classic trypsin and subtilisin families this catalytic triad is composed of serine, histidine and aspartic acid residues and exhibits similar spatial arrangements, but the order of the residues in the amino acid sequence is different. By now several new families have been discovered, in which the nucleophile-base-acid pattern is generally conserved, but the individual components can vary. The variations illustrate how different groups and different protein structures achieve the same reaction.", "corpus_id": 3343824, "score": 0 }, { "doc_id": "55113598", "title": "CELL DETACHMENT BY PROLYL-SPECIFIC ENDOPEPTIDASE FROM WOLFIPORIA COCOS", "abstract": "As requirements for Advanced Therapy Medicinal Product (ATMP) production differ from other production processes (e.g., therapeutic protein production), cell detachment is often a crucial step for the process success. In most cases, cell detachment is done enzymatically. Although many peptidases are established in cell culture in R&D, e.g., Trypsin as gold standard, many of them seem to be unsuitable in ATMP production processes. Therefore, the present study investigated a novel endopeptidase used in food biotechnology for its applicability in ATMP processes where cell detachment is needed. The Prolyl-specific Peptidase (PsP) is of non-mammalian origin and considered as safe for humans. PsP was purified from the supernatant of the fungus Wolfiporia cocos. The isolation and purification resulted in an enzyme solution with 0.19 U mg-1 prolyl-specific activity. By in silico analysis it was confirmed that attachment-promoting proteins can be cleaved by PsP in a similar amount than with Trypsin. Further the proteolytic activity was determined for PsP and Trypsin by using the same enzymatic assay. Detachment with both enzymes was compared for cells used in typical therapeutic production processes namely a mesenchymal stem cell line (hMSC-TERT) as a model for a cell therapeutic, Vero and MA104 cells used for viral therapeutic or vaccine production. The cell detachment experiments were performed with comparable enzyme activities (1.6 U mL-1). hMSC-TERT detachment was faster with PsP than with Trypsin. For Vero cells the detachment with PsP was not only faster but also more efficient. For MA104 cells the detachment rate with PsP was similar to Trypsin. For all cell types, detachment with PsP showed less influence on cell growth and metabolism compared to standard Trypsin.Thus, three cell types used in ATMP, viral therapeutics or vaccine production can be detached efficiently and gently with PsP. Therefore, PsP shows potential for cell detachment in ATMP and viral/vaccine production processes.", "corpus_id": 55113598, "score": 0 }, { "doc_id": "34595561", "title": "Process engineering of human pluripotent stem cells for clinical application.", "abstract": "Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells, constitute an extremely attractive tool for cell therapy. However, flexible platforms for the large-scale production and storage of hPSCs in tightly controlled conditions are necessary to deliver high-quality cells in relevant quantities to satisfy clinical demands. Here we discuss the main principles for the bioprocessing of hPSCs, highlighting the impact of environmental factors, novel 3D culturing approaches and integrated bioreactor strategies for controlling hPSC culture outcome. Knowledge on hPSC bioprocessing accumulated during recent years provides important insights for the establishment of more robust production platforms and should potentiate the implementation of novel hPSC-based therapies.", "corpus_id": 34595561, "score": 0 }, { "doc_id": "42526761", "title": "Allogeneic cell therapy bioprocess economics and optimization: downstream processing decisions.", "abstract": "AIM\nTo develop a decisional tool to identify the most cost effective process flowsheets for allogeneic cell therapies across a range of production scales.\n\n\nMATERIALS & METHODS\nA bioprocess economics and optimization tool was built to assess competing cell expansion and downstream processing (DSP) technologies.\n\n\nRESULTS\nTangential flow filtration was generally more cost-effective for the lower cells/lot achieved in planar technologies and fluidized bed centrifugation became the only feasible option for handling large bioreactor outputs. DSP bottlenecks were observed at large commercial lot sizes requiring multiple large bioreactors. The DSP contribution to the cost of goods/dose ranged between 20-55%, and 50-80% for planar and bioreactor flowsheets, respectively.\n\n\nCONCLUSION\nThis analysis can facilitate early decision-making during process development.", "corpus_id": 42526761, "score": 0 }, { "doc_id": "97204010", "title": "Filtration methodologies for the clarification and concentration of human mesenchymal stem cells", "abstract": "Abstract Currently human mesenchymal stem cells (hMSC) are expanded using microcarrier-based stirred culture systems from one to hundreds of liters of culture volume to guarantee the required cell numbers to be delivered to the clinic. Such culture volumes need to be clarified, ensuring efficient removal of microcarriers, and concentrated without compromising the cells׳ characteristics. The aim of this work was to evaluate the applicability of filtration methodologies, as dead end filtration and tangential flow filtration, for the clarification and concentration of hMSC, respectively. Different process variables and their impact on hMSC quality were evaluated, showing that polypropylene filters with pore sizes higher than 75 μm can ensure the removal of microcarriers from the cell suspension bulk, without compromising cells׳ recovery or viability. Furthermore, hMSC could be successfully concentrated up to a factor of ten while maintaining their identity, potency and high cell viability, allowing for the recovery of over 80% of viable cells; an initial cell concentration higher than 2×10 5 cell/mL, and polysulfone membranes with pore sizes higher than 0.45 μm were identified to be key conditions to obtain such concentration factors; shear rate and permeate flux were also shown to impact the cells׳ recovery yields, viability and quality.", "corpus_id": 97204010, "score": 1 }, { "doc_id": "40945346", "title": "Industrial scale harvest of proteins from mammalian cell culture by tangential flow filtration", "abstract": "An industrial‐scale methods for harvest of biologically active proteins form mammalian cell culture has been developed using tangential flow filtration. A robust and economical process capable of processing approximately 5000 L conditioned media/h with protein yields in excess of 99% has been achieved. A completely contained system has been designed in which total cell number and viability are maintained throughout the process. The process has successfully been implemented at 1.25 × 104 L scale for the recovery of kilogram quantities of pharmaceutical proteins such as recombinant tissue type plasminogen activator (rt‐PA).", "corpus_id": 40945346, "score": 0 }, { "doc_id": "2508019", "title": "Influence of stress on adherent cells.", "abstract": "Stress is a broad term often used with animal cells. Frequently mechanical forces are meant using this term but chemical stress is also important cultivating animal cells. The chemical environment of the cell in a reactor have to be considered very carefully. The complexity of the medium requirements and the metabolic pathway cause very often growth limitations. Studying these limitations in order to find the reasons showed to be difficulty because of the complexity of the system. Nevertheless, glucose, glutamine, lactate and ammonia are found to be critical parameter as well as the osmotic pressure. The influence of mechanical forces on cell viability is of great importance when growing the cells in agitated systems. By far the greatest amount of work reported in the literature has been done on suspension cells but adherent cells also experience shear forces not only in bioreactors also in vivo. Therefore, most research has be done on endothelial cells but studies exists done on non-endothelial cells. The influence of shear forces on cell growth, morphology and productivity will be discussed as well as possibilities of making the cells more resistant.", "corpus_id": 2508019, "score": 0 }, { "doc_id": "10318203", "title": "Response of mesenchymal stem cells to shear stress in tissue-engineered vascular grafts", "abstract": "AbstractAim:Recent studies have demonstrated that mesenchymal stem cells (MSCs) can differentiate into endothelial cells. The effect of shear stress on MSC differentiation is incompletely understood, and most studies have been based on two-dimensional systems. We used a model of tissue-engineered vascular grafts (TEVGs) to investigate the effects of shear stress on MSC differentiation.Methods:MSCs were isolated from canine bone marrow. The TEVG was constructed by seeding MSCs onto poly-ɛ-caprolactone and lactic acid (PCLA) scaffolds and subjecting them to shear stress provided by a pulsatile bioreactor for four days (two days at 1 dyne/cm2 to 15 dyne/cm2 and two days at 15 dyne/cm2).Results:Shear stress significantly increased the expression of endothelial cell markers, such as platelet-endothelial cell adhesion molecule-1 (PECAM-1), VE-cadherin, and CD34, at both the mRNA and protein levels as compared with static control cells. Protein levels of alpha-smooth muscle actin (α-SMA) and calponin were substantially reduced in shear stress-cultured cells. There was no significant change in the expression of α-SMA, smooth muscle myosin heavy chain (SMMHC) or calponin at the mRNA level.Conclusion:Shear stress upregulated the expression of endothelial cell-related markers and downregulated smooth muscle-related markers in canine MSCs. This study may serve as a basis for further investigation of the effects of shear stress on MSC differentiation in TEVGs.", "corpus_id": 10318203, "score": 0 }, { "doc_id": "95121292", "title": "Additional techniques to improve microfiltration", "abstract": "Abstract Concentration polarisation, cake formation and pore fouling lead to a performance loss of microfiltration membranes in terms of reduced permeate flux. Causes of these phenomena are varied and depend largely on components and properties of the feed suspension, the most common causes are summarised in this paper. Techniques to limit this reduction or retard fouling are available and are reviewed, the range of methods covered include feed pre-treatment, choice of membrane material, flow manipulation, the use of high shear, gas sparging and additional force fields.", "corpus_id": 95121292, "score": 0 }, { "doc_id": "22354267", "title": "Mechanisms of cryoinjury in living cells.", "abstract": "Biological metabolism in living cells dramatically diminishes at low temperatures, a fact that permits the long-term preservation of living cells and tissues for either scientific research or many medical and industrial applications (e.g., blood transfusion, bone marrow transplantation, artificial insemination, in vitro fertilization, food storage). However, there is an apparent contradiction between the concept of preservation and experimental findings that living cells can be damaged by the cryopreservation process itself. The challenge to cells during freezing is not their ability to endure storage at very low temperatures (less than -180 degrees C); rather, it is the lethality of an intermediate zone of temperature (-15 to -60 degrees C) that a cell must traverse twice--once during cooling and once during warming. Cryobiological research studies the underlying physical and biological factors affecting survival of cells at low temperatures (during the cooling and warming processes). These factors and mechanisms (or hypotheses) of cryoinjury and its prevention are reviewed and discussed, including the most famous two-factor hypothesis theory of Peter Mazur, concepts of cold shock, vitrification, cryoprotective agens (CPAs), lethal intracellular ice formation, osmotic injury during the addition/removal of CPAs and during the cooling/warming process, as well as modeling/methods in the cryobiological research.", "corpus_id": 22354267, "score": 0 }, { "doc_id": "36918157", "title": "Long-term storage of tissues by cryopreservation: critical issues.", "abstract": "The technique of cryopreservation (maintenance of biological samples in a state of 'suspended animation' at cryogenic temperatures), its potential use in tissue engineering applications and current obstacles to the development of effective cryopreservation methods for tissues are reviewed. A didactic overview of the principles of cryobiology and the methodology of cryopreservation is given, with emphasis on the processes of injury to cells during freezing and thawing, and how these are related to the physicochemical and biophysical changes occurring during cryopreservation. Critical issues relevant to the application of cryopreservation methods to tissues are then addressed, including heat and mass transfer limitations in these bulk systems, intrinsic differences between isolated and cultured cells, and mechanisms of freezing injury unique to tissue systems.", "corpus_id": 36918157, "score": 0 }, { "doc_id": "7127257", "title": "Cryopreservation of rabbit spermatozoa using acetamide in combination with trehalose and methyl cellulose.", "abstract": "Glycerol is not an effective cryoprotectant for rabbit spermatozoa; therefore, rabbit spermatozoa were used as a model for developing cryopreservation procedures for other cell types which also freeze poorly when glycerol is used as the cryoprotectant. Experiments were conducted to 1) compare several published protocols for cryopreserving rabbit spermatozoa; 2) determine if removal of seminal granules, required for flow cytometry analysis, affects the motility of rabbit spermatozoa; and 3) determine if using a combination of cell permeating cryoprotectants (acetamide) with cell nonpermeating cryoprotectants (trehalose and methyl cellulose; MC), can increase the recovery of viable rabbit spermatozoa after cryopreservation. Media containing acetamide as a cryoprotectant were found to be most effective for rabbit spermatozoa. The cryoprotectants ethylene glycol, dimethylsulfoxide and glycerol were not effective for cryopreserving rabbit spermatozoa. Second, rabbit spermatozoa could be centrifuged through a Percoll gradient composed of equal volumes of Prcoll and a HEPES-buffered sperm medium. This centrifugation removed all seminal granules without affecting the percentage of motile spermatozoa after initial sperm dilution (85 vs 74%) or after cryopreservation (35 vs 30%), when sperm were either centrifuged or not centrifuged, respectively. The substitution of trehalose in the cryopreservation medium for raffinose did not improve recovery of motile cells following cryopreservation (P > 0.05). However, addition of MC resulted in higher percentages of motile sperm after cryopreservation (43 vs 31%; P < 0.05). In addition, sperm viability and acrosomal integrity were simultaneously evaluated using flow cytometry. The addition of both trehalose and MC to media containing acetamide resulted in higher percentages of live acrosome-intact cells than acetamide alone (53 vs 37%; P < 0.05). These results indicate that a combination of permeating and nonpermeating cryoprotectants (acetamide, trehalose and MC) were more effective in preserving rabbit spermatozoa than acetamide alone and that analyzing multiple sperm characteristics, by flow cytometry, can assess sperm damage not detected by analyzing sperm motion characteristics.", "corpus_id": 7127257, "score": 0 }, { "doc_id": "5478998", "title": "Mesenchymal stromal cells derived from various tissues: Biological, clinical and cryopreservation aspects.", "abstract": "Originally isolated from bone marrow, mesenchymal stromal cells (MSCs) have since been obtained from various fetal and post-natal tissues and are the focus of an increasing number of clinical trials. Because of their tremendous potential for cellular therapy, regenerative medicine and tissue engineering, it is desirable to cryopreserve and bank MSCs to increase their access and availability. A remarkable amount of research and resources have been expended towards optimizing the protocols, freezing media composition, cooling devices and storage containers, as well as developing good manufacturing practices in order to ensure that MSCs retain their therapeutic characteristics following cryopreservation and that they are safe for clinical use. Here, we first present an overview of the identification of MSCs, their tissue sources and the properties that render them suitable as a cellular therapeutic. Next, we discuss the responses of cells during freezing and focus on the traditional and novel approaches used to cryopreserve MSCs. We conclude that viable MSCs from diverse tissues can be recovered after cryopreservation using a variety of freezing protocols, cryoprotectants, storage periods and temperatures. However, alterations in certain functions of MSCs following cryopreservation warrant future investigations on the recovery of cells post-thaw followed by expansion of functional cells in order to achieve their full therapeutic potential.", "corpus_id": 5478998, "score": 0 }, { "doc_id": "31783619", "title": "Preserving human cells for regenerative, reproductive, and transfusion medicine", "abstract": "Cell cryopreservation maintains cellular life at sub‐zero temperatures by slowing down biochemical processes. Various cell types are routinely cryopreserved in modern reproductive, regenerative, and transfusion medicine. Current cell cryopreservation methods involve freezing (slow/rapid) or vitrifying cells in the presence of a cryoprotective agent (CPA). Although these methods are clinically utilized, cryo‐injury due to ice crystals, osmotic shock, and CPA toxicity cause loss of cell viability and function. Recent approaches using minimum volume vitrification provide alternatives to the conventional cryopreservation methods. Minimum volume vitrification provides ultra‐high cooling and rewarming rates that enable preserving cells without ice crystal formation. Herein, we review recent advances in cell cryopreservation technology and provide examples of techniques that are utilized in oocyte, stem cell, and red blood cell cryopreservation.", "corpus_id": 31783619, "score": 0 }, { "doc_id": "8133083", "title": "Recent advances in serum-free microcarrier expansion of mesenchymal stromal cells: Parameters to be optimized.", "abstract": "Mesenchymal stromal cells (MSCs) are being investigated for a variety of therapeutic indications. However, current 2D planar technology cannot meet the anticipated demand and a shift to serum-free microcarrier cultures is needed in order to meet the quality and quantity of cells required. Here we summarize several recent attempts to grow cells in such conditions, and identify several variables that affect cell expansion, including tissue source, serum-free medium formulation, microcarrier type and matrix, and agitation regime (continuous versus intermittent). Optimization of these culture conditions will be necessary to ensure success in bioreactor-scale production of MSCs for cell therapies.", "corpus_id": 8133083, "score": 0 }, { "doc_id": "39882269", "title": "Manufacturing of Human Umbilical Cord Mesenchymal Stromal Cells on Microcarriers in a Dynamic System for Clinical Use", "abstract": "The great properties of human mesenchymal stromal cells (hMSCs) make these cells an important tool in regenerative medicine. Because of the limitations of hMSCs derived from the bone marrow during isolation and expansion, hMSCs derived from the umbilical cord stroma are a great alternative to overcome these issues. For a large expansion of these cells, we performed a process transfer from static culture to a dynamic system. For this reason, a microcarrier selection out of five microcarrier types was made to achieve a suitable growth surface for the cells. The growth characteristics and metabolite consumption and production were used to compare the cells growth in 12-well plate and spinner flask. The goal to determine relevant process parameters to transfer the expansion process into a stirred tank bioreactor was achieved.", "corpus_id": 39882269, "score": 0 }, { "doc_id": "13223544", "title": "A xenogeneic‐free bioreactor system for the clinical‐scale expansion of human mesenchymal stem/stromal cells", "abstract": "The large cell doses (>1 × 106 cells/kg) used in clinical trials with mesenchymal stem/stromal cells (MSC) will require an efficient production process. Moreover, monitoring and control of MSC ex‐vivo expansion is critical to provide a safe and reliable cell product. Bioprocess engineering approaches, such as bioreactor technology, offer the adequate tools to develop and optimize a cost‐effective culture system for the rapid expansion of human MSC for cellular therapy. Herein, a xenogeneic (xeno)‐free microcarrier‐based culture system was successfully established for bone marrow (BM) MSC and adipose tissue‐derived stem/stromal cell (ASC) cultivation using a 1L‐scale controlled stirred‐tank bioreactor, allowing the production of (1.1 ± 0.1) × 108 and (4.5 ± 0.2) × 107 cells for BM MSC and ASC, respectively, after 7 days. Additionally, the effect of different percent air saturation values (%Airsat) and feeding regime on the proliferation and metabolism of BM MSC was evaluated. No significant differences in cell growth and metabolic patterns were observed under 20% and 9%Airsat. Also, the three different feeding regimes studied—(i) 25% daily medium renewal, (ii) 25% medium renewal every 2 days, and (iii) fed‐batch addition of concentrated nutrients and growth factors every 2 days—yielded similar cell numbers, and only slight metabolic differences were observed. Moreover, the immunophenotype (positive for CD73, CD90 and CD105 and negative for CD31, CD80 and HLA‐DR) and multilineage differentiative potential of expanded cells were not affected upon bioreactor culture. These results demonstrated the feasibility of expanding human MSC from different sources in a clinically relevant expansion configuration in a controlled microcarrier‐based stirred culture system under xeno‐free conditions. The further optimization of this bioreactor culture system will represent a crucial step towards an efficient GMP‐compliant clinical‐scale MSC production system. Biotechnol. Bioeng. 2014;111: 1116–1127. © 2014 Wiley Periodicals, Inc.", "corpus_id": 13223544, "score": 0 }, { "doc_id": "4877218", "title": "Long Term Expansion of Bone Marrow-Derived hMSCs on Novel Synthetic Microcarriers in Xeno-Free, Defined Conditions", "abstract": "Human mesenchymal stem cells (hMSCs) present an attractive target for cell therapy given their wide availability, immunomodulatory properties, and multipotent nature for differentiation into chondrocytes, osteocytes, and adipocytes. With the progression of hMSC clinical studies, there is an increasing demand for development of technologies that enable efficient cell scale-up into clinically relevant quantities. Commercial scale manufacturing of hMSCs will require a large surface area which is not cost effective with available two-dimensional culture vessels. Recent studies showed that microcarriers provide a three-dimensional culture environment suitable for hMSC expansion. Traditionally, biological coatings and/or serum-containing medium are required to facilitate hMSC attachment and expansion in dynamic conditions. These limitations may hinder the use of microcarriers as a scale-up technology for hMSC therapeutics, where cell products, and therefore patient safety, are more controlled with the use of xeno-free, defined culture conditions. Here we report the long term culture of hMSCs on novel synthetic Synthemax II microcarriers in two different xeno-free media. Cells were maintained over 40 days on sterile, ready-to-use microcarriers in spinner flasks with programmed agitation. hMSC expansion was obtained by addition of fresh beads without the need for enzymatic dissociation. We achieved a cumulative cell expansion of >10,000 fold, and cells retained normal hMSC phenotype, karyotype, and tri-lineage differentiation potential. To our knowledge, this report is the first example of long term culture of hMSCs on synthetic microcarriers in xeno-free, defined conditions.", "corpus_id": 4877218, "score": 0 }, { "doc_id": "16169976", "title": "Culture of human mesenchymal stem cells on microcarriers in a 5 l stirred-tank bioreactor", "abstract": "For the first time, fully functional human mesenchymal stem cells (hMSCs) have been cultured at the litre-scale on microcarriers in a stirred-tank 5 l bioreactor, (2.5 l working volume) and were harvested via a potentially scalable detachment protocol that allowed for the successful detachment of hMSCs from the cell-microcarrier suspension. Over 12 days, the dissolved O2 concentration was >45 % of saturation and the pH between 7.2 and 6.7 giving a maximum cell density in the 5 l bioreactor of 1.7 × 105 cells/ml; this represents >sixfold expansion of the hMSCs, equivalent to that achievable from 65 fully-confluent T-175 flasks. During this time, the average specific O2 uptake of the cells in the 5 l bioreactor was 8.1 fmol/cell h and, in all cases, the 5 l bioreactors outperformed the equivalent 100 ml spinner-flasks run in parallel with respect to cell yields and growth rates. In addition, yield coefficients, specific growth rates and doubling times were calculated for all systems. Neither the upstream nor downstream bioprocessing unit operations had a discernible effect on cell quality with the harvested cells retaining their immunophenotypic markers, key morphological features and differentiation capacity.", "corpus_id": 16169976, "score": 0 }, { "doc_id": "36094299", "title": "Growth of three established cell lines on glass microcarriers", "abstract": "Three established cell lines were examined for growth on a newly developed microcarrier which consists of glass beads. The cells were simultaneously exmined for growth on commercially available microcarriers made from DEAE‐dextran and from plastic. Cell yields on the glass microcarriers were comparble to the cell yields on the commercially available products. Cells grown on the glass microcarriers were easily separated from the substratum by trypsinization (as were the cells grown on the plastic substratum) while the cells grown on the DEAE‐dextran particles were much more trypsin resistant. After removal of cells from the glass microcarriers, the cells reattached and spread out in plastic flasks as readily as cells harvested from monolayer. Scanning electron microscopy revealed dramatic differences in the appearence of the cell grown on the glass microcarriers and cells grown on the DEAE‐dextran microcarriers. On the glass microcarriers, cells attached to the substratum through lond, slender filopodia while on the DEAE‐dextran microcarriers, the entire edge of the cell appeared to be in contact with the substratum. This dissimilarity in attachment could underly the difference in sensitivity to trypsin‐mediated detachment. Finally, the glass microcarriers were washed after being used once and retested for their ability to support cell growth a second time. Nearly identical results were obtained with the reprocessed beads as with previously unused ones.", "corpus_id": 36094299, "score": 0 }, { "doc_id": "3169620", "title": "Enzymatic Detachment of Therapeutic Mesenchymal Stromal Cells Grown on Glass Carriers in a Bioreactor", "abstract": "Cell therapies require the in vitro expansion of adherent cells such as mesenchymal stromal cells (hMSCs) in bioreactor systems or other culture environments, followed by cell harvest. As hMSCs are strictly adherent cells, cell harvest requires cell detachment. The use of hMSCs for cell therapy requires GMP production in accordance with the guidelines for advanced therapeutic medical products. Therefore, several GMP-conform available proteolytic enzymes were investigated for their ability to promote hMSC detachment. An allogeneic hMSC cell line (hMSC-TERT) that is used in clinical trials in the form of alginate cell capsules was chosen as a model. This study investigated the influence of several factors on the outcome of proteolytic hMSC-TERT detachment. Therefore, hMSC-TERT detachment was analyzed in different cultivation systems (static, dynamic) and in combination with further cell processing including encapsulation. Only two of the commercially available enzymes (AccutaseTM, TrypZeanTM) that fulfill all process requirements (commercial availability, cost, GMP conditions during manufacturing and non-animal origin) are found to be generally suitable for detaching hMSC-TERT. Combining cell detachment with encapsulation demonstrated a high impact of the experimental set up on cell damage. It was preferable to reduce the temperature during detachment and limit the detachment time to a maximum of 20 minutes. Cell detachment in static systems was not comparable with detachment in dynamic systems. Detachment yields in dynamic systems were lower and cell damage was higher for the same experimental conditions. Finally, only TrypZeanTM seemed to be suitable for the detachment of hMSC-TERT from dynamic reactor systems.", "corpus_id": 3169620, "score": 1 }, { "doc_id": "17407929", "title": "Systematic microcarrier screening and agitated culture conditions improves human mesenchymal stem cell yield in bioreactors", "abstract": "Abstract Production of human mesenchymal stem cells for allogeneic cell therapies requires scalable, cost‐effective manufacturing processes. Microcarriers enable the culture of anchorage‐dependent cells in stirred‐tank bioreactors. However, no robust, transferable methodology for microcarrier selection exists, with studies providing little or no reason explaining why a microcarrier was employed. We systematically evaluated 13 microcarriers for human bone marrow‐derived MSC (hBM‐MSCs) expansion from three donors to establish a reproducible and transferable methodology for microcarrier selection. Monolayer studies demonstrated input cell line variability with respect to growth kinetics and metabolite flux. HBM‐MSC1 underwent more cumulative population doublings over three passages in comparison to hBM‐MSC2 and hBM‐MSC3. In 100 mL spinner flasks, agitated conditions were significantly better than static conditions, irrespective of donor, and relative microcarrier performance was identical where the same microcarriers outperformed others with respect to growth kinetics and metabolite flux. Relative growth kinetics between donor cells on the microcarriers were the same as the monolayer study. Plastic microcarriers were selected as the optimal microcarrier for hBM‐MSC expansion. HBM‐MSCs were successfully harvested and characterised, demonstrating hBM‐MSC immunophenotype and differentiation capacity. This approach provides a systematic method for microcarrier selection, and the findings identify potentially significant bioprocessing implications for microcarrier‐based allogeneic cell therapy manufacture.", "corpus_id": 17407929, "score": 0 }, { "doc_id": "20558154", "title": "Online- and offline- monitoring of stem cell expansion on microcarrier", "abstract": "In the biopharmaceutical industry, adherent growing stem cell cultures gain worldwide importance as cell products. The cultivation process of these cells, such as in stirred tank reactors or in fixed bed reactors, is highly sophisticated. Cultivations need to be monitored and controlled to guarantee product quality and to satisfy GMP requirements. With the process analytical technology (PAT) initiative, requirements regarding process monitoring and control have changed and real-time on-line monitoring tools are recommended. A tool meeting the new requirements may be the dielectric spectroscopy for online viable cell mass determination by measurement of the permittivity. To establish these tools, proper offline methods for data correlation are required. The cell number determination of adherent cells on microcarrier is difficult, as it requires cell detachment from the carrier, which highly increases the statistical error. As an offline method, a fluorescence assay based on SYBR®GreenI was developed allowing fast and easy total cell concentration determination without the need to detach the cells from the carrier. The assay is suitable for glass carriers used in stirred tank reactor systems or in fixed bed systems, may be suitable for different cell lines and can be applied to high sample numbers easily. The linear dependency of permittivity to cell concentration of suspended stem cells with the dielectric spectroscopy is shown for even very small cell concentrations. With this offline-method, a correlation of the cell concentration grown on carrier to the permittivity data measured by the dielectric spectroscopy was done successfully.", "corpus_id": 20558154, "score": 1 }, { "doc_id": "23003804", "title": "Process analytical technology (PAT) in insect and mammalian cell culture processes: dielectric spectroscopy and focused beam reflectance measurement (FBRM).", "abstract": "Modern bioprocesses demand for a careful definition of the critical process parameters (CPPs) already during the early stages of process development in order to ensure high-quality products and satisfactory yields. In this context, online monitoring tools can be applied to recognize unfavorable changes of CPPs during the production processes and to allow for early interventions in order to prevent losses of production batches due to quality issues. Process analytical technologies such as the dielectric spectroscopy or focused beam reflectance measurement (FBRM) are possible online monitoring tools, which can be applied to monitor cell growth as well as morphological changes. Since the dielectric spectroscopy only captures cells with intact cell membranes, even information about dead cells with ruptured or leaking cell membranes can be derived. The following chapter describes the application of dielectric spectroscopy on various virus-infected and non-infected cell lines with respect to adherent as well as suspension cultures in common stirred tank reactors. The adherent mammalian cell lines Vero (African green monkey kidney cells) and hMSC-TERT (telomerase-immortalized human mesenchymal stem cells) are thereby cultured on microcarrier, which provide the required growth surface and allow the cultivation of these cells even in dynamic culture systems. In turn, the insect-derived cell lines S2 and Sf21 are used as examples for cells typically cultured in suspension. Moreover, the FBRM technology as a further monitoring tool for cell culture applications has been included in this chapter using the example of Drosophila S2 insect cells.", "corpus_id": 23003804, "score": 0 }, { "doc_id": "31222884", "title": "Monitoring the ex‐vivo expansion of human mesenchymal stem/stromal cells in xeno‐free microcarrier‐based reactor systems by MIR spectroscopy", "abstract": "Human mesenchymal stem/stromal cells (MSCs) have received considerable attention in the field of cell‐based therapies due to their high differentiation potential and ability to modulate immune responses. However, since these cells can only be isolated in very low quantities, successful realization of these therapies requires MSCs ex‐vivo expansion to achieve relevant cell doses. The metabolic activity is one of the parameters often monitored during MSCs cultivation by using expensive multi‐analytical methods, some of them time‐consuming. The present work evaluates the use of mid‐infrared (MIR) spectroscopy, through rapid and economic high‐throughput analyses associated to multivariate data analysis, to monitor three different MSCs cultivation runs conducted in spinner flasks, under xeno‐free culture conditions, which differ in the type of microcarriers used and the culture feeding strategy applied. After evaluating diverse spectral preprocessing techniques, the optimized partial least square (PLS) regression models based on the MIR spectra to estimate the glucose, lactate and ammonia concentrations yielded high coefficients of determination (R2 ≥ 0.98, ≥0.98, and ≥0.94, respectively) and low prediction errors (RMSECV ≤ 4.7%, ≤4.4% and ≤5.7%, respectively). Besides PLS models valid for specific expansion protocols, a robust model simultaneously valid for the three processes was also built for predicting glucose, lactate and ammonia, yielding a R2 of 0.95, 0.97 and 0.86, and a RMSECV of 0.33, 0.57, and 0.09 mM, respectively. Therefore, MIR spectroscopy combined with multivariate data analysis represents a promising tool for both optimization and control of MSCs expansion processes. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:447–455, 2016", "corpus_id": 31222884, "score": 0 }, { "doc_id": "15206961", "title": "Cultivation and Differentiation of Encapsulated hMSC-TERT in a Disposable Small-Scale Syringe-Like Fixed Bed Reactor", "abstract": "The use of commercially available plastic syringes is introduced as disposable small-scale fixed bed bioreactors for the cultivation of implantable therapeutic cell systems on the basis of an alginate-encapsulated human mesenchymal stem cell line. The system introduced is fitted with a noninvasive oxygen sensor for the continuous monitoring of the cultivation process. Fixed bed bioreactors offer advantages in comparison to other systems due to their ease of automation and online monitoring capability during the cultivation process. These benefits combined with the advantage of single-use make the fixed bed reactor an interesting option for GMP processes. The cultivation of the encapsulated cells in the fixed bed bioreactor system offered vitalities and adipogenic differentiation similar to well-mixed suspension cultures.", "corpus_id": 15206961, "score": 0 }, { "doc_id": "16441552", "title": "Packed Bed Bioreactor for the Isolation and Expansion of Placental-Derived Mesenchymal Stromal Cells", "abstract": "Large numbers of Mesenchymal stem/stromal cells (MSCs) are required for clinical relevant doses to treat a number of diseases. To economically manufacture these MSCs, an automated bioreactor system will be required. Herein we describe the development of a scalable closed-system, packed bed bioreactor suitable for large-scale MSCs expansion. The packed bed was formed from fused polystyrene pellets that were air plasma treated to endow them with a surface chemistry similar to traditional tissue culture plastic. The packed bed was encased within a gas permeable shell to decouple the medium nutrient supply and gas exchange. This enabled a significant reduction in medium flow rates, thus reducing shear and even facilitating single pass medium exchange. The system was optimised in a small-scale bioreactor format (160 cm2) with murine-derived green fluorescent protein-expressing MSCs, and then scaled-up to a 2800 cm2 format. We demonstrated that placental derived MSCs could be isolated directly within the bioreactor and subsequently expanded. Our results demonstrate that the closed system large-scale packed bed bioreactor is an effective and scalable tool for large-scale isolation and expansion of MSCs.", "corpus_id": 16441552, "score": 0 }, { "doc_id": "41191998", "title": "Bioreactor expansion of human mesenchymal stem cells according to GMP requirements.", "abstract": "In cell therapy, the use of autologous and allogenic human mesenchymal stem cells is rising. Accordingly, the supply of cells for clinical applications in highest quality is required. As hMSCs are considered as an advanced therapy medicinal products (ATMP), they underlie the requirements of GMP and PAT according to the authorities (FDA and EMA). The production process of these cells must therefore be documented according to GMP, which is usually performed via a GMP protocol based on standard operating procedures. This chapter provides an example of such a GMP protocol for hMSC, here a genetically modified allogenic cell line, based on a production process in a microcarrier-based stirred tank reactor including process monitoring according to PAT and final product quality assurance.", "corpus_id": 41191998, "score": 0 }, { "doc_id": "19659269", "title": "Scalable ex vivo expansion of human mesenchymal stem/stromal cells in microcarrier-based stirred culture systems.", "abstract": "The clinical demand for human mesenchymal stem/stromal cells (MSC) drives the need for reproducible, cost-effective, and good manufacturing practices (GMP)-compliant ex vivo expansion protocols. Bioprocess engineering strategies, namely controlled stirred bioreactor systems combined with the use of xenogeneic(xeno)-free materials, provide proper tools to develop and optimize cell manufacturing for the rapid expansion of human MSC for cellular therapies. Herein we describe a microcarrier-based stirred culture system operating under xeno-free conditions using a controlled stirred-tank bioreactor for an efficient and controlled ex vivo expansion of human MSC. This culture platform can be applied to MSC from different human sources, as well as different microcarriers and xeno-free medium formulations.", "corpus_id": 19659269, "score": 0 }, { "doc_id": "22289403", "title": "Exploring continuous and integrated strategies for the up- and downstream processing of human mesenchymal stem cells.", "abstract": "The integration of up- and downstream unit operations can result in the elimination of hold steps, thus decreasing the footprint, and ultimately can create robust closed system operations. This type of design is desirable for the bioprocess of human mesenchymal stem cells (hMSC), where high numbers of pure cells, at low volumes, need to be delivered for therapy applications. This study reports a proof of concept of the integration of a continuous perfusion culture in bioreactors with a tangential flow filtration (TFF) system for the concentration and washing of hMSC. Moreover, we have also explored a continuous alternative for concentrating hMSC. Results show that expanding cells in a continuous perfusion operation mode provided a higher expansion ratio, and led to a shift in cells' metabolism. TFF operated either in continuous or discontinuous allowed to concentrate cells, with high cell recovery (>80%) and viability (>95%); furthermore, continuous TFF permitted to operate longer with higher cell concentrations. Continuous diafiltration led to higher protein clearance (98%) with lower cell death, when comparing to discontinuous diafiltration. Overall, an integrated process allowed for a shorter process time, recovering 70% of viable hMSC (>95%), with no changes in terms of morphology, immunophenotype, proliferation capacity and multipotent differentiation potential.", "corpus_id": 22289403, "score": 0 }, { "doc_id": "86861296", "title": "A potentially scalable method for the harvesting of hMSCs from microcarriers", "abstract": "The use of hMSCs for allogeneic therapies requiring lot sizes of billions of cells will necessitate large-scale culture techniques such as the expansion of cells on microcarriers in bioreactors. Whilst much research investigating hMSC culture on microcarriers has focused on growth, much less involves their harvesting for passaging or as a step towards cryopreservation and storage. A successful new harvesting method has recently been outlined for cells grown on SoloHill microcarriers in a 5L bioreactor [1]. Here, this new method is set out in detail, harvesting being defined as a two-step process involving cell 'detachment' from the microcarriers' surface followed by the 'separation' of the two entities. The new detachment method is based on theoretical concepts originally developed for secondary nucleation due to agitation. Based on this theory, it is suggested that a short period (here 7min) of intense agitation in the presence of a suitable enzyme should detach the cells from the relatively large microcarriers. In addition, once detached, the cells should not be damaged because they are smaller than the Kolmogorov microscale. Detachment was then successfully achieved for hMSCs from two different donors using microcarrier/cell suspensions up to 100mL in a spinner flask. In both cases, harvesting was completed by separating cells from microcarriers using a Steriflip® vacuum filter. The overall harvesting efficiency was >95% and after harvesting, the cells maintained all the attributes expected of hMSC cells. The underlying theoretical concepts suggest that the method is scalable and this aspect is discussed too.", "corpus_id": 86861296, "score": 1 }, { "doc_id": "6841124", "title": "Expansion, harvest and cryopreservation of human mesenchymal stem cells in a serum‐free microcarrier process", "abstract": "Human mesenchymal stem cell (hMSC) therapies are currently progressing through clinical development, driving the need for consistent, and cost effective manufacturing processes to meet the lot‐sizes required for commercial production. The use of animal‐derived serum is common in hMSC culture but has many drawbacks such as limited supply, lot‐to‐lot variability, increased regulatory burden, possibility of pathogen transmission, and reduced scope for process optimization. These constraints may impact the development of a consistent large‐scale process and therefore must be addressed. The aim of this work was therefore to run a pilot study in the systematic development of serum‐free hMSC manufacturing process. Human bone‐marrow derived hMSCs were expanded on fibronectin‐coated, non‐porous plastic microcarriers in 100 mL stirred spinner flasks at a density of 3 × 105 cells.mL−1 in serum‐free medium. The hMSCs were successfully harvested by our recently‐developed technique using animal‐free enzymatic cell detachment accompanied by agitation followed by filtration to separate the hMSCs from microcarriers, with a post‐harvest viability of 99.63 ± 0.03%. The hMSCs were found to be in accordance with the ISCT characterization criteria and maintained hMSC outgrowth and colony‐forming potential. The hMSCs were held in suspension post‐harvest to simulate a typical pooling time for a scaled expansion process and cryopreserved in a serum‐free vehicle solution using a controlled‐rate freezing process. Post‐thaw viability was 75.8 ± 1.4% with a similar 3 h attachment efficiency also observed, indicating successful hMSC recovery, and attachment. This approach therefore demonstrates that once an hMSC line and appropriate medium have been selected for production, multiple unit operations can be integrated to generate an animal component‐free hMSC production process from expansion through to cryopreservation. Biotechnol. Bioeng. 2015;112: 1696–1707. © 2015 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.", "corpus_id": 6841124, "score": 1 }, { "doc_id": "36858247", "title": "Continuous harvest of stem cells via partial detachment from thermoresponsive nanobrush surfaces.", "abstract": "Stem cell culture is typically based on batch-type culture, which is laborious and expensive. Here, we propose a continuous harvest method for stem cells cultured on thermoresponsive nanobrush surfaces. In this method, stem cells are partially detached from the nanobrush surface by reducing the temperature of the culture medium below the critical solution temperature needed for thermoresponse. The detached stem cells are harvested by exchange into fresh culture medium. Following this, the remaining cells are continuously cultured by expansion in fresh culture medium at 37 °C. Thermoresponsive nanobrush surfaces were prepared by coating block copolymers containing polystyrene (for hydrophobic anchoring onto culture dishes) with three types of polymers: (a) polyacrylic acid with cell-binding oligopeptides, (b) thermoresponsive poly-N-isopropylacrylamide, and (c) hydrophilic poly(ethyleneglycol)methacrylate. The optimal coating durations and compositions for these copolymers to facilitate adequate attachment and detachment of human adipose-derived stem cells (hADSCs) and embryonic stem cells (hESCs) were determined. hADSCs and hESCs were continuously harvested for 5 and 3 cycles, respectively, via the partial detachment of cells from thermoresponsive nanobrush surfaces.", "corpus_id": 36858247, "score": 0 }, { "doc_id": "2415975", "title": "Suspension Culture of Mammalian Cells Using Thermosensitive Microcarrier that Allows Cell Detachment without Proteolytic Enzyme Treatment", "abstract": "Microcarriers are used to expand anchorage-dependent cells in large-scale suspension bioreactors. Proteolytic enzyme treatment is necessary to detach cells cultured on microcarriers for cell harvest or scale-up, but the enzyme treatment damages the cells and extracellular matrices and complicates the culture process. Here, we fabricated thermosensitive microcarriers from which cells can be detached by temperature change without proteolytic enzyme treatment. A thermosensitive polymer, poly-N-isopropylacrylamide (pNIPAAm), was incorporated on the surface of Cytodex-3® microcarriers. pNIPAAm-grafted microcarriers allowed human bone marrow-derived mesenchymal stem cells (hBMMSCs) to adhere, spread, and grow successfully on the microcarriers as nongrafted microcarriers did. By dropping temperature below 32°C, more than 82.5% of hBMMSCs were detached from pNIPAAm-grafted microcarriers. The trypsin treatment for cell detachment induced apoptosis and death of some of the detached cells, but cell detachment from pNIPAAm-grafted microcarriers by temperature change significantly reduced the apoptosis and cell death. pNIPAAm-grafted microcarriers can significantly reduce cell extracellular matrix damage in the cell detachment process and simplify the cell detachment process by avoiding proteolytic enzyme treatment. pNIPAAm-grafted microcarriers would be valuable to a variety of potential fields demanding a large amount of cells without cell damage, such as cell therapy, tissue engineering, and other biological and clinical applications.", "corpus_id": 2415975, "score": 0 }, { "doc_id": "207044810", "title": "In vitro culture and harvest of BMMSCs on the surface of a novel thermosensitive glass microcarrier.", "abstract": "Traditional two-dimensional (2D) static culture environment for stem cells followed by enzymatic cell detachment or mechanical treatment is routinely used in research laboratories. However, this method is not ideal as stem cells expand slowly, with cell damage and partial loss of specific stemness. For this reason, a better culture condition is urgently needed to improve stem cell recovery. A novel thermosensitive P(NIPAAm-co-HPM)-g-TMSPM-g-microcarrier was prepared here as a three-dimensional (3D) culture substitute. This novel microcarrier was prepared by grafting NIPAAm and HPM to the surface of glass microcarrier using TMSPM through surface free radical copolymerization. The prepared material was tested in cell culture and via cooling harvest method. We found that NIPAAm was successfully grafted on to the surface of the microcarriers, providing an excellent biocompatible environment for BMMSC adhesion and growth. More importantly, BMMSCs could be fully removed from the thermosensitive glass microcarriers with remained cell viability.", "corpus_id": 207044810, "score": 0 }, { "doc_id": "31510517", "title": "Derivation, characterization and expansion of fetal chondrocytes on different microcarriers", "abstract": "Fetal chondrocytes (FCs) have recently been identified as an alternative cell source for cartilage tissue engineering applications because of their partially chondrogenically differentiated phenotype and developmental plasticity. In this study, chondrocytes derived from fetal bovine cartilage were characterized and then cultured on commercially available Cytodex-1 and Biosilon microcarriers and thermosensitive poly(hydroxyethylmethacrylate)-poly(N-isopropylacrylamide) (PHEMA-PNIPAAm) beads produced by us. Growth kinetics of FCs were estimated by means of specific growth rate and metabolic activity assay. Cell detachment from thermosensitive microcarriers was induced by cold treatment at 4 °C for 20 min or enzymatic treatment was applied for the detachment of cells from Cytodex-1 and Biosilon. Although attachment efficiency and proliferation of FCs on PHEMA-PNIPAAm beads were lower than that of commercial Cytodex-1 and Biosilon microcarriers, these beads also supported growth of FCs. Detached cells from thermosensitive beads by cold induction exhibited a normal proliferative activity. Our results indicated that Cytodex-1 microcarrier was the most suitable material for the production of FCs in high capacity, however, ‘thermosensitive microcarrier model’ could be considered as an attractive solution to the process scale up for cartilage tissue engineering by improving surface characteristics of PHEMA-PNIPAAm beads.", "corpus_id": 31510517, "score": 0 }, { "doc_id": "85219694", "title": "A novel filtration device for point of care preparation of cellular therapies", "abstract": "Many biological samples are stored at cryogenic temperatures (i.e. temperatures below -1500C) to preserve their viability. Typically, these samples are stored in liquid nitrogen vapor-phase freezers. The underlying assumption is that biological samples show highly reduced degradation and metabolic activity while below Tg (the glass transition temperature). On the other hand, every time a sample is manipulated or temporarily removed from an LN2 freezer, the sample will experience thermal excursions marked by warm-up rates of several degrees per second. In these cases, the risk of harming a sample by inadvertently crossing the Tg threshold is very likely. This paper’s objective is to provide supporting data to fully characterize the thermal excursions of cryogenically frozen single vials filled with H2O during typical transient temperature events. Specifically, we focus our attention on the cold-chain steps that involve transferring a single vial from an LN2 vapor environment to either an ambient temperature or transportable dry ice (-800C) environment. In general, the warm-up rates experienced by the biological sample correlate to the thermal energy exchanged with the warmer environment via convective and conductive heat transfer. The magnitude of the heat transfer is driven by multiple factors: the warmer environment temperature and the overall time of exposure, the size and shape of the vial, its placement in a cryobox, the type of handling (manual or automated), the handling speed, etc. In this paper, we rationalize all the above factors and present experimental measurements supported by calibrated finite elements simulations showing typical expected warm-up rates. As a result, best-practice time constants for handling vials of biological samples without risking excessive thermal excursions above Tg are suggested.", "corpus_id": 85219694, "score": 0 }, { "doc_id": "45943795", "title": "Improving washing strategies of human mesenchymal stem cells using negative mode expanded bed chromatography.", "abstract": "The use of human mesenchymal stem cells (hMSC) in clinical applications has been increasing over the last decade. However, to be applied in a clinical setting hMSC need to comply with specific requirements in terms of identity, potency and purity. This study reports the improvement of established tangential flow filtration (TFF)-based washing strategies, further increasing hMSC purity, using negative mode expanded bed adsorption (EBA) chromatography with a new multimodal prototype matrix based on core-shell bead technology. The matrix was characterized and a stable, expanded bed could be obtained using standard equipment adapted from what is used for conventional packed bed chromatography processes. The effect of different expansion rates on cell recovery yield and protein removal capacity was assessed. The best trade-off between cell recovery (89%) and protein clearance (67%) was achieved using an intermediate expansion bed rate (1.4). Furthermore, we also showed that EBA chromatography can be efficiently integrated on the already established process for the downstream processing (DSP) of hMSC, where it improved the washing efficiency more than 10-fold, recovering approximately 70% of cells after global processing. This strategy showed not to impact cell viability (>95%), neither hMSC's characteristics in terms of morphology, immunophenotype, proliferation, adhesion capacity and multipotent differentiation potential.", "corpus_id": 45943795, "score": 0 }, { "doc_id": "8034135", "title": "Systematic parameter optimization of a Me(2)SO- and serum-free cryopreservation protocol for human mesenchymal stem cells.", "abstract": "Human mesenchymal stem cells (hMSCs) have great potential for clinical therapy and regenerative medicine. One major challenge concerning their application is the development of an efficient cryopreservation protocol since current methods result in a poor viability and high differentiation rates. A high survival rate of cryopreserved cells requires an optimal cooling rate and the presence of cryoprotective agents (CPA) in sufficient concentrations. The most widely used CPA, dimethylsulfoxide (Me(2)SO), is toxic at high concentrations at temperatures >4°C and has harmful effects on the biological functionality of stem cell as well as on treated patients. Thus, this study investigates different combinations of non-cytotoxic biocompatible substances, such as ectoin and proline, as potential CPAs in a systematic parametric optimization study in comparison to Me(2)SO as control and a commercial freezing medium (Biofreeze®, Biochrom). Using a freezing medium containing a low proline (1%, w/v) and higher ectoin (10%, w/v) amount revealed promising results although the highest survival rate was achieved with the Biofreeze® medium. Cryomicroscopic experiments of hMSCs revealed nucleation temperatures ranging from -16 to -25°C. The CPAs, beside Me(2)SO, did not affect the nucleation temperature. In most cases, cryomicroscopy revealed intracellular ice formation (IIF) during the cryopreservation cycle for all cryoprotocols. The occurence of IIF during thawing increased with the cooling rate. In case of hMSC there was no correlation between the rate of IIF and the post-thaw cell survival. After thawing adipogenic differentiation of the stem cells demonstrated cell functionality.", "corpus_id": 8034135, "score": 1 }, { "doc_id": "26165082", "title": "Frozen adipose-derived mesenchymal stem cells maintain high capability to grow and differentiate.", "abstract": "In recent years, there has been a shift toward tissue-engineering strategies using stem cells for plastic and reconstructive surgical procedures. Therefore, it is important to develop safe and reproducible protocols for the extraction of adipose-derived stromal cells (ASCs) to allow cells to be stored in liquid nitrogen for future needs. The aspirated liposuction obtained from healthy donors were immediately processed after the suction using a protocol developed in our laboratory. The resulting stromal vascular fraction (SVF) was then characterized by the presence of adipose-derived stromal cells, at later stage frozen in liquid nitrogen. After that, cells were thawed and again characterized by adipose-derived stromal cells, cellular survival, differentiation ability and Colony Forming Unit-Fibroblast like colonies (CFU-F). Extraction and freezing of cells contained in the stromal vascular fraction demonstrate that thawed cells maintain the full capability to grow and differentiate in culture. The advent of adipose-derived stromal cells use in tissue engineering will assume a wide role in esthetic restoration in plastic surgery. It is thus important to develop clinically translatable protocols for the preparation and storage of adipose-derived stromal cells. Our results show that adipose-derived stromal cells in serum free can easily be frozen and stored in liquid nitrogen with retention of 85% of cell viability and 180,890 cell/g yield plus normal proliferative capacity and differentiation potential compared with fresh controls. These observations set the basis for adipose-derived stromal cells banking.", "corpus_id": 26165082, "score": 0 }, { "doc_id": "12002502", "title": "Boron increases the cell viability of mesenchymal stem cells after long-term cryopreservation.", "abstract": "The field of stem-cell biology has emerged as a key technology for the treatment of various disorders and tissue regeneration applications. However, a major problem remains in clinical practice, which is the question of whether stem cells preserve their self-renewal and differentiation potential in the culture conditions or not. In the current study, effects of boron on the cryopreservation of human tooth germ stem cells (hTGSCs) were evaluated for the first time. The impacts of various boron concentrations (sodium pentaborate pentahydrate (NaB)) were tested on characterized hTGSCs viability for different time intervals (24, 48, and 72 h). 20 μg/ml NaB with lower Me(2)SO concentration was found to display positive effects on hTGSCs during repeated freezing and defrosting cycles, and long-term cryopreservation. After thawing, cells were analyzed for their surface antigens and differentiation capacity. hTGSCs were successfully cryopreserved without any change in their mesenchymal stem cell characteristics as they were treated with boron containing freezing medium. In addition, fatty acid composition was examined to demonstrate membrane fatty acid profiles after freeze-thawing. Besides, NaB treatment extended osteogenic and chondrogenic differentiation of hTGSCs remarkably after long-term cryopreservation with respect to control groups. The study clearly suggests that NaB has a protective role on the survival of hTGSCs in short- and long-term cryopreservation. Due to the possible storage of hTGSCs at early ages, development of a functional and reliable cryopreservation media can be designed as a future solution to the dental stem cell banking.", "corpus_id": 12002502, "score": 0 }, { "doc_id": "24691022", "title": "Biological and Physicochemical Characterization of a Serum-and Xeno-Free Chemically Defined Cryopreservation Procedure for Adult Human Progenitor Cells", "abstract": "While therapeutic cell transplantations using progenitor cells are increasingly evolving towards phase I and II clinical trials and chemically defined cell culture is established, standardization in biobanking is still in the stage of infancy. In this study, the EU FP6-funded CRYSTAL (CRYo-banking of Stem cells for human Therapeutic AppLication) consortium aimed to validate novel Standard Operating Procedures (SOPs) to perform and validate xeno-free and chemically defined cryopreservation of human progenitor cells and to reduce the amount of the potentially toxic cryoprotectant additive (CPA) dimethyl sulfoxide (DMSO). To achieve this goal, three human adult progenitor and stem cell populations—umbilical cord blood (UCB)-derived erythroid cells (UCB-ECs), UCB-derived endothelial colony forming cells (UCB-ECFCs), and adipose tissue (AT)-derived mesenchymal stromal cells (AT-MSCs)—were cryopreserved in chemically defined medium supplemented with 10% or 5% DMSO. Cell recovery, cell repopulation, and functionality were evaluated postthaw in comparison to cryopreservation in standard fetal bovine serum (FBS)-containing freezing medium. Even with a reduction of the DMSO CPA to 5%, postthaw cell count and viability assays indicated no overall significant difference versus standard cryomedium. Additionally, to compare cellular morphology/membrane integrity and ice crystal formation during cryopreservation, multiphoton laser-scanning cryomicroscopy (cryo-MPLSM) and scanning electron microscopy (SEM) were used. Neither cryo-MPLSM nor SEM indicated differences in membrane integrity for the tested cell populations under various conditions. Moreover, no influence was observed on functional properties of the cells following cryopreservation in chemically defined freezing medium, except for UCB-ECs, which showed a significantly reduced differentiation capacity after cryopreservation in chemically defined medium supplemented with 5% DMSO. In summary, these results demonstrate the feasibility and robustness of standardized xeno-free cryopreservation of different human progenitor cells and encourage their use even more in the field of tissue-engineering and regenerative medicine.", "corpus_id": 24691022, "score": 0 }, { "doc_id": "46177088", "title": "Clinical grade adult stem cell banking", "abstract": "There has been a great deal of scientific interest recently generated by the potential therapeutic applications of adult stem cells in human care but there are several challenges regarding quality and safety in clinical applications and a number of these challenges relate to the processing and banking of these cells ex-vivo. As the number of clinical trials and the variety of adult cells used in regenerative therapy increases, safety remains a primary concern. This has inspired many nations to formulate guidelines and standards for the quality of stem cell collection, processing, testing, banking, packaging and distribution. Clinically applicable cryopreservation and banking of adult stem cells offers unique opportunities to advance the potential uses and widespread implementation of these cells in clinical applications. Most current cryopreservation protocols include animal serum proteins and potentially toxic cryoprotectant additives (CPAs) which prevent direct use of these cells in human therapeutic applications. Long term cryopreservation of adult stem cells under good manufacturing conditions using animal product free solutions is critical to the widespread clinical implementation of ex-vivo adult stem cell therapies. Furthermore, to avoid any potential cryoprotectant related complications, reduced CPA concentrations and efficient post-thaw washing to remove CPA are also desirable. The present review focuses on the current strategies and important aspects of adult stem cell banking for clinical applications. These include current good manufacturing practices (cGMPs), animal protein free freezing solutions, cryoprotectants, freezing & thawing protocols, viability assays, packaging and distribution. The importance and benefits of banking clinical grade adult stem cells are also discussed.", "corpus_id": 46177088, "score": 0 }, { "doc_id": "207490054", "title": "Advances in cell encapsulation technology and its application in drug delivery", "abstract": "Introduction: Cell encapsulation technology has improved enormously since it was proposed 50 years ago. The advantages offered over other alternative systems, such as the prevention of repetitive drug administration, have triggered the use of this technology in multiple therapeutic applications. Areas covered: In this article, improvements in cell encapsulation technology and strategies to overcome the drawbacks that prevent its use in the clinic have been summarized and discussed. Different studies and clinical trials that have been performed in several therapeutic applications have also been described. Expert opinion: The authors believe that the future translation of this technology from bench to bedside requires the optimization of diverse aspects: i) biosafety, controlling and monitoring cell viability; ii) biocompatibility, reducing pericapsular fibrotic growth and hypoxia suffered by the graft; iii) control over drug delivery; iv) and the final scale up. On the other hand, an area that deserves more attention is the cryopreservation of encapsulated cells as this will facilitate the arrival of these biosystems to the clinic.", "corpus_id": 207490054, "score": 0 }, { "doc_id": "35251774", "title": "Cell-based delivery of glucagon-like peptide-1 using encapsulated mesenchymal stem cells", "abstract": "Glucagon-like peptide-1 (GLP-1) CellBeads are cell-based implants for the sustained local delivery of bioactive factors. They consist of GLP-1 secreting mesenchymal stem cells encapsulated in a spherically shaped immuno-isolating alginate matrix. A highly standardized and reproducible encapsulation method is described for the manufacturing of homogeneous CellBeads. Viability and sustained secretion was shown for the recombinant GLP-1 and the cell endogenous bioactive factors like vascular endothelial growth factor, neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic factor. Manufacturing and quality control is performed in compliance with good manufacturing practice and fulfils all regulatory requirements for human clinical use. GLP-1 CellBeads combine the neuro- and cardioprotective properties of both GLP-1 and mesenchymal stem cells. First promising results were obtained from preclinical studies and an ongoing safety trial in humans but further studies have to prove the overall potential of CellBead technology in cell-based regenerative medicine.", "corpus_id": 35251774, "score": 0 }, { "doc_id": "4964577", "title": "Alginate micro-encapsulation of mesenchymal stromal cells enhances modulation of the neuro-inflammatory response.", "abstract": "BACKGROUND AIMS\nModulation of inflammation after brain trauma is a key therapeutic goal aimed at limiting the consequences of the subsequent injury cascade. Mesenchymal stromal cells (MSCs) have been demonstrated to dynamically regulate the inflammatory environment in several tissue systems, including the central nervous system. There has been limited success, however, with the use of direct implantation of cells in the brain caused by low viability and engraftment at the injury site. To circumvent this, we encapsulated MSCs in alginate microspheres and evaluated the ability of these encapsulated MSCs to attenuate inflammation in rat organotypic hippocampal slice cultures (OHSC).\n\n\nMETHODS\nOHSC were administered lipopolysaccharide to induce inflammation and immediately co-cultured with encapsulated or monolayer human MSCs. After 24 h, culture media was assayed for the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) produced by OHSC, as well as MSC-produced trophic mediators.\n\n\nRESULTS\nEncapsulated MSCs reduced TNF-α more effectively than did monolayer MSCs. Additionally, there was a strong correlation between increased prostaglandin E2 (PGE2) and reduction of TNF-α. In contrast to monolayer MSCs, inflammatory signals were not required to stimulate PGE2 production by encapsulated MSCs. Further encapsulation-stimulated changes were revealed in a multiplex panel analyzing 27 MSC-produced cytokines and growth factors, from which additional mediators with strong correlations to TNF-α levels were identified.\n\n\nCONCLUSIONS\nThese results suggest that alginate encapsulation of MSCs may not only provide an improved delivery vehicle for transplantation but may also enhance MSC therapeutic benefit for treating neuro-inflammation.", "corpus_id": 4964577, "score": 0 }, { "doc_id": "207040493", "title": "Process engineering of high voltage alginate encapsulation of mesenchymal stem cells.", "abstract": "Encapsulation of stem cells in alginate beads is promising as a sophisticated drug delivery system in treatment of a wide range of acute and chronic diseases. However, common use of air flow encapsulation of cells in alginate beads fails to produce beads with narrow size distribution, intact spherical structure and controllable sizes that can be scaled up. Here we show that high voltage encapsulation (≥ 15 kV) can be used to reproducibly generate spherical alginate beads (200-400 μm) with narrow size distribution (± 5-7%) in a controlled manner under optimized process parameters. Flow rate of alginate solution ranged from 0.5 to 10 ml/h allowed producing alginate beads with a size of 320 and 350 μm respectively, suggesting that this approach can be scaled up. Moreover, we found that applied voltages (15-25 kV) did not alter the viability and proliferation of encapsulated mesenchymal stem cells post-encapsulation and cryopreservation as compared to air flow. We are the first who employed a comparative analysis of electro-spraying and air flow encapsulation to study the effect of high voltage on alginate encapsulated cells. This report provides background in application of high voltage to encapsulate living cells for further medical purposes. Long-term comparison and work on alginate-cell interaction within these structures will be forthcoming.", "corpus_id": 207040493, "score": 0 }, { "doc_id": "2733957", "title": "Use of Encapsulated Stem Cells to Overcome the Bottleneck of Cell Availability for Cell Therapy Approaches", "abstract": "Nowadays cell-based therapy is rarely in clinical practice because of the limited availability of appropriate cells. To apply cells therapeutically, they must not cause any immune response wherefore mainly autologous cells have been used up to now. The amount of vital cells in patients is limited, and under certain circumstances in highly degenerated tissues no vital cells are left. Moreover, the extraction of these cells is connected with additional surgery; also the expansion in vitro is difficult. Other approaches avoid these problems by using allo-or even xenogenic cells. These cells are more stable concerning their therapeutic behavior and can be produced in stock. To prevent an immune response caused by these cells, cell encapsulation (e.g. with alginate) can be performed. Certain studies showed that encapsulated allo-and xenogenic cells achieve promising results in treatment of several diseases. For such cell therapy approaches, stem cells, particularly mesenchymal stem cells, are an interesting cell source. This review deals on the one hand with the use of encapsulated cells, especially stem cells, in cell therapy and on the other hand with bioreactor systems for the expansion and differentiation of mesenchymal stem cells in reproducible and sufficient amounts for potential clinical use.", "corpus_id": 2733957, "score": 0 }, { "doc_id": "14403562", "title": "Microencapsulation Technology: A Powerful Tool for Integrating Expansion and Cryopreservation of Human Embryonic Stem Cells", "abstract": "The successful implementation of human embryonic stem cells (hESCs)-based technologies requires the production of relevant numbers of well-characterized cells and their efficient long-term storage. In this study, cells were microencapsulated in alginate to develop an integrated bioprocess for expansion and cryopreservation of pluripotent hESCs. Different three-dimensional (3D) culture strategies were evaluated and compared, specifically, microencapsulation of hESCs as: i) single cells, ii) aggregates and iii) immobilized on microcarriers. In order to establish a scalable bioprocess, hESC-microcapsules were cultured in stirred tank bioreactors. The combination of microencapsulation and microcarrier technology resulted in a highly efficient protocol for the production and storage of pluripotent hESCs. This strategy ensured high expansion ratios (an approximately twenty-fold increase in cell concentration) and high cell recovery yields (>70%) after cryopreservation. When compared with non-encapsulated cells, cell survival post-thawing demonstrated a three-fold improvement without compromising hESC characteristics. Microencapsulation also improved the culture of hESC aggregates by protecting cells from hydrodynamic shear stress, controlling aggregate size and maintaining cell pluripotency for two weeks. This work establishes that microencapsulation technology may prove a powerful tool for integrating the expansion and cryopreservation of pluripotent hESCs. The 3D culture strategy developed herein represents a significant breakthrough towards the implementation of hESCs in clinical and industrial applications.", "corpus_id": 14403562, "score": 0 }, { "doc_id": "41000613", "title": "Cryopreservation of alginate encapsulated mesenchymal stromal cells.", "abstract": "Human mesenchymal stromal cells (MSCs) can differentiate into various cell types, which makes them attractive for regenerative medicine and tissue engineering. Encapsulation of MSCs in alginate microspheres (AMS) is a novel and promising approach of tissue engineering. Application and research of such cell-hydrogel systems require selection of adequate cryopreservation protocols. In this study we investigated the response of MSCs encapsulated in AMS to different cryopreservation protocols. Bone marrow MSCs either encapsulated in AMS and or as cells in suspension, were cryopreserved with 5% and 10% of dimethyl sulfoxide (ME₂SO) using conventional 2-step slow cooling (protocol 1). The viability and metabolism of MSCs in AMS following cryopreservation with 5% Me₂SO were lower than in the group cryopreserved with 10% Me₂SO. MSCs in suspension were more resistant to cryopreservation than cells in AMS when cryopreserved with 5% Me₂SO, although when using a concentration of 10% Me₂SO, no differences were detected. Comparisons of the viability and metabolic activity of MSC cryopreserved either in AMS or as cell suspensions with 10% ME₂SO using protocol 1 (2-step cooling), protocol 2 (3-step slow cooling with induced ice nucleation) or protocol 3 (rapid 1-step freezing), showed that the highest viabilities and metabolic rates were obtained following cryopreservation of MSCs in AMS by protocol 2 (with controlled ice nucleation). Cryopreservation with protocol 3 resulted in critical damage of the encapsulated MSCs. After cryopreservation by protocol 2, AMS encapsulated MSCs were capable of achieving multilineage differentiation directed towards osteogenic, adipogenic and chondrogenic lineages. The data obtained indicate that cryo-banking of AMS encapsulated MSCs is feasible for future regenerative medicine projects.", "corpus_id": 41000613, "score": 0 }, { "doc_id": "36563156", "title": "Cryopreservation of microencapsulated murine mesenchymal stem cells genetically engineered to secrete erythropoietin.", "abstract": "The ability to cryopreserve and store for long term the structure and function of therapeutic cells and tissues plays a pivotal role in clinical medicine. In fact, it is an essential pre-requisite for the commercial and clinical application of stem cells since preserves cells at low temperature and creates a reserve for future uses. This requisite may also affect the encapsulated stem cells. Several parameters should be considered on encapsulated cell cryopreservation such as the time and temperature during the cryopreservation process, or the cryoprotectant solutions used. In this study, we have compared the influence of penetrating and nonpenetrating cryoprotectants on the viability and functionality of encapsulated mesenchymal stem cells genetically modified to secrete erythropoeitin. Several cryoprotectant solutions combining DMSO, glycerol and trehalose at different concentrations were studied. Although almost no differences among the studied cryoprotectant solutions were observed on the differentiation potential of encapsulated mesenchymal stem cells, the penetrating cryoprotectant DMSO at a concentration of 10% displayed the best viability and erythropoietin secretion profile compared to the other cryoprotectant solutions. These results were confirmed after subcutaneous implantation of thawed encapsulated mesenchymal stem cells secreting erythropoeitin on Balb/c mice. The hematocrit levels of these animals increased to similar levels of those detected on animals transplanted with noncryopreserved encapsulated cells. Therefore, DMSO 10% represents the most suitable cryoprotectant solution among the solutions here studied, for encapsulated mesenchymal stem cells cryopreservation and its translation into the clinic. Similar studies should be performed for the encapsulation of other cell types before they can be translated into the clinic.", "corpus_id": 36563156, "score": 0 }, { "doc_id": "206267036", "title": "A novel alternative to cryopreservation for the short-term storage of stem cells for use in cell therapy using alginate encapsulation.", "abstract": "Efficient transport of stem/progenitor cells without affecting their survival and function is a key factor in any practical cell-based therapy. However, the current approach using liquid nitrogen for the transfer of stem cells requires a short delivery time window is technically challenging and financially expensive. The present study aims to use semipermeable alginate hydrogels (crosslinked by strontium) to encapsulate, store, and release stem cells, to replace the conventional cryopreservation method for the transport of therapeutic cells within world-wide distribution time frame. Human mesenchymal stem cell (hMSC) and mouse embryonic stem cells (mESCs) were successfully stored inside alginate hydrogels for 5 days under ambient conditions in an air-tight environment (sealed cryovial). Cell viability, of the cells extracted from alginate gel, gave 74% (mESC) and 80% (hMSC) survival rates, which compared favorably to cryopreservation. More importantly, the subsequent proliferation rate and detection of common stem cell markers (both in mRNA and protein level) from hMSCs and mESCs retrieved from alginate hydrogels were also comparable to (if not better than) results gained following cryopreservation. In conclusion, this new and simple application of alginate hydrogel encapsulation may offer a cheap and robust alternative to cryopreservation for the transport and storage of stem cells for both clinical and research purposes.", "corpus_id": 206267036, "score": 0 }, { "doc_id": "27004484", "title": "Alginate‐Encapsulation for the Improved Hypothermic Preservation of Human Adipose‐Derived Stem Cells", "abstract": "Despite considerable progress within the cell therapy industry, unmet bioprocessing and logistical challenges associated with the storage and distribution of cells between sites of manufacture and the clinic exist. We examined whether hypothermic (4°C–23°C) preservation of human adipose‐derived stem cells could be improved through their encapsulation in 1.2% calcium alginate. Alginate encapsulation improved the recovery of viable cells after 72 hours of storage. Viable cell recovery was highly temperature‐dependent, with an optimum temperature of 15°C. At this temperature, alginate encapsulation preserved the ability for recovered cells to attach to tissue culture plastic on rewarming, further increasing its effect on total cell recovery. On attachment, the cells were phenotypically normal, displayed normal growth kinetics, and maintained their capacity for trilineage differentiation. The number of cells encapsulated (up to 2 × 106 cells per milliliter) did not affect viable cell recovery nor did storage of encapsulated cells in a xeno‐free, serum‐free,current Good Manufacturing Practice‐grade medium. We present a simple, low‐cost system capable of enhancing the preservation of human adipose‐derived stem cells stored at hypothermic temperatures, while maintaining their normal function. The storage of cells in this manner has great potential for extending the time windows for quality assurance and efficacy testing, distribution between the sites of manufacture and the clinic, and reducing the wastage associated with the limited shelf life of cells stored in their liquid state.", "corpus_id": 27004484, "score": 0 }, { "doc_id": "206675578", "title": "Assays of osteogenic differentiation by cultured human mesenchymal stem cells.", "abstract": "One of the most noteworthy characteristics of mesenchymal stem cells (MSCs) is their ability to differentiate into osteoblasts in vitro and in vivo. In vitro, this is easily achieved by culturing in the appropriate induction medium. It is because of the reliability and ease of this process that osteogenic differentiation has become a popular assay for the demonstration of MSC plasticity. Although the conditions required for inducing osteogenic differentiation by MSCs typically do not vary particularly between investigators, many methods are employed to measure the extent of differentiation. These methods include, but are not limited to, reverse transcriptase PCR (RT-PCR) for detection of osteogenic transcripts, enzyme linked immunosorbent assay (ELISA) for secreted protein markers, colorimetric assays for osteogenic enzymes, and direct staining of matrix components. This chapter reviews the protocols most commonly utilized for the evaluation of osteogenic differentiation for cultured MSCs.", "corpus_id": 206675578, "score": 0 }, { "doc_id": "32948349", "title": "Adipogenic differentiation of human mesenchymal stem cells.", "abstract": "Mesenchymal stem cells have the capability to differentiate into a number of cell types including adipocytes. The adipocytic phenotype is characterized by intracellular accumulation of lipid droplets as well as transcription of adipocyte-specific genes. This paper details a basic protocol for adipogenic induction of bone marrow and adipose tissue-derived stem cells, as well as protocols for staining lipid accumulation and the transcriptional analysis of PPAR-γ and aP2 by real-time RT-PCR.", "corpus_id": 32948349, "score": 0 }, { "doc_id": "206675588", "title": "Chondrogenic differentiation of bone marrow-derived mesenchymal stem cells: tips and tricks.", "abstract": "It is well known that adult cartilage lacks the ability to repair itself; this makes articular cartilage a very attractive target for tissue engineering. The majority of articular cartilage repair models attempt to deliver or recruit reparative cells to the site of injury. A number of efforts are directed to the characterization of progenitor cells and the understanding of the mechanisms involved in their chondrogenic differentiation. Our laboratory has focused on cartilage repair using mesenchymal stem cells and studied their differentiation into cartilage. Mesenchymal stem cells are attractive candidates for cartilage repair due to their osteogenic and chondrogenic potential, ease of harvest, and ease of expansion in culture. However, the need for chondrogenic differentiation is superposed on other technical issues associated with cartilage repair; this adds a level of complexity over using mature chondrocytes. This chapter will focus on the methods involved in the isolation and expansion of human mesenchymal stem cells, their differentiation along the chondrogenic lineage, and the qualitative and quantitative assessment of chondrogenic differentiation.", "corpus_id": 206675588, "score": 0 }, { "doc_id": "206267902", "title": "Single-Step RNA Extraction from Different Hydrogel-Embedded Mesenchymal Stem Cells for Quantitative Reverse Transcription-Polymerase Chain Reaction Analysis.", "abstract": "For many tissue engineering applications, cells such as human mesenchymal stem cells (hMSCs) must be embedded in hydrogels. The analysis of embedded hMSCs requires RNA extraction, but common extraction procedures often produce low yields and/or poor quality RNA. We systematically investigated four homogenization methods combined with eight RNA extraction protocols for hMSCs embedded in three common hydrogel types (alginate, agarose, and gelatin). We found for all three hydrogel types that using liquid nitrogen or a rotor-stator produced low RNA yields, whereas using a microhomogenizer or enzymatic/chemical hydrogel digestion achieved better yields regardless of which extraction protocol was subsequently applied. The hot phenol extraction protocol generally achieved the highest A260 values (representing up to 40.8 μg RNA per 10(6) cells), but the cetyltrimethylammonium bromide (CTAB) method produced RNA of better quality, with A260/A280 and A260/A230 ratios and UV spectra similar to the pure RNA control. The RNA produced by this method was also suitable as a template for endpoint and quantitative reverse transcription-PCR (qRT-PCR), achieving low Ct values of ∼20. The prudent choice of hydrogel homogenization and RNA extraction methods can ensure the preparation of high-quality RNA that generates reliable endpoint and quantitative RT-PCR data. We therefore propose a universal method that is suitable for the extraction of RNA from cells embedded in all three hydrogel types commonly used for tissue engineering.", "corpus_id": 206267902, "score": 0 }, { "doc_id": "29698841", "title": "Risk of tumorigenicity in mesenchymal stromal cell-based therapies--bridging scientific observations and regulatory viewpoints.", "abstract": "In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products.", "corpus_id": 29698841, "score": 0 }, { "doc_id": "44986454", "title": "Defining the risks of mesenchymal stromal cell therapy.", "abstract": "Abstract We address the issue of the potential for malignant transformation of cultured mesenchymal stromal cells (MSC) commonly used in clinical cell-therapy protocols and describe the culture conditions under which tumorigenesis is likely to be an extremely uncommon event.", "corpus_id": 44986454, "score": 0 }, { "doc_id": "29057096", "title": "Frequent occurrence of non-malignant genetic alterations in clinical grade mesenchymal stromal cells expanded for cell therapy protocols", "abstract": "Human bone marrow mesenchymal stromal cells (BM-MSC) represent one of the most investigated “advanced therapeutic medicinal products”.[1][1] Recent safety concerns have focused attention on the possible malignant transformation due to mutations acquired during their large-scale in vitro", "corpus_id": 29057096, "score": 0 } ]

{ "doc_id": "46453379", "title": "Perceptual learning in an appetitive Pavlovian procedure: Analysis of the effectiveness of the common element", "abstract": "Non-reinforced preexposure to two stimuli often enhances discrimination between them. Analyses of this perceptual learning phenomenon have mainly focused on the role played by the distinctive stimulus features; this study examined the contribution of the non-distinctive common elements. A standard appetitive Pavlovian procedure was used. Rats received two different schedules of exposure--alternated or blocked--to two compound auditory stimuli, AX and BX. In Experiment 1 a generalization test to BX that followed conditioning to AX showed that animals responded less, and hence discriminated better, following alternated exposure, thus extending the generality of this perceptual learning effect to standard appetitive Pavlovian procedures. The degree to which the common element X was mediating this effect was explored in the next three experiments. Experiment 2 assessed the effectiveness of X following conditioning to AX. Experiment 3 explored X's effectiveness throughout extensive conditioning to X. Experiment 4 tested the ability of X to overshadow a novel stimulus Y. The results were consistent with the suggestion that alternated preexposure can reduce the relative effectiveness of the common element.", "corpus_id": 46453379 }

[ { "doc_id": "712251", "title": "Learned Changes in the Sensitivity of Stimulus Representations: Associative and Nonassociative Mechanisms", "abstract": "Central to associative learning theory is the proposal that the concurrent activation of a pair of event representations will establish or strengthen a link between them. Associative theorists have devoted much energy to establishing what representations are involved in any given learning paradigm and the rules that determine the degree to which the link is strengthened. They have paid less attention to the question of what determines that a representation will be activated, assuming, for the case of classical conditioning, that presentation of an appropriately intense stimulus from an appropriate modality will be enough. But this assumption is unjustified. Ipresent the results of experiments on the effects of stimulus exposure in rats that suggest that mere exposure to a stimulus can influence its perceptual effectiveness—that the ability of a stimulus to activate its representation can be changed by experience. This conclusion is of interest for two reasons. First, it supplies a direct explanation for the phenomenon of perceptual learning—the enhancement of stimulus discriminability produced by some forms of stimulus exposure. Second, it poses a theoretical challenge in that it seems to require the existence of a learning mechanism outside the scope of those envisaged by current formal theories of associative learning. I offer some speculations as to how this mechanism might be incorporated into such theories.", "corpus_id": 712251, "score": 1 }, { "doc_id": "144694032", "title": "Latent Inhibition and Conditioned Attention Theory", "abstract": "Preface 1. Introduction 2. Latent inhibition testing procedures 3. Variables affecting latent inhibition 4. Organismic variables affecting latent inhibition 5. Associative learning tests of the effects of stimulus preexposure in children and adults 6. Neural substrates of latent inhibition 7. Theories and explanations of latent inhibition in animals 8. Conditioned attention theory of latent inhibition 9. Conditioned attention theory as applied to latent inhibition in humans 10. Some applications of conditioned attention theory: learned helplessness and schizophrenia Notes References Author index Subject index.", "corpus_id": 144694032, "score": 0 }, { "doc_id": "11257671", "title": "Perceptual learning; differentiation or enrichment?", "abstract": "The term \"perceptual learning\" means different things to different psychologists. To some it implies that human perception is, in large part, learned—that we learn to see depth, for instance, or form, or meaningful objects. In that case the theoretical issue involved is how much of perception is learned, and the corresponding controversy is that of nativism or empiricism. To others the term implies that human learning is in whole or part a matter of perception—that learning depends on comprehension, expectation, or insight, and that the learning process is to be found in a central process of cognition rather than in a motor process of performance. . In this second case, the theoretical issue involved is whether or not one has to study a man's perceptions before one can understand his behavior, and the controversy is one of long standing which began with oldfashioned behaviorism. These two sets of implications are by no means the same, and the two problems should be separated. The problem of the role of learning in perception has to do with perception and the effect of past experience or practice on it. The problem of the role of perception in learning has to do with behavior and the question of whether we can learn to do something by perceiving, or whether we can only learn by doing it. The questions, then, are these: (a) In", "corpus_id": 11257671, "score": 0 }, { "doc_id": "14124815", "title": "The effect of prolonged exposure to visually presented patterns on learning to discriminate them.", "abstract": "Recent literature on the development of discrimination has shown an increasing trend toward acceptance of empiricistic explanations (2, 9). That ability to discriminate visually presented patterns develops with the experience and environmental reinforcement of the growing animal may be the case, but the evidence for this view is still inconclusive. Early studies by Lashlcy and Russell (11) and by Hebb (8) on the rat favored a nativistic interpretation of the differentiation of visual qualities, but later comparable studies with the chimpanzee and pigeon (13, 14) apparently favored an empiricistic explanation. Recent experiments by students of Hebb (5, 6, 10) have employed, an \"enrichment\" technique, with results which appear to favor a learning hypothesis. These studies attempted to provide a generally \"rich\" environment and used as criteria tests of a rather general type. If opportunity to view a varied and patterned environment is important in the differentiation of visual qualities, we do not know how general or how specific the relevant experience must be. The experiment to be reported proposed to investigate the dependence of visual form discrimination in adult rats on a specific variation in visual stimulation during growth. To this end, an experimental group of animals was raised from birth in cages which exhibited on the walls circles and triangles identical in form with ones later to be discriminated. The control group was raised under the same standard conditions but without opportunity to see these forms before the discrimination learning began. If the opportunity to view specific form,s favors development of the ability to differentiate them in a later discrimination learning problem, the experimental animals should learn faster and show a higher proportion of 5s reaching the criterion than the control group.", "corpus_id": 14124815, "score": 0 }, { "doc_id": "53200870", "title": "Exposure learning in young and adult laboratory rats", "abstract": "Abstract Hooded rats born in the laboratory were exposed in their home cages to objects (cut-out triangles and circles) which were to be used as the stimuli in a subsequent visual simultaneous discrimination task. Control subjects received no prior exposure. In confirmation of the results of Gibson & Walk (1956) it was found that rats given exposure to the stimuli when still immature showed positive transfer to discrimination learning in adulthood. Facilitation of learning was also found in subjects exposed to the stimuli in adulthood. The relevance of these findings to theories of the ‘special’ effects of early experience and to current theories of the effects of stimulus-exposure is discussed.", "corpus_id": 53200870, "score": 0 }, { "doc_id": "143465766", "title": "Exposure learning in animals", "abstract": "Reviews experimental studies (using animal Ss) that investigated the effects of prior exposure to a pair of stimuli on subsequent visual discrimination learning. The bulk of these experiments used young rats as Ss, with stimulus exposure taking place in the home cage over a long period of time. When", "corpus_id": 143465766, "score": 0 }, { "doc_id": "151372582", "title": "Latent learning and latent inhibition in maze discriminations", "abstract": "Rats were trained on an elevated maze where the rewarded alternative was defined either in terms of intra-maze or in terms of extra-maze cues. Pre-exposure to these cues produced a small latent or perceptual learning effect, i.e. facilitated subsequent learning of both problems, by comparison with animals pre-exposed to the maze with no cues present. Experiment 2 examined whether the effect of pre-exposure on intra-maze discrimination learning varied with the nature of the intra-maze cues. When positive and negative arms were further differentiated by painting the walls white and black, a marginal perceptual learning effect was turned into significant latent inhibition, i.e. a retardation of subsequent learning. Pre-exposure thus reliably facilitated extra-maze discrimnation learning, and its beneficial effects on intra-maze discrimination could be reversed by reducing the overlap between the intra-maze cues. Perceptual learning may therefore depend on requiring animals to discriminate between stimuli containing many common elements.", "corpus_id": 151372582, "score": 0 }, { "doc_id": "22229554", "title": "Perceptual Learning in Maze Discriminations", "abstract": "In Experiment 1, rats were trained on a discrimination between rubber- and sandpaper-covered arms of a maze after one group had been pre-exposed to these intra-maze cues. Pre-exposure facilitated subsequent discrimination learning, unless the discrimination was made easier by adding further discriminative stimuli, when it now significantly retarded learning. In Experiment 2, rats were trained on an extra-maze spatial discrimination, again after one group, but not another, had been pre-exposed to the extra-maze landmarks. Here too, pre-exposure facilitated subsequent discrimination learning, unless the discrimination was made substantially easier by arranging that the two arms between which rats had to choose were always separated by 135°. The results of both experiments can be explained by supposing that perceptual learning depends on the presence of features common to S+ and S-.", "corpus_id": 22229554, "score": 0 }, { "doc_id": "27538", "title": "Latent inhibition and perceptual learning in a swimming-pool navigation task.", "abstract": "In each of 3 experiments, rats were preexposed to the 4 distinct landmarks surrounding a circular pool before being trained to find a submerged platform located in a fixed position in the pool. When preexposure was to pairs of adjacent landmarks, it consistently retarded subsequent learning (a latent inhibition effect). When preexposure was to 1 landmark at a time, then, provided the 4 landmarks all contained a salient feature in common, preexposure facilitated subsequent learning (a perceptual learning effect). The results provide little support for the notion of a cognitive map and are quite consistent with an associative analysis.", "corpus_id": 27538, "score": 0 }, { "doc_id": "30971947", "title": "Stimulus Comparison and Perceptual Learning: Further Evidence and Evaluation from an Imprinting Procedure", "abstract": "Two experiments used chicks to investigate the role of stimulus comparison in perceptual learning. In Experiment 1, chicks received exposure to two views of a jungle fowl, SV (side view) and BV (back view), intermixed within a session (mixed exposure), exposure to SV in one session and BV in a different session (separate exposure), or no exposure to either view. All chicks then received a heat-reinforced discrimination with SV and BV serving as discriminanda. Chicks given mixed exposure acquired the discrimination more readily than did either those given separate exposure or those given no exposure. In Experiment 2, all chicks received mixed exposure to the two stimuli. For one group the interval between presentations of the stimuli was short (short-mixed), for the other group it was long (long-mixed). Subjects in the long-mixed condition acquired the heat-reinforced discrimination more rapidly than those in the short-mixed condition. These results suggest that the intermixed nature of stimulus exposure is an important determinant of the magnitude of perceptual learning effects.", "corpus_id": 30971947, "score": 0 }, { "doc_id": "40440242", "title": "The Role of Stimulus Comparison in Perceptual Learning: An Investigation with the Domestic Chick", "abstract": "In two experiments an imprinting procedure was used to familiarize chicks with two stimuli, A and B, that subsequently served as the discriminanda in a simultaneous discrimination. On the first day of each experiment, subjects either received presentations of A and B that were intermixed within a session (mixed exposure) or presentations of A in one session and of B in another (separate exposure). For half of the subjects in each of the exposure conditions, A and B differed in both colour and form; for the remainder A and B differed in form alone. On the second day of the experiments, the chicks were placed into a cool test apparatus and given training in which approaching A was rewarded by the delivery of a stream of warm air, but approaching B was not. Acquisition of this discrimination was more rapid when A and B differed in two respects than when they differed in form alone. When A and B differed in both colour and form, the heat-reinforced discrimination was acquired more rapidly after separate exposure than after mixed exposure; but when A and B differed in form alone, discrimination learning was more rapid following mixed exposure than separate exposure. The latter finding, that the opportunity to compare stimuli differing in only one dimension facilitates subsequent discrimination learning, is consistent with earlier suggestions (Gibson, 1969) regarding the conditions that promote perceptual learning.", "corpus_id": 40440242, "score": 1 }, { "doc_id": "143915775", "title": "Enhanced discriminability and reduced associability following flavor preexposure", "abstract": "Four experiments examined generalization of a flavor aversion to novel and familiar test stimuli. Experiment 1 showed that the generalization of an aversion from one stimulus, A, to another, B, was reduced when B had been preexposed (cf. M. R. Best and J. D. Batson, 1977, Journal of Experimental Psychology: Animal Behavior Processes, 3, 132–143). Experiments 2, 3, and 4 demonstrated that generalization of an aversion to a novel simulus was greater than to a familiar B stimulus irrespective of whether the A flavor had itself been preexposed. Experiment 3 also showed that preeposure to A retarded the acquisition of an aversion to A. These results were interpreted as indicating that exposure to flavors reduces their associability and increases their discriminability. Two possible mechanisms for these effects were explored.", "corpus_id": 143915775, "score": 0 }, { "doc_id": "10822637", "title": "Perceptual learning in flavor aversion conditioning: Roles of stimulus comparison and latent inhibition of common stimulus elements☆", "abstract": "Abstract In three experiments, rats received training in which an aversion was established to one flavor and the extent to which this aversion generalized to a second flavor was tested. Experiment 1 showed that nonreinforced preexposure to both flavors resulted in reduced generalization between them. Experiments 2 and 3 demonstrated that this reduction in generalization required the two flavors to be presented on alternate trials during preexposure. Subjects given preexposure consisting of a block of trials with one flavor followed by a block of trials with the other showed the same degree of generalization as subjects given no preexposure. The two schedules of stimulus presentation were equated in the total amount of exposure given to each stimulus, making it unlikely that differences in latent inhibition could be responsible for the difference seen on the test. It is suggested that the opportunity for stimulus comparison offered by the alternating schedule might be important in a process of perceptual learning that is responsible for the reduced generalization.", "corpus_id": 10822637, "score": 1 }, { "doc_id": "7021566", "title": "Perceptual learning in humans: Roles of preexposure schedule, feedback, and discrimination assay", "abstract": "In three experiments, humans received preexposure to two compound flavours (AX and BX: saline–lemon and sucrose–lemon) that were presented either in an intermixed (e.g., AX, BX,… BX, AX,…) or a blocked (e.g., AX, AX,… BX, BX…) fashion. Subsequently, AX was paired with an unpleasant bitter taste, and the discriminability of AX and BX was assessed using the accuracy of same/different judgements and by the extent to which any learned dislike of AX generalized to BX. When participants received feedback about the accuracy of their same/different judgements during preexposure those given intermixed preexposure were more accurate in making these judgements during the test than those given blocked preexposure (Experiments 1 and 2A), however, there was no evidence of any learned dislike in these experiments. In Experiment 2B, in which participants did not receive feedback about the accuracy of their judgements, there was no effect of the preexposure regime on same/different judgements, but there was a learned dislike of AX, and this generalized less to BX in participants given intermixed than in those given blocked preexposure. The beneficial effects of intermixed preexposure are consistent with results from other species (chicks and rats), but the differences created by the presence or absence of feedback place constraints on the analysis of these effects.", "corpus_id": 7021566, "score": 0 }, { "doc_id": "44411447", "title": "Effects of Preexposure on Stimulus Discrimination: An Investigation of the Mechanisms Responsible for Human Perceptual Learning", "abstract": "The effect of preexposure on human perceptual learning was investigated in four experiments. In Experiments 1a and 1b, participants were preexposed to one pair of visual stimuli on an intermixed schedule (AX/BX) and one on a blocked schedule (CX_DX). The ability to discriminate between AX and BX and between CX and DX was then assessed by examining the extent to which key presses assigned to each member of a stimulus pair generalized to the other member (Experiment 1a) and by looking at the accuracy of same–different responses (Experiment 1b). Stimuli were more easily discriminated following intermixed than following blocked preexposure on both the generalization and same–different tasks. This suggests that two stimuli are more perceptually distinct after intermixed preexposure. Experiments 2a and 2b investigated the mechanisms responsible for perceptual learning using same–different tasks. The results support the suggestion that the enhanced discrimination observed after intermixed preexposure is due to increases in the salience of the unique elements.", "corpus_id": 44411447, "score": 0 }, { "doc_id": "13713607", "title": "An elemental model of associative learning: I. Latent inhibition and perceptual learning", "abstract": "This paper presents a brief, informal outline followed by a formal statement of an elemental associative learning model first described by McLaren, Kaye, and Mackintosh (1989). The model assumes representation of stimuli by sets of elements (i.e., microfeatures) and a set of associative algorithms that incorporate the following: real-time simulation of learning; an error-correcting learning rule; weight decay that distinguishes between transient and permanent associations; and modulation of associative learning that gives high salience to and, hence, promotes rapid learning with novel, unpredicted stimuli and reduces the salience for a stimulus as its error term declines. The model is applied in outline fashion to some of the basic phenomena of simple conditioning and, in greater detail, to the phenomena of latent inhibition and perceptual learning. A detailed account of generalization and discrimination will be provided in a later paper.", "corpus_id": 13713607, "score": 1 }, { "doc_id": "14438847", "title": "Perceptual learning.", "abstract": "Perceptual learning involves relatively long-lasting changes to an organism's perceptual system that improve its ability to respond to its environment. Four mechanisms of perceptual learning are discussed: attention weighting, imprinting, differentiation, and unitization. By attention weighting, perception becomes adapted to tasks and environments by increasing the attention paid to important dimensions and features. By imprinting, receptors are developed that are specialized for stimuli or parts of stimuli. By differentiation, stimuli that were once indistinguishable become psychologically separated. By unitization, tasks that originally required detection of several parts are accomplished by detecting a single constructed unit representing a complex configuration. Research from cognitive psychology, psychophysics, neuroscience, expert/novice differences, development, computer science, and cross-cultural differences is described that relates to these mechanisms. The locus, limits, and applications of perceptual learning are also discussed.", "corpus_id": 14438847, "score": 0 }, { "doc_id": "35160006", "title": "Stimulus generalization: some predictions from a model of Pavlovian conditioning.", "abstract": "Three experiments examined predictions generated by incorporating a common-elements account of stimulus generalization within the Rescorla-Wagner model of conditioning. All experiments employed rats in a conditioned suppression situation. Experiments 1 and 2 found that conditioning of a similar stimulus augmented the excitation controlled by a near-asymptotic target stimulus more than did further conditioning of the target itself. Prior discrimination training between the target and the similar stimulus enlarged this effect, compared with prior discrimination between the target and another dissimilar stimulus. Nonreinforced exposure of the similar stimulus prior to its reinforcement also increased the effect. Experiment 3 examined a related prediction for inhibition. After discrimination training, extinction of the previously reinforced stimulus revealed more inhibition to the previously nonreinforced stimulus when those two stimuli were more similar. These outcomes are consistent with deductions from the present model and encourage further testing of its expansion to the case of stimulus generalization.", "corpus_id": 35160006, "score": 0 }, { "doc_id": "4845131", "title": "Analysis of the Perceptual Learning Effect in Flavour Aversion Learning: Evidence for Stimulus Differentiation", "abstract": "Rats received exposure to two compound flavours, AX and BX, where A and B were sucrose and saline and X was acid. For group intermixed (I), exposure consisted of alternating trials with AX and BX; group blocked (B) received a block of AX trials and a separate block of BX trials. Experiment 1 showed that generalization to BX after conditioning with AX was less profound in group I than in group B. Separate examination of the elements of the compound showed that the source of this difference lay in the strength acquired by the X element. X acquired less strength in group I than in group B (Experiments 1 and 2), whereas for the A element (Experiments 3 and 4) the reverse pattern was obtained. These results support the proposal that the perceptual learning effect (restricted generalization from AX to BX in group I) depends on a process that enhances the effectiveness of unique stimulus elements (A and B) and reduces that of common elements (such as X).", "corpus_id": 4845131, "score": 1 }, { "doc_id": "7755061", "title": "Stimulus generalization as a function of stimulus novelty and familiarity in rats.", "abstract": "Three experiments used rats as subjects to investigate the generalization of conditioned responding between stimuli as a function of the subjects' exposure to these cues prior to conditioning. Experiment 1 used a between-subjects design, food as the reinforcer, and measured the tendency of subjects to approach the site of food delivery during the stimuli. Generalization of this response was more marked when the training and test stimuli were equated in terms of their novelty (i.e., when both were novel or both were familiar) than when the stimuli differed in this respect (i.e., when one was novel and the other was familiar). Experiments 2a and 2b used within-subjects designs to confirm the reliability of the results of Experiment 1. Implications of these results for current theories of stimulus representation are discussed.", "corpus_id": 7755061, "score": 1 }, { "doc_id": "40543386", "title": "Perceptual learning in flavor aversion: evidence for learned changes in stimulus effectiveness.", "abstract": "Rats were exposed to the compound flavors AX and BX, presented in alternation, and to CX on a separate block of trials. Generalization to BX after aversion conditioning with AX was less than to CX. An equivalent effect was found when the nature of the common element was changed after preexposure but not when the common element was omitted during preexposure, during conditioning and test, or both. Rats conditioned with X alone again showed less aversion to BX than to CX; similarly, rats conditioned with a novel flavor (Y) showed less aversion to BY than to CY. These effects support the proposal that intermixed preexposure to AX and BX enhances the perceptual effectiveness of their unique features, A and B.", "corpus_id": 40543386, "score": 0 }, { "doc_id": "22307154", "title": "Evidence for Inhibitory Associations between the Unique Elements of two Compound Flavours", "abstract": "In each of two experiments, rats were pre-exposed to two flavoured solutions, saline-lemon and sucrose-lemon. For group ALT, trials with one solution alternated with trials with the other. Group BLK received all trials with one solution in a block, before any trials with the other. An associative theory suggests that the alternating, but not the blocked, schedule would establish an inhibitory association between sucrose and saline. To provide a retardation test of this inhibition, some animals in each group were then given a single pairing of saline and sucrose, experienced sodium depletion, and were finally tested for their consumption of sucrose. Sodium depletion increased consumption of sucrose more in group BLK than in group ALT. In groups given no saline-sucrose pairing, sodium depletion had only a small effect on sucrose consumption, which was the same in both groups. After multiple pairings of saline and sucrose, sodium depletion had an equally large effect on sucrose consumption in both ALT and BLK groups. These results imply that alternating pre-exposure to two compound solutions does establish an inhibitory association between their unique elements, and thus provide support for an associative theory of perceptual learning.", "corpus_id": 22307154, "score": 0 }, { "doc_id": "22774250", "title": "Alternating exposure to two compound flavors creates inhibitory associations between their unique features", "abstract": "Rats were exposed to two compound solutions, saline-lemon and sucrose-lemon. In Group ALT, trials with one solution alternated with trials with the other. Group BLK received all trials with one solution before any trials with the other. Previous retardation tests had implied that only alternating exposure would establish sucrose as an inhibitor of saline. To provide a complementary summation test for this inhibition, in Experiment 1, all the animals received pairings of peppermint and saline and were tested for consumption of peppermint-sucrose under sodium depletion. Consumption was increased by sodium depletion only in Group BLK. In Experiment 2, a retardation test was used to show that presentation of saline-lemon before sucrose-lemon on each exposure day would establish sucrose as an inhibitor of saline. Neither exposure to sucrose-lemon before saline-lemon nor alternating exposure to sucrose and saline alone had the same effect. These results provide support for an associative theory of perceptual learning that suggests that exposure to complex stimuli aids later discrimination partially as a result of establishing inhibitory associations between their unique elements.", "corpus_id": 22774250, "score": 0 }, { "doc_id": "29214298", "title": "Comparison and Contrast as a Mechanism of Perceptual Learning?", "abstract": "In a series of flavour aversion experiments, rats received different schedules of pre-exposure to two compound flavours (AX and BX). Discrimination between them was assessed by establishing an aversion to AX and measuring generalization of this aversion to BX. Experiment 1 demonstrated that alternating pre-exposure to AX and BX resulted in less generalization than did blocked exposure, where animals received all exposure to AX before exposure to BX (or vice versa). This difference was not accompanied by any difference in the strength of the aversion conditioned to the common X element. Varying the interval between exposure to AX and BX in the alternating condition from a minute or two to several hours had no effect on generalization. However, Experiments 2 and 3 showed that when the interval between exposure to AX and that to BX was reduced to zero sec, the alternating schedule increased generalization between AX and BX. In this case, the increase in generalization was accompanied by an increase in the strength of the aversion conditioned to X.", "corpus_id": 29214298, "score": 1 }, { "doc_id": "197656244", "title": "A model for Pavlovian learning: Variations in the effectiveness of conditioned but not of unconditioned stimuli.", "abstract": "Several formal models of excitatory classical conditioning are reviewed. It is suggested that a central problem for all of them is the explanation of cases in which learning does not occur in spite of the fact that the conditioned stimulus is a signal for the reinforcer. We propose a new model that deals with this problem by specifying that certain procedures cause a conditioned stimulus (CS) to lose effectiveness; in particular, we argue that a CS will lose associability when its consequences are accurately predicted. In contrast to other current models, the effectiveness of the reinforcer remains constant throughout conditioning. The second part of the article presents a reformulation of the nature of the learning produced by inhibitory-conditioning procedures and a discussion of the way in which such learning can be accommodated within the model outlined for excitatory learning.", "corpus_id": 197656244, "score": 0 }, { "doc_id": "2039105", "title": "Stimulus Preexposure, Comparison, and Changes in the Associability of Common Stimulus Features", "abstract": "In four experiments, rats received preexposure either to both of two compound flavours (AX and BX), or to just one (BX). Experiment 1 demonstrated a perceptual learning effect, showing that, for animals given preexposure to both flavours, an aversion conditioned to AX generalized only poorly to BX. Subsequent experiments assessed the properties of the common feature, X. Experiment 3 showed that the two preexposure treatments did not differ in the extent to which they produced habituation of the neophobia evoked by X. Experiment 2 showed that conditioning to X proceeded more rapidly in subjects given preexposure to both AX and BX than in subjects preexposed to BX alone. In Experiment 4, a similar effect was found when the elements of the compounds were presented serially. It is concluded that the perceptual learning effect of Experiment 1 occurs in spite of the fact that preexposure to two stimuli tends to maintain the associability of their common elements.", "corpus_id": 2039105, "score": 0 } ]

{ "doc_id": "21688869", "title": "Age‐adjusted comorbidity and survival in locally advanced laryngeal cancer", "abstract": "The purpose of this study was to quantify the relationship among age, pretreatment comorbidity, and survival outcomes in patients with locally advanced laryngeal cancer.", "corpus_id": 21688869 }

[ { "doc_id": "18889458", "title": "Competing Causes of Death and Second Primary Tumors in Patients with Locoregionally Advanced Head and Neck Cancer Treated with Chemoradiotherapy", "abstract": "Purpose: The purpose of this retrospective analysis was to evaluate the emergence of second primary malignancies and the contribution of different causes of death to the outcome of patients with locoregionally advanced head and cancer receiving primary chemoradiotherapy. Experimental Design: We studied 324 patients with stage IV squamous cell head and neck cancer who were enrolled on five consecutive multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T-FHX). The cumulative incidence of second primary tumors or death from any cause was estimated using methods of competing risk analysis. Results: Median follow-up of surviving patients was 5.2 years (2–10.6 years). The 5-year overall survival and progression-free survival of the cohort were 46% and 65%, respectively. Causes of death and median time of occurrence were as follows: disease (n = 88; 1.5 years), treatment-associated acute or late complications (n = 30; 4 months), second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second primary tumor at a median time of 2.8 years (4 months to 10 years). The cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10 years, respectively. The most frequent site of second primaries was the lung (n = 13), followed by the esophagus (n = 3) and head and neck (n = 2) Conclusions: Patients with locoregionally advanced head and neck cancer treated with concurrent chemoradiotherapy are potentially curable but face significant risks of mortality from causes other than disease progression. Ameliorating toxicity, and implementing secondary screening and chemoprevention strategies are major goals in the management of head and neck cancer.", "corpus_id": 18889458, "score": 1 }, { "doc_id": "24077775", "title": "The impact of comorbidity on the survival of patients with squamous cell carcinoma of the head and neck", "abstract": "In North America, cigarette smoking and/or alcohol consumption not only cause head and neck cancer, they also cause many of the other diseases, illnesses, and conditions, also known as comorbidities, frequently found in our patients. Comorbidities can influence treatment decision making and treatment outcome. The aim of this study is to quantify the increased risk of comorbidity in our patients.", "corpus_id": 24077775, "score": 1 }, { "doc_id": "25776237", "title": "Predictors of competing mortality in advanced head and neck cancer.", "abstract": "PURPOSE Death from noncancer causes (competing mortality) is an important event in head and neck cancer, but studies identifying predictors of this event are lacking. We sought to identify predictors of competing mortality and develop a risk stratification model for competing events. PATIENTS AND METHODS Cohort study of 479 patients with stage III to IV carcinoma of the head and neck diagnosed between August 1993 and November 2004. Patients were treated on consecutive prospective clinical trials involving organ-preserving chemoradiotherapy and surgery. We used multivariable competing risks regression models to analyze factors associated with the cumulative incidence of competing mortality, locoregional and distant failure, and second malignancies as first events. Results Median follow-up was 52 months median for survivors. The 5-year cumulative incidence of competing mortality was 19.6% (95% CI, 15.8 to 23.4). On multivariable analysis, competing mortality was associated with female sex (hazard ratio [HR], 1.72; 95% CI, 1.13 to 2.63), increasing age (HR, 1.30; 95% CI, 1.04 to 1.62), increasing Charlson Comorbidity Index (HR, 1.24; 95% CI, 1.05 to 1.47), decreasing body mass index (HR, 0.33; 95% CI, 0.13 to 0.84), and decreasing distance traveled to the treating center (HR, 0.65; 95% CI, 0.44 to 0.98). Patients with zero, one, two, and > or = three risk factors had 5-year competing mortality of 8.9% (95% CI, 3.0% to 14.8%), 12.4% (95% CI, 7.0% to 17.8%), 22.1% (95% CI, 14.5% to 29.7%), and 39.3% (95% CI, 28.6% to 50.1%), respectively. CONCLUSION Competing mortality in advanced head and neck cancer is associated with several demographic and health status characteristics. Analyses of risk factors for competing mortality may be useful in outcomes reporting and designing clinical trials.", "corpus_id": 25776237, "score": 1 }, { "doc_id": "12041658", "title": "The impact of comorbidity on the survival of patients with laryngeal squamous cell carcinoma", "abstract": "Abstract Conclusions: In survival analysis, the combined Charlson comorbidity index (CCI) can be considered as a prognostic factor independent of the tumor node metastasis (TNM) classification, tumor stage, and tumor location. Severe comorbidity was the factor that had the greatest impact on prognosis in cases of initial tumor. Objective: To study the influence of comorbidity on the survival of patients undergoing surgery for larynx cancer. Methods: This was a retrospective study of the survival of 231 patients with laryngeal cancer who underwent surgery between 1995 and 2002. The CCI was used to assess comorbidity, the Kaplan–Meier method was used for survival analysis, and the Cox proportional risk regression model was used to identify independent prognostic factors. Results: The multivariate analysis of specific mortality showed that patients classified as having severe comorbidity (CCI) were more likely to die (adjusted hazard ratio (adjHR) 1.85, 95% confidence interval (CI) 1.07–3.17). This difference was more important in patients with early tumor stages than in those with advanced stages.", "corpus_id": 12041658, "score": 0 }, { "doc_id": "23282922", "title": "The significance of comorbidity in advanced laryngeal cancer", "abstract": "Cancer patients often have concurrent diseases and conditions known as comorbidities. The aim of this project is to demonstrate the significance of comorbidity in the treatment and outcomes of advanced laryngeal carcinoma.", "corpus_id": 23282922, "score": 1 }, { "doc_id": "33101563", "title": "The Impact of Comorbidity and Age on Survival with Laryngeal Cancer", "abstract": "Previous studies have evaluated the effects of comorbidity on survival in patients with cancer. We applied the Charlson comorbidity index (CCI) to a cohort of patients with laryngeal cancer to validate its use and to assess the prognostic impact of age. Our study population consisted of 152 patients with laryngeal cancer who were seen over a 10-year period. Patients were assigned CCI scores and were categorized into low- and high-grade comorbidity groups for comparison. Age adjustments were performed by adding 1 point to the Charlson score for each decade over the median age. Low- vs. high-grade comorbidity was a valid predictor of survival independent of TNM (tumor, nodes, and metastases) stage. Low-grade comorbidity was present in 126 patients; their median survival was 41 months. High-grade comorbidity was present in 26 patients; their median survival was 8 months (p = 0.0002). The addition of the age factor to the CCI did not improve our prognostic ability. There was no difference in CCI groups with respect to tobacco and alcohol use, gender, treatment modality, or mean time to recurrence. The incidence and severity of complications were also similar in the two groups. We conclude that the CCI is a strong predictor of survival inpatients with laryngeal cancer. The confounding effects of comorbidity should be considered in the TNM staging of laryngeal cancer to improve our prognostic ability. Further investigations are necessary to assess the validity of this index inpatients with other head and neck cancers.", "corpus_id": 33101563, "score": 1 }, { "doc_id": "24251260", "title": "Impact of comorbidity on the outcome of laryngeal squamous cancer", "abstract": "Comorbidity has been shown to be a determinant in treatment selection and survival in various cancers. We have previously shown that the Adult Comorbidity Evaluation—27 index is applicable in a United Kingdom setting, and the process of comorbidity grading by retrospective notes evaluation is an accurate and reliable process.", "corpus_id": 24251260, "score": 1 }, { "doc_id": "45109928", "title": "Importance of Comorbidity in Head and Neck Cancer", "abstract": "Objectives/Hypothesis Patients with head and neck cancer are staged according to the morphology of the tumor with little or no attention given to the importance of the other diseases, illnesses, or conditions. These other conditions are generally referred to as comorbidities. Although not a feature of the cancer itself, comorbidity is an important attribute of the patient with cancer. Comorbidity has direct impact on the care of patients, selection of initial treatment, and evaluation of treatment effectiveness. The objective of this thesis is to demonstrate the importance of comorbidity in head and neck cancer. Specifically, the aims are 1) to demonstrate the burden of comorbidity among head and neck cancer patients by comparing the incidence of none, mild, moderate, and severe comorbidity among patients with head and neck cancer to patients with cancers of the colorectum, lung, breast, gynecological sites, or prostate, 2) to demonstrate the independent impact of comorbidity on overall survival, and 3) to demonstrate the importance of comorbidity in the assessment of initial treatment effectiveness.", "corpus_id": 45109928, "score": 0 }, { "doc_id": "10105641", "title": "Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer.", "abstract": "BACKGROUND\nWe performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation.\n\n\nMETHODS\nThree hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy.\n\n\nRESULTS\nAfter two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease.\n\n\nCONCLUSIONS\nThese preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.", "corpus_id": 10105641, "score": 0 }, { "doc_id": "23079942", "title": "Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer.", "abstract": "BACKGROUND\nInduction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the standard alternative to total laryngectomy for patients with locally advanced laryngeal cancer. The value of adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown.\n\n\nMETHODS\nWe randomly assigned patients with locally advanced cancer of the larynx to one of three treatments: induction cisplatin plus fluorouracil followed by radiotherapy, radiotherapy with concurrent administration of cisplatin, or radiotherapy alone. The primary end point was preservation of the larynx.\n\n\nRESULTS\nA total of 547 patients were randomly assigned to one of the three study groups. The median follow-up period was 3.8 years. At two years, the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin (88 percent) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy (75 percent, P=0.005) or radiotherapy alone (70 percent, P<0.001). The rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin (78 percent, vs. 61 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 56 percent with radiotherapy alone). Both of the chemotherapy-based regimens suppressed distant metastases and resulted in better disease-free survival than radiotherapy alone. However, overall survival rates were similar in all three groups. The rate of high-grade toxic effects was greater with the chemotherapy-based regimens (81 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 82 percent with radiotherapy with concurrent cisplatin, vs. 61 percent with radiotherapy alone). The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy.\n\n\nCONCLUSIONS\nIn patients with laryngeal cancer, radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control.", "corpus_id": 23079942, "score": 0 }, { "doc_id": "23999885", "title": "Population-based study of competing mortality in head and neck cancer.", "abstract": "PURPOSE\nPatients with head and neck cancer (HNC) are at high risk of death resulting from noncancer causes and second malignancies (ie, competing mortality). Variation in competing mortality risk complicates individual treatment choices and design and interpretation of clinical studies.\n\n\nMETHODS\nUsing the Surveillance, Epidemiology, and End Results registry, we identified 34,568 patients with nonmetastatic squamous cell carcinoma of the head and neck diagnosed between 1994 and 2003. We developed a multivariable competing-risk regression model to stratify patients according to competing mortality risk and evaluate the impact of this risk on power loss in clinical studies.\n\n\nRESULTS\nThe 5-year cumulative incidences of all-cause mortality, HNC-specific mortality, and competing mortality were 51.3% (95% CI, 50.8% to 51.9%), 23.8% (95% CI, 23.3% to 24.2%), and 27.6% (95% CI, 26.8% to 28.3%), respectively. Factors associated with increased competing mortality were increasing age, male sex, black race, unmarried status, localized disease, higher socioeconomic status, nonsurgical treatment, and hypopharyngeal, nasopharyngeal, and oral cavity subsites. The 5-year cumulative incidences of competing mortality for patients in low-, medium-, and high-risk score tertiles were 20.0% (95% CI, 18.8% to 21.3%), 27.7% (95% CI, 26.3% to 29.1%), and 33.7% (95% CI, 32.2% to 35.2%), respectively. Compared with patients with low competing mortality risk, relative sample sizes required to show benefit of a treatment regarding all-cause mortality were 12% and 42% higher in the medium- and high-risk groups, respectively.\n\n\nCONCLUSION\nMultiple factors affect risk of competing mortality among patients with HNC. Risk stratification would be useful to identify patients most likely to benefit from treatment intensification.", "corpus_id": 23999885, "score": 1 }, { "doc_id": "26747477", "title": "Cancer-Specific Mortality and Competing Mortality in Patients with Head and Neck Squamous Cell Carcinoma: A Competing Risk Analysis", "abstract": "BackgroundThe objective of this study was to estimate probabilities of cancer-specific death and competing death for patients with head and neck squamous cell carcinoma (HNSCC). In addition, we attempted to construct competing risk nomograms to predict prognosis for patients with HNSCC using a large population-based cohort.MethodsPatients diagnosed with nonmetastatic HNSCC between 2000 and 2010 were identified from the Surveillance Epidemiology and End Results Program to form the analytic cohort. We estimated cumulative incident function (CIF) of cancer-specific mortality and competing mortality. Nomograms for predicting probability of death were built with proportional subdistribution hazard models.ResultsThe study cohort included 23,494 patients with HNSCC. The 5-year CIF for cancer-specific death and competing death were 26.7 % (95 % confidence interval [CI] 26–27.3 %) and 12.7 % (95 % CI 12.2–13.3 %), respectively; 10-year CIF were 32.8 % (95 % CI 31.9–33.6 %) and 23 % (95 % CI 22.1–24 %), respectively. On multivariate analysis, increasing cause-specific mortality was associated with increasing age, increasing tumor size, black race, single status, advanced T and N classifications, and high tumor grade. Increasing probability of competing mortality had a relationship with increasing age, male, black race, single status and nonradiotherapy. Models showed good accuracy with c-index of 0.73 for cause-specific mortality model and 0.69 for competing mortality model.ConclusionsWe constructed competing risk nomograms for HNSCC using population-based data. The model used for building nomograms represented good performance. These nomograms can serve to guide management of patients with HNSCC.", "corpus_id": 26747477, "score": 0 }, { "doc_id": "3561078", "title": "Long‐term outcomes after multidisciplinary management of T3 laryngeal squamous cell carcinomas: Improved functional outcomes and survival with modern therapeutic approaches", "abstract": "The purpose of this study was to evaluate the long‐term outcomes after initial definitive or adjuvant radiotherapy (RT) for T3 laryngeal cancers.", "corpus_id": 3561078, "score": 0 }, { "doc_id": "14158422", "title": "Noncancer health events as a leading cause of competing mortality in advanced head and neck cancer.", "abstract": "BACKGROUND\nThe survival of patients with head and neck squamous cell carcinoma (HNSCC) can be affected by noncancer health events (NCHE) as well as by index cancer progression and second primary cancer (SPC). This study aimed to investigate the risk factors for NCHE and noncancer mortality (NCM) in patients with advanced-stage HNSCC.\n\n\nPATIENTS AND METHODS\nThis cohort study involved 600 consecutive patients with overall stage III to IV HNSCC who were treated between 2001 and 2010 at our tertiary referral hospital. NCHE was defined as re-admission (i.e. after the primary treatments for the index tumors) due to noncancer-related causes. The incidences of NCHE and NCM and their risk factors were analyzed by using cumulative incidence and cause-specific hazard functions.\n\n\nRESULTS\nDuring a median follow-up period of 54 months, 224 (37.3%) and 55 (9.2%) of the 600 patients had NCHE and NCM, respectively. The 5-year index cancer mortality, SPC mortality, and NCM rates were 23.8%, 4.2%, and 8.9%, respectively. Multivariate analyses revealed that body mass index <20 kg/m(2) (P = 0.018), Charlson comorbidity index (CCI) ≥1 (P < 0.001), tumor recurrence (P < 0.001), SPC occurrence (P < 0.001), and initial chemotherapy (P = 0.049) were independent NCHE predictors. Older age (P < 0.001), CCI ≥1 (P = 0.008), tumor recurrence (P < 0.001), and SPC occurrence (P = 0.047) were independent NCM predictors. Patients with respiratory NCHE were at a higher risk of NCM than patients with other NCHE types (P < 0.001).\n\n\nCONCLUSIONS\nOne or more comorbidities, tumor recurrence, and SPC occurrence were independent predictors of both NCHE and NCM. Patients with respiratory NCHE had a particularly high risk of NCM.", "corpus_id": 14158422, "score": 0 }, { "doc_id": "293058", "title": "Long‐term outcomes after surgical or nonsurgical initial therapy for patients with T4 squamous cell carcinoma of the larynx: A 3‐decade survey", "abstract": "The current study was conducted to evaluate long‐term disease control, survival, and functional outcomes after surgical and nonsurgical initial treatment for patients with T4 larynx cancer.", "corpus_id": 293058, "score": 0 }, { "doc_id": "7287329", "title": "A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.", "abstract": "The objective of this study was to develop a prospectively applicable method for classifying comorbid conditions which might alter the risk of mortality for use in longitudinal studies. A weighted index that takes into account the number and the seriousness of comorbid disease was developed in a cohort of 559 medical patients. The 1-yr mortality rates for the different scores were: \"0\", 12% (181); \"1-2\", 26% (225); \"3-4\", 52% (71); and \"greater than or equal to 5\", 85% (82). The index was tested for its ability to predict risk of death from comorbid disease in the second cohort of 685 patients during a 10-yr follow-up. The percent of patients who died of comorbid disease for the different scores were: \"0\", 8% (588); \"1\", 25% (54); \"2\", 48% (25); \"greater than or equal to 3\", 59% (18). With each increased level of the comorbidity index, there were stepwise increases in the cumulative mortality attributable to comorbid disease (log rank chi 2 = 165; p less than 0.0001). In this longer follow-up, age was also a predictor of mortality (p less than 0.001). The new index performed similarly to a previous system devised by Kaplan and Feinstein. The method of classifying comorbidity provides a simple, readily applicable and valid method of estimating risk of death from comorbid disease for use in longitudinal studies. Further work in larger populations is still required to refine the approach because the number of patients with any given condition in this study was relatively small.", "corpus_id": 7287329, "score": 0 }, { "doc_id": "20979343", "title": "Validation of the Charlson Comorbidity Index in Patients With Head and Neck Cancer: A Multi‐institutional Study", "abstract": "Comorbid conditions are medical illnesses that accompany cancer. The impact of these conditions on the outcome of patients with head and neck cancer is well established. However, all of the comorbidity studies in patients with head and neck cancer reported in the literature have been performed using the Kaplan‐Feinstein index (KFI), which may be too complicated for routine use. This study was performed to introduce and validate the use of the Charlson comorbidity index (CI) in patients with head and neck cancer and to compare it with the Kaplan‐Feinstein comorbidity index for accuracy and ease of use. Study design was a retrospective cohort study. The study population was drawn for three academic tertiary care centers and included 88 patients 45 years of age and under who underwent curative treatment for head and neck cancer. All patients were staged by the KFI and the CI for comorbidity and divided into two groups based on the comorbidity severity staging. Group 1 included patients with advanced comorbidity (stages 2 or 3), and group 2 included those with low‐level comorbidity (stages 0 or 1). Outcomes were compared based on these divisions. The KFI was successfully applied to 80% of this study population, and the CI was successfully applied in all cases ( P < 0.0001). In addition, the KFI was found to be more difficult to use than the CI ( P < 0.0001). However, both indices independently predicted the tumor‐specific survival ( P = 0.007), even after adjusting for the confounding effects of TNM stage by multivariate analysis. Overall, the CI was found to be a valid prognostic indicator in patients with head and neck cancer. In addition, because comorbidity staging by the CI independently predicted survival, was easier to use, and more readily applied, it may be better suited for use for retrospective comorbidity studies.", "corpus_id": 20979343, "score": 0 }, { "doc_id": "36858092", "title": "Validation of a combined comorbidity index.", "abstract": "The basic objective of this paper is to evaluate an age-comorbidity index in a cohort of patients who were originally enrolled in a prospective study to identify risk factors for peri-operative complications. Two-hundred and twenty-six patients were enrolled in the study. The participants were patients with hypertension or diabetes who underwent elective surgery between 1982 and 1985 and who survived to discharge. Two-hundred and eighteen patients survived until discharge. These patients were followed for at least five years post-operatively. The estimated relative risk of death for each comorbidity rank was 1.4 and for each decade of age was 1.4. When age and comorbidity were modelled as a combined age-comorbidity score, the estimated relative risk for each combined age-comorbidity unit was 1.45. Thus, the estimated relative risk of death from an increase of one in the comorbidity score proved approximately equal to that from an additional decade of age. The combined age-comorbidity score may be useful in some longitudinal studies to estimate relative risk of death from prognostic clinical covariates.", "corpus_id": 36858092, "score": 0 }, { "doc_id": "4636226", "title": "Validity of the Age-Adjusted Charlson Comorbidity Index on Clinical Outcomes for Patients with Nasopharyngeal Cancer Post Radiation Treatment: A 5-Year Nationwide Cohort Study", "abstract": "Purpose To characterize the impact of comorbidity on survival outcomes for patients with nasopharyngeal carcinoma (NPC) post radiotherapy (RT). Methods A total of 4095 patients with NPC treated by RT or RT plus chemotherapy (CT) in the period from 2007 to 2011 were included through Taiwan’s National Health Insurance Research Database. Information on comorbidity present prior to the NPC diagnosis was obtained and adapted to the Charlson Comorbidity Index (CCI), Age-Adjusted Charlson Comorbidity Index (ACCI) and a revised head and neck comorbidity index (HN-CCI). The prevalence of comorbidity and the influence on survival were calculated and analyzed. Results Most of the patients (75%) were male (age 51±13 years) and 2470 of them (60%) had at least one comorbid condition. The most common comorbid condition was diabetes mellitus. According to these three different comorbidity index (CCI, ACCI and HN-CCI), higher scores were associated with worse overall survival (P< 0.001). The Receiver Operating Characteristic (ROC) curve was used to assess the discriminating ability of CCI, AACI and HN-CCI scores and it demonstrated the predictive ability for mortality with the ACCI (0.693, 95% CI 0.670–0.715) was superior to that of the CCI (0.619, 95% CI 0.593–0.644) and HN-CCI (0.545, 95%CI 0.519–0.570). Conclusion Comorbidities greatly influenced the clinical presentations, therapeutic interventions, and outcomes of patients with NPC post RT. Higher comorbidity index scores accurately was associated with worse survival. The ACCI seems to be a more appropriate prognostic indicator and should be considered in further clinical studies.", "corpus_id": 4636226, "score": 0 }, { "doc_id": "122534821", "title": "Bayesian Model Selection in Social Research", "abstract": "It is argued that P-values and the tests based upon them give unsatisfactory results, especially in large samples. It is shown that, in regression, when there are many candidate independent variables, standard variable selection procedures can give very misleading results. Also, by selecting a single model, they ignore model uncertainty and so underestimate the uncertainty about quantities of interest. The Bayesian approach to hypothesis testing, model selection, and accounting for model uncertainty is presented. Implementing this is straightforward through the use of the simple and accurate BIC approximation, and it can be done using the output from standard software. Specific results are presented for most of the types of model commonly used in sociology. It is shown that this approach overcomes the difficulties with P-values and standard model selection procedures based on them. It also allows easy comparison of nonnested models, and permits the quantification of the evidence for a null hypothesis of interest, such as a convergence theory or a hypothesis about societal norms.", "corpus_id": 122534821, "score": 0 }, { "doc_id": "207294779", "title": "Predictive factors of survival and treatment tolerance in older patients treated with chemotherapy and radiotherapy for locally advanced head and neck cancer.", "abstract": "PURPOSE\nTo report outcomes and predictive factors of overall survival, hospitalization and treatment completion rates in elderly patients with locally advanced head and neck cancer treated with concurrent chemoradiotherapy (CRT).\n\n\nMATERIAL AND METHODS\nA retrospective analysis of patients aged 70years or older treated with concurrent CRT for locally advanced head and neck cancer was conducted. Univariate and multivariate analysis as well as competing risk survival analysis were used to determine predictors of mortality. Logistic regression was used to predict for hospitalization and treatment completion rates.\n\n\nRESULTS\nIn total, 129 patients were included. Median follow-up was 27months (range: 1.7-125months). Completion rate of combined CRT was 84%. Actuarial OS and DSS at 4years were 56% and 75%. Hospitalization rate was 36%. On multivariate analysis, a Karnofsky performance status (KPS) ⩽80 was predictive of mortality. Using competing risks, KPS ⩽80 and weight loss >5% were predictive of cancer mortality whereas Charlson score ⩾3 was predictive of mortality due to other causes. On logistic regression, patients with abnormal renal function and lower body mass index were more likely to be hospitalized during their treatment course. Charlson score and chemotherapy regimen were predictive of treatment completion.\n\n\nCONCLUSION\nConcurrent CRT may be a feasible treatment option for healthier older patients at the cost of high hospitalization rates. Pre-treatment factors linked to physiological age such as KPS ⩽80, Charlson score ⩾3, abnormal renal function should be considered at the time of treatment decision.", "corpus_id": 207294779, "score": 0 } ]

{ "doc_id": "203616909", "title": "D ec 2 01 0 Compressive Sensing Over Networks", "abstract": "In this paper, we demonstrate some applications of compressive sensing over networks. We make a connection between compressive sensing and traditional information t heoretic techniques in source coding and channel coding. Our results provide an explicit trade-off between the rate and t he decoding complexity. The key difference of compressive sen si g and traditional information theoretic approaches is at their decoding side. Although optimal decoders to recover the ori g nal signal, compressed by source coding have high complexity, t he compressive sensing decoder is a linear or convex optimizat ion. First, we investigate applications of compressive sensingon distributed compression of correlated sources. Here, by us ing compressive sensing, we propose a compression scheme for a family of correlated sources with a modularized decoder, providing a trade-off between the compression rate and the decoding complexity. We call this schemeSparse Distributed Compression. We use this compression scheme for a general multicast network with correlated sources. Here, we first decode some of the sources by a network decoding technique and then, we use a compressive sensing decoder to obtain the whole sources. Then, we investigate applications of compre ssive sensing on channel coding. We propose a coding scheme that combines compressive sensing and random channel coding for a high-SNR point-to-point Gaussian channel. We call this sch eme Sparse Channel Coding. We propose a modularized decoder providing a trade-off between the capacity loss and the deco ding complexity. At the receiver side, first, we use a compressive sensing decoder on a noisy signal to obtain a noisy estimate of the original signal and then, we apply a traditional channel coding decoder to find the original signal.", "corpus_id": 203616909 }

[ { "doc_id": "119159284", "title": "Stable signal recovery from incomplete and inaccurate measurements", "abstract": "Suppose we wish to recover a vector x_0 Є R^m (e.g., a digital signal or image) from incomplete and contaminated observations y = Ax_0 + e; A is an n by m matrix with far fewer rows than columns (n « m) and e is an error term. Is it possible to recover x_0 accurately based on the data y? \nTo recover x_0, we consider the solution x^# to the l_(1-)regularization problem min ‖x‖l_1 subject to ‖Ax - y‖l(2) ≤ Є, where Є is the size of the error term e. We show that if A obeys a uniform uncertainty principle (with unit-normed columns) and if the vector x_0 is sufficiently sparse, then the solution is within the noise level ‖x^# - x_0‖l_2 ≤ C Є. As a first example, suppose that A is a Gaussian random matrix; then stable recovery occurs for almost all such A's provided that the number of nonzeros of x_0 is of about the same order as the number of observations. As a second instance, suppose one observes few Fourier samples of x_0; then stable recovery occurs for almost any set of n coefficients provided that the number of nonzeros is of the order of n/[log m]^6. In the case where the error term vanishes, the recovery is of course exact, and this work actually provides novel insights into the exact recovery phenomenon discussed in earlier papers. The methodology also explains why one can also very nearly recover approximately sparse signals.", "corpus_id": 119159284, "score": 1 }, { "doc_id": "85699", "title": "Sparsity and incoherence in compressive sampling", "abstract": "We consider the problem of reconstructing a sparse signal x 0 2 R n from a limited number of linear measurements. Given m randomly selected samples of Ux 0 , where U is an orthonormal matrix, we show that ‘1 minimization recovers x 0 exactly when the number of measurements exceeds m Const ·µ 2 (U) ·S · logn, where S is the number of nonzero components in x 0 , and µ is the largest entry in U properly normalized: µ(U) = p n · maxk,j |Uk,j|. The smaller µ, the fewer samples needed. The result holds for “most” sparse signals x 0 supported on a fixed (but arbitrary) set T. Given T, if the sign of x 0 for each nonzero entry on T and the observed values of Ux 0 are drawn at random, the signal is recovered with overwhelming probability. Moreover, there is a sense in which this is nearly optimal since any method succeeding with the same probability would require just about this many samples.", "corpus_id": 85699, "score": 1 }, { "doc_id": "206737254", "title": "Compressed sensing", "abstract": "Suppose x is an unknown vector in Ropfm (a digital image or signal); we plan to measure n general linear functionals of x and then reconstruct. If x is known to be compressible by transform coding with a known transform, and we reconstruct via the nonlinear procedure defined here, the number of measurements n can be dramatically smaller than the size m. Thus, certain natural classes of images with m pixels need only n=O(m1/4log5/2(m)) nonadaptive nonpixel samples for faithful recovery, as opposed to the usual m pixel samples. More specifically, suppose x has a sparse representation in some orthonormal basis (e.g., wavelet, Fourier) or tight frame (e.g., curvelet, Gabor)-so the coefficients belong to an lscrp ball for 0<ples1. The N most important coefficients in that expansion allow reconstruction with lscr2 error O(N1/2-1p/). It is possible to design n=O(Nlog(m)) nonadaptive measurements allowing reconstruction with accuracy comparable to that attainable with direct knowledge of the N most important coefficients. Moreover, a good approximation to those N important coefficients is extracted from the n measurements by solving a linear program-Basis Pursuit in signal processing. The nonadaptive measurements have the character of \"random\" linear combinations of basis/frame elements. Our results use the notions of optimal recovery, of n-widths, and information-based complexity. We estimate the Gel'fand n-widths of lscrp balls in high-dimensional Euclidean space in the case 0<ples1, and give a criterion identifying near- optimal subspaces for Gel'fand n-widths. We show that \"most\" subspaces are near-optimal, and show that convex optimization (Basis Pursuit) is a near-optimal way to extract information derived from these near-optimal subspaces", "corpus_id": 206737254, "score": 1 }, { "doc_id": "2589993", "title": "Shannon-Theoretic Limits on Noisy Compressive Sampling", "abstract": "In this paper, we study the number of measurements required to recover a sparse signal in CM with L nonzero coefficients from compressed samples in the presence of noise. We consider a number of different recovery criteria, including the exact recovery of the support of the signal, which was previously considered in the literature, as well as new criteria for the recovery of a large fraction of the support of the signal, and the recovery of a large fraction of the energy of the signal. For these recovery criteria, we prove that O(L) (an asymptotically linear multiple of L) measurements are necessary and sufficient for signal recovery, whenever L grows linearly as a function of M. This improves on the existing literature that is mostly focused on variants of a specific recovery algorithm based on convex programming, for which O(L log(M - L)) measurements are required. In contrast, the implementation of our proof method would have a higher complexity. We also show that O(L log(M - L)) measurements are required in the sublinear regime (L - o(M)). For our sufficiency proofs, we introduce a Shannon-theoretic decoder based on joint typicality, which allows error events to be defined in terms of a single random variable in contrast to previous information-theoretic work, where comparison of random variables are required. We also prove concentration results for our error bounds implying that a randomly selected Gaussian matrix will suffice with high probability. For our necessity proofs, we rely on results from channel coding and rate-distortion theory.", "corpus_id": 2589993, "score": 0 }, { "doc_id": "14189698", "title": "Measurements vs. Bits: Compressed Sensing meets Information Theory", "abstract": "Compressed sensing is a new framework for acquiring sparse signals based on the revelation that a small number of linear projections (measurements) of the signal contain enough information for its reconstruction. The foundation of Compressed sensing is built on the availability of noise-free measurements. However, measurement noise is unavoidable in analog systems and must be accounted for. We demonstrate that measurement noise is the crucial factor that dictates the number of measurements needed for reconstruction. To establish this result, we evaluate the information contained in the measurements by viewing the measurement system as an information theoretic channel. Combining the capacity of this channel with the ratedistortion function of the sparse signal, we lower bound the rate-distortion performance of a compressed sensing system. Our approach concisely captures the effect of measurement noise on the performance limits of signal reconstruction, thus enabling to benchmark the performance of specific reconstruction algorithms.", "corpus_id": 14189698, "score": 0 }, { "doc_id": "2329522", "title": "Performance tradeoffs for exact support recovery of sparse signals", "abstract": "We study the tradeoffs between the number of measurements, the signal sparsity level, and the measurement noise level for exact support recovery of sparse signals via random noisy measurements. By drawing analogy between exact support recovery and communication over the Gaussian multiple access channel, and exploiting mathematical tools developed for the latter problem, we derive sharp asymptotic sufficient and necessary conditions for exact support recovery. Specifically, when the number of nonzero entries is held fixed, the exact asymptotics on the number of measurements for support recovery is developed. When the number of nonzero entries increases in certain manners, we obtain sufficient conditions tighter than existing results. The proposed information theoretic framework for analyzing the performance of support recovery is further demonstrated to be capable of dealing with a variety of sparse signal recovery models.", "corpus_id": 2329522, "score": 0 }, { "doc_id": "12605120", "title": "Decoding by linear programming", "abstract": "This paper considers a natural error correcting problem with real valued input/output. We wish to recover an input vector f/spl isin/R/sup n/ from corrupted measurements y=Af+e. Here, A is an m by n (coding) matrix and e is an arbitrary and unknown vector of errors. Is it possible to recover f exactly from the data y? We prove that under suitable conditions on the coding matrix A, the input f is the unique solution to the /spl lscr//sub 1/-minimization problem (/spl par/x/spl par//sub /spl lscr/1/:=/spl Sigma//sub i/|x/sub i/|) min(g/spl isin/R/sup n/) /spl par/y - Ag/spl par//sub /spl lscr/1/ provided that the support of the vector of errors is not too large, /spl par/e/spl par//sub /spl lscr/0/:=|{i:e/sub i/ /spl ne/ 0}|/spl les//spl rho//spl middot/m for some /spl rho/>0. In short, f can be recovered exactly by solving a simple convex optimization problem (which one can recast as a linear program). In addition, numerical experiments suggest that this recovery procedure works unreasonably well; f is recovered exactly even in situations where a significant fraction of the output is corrupted. This work is related to the problem of finding sparse solutions to vastly underdetermined systems of linear equations. There are also significant connections with the problem of recovering signals from highly incomplete measurements. In fact, the results introduced in this paper improve on our earlier work. Finally, underlying the success of /spl lscr//sub 1/ is a crucial property we call the uniform uncertainty principle that we shall describe in detail.", "corpus_id": 12605120, "score": 1 }, { "doc_id": "15911073", "title": "A Simple Proof of the Restricted Isometry Property for Random Matrices", "abstract": "Abstract\nWe give a simple technique for verifying the Restricted Isometry Property (as introduced by Candès and Tao) for random matrices that underlies Compressed Sensing. Our approach has two main ingredients: (i) concentration inequalities for random inner products that have recently provided algorithmically simple proofs of the Johnson–Lindenstrauss lemma; and (ii) covering numbers for finite-dimensional balls in Euclidean space. This leads to an elementary proof of the Restricted Isometry Property and brings out connections between Compressed Sensing and the Johnson–Lindenstrauss lemma. As a result, we obtain simple and direct proofs of Kashin’s theorems on widths of finite balls in Euclidean space (and their improvements due to Gluskin) and proofs of the existence of optimal Compressed Sensing measurement matrices. In the process, we also prove that these measurements have a certain universality with respect to the sparsity-inducing basis.\n", "corpus_id": 15911073, "score": 0 }, { "doc_id": "18931062", "title": "Database-friendly random projections: Johnson-Lindenstrauss with binary coins", "abstract": "A classic result of Johnson and Lindenstrauss asserts that any set of n points in d-dimensional Euclidean space can be embedded into k-dimensional Euclidean space---where k is logarithmic in n and independent of d--so that all pairwise distances are maintained within an arbitrarily small factor. All known constructions of such embeddings involve projecting the n points onto a spherically random k-dimensional hyperplane through the origin. We give two constructions of such embeddings with the property that all elements of the projection matrix belong in {-1, 0, +1 }. Such constructions are particularly well suited for database environments, as the computation of the embedding reduces to evaluating a single aggregate over k random partitions of the attributes.", "corpus_id": 18931062, "score": 0 }, { "doc_id": "1324170", "title": "A Random Linear Network Coding Approach to Multicast", "abstract": "We present a distributed random linear network coding approach for transmission and compression of information in general multisource multicast networks. Network nodes independently and randomly select linear mappings from inputs onto output links over some field. We show that this achieves capacity with probability exponentially approaching 1 with the code length. We also demonstrate that random linear coding performs compression when necessary in a network, generalizing error exponents for linear Slepian-Wolf coding in a natural way. Benefits of this approach are decentralized operation and robustness to network changes or link failures. We show that this approach can take advantage of redundant network capacity for improved success probability and robustness. We illustrate some potential advantages of random linear network coding over routing in two examples of practical scenarios: distributed network operation and networks with dynamically varying connections. Our derivation of these results also yields a new bound on required field size for centralized network coding on general multicast networks", "corpus_id": 1324170, "score": 1 }, { "doc_id": "18528474", "title": "Distributed source coding using syndromes (DISCUS): design and construction", "abstract": "We address the problem of compressing correlated distributed sources, i.e., correlated sources which are not co-located or which cannot cooperate to directly exploit their correlation. We consider the related problem of compressing a source which is correlated with another source that is available only at the decoder. This problem has been studied in the information theory literature under the name of the Slepian-Wolf (1973) source coding problem for the lossless coding case, and as \"rate-distortion with side information\" for the lossy coding case. We provide a constructive practical framework based on algebraic trellis codes dubbed as DIstributed Source Coding Using Syndromes (DISCUS), that can be applicable in a variety of settings. Simulation results are presented for source coding of independent and identically distributed (i.i.d.) Gaussian sources with side information available at the decoder in the form of a noisy version of the source to be coded. Our results reveal the promise of this approach: using trellis-based quantization and coset construction, the performance of the proposed approach is 2-5 dB from the Wyner-Ziv (1976) bound.", "corpus_id": 18528474, "score": 0 }, { "doc_id": "1879649", "title": "Low-Complexity Approaches to Slepian&#8211;Wolf Near-Lossless Distributed Data Compression", "abstract": "This paper discusses the Slepian-Wolf problem of distributed near-lossless compression of correlated sources. We introduce practical new tools for communicating at all rates in the achievable region. The technique employs a simple \"source-splitting\" strategy that does not require common sources of randomness at the encoders and decoders. This approach allows for pipelined encoding and decoding so that the system operates with the complexity of a single user encoder and decoder. Moreover, when this splitting approach is used in conjunction with iterative decoding methods, it produces a significant simplification of the decoding process. We demonstrate this approach for synthetically generated data. Finally, we consider the Slepian-Wolf problem when linear codes are used as syndrome-formers and consider a linear programming relaxation to maximum-likelihood (ML) sequence decoding. We note that the fractional vertices of the relaxed polytope compete with the optimal solution in a manner analogous to that observed when the \"min-sum\" iterative decoding algorithm is applied. This relaxation exhibits the ML-certificate property: if an integral solution is found, it is the ML solution. For symmetric binary joint distributions, we show that selecting easily constructable \"expander\"-style low-density parity check codes (LDPCs) as syndrome-formers admits a positive error exponent and therefore provably good performance", "corpus_id": 1879649, "score": 0 }, { "doc_id": "12709402", "title": "Low-density parity-check codes", "abstract": "A low-density parity-check code is a code specified by a parity-check matrix with the following properties: each column contains a small fixed number j \\geq 3 of l's and each row contains a small fixed number k > j of l's. The typical minimum distance of these codes increases linearly with block length for a fixed rate and fixed j . When used with maximum likelihood decoding on a sufficiently quiet binary-input symmetric channel, the typical probability of decoding error decreases exponentially with block length for a fixed rate and fixed j . A simple but nonoptimum decoding scheme operating directly from the channel a posteriori probabilities is described. Both the equipment complexity and the data-handling capacity in bits per second of this decoder increase approximately linearly with block length. For j > 3 and a sufficiently low rate, the probability of error using this decoder on a binary symmetric channel is shown to decrease at least exponentially with a root of the block length. Some experimental results show that the actual probability of decoding error is much smaller than this theoretical bound.", "corpus_id": 12709402, "score": 0 }, { "doc_id": "45440142", "title": "Compression of correlated sources using LDPC codes", "abstract": "Summary form only given. The problem of compressing correlated binary sources when the correlation between sources is defined by a hidden Markov model (HMM) was considered. Specifically, the HMM describes the correlation pattern such as the modulo-2 addition of the two sources. A density evolution analysis of a compression system was developed using irregular LDPC codes as source codes. To achieve this goal, the standard density evolution approach was modified to incorporate the HMM. It was then applied to the design of irregular codes to optimize system performance. The key to the incorporation of HMM in density evolution is to find the input-output characteristic of the forward-backward (F-B) decoding algorithm. The output of the F-B block subtitles the a priori message in the traditional density evolution case. Theoretical results agree with the simulations and show that it is possible to achieve a performance loss close to the theoretical Slepian-Wolf limit.", "corpus_id": 45440142, "score": 0 }, { "doc_id": "18920370", "title": "Compression of correlated binary sources using turbo codes", "abstract": "We propose the use of punctured turbo codes for compression of correlated binary sources. Compression is achieved because of puncturing. The resulting performance is close to the theoretical limit provided by the Slepian-Wolf (1973) theorem. No information about the correlation between sources is required in the encoding process. The proposed source decoder utilizes iterative schemes, and performs well even when the correlation between the sources is not known in the decoder, since it can be estimated jointly with the iterative decoding process.", "corpus_id": 18920370, "score": 0 }, { "doc_id": "2981839", "title": "Separating distributed source coding from network coding", "abstract": "This correspondence considers the problem of distributed source coding of multiple sources over a network with multiple receivers. Each receiver seeks to reconstruct all of the original sources. The work by Ho et al. 2004 demonstrates that random network coding can solve this problem at the potentially high cost of jointly decoding the source and the network code. Motivated by complexity considerations we consider the performance of separate source and network codes. Previous work by Effros et al. 2003 demonstrates the failure of separation between source and network codes for nonmulticast networks. We demonstrate that failure for multicast networks. We study networks with capacity constraints on edges. It is shown that the problem with two sources and two receivers is always separable. Counterexamples are presented for other cases.", "corpus_id": 2981839, "score": 0 }, { "doc_id": "2856768", "title": "Practical source-network decoding", "abstract": "When correlated sources are to be communicated over a network to more than one sink, joint source-network coding is, in general, required for information theoretically optimal transmission. Whereas on the encoder side simple randomized schemes based on linear codes suffice, the decoder is required to perform joint source-network decoding which is computationally expensive. Focusing on maximum a-posteriori decoders (or, in the case of continuous sources, conditional mean estimators), we show how to exploit (structural) knowledge about the network topology as well as the source correlations giving rise to an efficient decoder implementation (in some cases even with linear dependency on the number of nodes). In particular, we show how to statistically represent the overall system (including the packets) by a factor-graph on which the sum-product algorithm can be run. A proof-of-concept is provided in the form of a working decoder for the case of three sources and two sinks.", "corpus_id": 2856768, "score": 1 }, { "doc_id": "2426410", "title": "Network information flow", "abstract": "We introduce a new class of problems called network information flow which is inspired by computer network applications. Consider a point-to-point communication network on which a number of information sources are to be multicast to certain sets of destinations. We assume that the information sources are mutually independent. The problem is to characterize the admissible coding rate region. This model subsumes all previously studied models along the same line. We study the problem with one information source, and we have obtained a simple characterization of the admissible coding rate region. Our result can be regarded as the max-flow min-cut theorem for network information flow. Contrary to one's intuition, our work reveals that it is in general not optimal to regard the information to be multicast as a \"fluid\" which can simply be routed or replicated. Rather, by employing coding at the nodes, which we refer to as network coding, bandwidth can in general be saved. This finding may have significant impact on future design of switching systems.", "corpus_id": 2426410, "score": 0 }, { "doc_id": "58028893", "title": "An algebraic approach to network coding", "abstract": "We consider the problem of information flow in networks. In particular, we relate the question whether a set of desired connections can be accommodated in a network to the problem of finding a point on a variety defined over a suitable field. This approach lends itself to the derivation of a number of theorems concerning the feasibility of a communication scenario involving failures.", "corpus_id": 58028893, "score": 0 } ]

{ "doc_id": "3956267", "title": "Drosophila eggshell is patterned by sequential action of feedforward and feedback loops", "abstract": "During Drosophila oogenesis, patterning activities of the EGFR and Dpp pathways specify several subpopulations of the follicle cells that give rise to dorsal eggshell structures. The roof of dorsal eggshell appendages is formed by the follicle cells that express Broad (Br), a zinc-finger transcription factor regulated by both pathways. EGFR induces Br in the dorsal follicle cells. This inductive signal is overridden in the dorsal midline cells, which are exposed to high levels of EGFR activation, and in the anterior cells, by Dpp signaling. We show that the resulting changes in the Br pattern affect the expression of Dpp receptor thickveins (tkv), which is essential for Dpp signaling. By controlling tkv, Br controls Dpp signaling in late stages of oogenesis and, as a result, regulates its own repression in a negative-feedback loop. We synthesize these observations into a model, whereby the dynamics of Br expression are driven by the sequential action of feedforward and feedback loops. The feedforward loop controls the spatial pattern of Br expression, while the feedback loop modulates this pattern in time. This mechanism demonstrates how complex patterns of gene expression can emerge from simple inputs, through the interaction of regulatory network motifs.", "corpus_id": 3956267 }

[ { "doc_id": "1092306", "title": "Patterning and morphogenesis of the follicle cell epithelium during Drosophila oogenesis.", "abstract": "CONTENTS Introduction . .... Morphology of Drosophila oogenesis ........................................ Egg chamber formation and early tollicle cell differentiation .. ... Polarity determination and germ line-soma interactions during oogenesis .................. Origin of polarity AP axis formation DVaxis formation Follicle cell migration and eggshell morphogenesis ...................................................... Border cell migration Migration over the oocyte Centripetal migration Dorsal-anterior follicle cell migration and dorsal appendage formation Summary ................................................................................... ................. 541 541 542 544 .................. ...............................", "corpus_id": 1092306, "score": 0 }, { "doc_id": "40231108", "title": "The Drosophila shell game: patterning genes and morphological change.", "abstract": "What are the mechanisms that convert cell-fate information into shape changes and movements, thus creating the biological forms that comprise tissues and organs? Tubulogenesis of the Drosophila dorsal eggshell structures provides an excellent system for studying the link between patterning and morphogenesis. Elegant genetic and molecular analyses from over a decade provide a strong foundation for understanding the combinatorial signaling events that specify dorsal anterior cell fates within the follicular epithelium overlying the oocyte. Recent studies reveal the morphogenetic events that alter that flat epithelial sheet into two tubes; these tubes form the mold for synthesizing the dorsal appendages--eggshell structures that facilitate respiration in the developing embryo. This review summarizes the mutant analyses that give insight into these patterning and morphogenetic processes.", "corpus_id": 40231108, "score": 1 }, { "doc_id": "39757637", "title": "Germ line and soma cooperate during oogenesis to establish the dorsoventral pattern of egg shell and embryo in Drosophila melanogaster", "abstract": "Mutations in gurken and torpedo cause a ventralization in the follicle cell epithelium during Drosophila oogenesis and in the pattern of the embryo that develops in the resultant egg. Both genes lie midway in an epistatic series between fs(1)K10 and dorsal; the mutations block the dorsalization normally observed in K10 eggs but have no effect on the phenotype of embryos derived from dorsal mothers. Analysis of germ-line mosaics demonstrates that both ovarian and embryonic phenotypes will be produced when either the gurken+ gene is removed from the germ line or torpedo+ is removed from the soma. This shows that the dorsoventral pattern of the Drosophila egg chamber depends on the transfer of spatial information from the germ line to the somatic follicle cells, and from somatic cells to the oocyte.", "corpus_id": 39757637, "score": 0 }, { "doc_id": "40063504", "title": "The TGF-beta signaling pathway is essential for Drosophila oogenesis.", "abstract": "We examine roles of signaling by secreted ligands of the TGF-beta family during Drosophila oogenesis. One family member, the DPP ligand encoded by the decapentaplegic (dpp) gene, is required for patterning of anterior eggshell structures. This requirement presumably reflects the expression pattern of dpp in an anterior subset of somatic follicle cells: the centripetally migrating and the nurse cell-associated follicle cells. Similar requirements are also revealed by mutations in the saxophone (sax)-encoded receptor, consistent with the idea that DPP signaling is, at least in part, mediated by the SAX receptor. A loss of germline sax function results in a block in oogenesis associated with egg chamber degeneration and a failure of the transfer of nurse cell contents to the oocyte, indicating that TGF-beta signaling is required for these events. Some phenotypes of sax mutations during oogenesis suggest that SAX responds to at least one other TGF-beta ligand as well in the posterior follicle cells.", "corpus_id": 40063504, "score": 0 }, { "doc_id": "13026511", "title": "Combined activities of Gurken and decapentaplegic specify dorsal chorion structures of the Drosophila egg.", "abstract": "During Drosophila oogenesis Gurken, associated with the oocyte nucleus, activates the Drosophila EGF receptor in the follicular epithelium. Gurken first specifies posterior follicle cells, which in turn signal back to the oocyte to induce the migration of the oocyte nucleus from a posterior to an anterior-dorsal position. Here, Gurken signals again to specify dorsal follicle cells, which give rise to dorsal chorion structures including the dorsal appendages. If Gurken signaling is delayed and starts after stage 6 of oogenesis the nucleus remains at the posterior pole of the oocyte. Eggs develop with a posterior ring of dorsal appendage material that is produced by main-body follicle cells expressing the gene Broad-Complex. They encircle terminal follicle cells expressing variable amounts of the TGFbeta homologue, decapentaplegic. By ectopically expressing decapentaplegic and clonal analysis with Mothers against dpp we show that Decapentaplegic signaling is required for Broad-Complex expression. Thus, the specification and positioning of dorsal appendages along the anterior-posterior axis depends on the intersection of both Gurken and Decapentaplegic signaling. This intersection also induces rhomboid expression and thereby initiates the positive feedback loop of EGF receptor activation, which positions the dorsal appendages along the dorsal-ventral egg axis.", "corpus_id": 13026511, "score": 1 }, { "doc_id": "36029574", "title": "Two signalling pathways specify localised expression of the Broad-Complex in Drosophila eggshell patterning and morphogenesis.", "abstract": "The Drosophila eggshell, which has a pair of chorionic appendages (dorsal appendages) located asymmetrically along both the anterior/posterior and dorsal/ventral axes, provides a good model to study signal instructed morphogenesis. We show that the Broad-Complex, a gene encoding zinc-finger transcription factors, is essential for the morphogenesis of dorsal appendages and is expressed in a bilaterally symmetrical pattern in the lateral-dorsal-anterior follicle cells during late oogenesis. This is induced and specified along the dorsoventral axis by an epidermal growth factor receptor signalling pathway, which includes a localised transforming growth factor-alpha like molecule, Gurken, in the oocyte and the Drosophila EGF receptor homologue, Torpedo, in the surrounding somatic follicle cells. Furthermore, the precisely localised expression of BR-C along the AP axis requires a separate signalling pathway, initiated by a transforming growth factor-beta homologue, Decapentaplegic, in nearby follicle cells. These two signalling pathways, one from the oocyte and the other from the follicle cells, co-ordinately specify patches of follicle cells to express the Broad-Complex in a unique position in respect to both major axes, which in turn directs the differentiation of the dorsal appendages in the correct position on the eggshell.", "corpus_id": 36029574, "score": 1 }, { "doc_id": "18691381", "title": "The function of the broad-complex during Drosophila melanogaster oogenesis.", "abstract": "The Broad-Complex (BR-C) is an early ecdysone response gene that functions during metamorphosis and encodes a family of zinc-finger transcription factors. It is expressed in a dynamic pattern during oogenesis. Its late expression in the lateral-dorsal-anterior follicle cells is related to the morphogenesis of the chorionic appendages. All four zinc-finger isoforms are expressed in oogenesis, which is consistent with the abnormal appendage phenotypes resulting from their ectopic expression. We investigated the mechanism by which the BR-C affects chorion deposition by using BrdU to follow the effects of BR-C misexpression on DNA replication and in situ hybridization to ovarian mRNA to evaluate chorion gene expression. Ectopic BR-C expression leads to prolonged endoreplication and to additional amplification of genes, besides the chorion genes, at other sites in the genome. The pattern of chorion gene expression is not affected along the anterior-posterior axis, but the follicle cells at the anterior of the oocyte fail to migrate correctly in an anterior direction when BR-C is misexpressed. We conclude that the target genes of the BR-C in oogenesis include a protein essential for endoreplication and chorion gene amplification. This may provide a link between steroid hormones and the control of DNA replication during oogenesis.", "corpus_id": 18691381, "score": 0 }, { "doc_id": "9026083", "title": "Drosophila Rhomboid-1 Defines a Family of Putative Intramembrane Serine Proteases", "abstract": "The polytopic membrane protein Rhomboid-1 promotes the cleavage of the membrane-anchored TGFalpha-like growth factor Spitz, allowing it to activate the Drosophila EGF receptor. Until now, the mechanism of this key signaling regulator has been obscure, but our analysis suggests that Rhomboid-1 is a novel intramembrane serine protease that directly cleaves Spitz. In accordance with the putative Rhomboid active site being in the membrane bilayer, Spitz is cleaved within its transmembrane domain, and thus is, to our knowledge, the first example of a growth factor activated by regulated intramembrane proteolysis. Rhomboid-1 is conserved throughout evolution from archaea to humans, and our results show that a human Rhomboid promotes Spitz cleavage by a similar mechanism. This growth factor activation mechanism may therefore be widespread.", "corpus_id": 9026083, "score": 0 }, { "doc_id": "15914672", "title": "Local Gurken signaling and dynamic MAPK activation during Drosophila oogenesis", "abstract": "During Drosophila melanogaster oogenesis Gurken, a TGF-alpha like protein localized close to the oocyte nucleus, activates the MAPK cascade via the Drosophila EGF receptor (DER). Activation of this pathway induces different cell fates in the overlying follicular epithelium, specifying the two dorsolaterally positioned respiratory appendages and the dorsalmost cells separating them. Signal-associated internalization of Gurken protein into follicle cells demonstrates that the Gurken signal is spatially restricted and of constant intensity during mid-oogenesis. At the same time MAPK activation evolves in a spatially and temporally dynamic way and resolves into a complex pattern that presages the position of the appendages. Therefore, different dorsal follicle cell fates are not determined by a Gurken morphogen gradient. Instead they are specified by secondary signal amplification and refinement processes that integrate the Gurken signal with positive and negative feedback mechanisms generated by target genes of the DER pathway.", "corpus_id": 15914672, "score": 0 }, { "doc_id": "11142401", "title": "Capicua regulates follicle cell fate in the Drosophila ovary through repression of mirror", "abstract": "The dorsoventral axis of the Drosophila egg is established by dorsally localized activation of the epidermal growth factor receptor (Egfr) in the ovarian follicular epithelium. Subsequent positive- and negative-feedback regulation generates two dorsolateral follicle cell primordia that will produce the eggshell appendages. A dorsal midline domain of low Egfr activity between the appendage primordia defines their dorsal boundary, but little is known about the mechanisms that establish their ventral limit. We demonstrate that the transcriptional repressor Capicua is required cell autonomously in ventral and lateral follicle cells to repress dorsal fates, and functions in this process through the repression of mirror. Interestingly, ectopic expression of mirror in the absence of capicua is observed only in the anterior half of the epithelium. We propose that Capicua regulates the pattern of follicle cell fates along the dorsoventral axis by blocking the induction of appendage determinants, such as mirror, by anterior positional cues.", "corpus_id": 11142401, "score": 0 }, { "doc_id": "14668129", "title": "The role of brinker in eggshell patterning", "abstract": "Drosophila oogenesis provides a useful system to study signal transduction pathways and their interactions. Through clonal analysis, we found that brinker (brk), a repressor of Dpp signaling, plays an important role in the Drosophila ovary, where its function is essential for dorsal appendage formation. In the absence of brk, operculum fates are specified at the expense of dorsal appendage fates. Brk is expressed by most of the oocyte associated follicle cells, starting from stage 8 of oogenesis. Transforming Growth Factor beta (TGFbeta) signaling represses brk expression in both the early stage egg chambers and in the anterior follicle cells. In brk mutant follicle cell clones at the dorsal anterior region, Broad Complex (BR-C) expression is down-regulated in a larger domain than in wild type. We show that BR-C is required for dorsal appendage development. In large anterior BR-C mutant clones, dorsal appendages are absent, and instead, the eggshell has an enlarged operculum like region at the anterior. In addition, we show that the Epidermal Growth Factor (EGF) receptor signaling represses the TGFbeta signaling in oogenesis by up-regulating brk expression. From our results and previously published data, it appears that anterior follicle cells integrate the levels of EGF receptor activation and TGFbeta receptor activation. Operculum fate results when the sum of the level of activation of both pathways reaches a threshold level, and reduction of activity of one pathway can be compensated to some extent by increase in the other pathway.", "corpus_id": 14668129, "score": 1 }, { "doc_id": "1306949", "title": "The role of Dpp and its inhibitors during eggshell patterning in Drosophila", "abstract": "The Drosophila eggshell is patterned by the combined action of the epidermal growth factor [EGF; Gurken (Grk)] and transforming growth factorβ [TGF-β; Decapentaplegic (Dpp)] signaling cascades. Although Grk signaling alone can induce asymmetric gene expression within the follicular epithelium, here we show that the ability of Grk to induce dorsoventral polarity within the eggshell strictly depends on Dpp. Dpp, however, specifies at least one anterior region of the eggshell in the absence of Grk. Dpp forms an anteriorposterior morphogen gradient within the follicular epithelium and synergizes with the dorsoventral gradient of Grk signaling. High levels of Grk and Dpp signaling induce the operculum, whereas lower levels of both pathways induce the dorsal appendages. We provide evidence that the crosstalk between both pathways occurs at least at two levels. First, Dpp appears to directly enhance the levels of EGF pathway activity within the follicular epithelium. Second, Dpp and EGF signaling collaborate in controlling the expression of Dpp inhibitors. One of these inhibitors is Drosophila sno (dSno), a homolog of the Ski/Sno family of vertebrate proto-oncogenes, which synergizes with daughters against dpp and brinker to set the posterior and lateral limits of the region, giving rise to dorsal follicle cells.", "corpus_id": 1306949, "score": 1 }, { "doc_id": "27594062", "title": "Relief of gene repression by torso RTK signaling: role of capicua in Drosophila terminal and dorsoventral patterning.", "abstract": "Differentiation of the embryonic termini in Drosophila depends on signaling by the Tor RTK, which induces terminal gene expression by inactivating at the embryonic poles a uniformly distributed repressor activity that involves the Gro corepressor. Here, we identify a new gene, cic, that acts as a repressor of terminal genes regulated by the Tor pathway. cic also mediates repression along the dorsoventral axis, a process that requires the Dorsal morphogen and Gro, and which is also inhibited by Tor signaling at the termini. cic encodes an HMG-box transcription factor that interacts with Gro in vitro. We present evidence that Tor signaling regulates terminal patterning by inactivating Cic at the embryo poles. cic has been evolutionarily conserved, suggesting that Cic-like proteins may act as repressors regulated by RTK signaling in other organisms.", "corpus_id": 27594062, "score": 0 }, { "doc_id": "2426344", "title": "The drosophila dorsoventral patterning gene gurken produces a dorsally localized RNA and encodes a TGFα-like protein", "abstract": "Cell-cell interactions in the Drosophila ovary play a crucial role in the establishment of dorsoventral polarity of both the egg shell and the future embryo. Torpedo/DER (top/DER), a homolog of the vertebrate epidermal growth factor receptor, is required for this signaling process in the somatic cells of the ovary. In contrast, gurken (grk), which also functions in this pathway, is required in the germline. We cloned the grk gene and found that it encodes a TGF alpha-like protein. Grk is, therefore, likely to be a ligand of top/DER, activating the receptor during oogenesis. During oogenesis, the grk transcript becomes asymmetrically localized to the dorsal corner of the oocyte. We propose that the dorsal localization of grk RNA results in a spatially restricted ligand that asymmetrically activates the receptor.", "corpus_id": 2426344, "score": 0 }, { "doc_id": "14106786", "title": "Ectopic activation of torpedo/Egfr, a Drosophila receptor tyrosine kinase, dorsalizes both the eggshell and the embryo.", "abstract": "The Drosophila gene torpedo/Egfr (top/Egfr) encodes a homolog of the vertebrate Epidermal Growth Factor receptor. This receptor is required several times during the life cycle of the fly for the transmisson of developmental cues. During oogenesis, Top/Egfr activation is required for the establishment of the dorsal/ventral axis of the egg and the embryo. To examine how ectopic Top/Egfr activation affects cell fate determination, we constructed an activated version of the protein. Expression of this activated form (lambda top) in the follicle cells of the ovary induces dorsal cell fates in both the follicular epithelium and the embryo. Different levels of expression resulted in different dorsal follicle cell fates. These dorsal cell fates were expanded in the anterior, but not the posterior, of the egg, even in cases where all the follicle cells covering the oocyte expressed lambda top. The expression of genes known to respond to top/Egfr activation, argos (aos), kekkon1 (kek 1) and rhomboid (rho), was also expanded in the presence of the lambda top construct. When lambda top was expressed in all the follicle cells covering the oocyte, kek 1 and argos expression was induced in follicle cells all along the anterior/posterior axis of the egg chamber. In contrast, rho RNA expression was only activated in the anterior of the egg chamber. These data indicate that the response to Top/Egfr signaling is regulated by an anterior/posterior prepattern in the follicle cells. Expression of lambda top in the entire follicular epithelium resulted in an embryo dorsalized along the entire anterior/posterior axis. Expression of lambda top in anterior or posterior subpopulations of follicle cells resulted in regionally autonomous dorsalization of the embryos. This result indicates that subpopulations of follicle cells along the anterior/posterior axis can respond to Top/Egfr activation independently of one another.", "corpus_id": 14106786, "score": 0 }, { "doc_id": "7466642", "title": "Quantitative analysis of the GAL4/UAS system in Drosophila oogenesis", "abstract": "The GAL4/UAS system is extensively used for targeted gene expression in Drosophila, but the strength of the GAL4 drivers and their effects on target genes are rarely quantified. Quantitative information about the strength of the perturbations introduced by the GAL4/UAS system would further expand the usefulness of the GAL4/UAS system in studying gene functions and developmental processes. We have developed an assay to determine the relative level of expression for target genes tagged with green fluorescent protein (GFP). Our assay enables the relative quantitation of fluorescent proteins within specific cell types and developmental time windows in living eggs/embryos, and permits the analysis of samples from a broad expression range. We illustrate the assay using a panel of four GAL4 drivers and three UAS responder lines in Drosophila oogenesis, discuss the issues associated with the interpretation of the quantitative data, and correlate our results with the analysis of the GAL4/UAS system at the transcript level. The imaging‐based strategy described here can be used to quantify other GAL4 drivers in Drosophila and other organisms. genesis 44:66–74, 2006. Published 2006 Wiley‐Liss, Inc.", "corpus_id": 7466642, "score": 0 }, { "doc_id": "5644643", "title": "Analysis of genetic mosaics in developing and adult Drosophila tissues.", "abstract": "We have constructed a series of strains to facilitate the generation and analysis of clones of genetically distinct cells in developing and adult tissues of Drosophila. Each of these strains carries an FRT element, the target for the yeast FLP recombinase, near the base of a major chromosome arm, as well as a gratuitous cell-autonomous marker. Novel markers that carry epitope tags and that are localized to either the cell nucleus or cell membrane have been generated. As a demonstration of how these strains can be used to study a particular gene, we have analyzed the developmental role of the Drosophila EGF receptor homolog. Moreover, we have shown that these strains can be utilized to identify new mutations in mosaic animals in an efficient and unbiased way, thereby providing an unprecedented opportunity to perform systematic genetic screens for mutations affecting many biological processes.", "corpus_id": 5644643, "score": 0 }, { "doc_id": "19979092", "title": "Identifying loci required for follicular patterning using directed mosaics.", "abstract": "We have developed a 'directed mosaic' system in Drosophila by using the GAL4 system to control the expression of the yeast recombinase, FLP, in a spatial and temporal fashion. By directing FLP expression, we show that it is possible to efficiently and specifically target loss-of-function studies for vital loci to the developmental pathway of interest. A simple F1 adult phenotypic screen demonstrated that most adult tissues can be analyzed with this approach. Using GAL4 lines expressed during oogenesis, we have refined the system to examine the roles of vital loci in the development of the follicular epithelium. We have identified essential genes involved in egg chamber organization, cell migration and cell shape. Further, we have used this technique to gain insights into the role of the Drosophila EGF receptor pathway in establishing the egg axes. Finally, using different UAS-FLP, GAL4 and existing FRT lines, we have built stocks that permit the analysis of approximately 95% of the genome in follicular mosaics.", "corpus_id": 19979092, "score": 0 }, { "doc_id": "1521076", "title": "The torso receptor tyrosine kinase can activate raf in a ras-independent pathway", "abstract": "Activation of the receptor tyrosine kinase (RTK) torso defines the spatial domains of expression of the transcription factors tailless and huckebein. Previous analyses have demonstrated that Ras1 (p21ras) operates upstream of the D-Raf (Raf1) serine/threonine kinase in this signaling pathway. By using a recently developed technique of germline mosaics, we find that D-Raf can be activated by torso in the complete absence of Ras1. This result is supported by analysis of D-Raf activation in the absence of either the exchange factor Son of sevenless (Sos) or the adaptor protein drk (Grb2), as well as by the phenotype of a D-Raf mutation that abolishes binding of Ras1 to D-Raf. Our study provides in vivo evidence that Raf can be activated by an RTK in a Ras-independent pathway.", "corpus_id": 1521076, "score": 0 }, { "doc_id": "25768626", "title": "Mosaic analyses reveal the function of Drosophila Ras in embryonic dorsoventral patterning and dorsal follicle cell morphogenesis.", "abstract": "In Drosophila melanogaster, the Ras signal transduction pathway is the primary effector of receptor tyrosine kinases, which govern diverse developmental programs. During oogenesis, epidermal growth factor receptor signaling through the Ras pathway patterns the somatic follicular epithelium, establishing the dorsoventral asymmetry of eggshell and embryo. Analysis of follicle cell clones homozygous for a null allele of Ras demonstrates that Ras is required cell-autonomously to repress pipe transcription, the critical first step in embryonic dorsoventral patterning. The effects of aberrant pipe expression in Ras mosaic egg chambers can be ameliorated, however, by post-pipe patterning events, which salvage normal dorsoventral polarity in most embryos derived from egg chambers with dorsal Ras clones. The patterned follicular epithelium also determines the final shape of the eggshell, including the dorsal respiratory appendages, which are formed by the migration of two dorsolateral follicle cell populations. Confocal analyses of mosaic egg chambers demonstrate that Ras is required both cell- and non cell-autonomously for morphogenetic behaviors characteristic of dorsal follicle cell migration, and reveal a novel, Ras-dependent pattern of basal E-cadherin localization in dorsal midline follicle cells.", "corpus_id": 25768626, "score": 0 }, { "doc_id": "43478668", "title": "Refining GAL4‐driven transgene expression in Drosophila with a GAL80 enhancer‐trap", "abstract": "We constructed an enhancer‐trap element, P{GAL80}, that encodes the yeast GAL80 repressor to refine expression of transgenes driven by the binary GAL4/UAS system. GAL80 blocks GAL4 activity by binding to its transcriptional activation domain. We screened GAL80 enhancer‐traps for repression of GAL4‐induced green fluorescent protein (GFP) in the intact larval nervous system. We selected one line that repressed GFP in a large set of cholinergic neurons. This line was used to refine GFP expression from a set of over 200 neurons to a subset of 20 neurons in a preselected GAL4 line. Expression of tetanus neurotoxin, a potent blocker of neurotransmitter release, in these 20 neurons reproduced an aberrant larval turning behavior previously assigned to the parental set of 200 neurons. Our results suggest that targeted GAL80 expression could become a useful means of spatially refining transgene expression in Drosophila. genesis 39:240–245, 2004. © 2004 Wiley‐Liss, Inc.", "corpus_id": 43478668, "score": 0 }, { "doc_id": "41583218", "title": "Analysis of cell migration using whole-genome expression profiling of migratory cells in the Drosophila ovary.", "abstract": "Cell migration contributes to normal development and homeostasis as well as to pathological processes such as inflammation and tumor metastasis. Previous genetic screens have revealed signaling pathways that govern follicle cell migrations in the Drosophila ovary, but few downstream targets of the critical transcriptional regulators have been identified. To characterize the gene expression profile of two migratory cell populations and identify Slbo targets, we purified border cells and centripetal cells expressing the mouse CD8 antigen and carried out whole-genome microarray analysis. Genes predicted to control actin dynamics and the endocytic and secretory pathways were overrepresented in the migratory cell transcriptome. Mutations in five genes, including ttk, failed to complement previously isolated mutations that cause cell migration defects in mosaic clones. Functional analysis revealed a role for the Notch-activating protease Kuzbanian in border cell migration and identified Tie as a guidance receptor for the border cells.", "corpus_id": 41583218, "score": 0 }, { "doc_id": "12232483", "title": "Regulatory mechanisms required for DE-cadherin function in cell migration and other types of adhesion", "abstract": "Cadherin-mediated adhesion can be regulated at many levels, as demonstrated by detailed analysis in cell lines. We have investigated the requirements for Drosophila melanogaster epithelial (DE) cadherin regulation in vivo. Investigating D. melanogaster oogenesis as a model system allowed the dissection of DE-cadherin function in several types of adhesion: cell sorting, cell positioning, epithelial integrity, and the cadherin-dependent process of border cell migration. We generated multiple fusions between DE-cadherin and α-catenin as well as point-mutated β-catenin and analyzed their ability to support these types of adhesion. We found that (1) although linking DE-cadherin to α-catenin is essential, regulation of the link is not required in any of these types of adhesion; (2) β-catenin is required only to link DE-cadherin to α-catenin; and (3) the cytoplasmic domain of DE-cadherin has an additional specific function for the invasive migration of border cells, which is conserved to other cadherins. The nature of this additional function is discussed.", "corpus_id": 12232483, "score": 0 }, { "doc_id": "2775838", "title": "Systems-level questions in Drosophila oogenesis.", "abstract": "This paper describes computational and experimental work on pattern formation in Drosophila egg development (oogenesis), an established experimental model for studying cell fate diversification in developing tissues. Epidermal growth factor receptor (EGFR) is a key regulator of pattern formation and morphogenesis in Drosophila oogenesis. EGFR signalling in oogenesis can be genetically manipulated and monitored at many levels, leading to large sets of heterogeneous data that enable the formulation of increasingly quantitative models of pattern formation in these systems.", "corpus_id": 2775838, "score": 0 }, { "doc_id": "18053449", "title": "D-cbl, a Negative Regulator of the Egfr Pathway, Is Required for Dorsoventral Patterning in Drosophila Oogenesis", "abstract": "During Drosophila oogenesis, asymmetrically localized Gurken activates the EGF receptor (Egfr) and determines dorsal follicle cell fates. Using a mosaic follicle cell system we have identified a mutation in the D-cbl gene which causes hyperactivation of the Egfr pathway. Cbl proteins are known to downregulate activated receptors. We find that the abnormal Egfr activation is ligand dependent. Our results show that the precise regulation of Egfr activity necessary to establish different follicle cell fates requires two levels of control. The localized ligand Gurken activates Egfr to different levels in different follicle cells. In addition, Egfr activity has to be repressed through the activity of D-cbl to ensure the absence of signaling in the ventral most follicle cells.", "corpus_id": 18053449, "score": 0 }, { "doc_id": "11663510", "title": "Quantifying the Gurken morphogen gradient in Drosophila oogenesis.", "abstract": "Quantitative information about the distribution of morphogens is crucial for understanding their effects on cell-fate determination, yet it is difficult to obtain through direct measurements. We have developed a parameter estimation approach for quantifying the spatial distribution of Gurken, a TGFalpha-like EGFR ligand that acts as a morphogen in Drosophila oogenesis. Modeling of Gurken/EGFR system shows that the shape of the Gurken gradient is controlled by a single dimensionless parameter, the Thiele modulus, which reflects the relative importance of ligand diffusion and degradation. By combining the model with genetic alterations of EGFR levels, we have estimated the value of the Thiele modulus in the wild-type egg chamber. This provides a direct characterization of the shape of the Gurken gradient and demonstrates how parameter estimation techniques can be used to quantify morphogen gradients in development.", "corpus_id": 11663510, "score": 0 }, { "doc_id": "14484273", "title": "Sequential activation of the EGF receptor pathway during Drosophila oogenesis establishes the dorsoventral axis.", "abstract": "Previous work has demonstrated a role for the Drosophila EGF receptor (Torpedo/DER) and its ligand, Gurken, in the determination of anterioposterior and dorsoventral axes of the follicle cells and oocyte. The roles of DER in establishing the polarity of the follicle cells were examined further, by following the expression of DER-target genes. One class of genes (e.g. kekon) is induced by the DER pathway at all stages. Broad expression of kekon at the stage in which the follicle cells migrate posteriorly over the oocyte, demonstrates the capacity of the pathway to pattern all follicle cells except the ventral-most rows. This may provide the spatial coordinates for the ventral-most follicle cell fates. A second group of target genes (e.g. rhomboid (rho)) is induced only at later stages of oogenesis, and may require additional inputs by signals emanating from the anterior, stretch follicle cells. The function of Rho was analyzed by ectopic expression in the stretch follicle cells, and shown to induce a non-autonomous dorsalizing activity that is independent of Gurken. Rho thus appears to be involved in processing a DER ligand in the follicle cells, to pattern the egg chamber and allow persistent activation of the DER pathway during formation of the dorsal appendages.", "corpus_id": 14484273, "score": 0 }, { "doc_id": "7089767", "title": "An Autoregulatory Cascade of EGF Receptor Signaling Patterns the Drosophila Egg", "abstract": "Intercellular signaling through the EGF receptor (EGFR) patterns the Drosophila egg. The TGF alpha-like ligand Gurken signals from the oocyte to the receptor in the overlying somatic follicle cells. We show that in the dorsal follicle cells this initial paracrine signaling event triggers an autocrine amplification by two other EGFR ligands, Spitz and Vein. Spitz only becomes an effective ligand in the presence of the multitransmembrane domain protein Rhomboid. Consequent high-level EGFR activation leads to localized expression of the diffusible inhibitor Argos, which alters the profile of signaling. This sequential activation, amplification, and local inhibition of the EGFR forms an autoregulatory cascade that leads to the splitting of an initial single peak of signaling into two, thereby patterning the egg.", "corpus_id": 7089767, "score": 1 }, { "doc_id": "28864722", "title": "Hrs mediates downregulation of multiple signalling receptors in Drosophila", "abstract": "Endocytosis and subsequent lysosomal degradation of activated signalling receptors can attenuate signalling. Endocytosis may also promote signalling by targeting receptors to specific compartments. A key step regulating the degradation of receptors is their ubiquitination. Hrs/Vps27p, an endosome‐associated, ubiquitin‐binding protein, affects sorting and degradation of receptors. Drosophila embryos mutant for hrs show elevated receptor tyrosine kinase (RTK) signalling. Hrs has also been proposed to act as a positive mediator of TGF‐β signalling. We find that Drosophila epithelial cells devoid of Hrs accumulate multiple signalling receptors in an endosomal compartment with high levels of ubiquitinated proteins: not only RTKs (EGFR and PVR) but also Notch and receptors for Hedgehog and Dpp (TGF‐β related). Hrs is not required for Dpp signalling. Instead, loss of Hrs increases Dpp signalling and the level of the type‐I receptor Thickveins (Tkv). Finally, most hrs‐dependent receptor turnover appears to be ligand independent. Thus, both active and inactive signalling receptors are targeted for degradation in vivo and Hrs is required for their removal.", "corpus_id": 28864722, "score": 0 }, { "doc_id": "5998789", "title": "Oogenic function of the myogenic factor D-MEF2: negative regulation of the decapentaplegic receptor gene thick veins.", "abstract": "The myogenic factor D-MEF2 is required for the proper differentiation of muscle cells during Drosophila embryogenesis and the correct patterning of indirect flight muscles assembled during later metamorphosis. In addition to these essential myogenic functions, mutant D-mef2 adult females are weakly fertile and produce defective eggs. D-MEF2 is expressed in nurse and follicle cells of the wild-type egg chamber. We have analyzed the D-mef2 oogenic phenotype and show that the gene is required for the normal patterning and differentiation of the centripetally migrating follicle cells that are crucial for development of the anterior chorionic structures. D-mef2 alleles exhibit a genetic interaction with a dominant-negative allele of thick veins (tkv), which encodes a type I receptor of the Decapentaplegic-signaling pathway. tkv RNA is overexpressed in D-mef2 mutant egg chambers, and, conversely, forced expression of D-mef2 represses tkv expression. These results indicate a role for D-MEF2 in the regulation of tkv gene expression and Decapentaplegic signal transduction that are essential for proper determination and/or differentiation of the anterior follicle cells. Additionally, they demonstrate a vital function for the D-MEF2 transcription factor in multiple genetic pathways during Drosophila development.", "corpus_id": 5998789, "score": 0 }, { "doc_id": "26535726", "title": "Pointed, an ETS domain transcription factor, negatively regulates the EGF receptor pathway in Drosophila oogenesis.", "abstract": "Spatially regulated activation of the Drosophila epidermal growth factor (EGF) receptor by its ligand, Gurken, is required for establishment of the dorsal/ventral axis of the oocyte and embryo. During mid-oogenesis, Gurken is concentrated at the dorsal-anterior of the oocyte and is thought to activate the EGF receptor pathway in adjacent follicle cells. In response to this signal, dorsal follicle cell fate is determined. These cells further differentiate into either appendage-producing or midline cells, resulting in patterning in the dorsal follicle cell layer. We show here that Pointed, an ETS transcription factor, is required in dorsal follicle cells for this patterning. Loss of pointed results in the loss of midline cells and an excess of appendage-forming cells, a phenotype associated with overactivation of the EGF receptor pathway in the dorsal region. Overexpression of pointed leads to a phenotype similar to that generated by loss of the EGF receptor pathway. This suggests that Pointed normally down-regulates EGF receptor signaling in the midline to generate patterning in the dorsal region. Interestingly, pointed expression is induced by the EGF receptor pathway. These data indicate a novel antagonistic function for Pointed in oogenesis; in response to activation of the EGF receptor, pointed is expressed and negatively regulates the EGF receptor pathway, possibly by integrating information from a second pathway.", "corpus_id": 26535726, "score": 0 }, { "doc_id": "3144048", "title": "Border of Notch activity establishes a boundary between the two dorsal appendage tube cell types.", "abstract": "Boundaries establish and maintain separate populations of cells critical for organ formation. We show that Notch signaling establishes the boundary between two types of post-mitotic epithelial cells, the Rhomboid- and the Broad-positive cells. These cells will undergo morphogenetic movements to generate the two sides of a simple organ, the dorsal appendage tube of the Drosophila egg chamber. The boundary forms due to a difference in Notch levels in adjacent cells. The Notch expression pattern mimics the boundary; Notch levels are high in Rhomboid cells and low in Broad cells. Notch(-) mutant clones generate an ectopic boundary: ectopic Rhomboid cells arise in Notch(+) cells adjacent to the Notch(-) mutant cells but not further away from the clonal border. Pangolin, a component of the Wingless pathway, is required for Broad expression and for rhomboid repression. We further show that Broad represses rhomboid cell autonomously. Our data provide a foundation for understanding how a single row of Rhomboid cells arises adjacent to the Broad cells in the dorsal appendage primordia. Generating a boundary by the Notch pathway might constitute an evolutionarily conserved first step during organ formation in many tissues.", "corpus_id": 3144048, "score": 0 }, { "doc_id": "17769723", "title": "Top–DER- and Dpp-dependent requirements for the Drosophila fos/kayak gene in follicular epithelium morphogenesis", "abstract": "The Drosophila fos (Dfos)/kayak gene has been previously identified as a key regulator of epithelial cell morphogenesis during dorsal closure of the embryo and fusion of the adult thorax. We show here that it is also required for two morphogenetic movements of the follicular epithelium during oogenesis. Firstly, it is necessary for the proper posteriorward migration of main body follicle cells during stage 9. Secondly, it controls, from stage 11 onwards, the morphogenetic reorganization of the follicle cells that are committed to secrete the respiratory appendages. We demonstrate that DER pathway activation and a critical level of Dpp/TGFbeta signalling are required to pattern a high level of transcription of Dfos at the anterior and dorsal edges of the two groups of cells that will give rise to the respiratory appendages. In addition, we provide evidence that, within the dorsal-anterior territory, the level of paracrine Dpp/TGFbeta signalling controls the commitment of follicle cells towards either an operculum or an appendage secretion fate. Finally, we show that Dfos is required in follicle cells for the dumping of the nurse cell cytoplasm into the oocyte and the subsequent apoptosis of nurse cells. This suggests that in somatic follicle cells, Dfos controls the expression of one or several factors that are necessary for these processes in underlying germinal nurse cells.", "corpus_id": 17769723, "score": 0 }, { "doc_id": "39753993", "title": "Hox Control of Organ Size by Regulation of Morphogen Production and Mobility", "abstract": "Selector genes modify developmental pathways to sculpt animal body parts. Although body parts differ in size, the ways in which selector genes create size differences are unknown. We have studied how the Drosophila Hox gene Ultrabithorax (Ubx) limits the size of the haltere, which, by the end of larval development, has ∼fivefold fewer cells than the wing. We find that Ubx controls haltere size by restricting both the transcription and the mobility of the morphogen Decapentaplegic (Dpp). Ubx restricts Dpp's distribution in the haltere by increasing the amounts of the Dpp receptor, thickveins. Because morphogens control tissue growth in many contexts, these findings provide a potentially general mechanism for how selector genes modify organ sizes.", "corpus_id": 39753993, "score": 0 }, { "doc_id": "4392409", "title": "A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila", "abstract": "Forward genetic screens in model organisms have provided important insights into numerous aspects of development, physiology and pathology. With the availability of complete genome sequences and the introduction of RNA-mediated gene interference (RNAi), systematic reverse genetic screens are now also possible. Until now, such genome-wide RNAi screens have mostly been restricted to cultured cells and ubiquitous gene inactivation in Caenorhabditis elegans. This powerful approach has not yet been applied in a tissue-specific manner. Here we report the generation and validation of a genome-wide library of Drosophila melanogaster RNAi transgenes, enabling the conditional inactivation of gene function in specific tissues of the intact organism. Our RNAi transgenes consist of short gene fragments cloned as inverted repeats and expressed using the binary GAL4/UAS system. We generated 22,270 transgenic lines, covering 88% of the predicted protein-coding genes in the Drosophila genome. Molecular and phenotypic assays indicate that the majority of these transgenes are functional. Our transgenic RNAi library thus opens up the prospect of systematically analysing gene functions in any tissue and at any stage of the Drosophila lifespan.", "corpus_id": 4392409, "score": 0 }, { "doc_id": "7169406", "title": "Network motifs: theory and experimental approaches", "abstract": "Transcription regulation networks control the expression of genes. The transcription networks of well-studied microorganisms appear to be made up of a small set of recurring regulation patterns, called network motifs. The same network motifs have recently been found in diverse organisms from bacteria to humans, suggesting that they serve as basic building blocks of transcription networks. Here I review network motifs and their functions, with an emphasis on experimental studies. Network motifs in other biological networks are also mentioned, including signalling and neuronal networks.", "corpus_id": 7169406, "score": 0 }, { "doc_id": "15323746", "title": "EDL/MAE regulates EGF-mediated induction by antagonizing Ets transcription factor Pointed", "abstract": "Inductive patterning mechanisms often use negative regulators to coordinate the effects and efficiency of induction. During Spitz EGF-mediated neuronal induction in the Drosophila compound eye and chordotonal organs, Spitz causes activation of Ras signaling in the induced cells, resulting in the activation of Ets transcription factor Pointed P2. We describe developmental roles of a novel negative regulator of Ras signaling, EDL/MAE, a protein with an Ets-specific Pointed domain but not an ETS DNA-binding domain. The loss of EDL/MAE function results in reduced number of photoreceptor neurons and chordotonal organs, suggesting a positive role in the induction by Spitz EGF. However, EDL/MAE functions as an antagonist of Pointed P2, by binding to its Pointed domain and abolishing its transcriptional activation function. Furthermore, edl/mae appears to be specifically expressed in cells with inducing ability. This suggests that inducing cells, which can respond to Spitz they themselves produce, must somehow prevent activation of Pointed P2. Indeed hyperactivation of Pointed P2 in inducing cells interferes with their inducing ability, resulting in the reduction in inducing ability. We propose that EDL/MAE blocks autocrine activation of Pointed P2 so that inducing cells remain induction-competent. Inhibition of inducing ability by Pointed probably represents a novel negative feedback system that can prevent uncontrolled spread of induction of similar cell fates.", "corpus_id": 15323746, "score": 0 }, { "doc_id": "14783869", "title": "The Transmembrane Molecule Kekkon 1 Acts in a Feedback Loop to Negatively Regulate the Activity of the Drosophila EGF Receptor during Oogenesis", "abstract": "We have identified the Drosophila transmembrane molecule kekkon 1 (kek1) as an inhibitor of the epidermal growth factor receptor (EGFR) and demonstrate that it acts in a negative feedback loop to modulate the activity of the EGFR tyrosine kinase. During oogenesis, kek1 is expressed in response to the Gurken/EGFR signaling pathway, and loss of kek1 activity is associated with an increase in EGFR signaling. Consistent with our loss-of-function studies, we demonstrate that ectopic overexpression of kek1 mimics a loss of EGFR activity. We show that the extracellular and transmembrane domains of Kek1 can inhibit and physically associate with the EGFR, suggesting potential models for this inhibitory mechanism.", "corpus_id": 14783869, "score": 0 }, { "doc_id": "2404299", "title": "Sprouty is a general inhibitor of receptor tyrosine kinase signaling.", "abstract": "Sprouty was originally identified as an inhibitor of Drosophila FGF receptor signaling during tracheal development. By following the capacity of ectopic Sprouty to abolish the pattern of activated MAP kinase in embryos, we show that Sprouty can inhibit other receptor tyrosine kinase (RTK) signaling pathways, namely the Heartless FGF receptor and the EGF receptor. Similarly, in wing imaginal discs, ectopic Sprouty abolishes activated MAP kinase induced by the EGF receptor pathway. Sprouty expression is induced by the EGFR pathway in some, but not all, tissues in which EGFR is activated, most notably in follicle cells of the ovary, the wing imaginal disc and the eye disc. In the ovary, induction of sprouty expression follows the pattern of EGFR activation in the follicle cells. Generation of homozygous sprouty mutant follicle-cell clones demonstrates an essential role for Sprouty in restricting EGFR activation throughout oogenesis. At the stage when dorso-ventral polarity of the follicle cells is established, Sprouty limits the ventral expansion of the activating Gurken signal. Later, when dorsal appendage fates are determined, reduction of signaling by Sprouty facilitates the induction of inter-appendage cell fates. The capacity of Sprouty to reduce or eliminate accumulation of activated MAP kinase indicates that in vivo it intersects with the pathway upstream to MAP kinase. The ability of ectopic Sprouty to rescue lethality caused by activated Raf suggests that it may impinge upon the pathway by interacting with Raf or downstream to it.", "corpus_id": 2404299, "score": 0 }, { "doc_id": "4413371", "title": "Argos inhibits epidermal growth factor receptor signalling by ligand sequestration", "abstract": "The epidermal growth factor receptor (EGFR) has critical functions in development and in many human cancers. During development, the spatial extent of EGFR signalling is regulated by feedback loops comprising both well-understood activators and less well-characterized inhibitors. In Drosophila melanogaster the secreted protein Argos functions as the only known extracellular inhibitor of EGFR, with clearly identified roles in multiple stages of development. Argos is only expressed when the Drosophila EGFR (DER) is activated at high levels, and downregulates further DER signalling. Although there is ample genetic evidence that Argos inhibits DER activation, the biochemical mechanism has not been established. Here we show that Argos inhibits DER signalling without interacting directly with the receptor, but instead by sequestering the DER-activating ligand Spitz. Argos binds tightly to the EGF motif of Spitz and forms a 1:1 (Spitz:Argos) complex that does not bind DER in vitro or at the cell surface. Our results provide an insight into the mechanism of Argos function, and suggest new strategies for EGFR inhibitor design.", "corpus_id": 4413371, "score": 0 } ]

{ "doc_id": "1895090", "title": "The effect of telemedicine in critically ill patients: systematic review and meta-analysis", "abstract": "IntroductionTelemedicine extends intensivists' reach to critically ill patients cared for by other physicians. Our objective was to evaluate the impact of telemedicine on patients' outcomes.MethodsWe searched electronic databases through April 2012, bibliographies of included trials, and indexes and conference proceedings in two journals (2001 to 2012). We selected controlled trials or observational studies of critically ill adults or children, examining the effects of telemedicine on mortality. Two authors independently selected studies and extracted data on outcomes (mortality and length of stay in the intensive care unit (ICU) and hospital) and methodologic quality. We used random-effects meta-analytic models unadjusted for case mix or cluster effects and quantified between-study heterogeneity by using I2 (the percentage of total variability across studies attributable to heterogeneity rather than to chance).ResultsOf 865 citations, 11 observational studies met selection criteria. Overall quality was moderate (mean score on Newcastle-Ottawa scale, 5.1/9; range, 3 to 9). Meta-analyses showed that telemedicine, compared with standard care, is associated with lower ICU mortality (risk ratio (RR) 0.79; 95% confidence interval (CI), 0.65 to 0.96; nine studies, n = 23,526; I2 = 70%) and hospital mortality (RR, 0.83; 95% CI, 0.73 to 0.94; nine studies, n = 47,943; I2 = 72%). Interventions with continuous patient-data monitoring, with or without alerts, reduced ICU mortality (RR, 0.78; 95% CI, 0.64 to 0.95; six studies, n = 21,384; I2 = 74%) versus those with remote intensivist consultation only (RR, 0.64; 95% CI, 0.20 to 2.07; three studies, n = 2,142; I2 = 71%), but effects were statistically similar (interaction P = 0.74). Effects were also similar in higher (RR, 0.83; 95% CI, 0.68 to 1.02) versus lower (RR, 0.69; 95% CI, 0.40 to 1.19; interaction, P = 0.53) quality studies. Reductions in ICU and hospital length of stay were statistically significant (weighted mean difference (telemedicine-control), -0.62 days; 95% CI, -1.21 to -0.04 days and -1.26 days; 95% CI, -2.49 to -0.03 days, respectively; I2 > 90% for both).ConclusionsTelemedicine was associated with lower ICU and hospital mortality among critically ill patients, although effects varied among studies and may be overestimated in nonrandomized designs. The optimal telemedicine technology configuration and dose tailored to ICU organization and case mix remain unclear.", "corpus_id": 1895090 }

[ { "doc_id": "30637059", "title": "Are Intensivists Safe?", "abstract": "Intensivists have an identity problem. We do not perform unique procedures, such as coronary angioplasty or endoscopy. We used to take pride in our skills placing and interpreting data from pulmonary artery catheters, but this art is dying rapidly as the evidence mounts against its utility (1). We do not have an organ focus, as do neurologists or nephrologists. Many of us are internists, but others are pediatricians, anesthesiologists, neurologists, and surgeons. Despite this identity crisis, critical care medicine has not faded into obscurity but rather is enjoying a period of focused attention and popularity. Among the reasons are recent epidemiologic studies that emphasize the burden of critical illness and prominent, if controversial, clinical trials that are finally creating an evidence base for our practice (25). Of note, we have attracted the attention of payers and quality assurance agencies, primarily because of studies showing that organized staffing by intensivists improves the outcome of critically ill patients (68). In most of the world, critically ill patients are managed in closed intensive care units (ICUs). Therefore, research about different intensivist staffing models is only possible in and primarily of interest to clinicians in the United States (9). The terminology for models of intensive care physician staffing is not standardized and can be confusing (see Glossary). In the most cited systematic review (7), high-intensity staffing referred to ICUs with policies that require transfer of responsibility for care of every critically ill patient to a single intensivist team (closed ICUs) or that mandate consultation by an intensivist. The high-intensity models evaluated in these studies were based on unit-level policies that reflect an environment of care rather than the individual physician (intensivist or nonintensivist) assigned to the patient. We use the term intensivist staffing to specifically refer to high-intensity models of care and not to the specialty of the individual physician assigned to the patient. In this issue, Levy and colleagues (10) explore the effects of ICU physician staffing models on mortality in Project IMPACT, a consortium of ICUs that receive benchmarking data in an effort to improve their care. Their findings not only refute the claim that intensivist-staffed ICUs improve outcomes but raise the possibility that intensivists are actually harmful. It is a complex study made more so by combining 2 separate research questions: one on the effect of intensivist care in choice ICUs and the other on intensivist care in no-choice ICUs. Most of the patients in this cohort received care in choice ICUs, where someone, presumably a physician, decided whether to involve an intensivist. The investigators found that elective management by an intensivist in choice ICUs was associated with increased mortality. Elective management by an intensivist in a choice ICU should not be confused with intensivist staffing. The choice ICUs would all be classified as low-intensity staffed ICUs because intensivist involvement with a patient's care was discretionary. The effect of intensivists in low-intensitystaffed ICUs has not been studied extensively, but Levy and colleagues are not the first to raise concerns about this model of care. Treggiari and colleagues (11) demonstrated that elective consultation by a pulmonologist in open ICUs was associated with no benefit in patients with acute lung injury. These authors attributed the lack of association to indication bias, arguing that physicians would be more likely to seek help in cases that they judged to have worse prognosis. Because physicians' predictions of outcome contribute to prognoses generated by mathematical models, indication bias is difficult to eliminate from observational studies with regression models (12). Estimates of prognosis probably affect the decision to involve an intensivist, making the analysis of the choice ICUs susceptible to the same bias. Despite these limitations, these 2 studies certainly raise concerns that elective intensivist consultation in open ICUs may not substitute for intensivist staffing of the entire unit. In a separate analysis, Levy and colleagues showed that no-choice ICUs, in which at least 95% of patients were cared for during their entire stay by an intensivist, had higher mortality rates than ICUs in which 5% or fewer of the patients received care by an intensivist (10). Presumably, the former would qualify as intensivist-staffed units, and the latter are not only open units but open units with no access to intensivists. This analysis should be comparable to previous studies of intensivist staffing. Moreover, indication bias is unlikely, because no one had a choice about whether to involve an intensivist. Although the overall cohort was subject to multiple sensitivity analyses to account for assumptions about patient mix and statistical models, the analysis of the no-choice ICUs was not. Because the findings of the primary analyses were robust across a wide range of assumptions, a cautious reader must ask, is it possible that intensivist-staffed ICUs are dangerous? In trying to answer this question, readers should consider the strength of the evidence supporting the alternate hypothesis (that intensivist-staffed ICUs reduce mortality) and the evidence supporting possible causal mechanisms for harms or benefits. The evidence that mortality is lower in intensivist-staffed ICUs is extensive and consistent across various study designs and patient populations (8, 9). In addition to studies involving general ICU patients, studies show that patients with acute lung injury, trauma, abdominal aortic surgery, and esophageal resection have better outcomes in intensivist-staffed ICUs (11, 13, 15). Curiously, an analysis of an earlier version of the same Project IMPACT data set that Levy and colleagues used to show that intensivists were harmful was used to demonstrate that intensivists with dedicated neuro-ICUs improved outcomes in patients with intracerebral hemorrhage (16). Are these associations between intensivist care and better outcomes examples of cause and effect? One way to answer this key question is to look for dose effects. If intensivists are dangerous, greater exposure to them should cause even greater harm. In fact, a higher dose of intensivists, even in intensivist-staffed ICUs, appears to confer additional benefit (17, 18). In assessing whether an association is causal, readers should also look for evidence for a causal mechanism. Intensivist-staffed ICUs are more likely to use evidence-based treatments and to initiate earlier end-of-life discussions, which may explain their effect on outcomes (11, 19, 20). Although Levy and colleagues speculate about mechanisms by which intensivists might increase mortality, they do not provide evidence to support a proposed mechanism. Patients cared for by intensivists were sicker and more likely to be mechanically ventilated and, not surprisingly, more likely to receive ICU procedures than patients in the care of nonintensivists. This more aggressive approach, which might be accompanied by nosocomial complications, is a plausible culprit. But patients who did not receive ICU procedures also had worse outcomes when they received care by an intensivist, making the procedures an unlikely explanation. Therefore, until someone replicates Levy and colleagues' results in another cohort and provides evidence for a mechanism by which intensivist-staffed ICUs increase mortality, their study will remain one observation against many. Another explanation for these data could present a unique opportunity to learn how to improve critical care. Although the intensivist-staffed no-choice units appear to be harmful, it is possible that they only appear harmful because they were being compared with 21 high performing units that achieved superior outcomes without intensivists. Zimmerman and colleagues (21) found that a similar group of high-performing ICUs did not have a single approach to intensivist staffing but did consistently use treatment protocols, participated in benchmarking studies like Project IMPACT, used specific criteria for selecting patients for ICU admission, and had extensive staff training. Although multiple lines of compelling evidence indicate that mortality and length of stay are better in intensivist-staffed ICUs, none of it precludes the possibility that some ICUs can, in the absence of an organized intensive care service, evolve alternative strategies to deliver high-quality care (22). With a looming shortfall in intensivists and many other barriers to creating intensivist-staffed ICUs in the United States, studies that explicitly identify these techniques are urgently needed (23). Although intensivist staffing is an evidence-based recommendation, it is probably only a first step toward, and hardly a guarantee of, the care that critically ill patients and their families deserve. Glossary Closed ICU: All patients are cared for by 1 team of intensivists in collaboration with a primary service. Only intensivists have admitting privileges to the ICU. Also called mandatory transfer. Open ICU: Any physician can admit patients to the ICU. Elective consultation Intensivists are available for consultation at the discretion of the responsible physician. Choice ICUs: An ICU in which an intensivist is the responsible physician for some patients but not others; presumably an open ICU with elective consultation. No-choice ICU: An ICU in which there is no choice about intensivist careeither all patients or no patients have an intensivist as their responsible physician. Intensivist: A physician with subspecialty training in critical care medicine High-intensity staffing: Includes both closed and mandatory consult models Low-intensity staffing: Any model other than closed or mandatory consult model", "corpus_id": 30637059, "score": 0 }, { "doc_id": "72060911", "title": "Physician Staffing Patterns and Clinical Outcomes in Critically Ill Patients: A Systematic Review", "abstract": "Searching MEDLINE was searched from 1 January 1965 to 30 September 2001, using the following MeSH terms: 'intensive care units', 'ICU', 'health resources/utilization', 'hospitalization', 'medical staff', 'hospital organization and administration', 'personnel staffing and scheduling', 'length of stay' and 'LOS'. The textwords used were 'staffing', 'intensivist', 'critical', 'care' and 'specialist'. Controlled clinical trials were retrieved using the search strategy proposed by Robinson and Dickersin (see Other Publications of Related Interest no.1). Observational studies were identified using the MeSH terms 'case-control study' and 'retrospective study'.", "corpus_id": 72060911, "score": 0 }, { "doc_id": "28475539", "title": "Impact of critical care physician workforce for intensive care unit physician staffing.", "abstract": "The Society for Critical Care Medicine has advocated for intensivist lead multi-disciplinary critical care for our 30 years; growing evidence supports their assertion. It is estimated that if intensive care unit (ICU) physician staffing (IPS) was implemented in non-rural United States hospitals, 53,000 lives and $5.4 billion would be saved annually. Despite the benefits of hiring physicians specialized in the treatment of critically ill patients, many hospitals worry about their ability to hire critical care physicians to staff their ICUs. In this essay, we discuss issues regarding the future supply of and demand for critical care physicians beginning with an overview of how to evaluate physician supply and demand in general. We then discuss supply and demand for critical care physicians considering emerging issues such as the Leapfrog standard that may impact estimates of the supply and demand for critical care physicians.", "corpus_id": 28475539, "score": 0 }, { "doc_id": "20015183", "title": "Reorganizing adult critical care delivery: the role of regionalization, telemedicine, and community outreach.", "abstract": "Variation in the quality of critical care services across hospitals coupled with an emerging workforce crisis necessitates system-level change in the organization of intensive care. In this review, we evaluate three alternative organizational models that may expand access to high-quality critical care: tiered regionalization, intensive care unit telemedicine, and quality improvement through regional outreach. These models share a potential to increase survival and reduce costs. Yet there are also major barriers to implementation, including the lack of a strong evidence base and the need for significant upfront financial investment. Reorganization of intensive care will also require the support of all involved stakeholders: patients and their families, critical care practitioners, administrative and public health professionals, and policy makers. To varying degrees these models require a central authority to implement and regulate the system, as well as specific legislation, investment in information technology, and financial incentives for providers. The existing evidence does not strongly support exclusive use of a particular model, and creation of a hybrid model that integrates the three complementary approaches is a practical option. A potential framework for implementation involves triage guidelines developed by professional societies leading to demonstration projects and national legislation in support of optimal systems. Additional research is needed to determine the comparative effectiveness and cost implications of these approaches, with a goal of best matching high-quality critical care to patients' needs and professional preferences at the hospital, regional, and national level.", "corpus_id": 20015183, "score": 0 }, { "doc_id": "29361702", "title": "Effect of a multiple-site intensive care unit telemedicine program on clinical and economic outcomes: An alternative paradigm for intensivist staffing*", "abstract": "ObjectiveTo examine whether a supplemental remote intensive care unit (ICU) care program, implemented by an integrated delivery network using a commercial telemedicine and information technology system, can improve clinical and economic performance across multiple ICUs. DesignBefore-and-after trial to assess the effect of adding the supplemental remote ICU telemedicine program. SettingTwo adult ICUs of a large tertiary care hospital. PatientsA total of 2,140 patients receiving ICU care between 1999 and 2001. InterventionsThe remote care program used intensivists and physician extenders to provide supplemental monitoring and management of ICU patients for 19 hrs/day (noon to 7 am) from a centralized, off-site facility (eICU). Supporting software, including electronic data display, physician note- and order-writing applications, and a computer-based decision-support tool, were available both in the ICU and at the remote site. Clinical and economic performance during 6 months of the remote intensivist program was compared with performance before the intervention. Measurements and Main ResultsHospital mortality for ICU patients was lower during the period of remote ICU care (9.4% vs. 12.9%; relative risk, 0.73; 95% confidence interval [CI], 0.55–0.95), and ICU length of stay was shorter (3.63 days [95% CI, 3.21–4.04] vs. 4.35 days [95% CI, 3.93–4.78]). Lower variable costs per case and higher hospital revenues (from increased case volumes) generated financial benefits in excess of program costs. ConclusionsThe addition of a supplemental, telemedicine-based, remote intensivist program was associated with improved clinical outcomes and hospital financial performance. The magnitude of the improvements was similar to those reported in studies examining the impact of implementing on-site dedicated intensivist staffing models; however, factors other than the introduction of off-site intensivist staffing may have contributed to the observed results, including the introduction of computer-based tools and the increased focus on ICU performance. Although further studies are needed, the apparent success of this on-going multiple-site program, implemented with commercially available equipment, suggests that telemedicine may provide a means for hospitals to achieve quality improvements associated with intensivist care using fewer intensivists.", "corpus_id": 29361702, "score": 1 }, { "doc_id": "32070971", "title": "Association of telemedicine for remote monitoring of intensive care patients with mortality, complications, and length of stay.", "abstract": "CONTEXT\nTelemedicine technology, which can enable intensivists to simultaneously monitor several intensive care units (ICUs) from an off-site location, is increasingly common, but there is little evidence to support its use.\n\n\nOBJECTIVE\nTo assess the association of remote monitoring of ICU patients (ICU telemedicine [tele-ICU]) with mortality, complications, and length of stay (LOS).\n\n\nDESIGN, SETTING, AND PATIENTS\nObservational study conducted in 6 ICUs of 5 hospitals in a large US health care system to assess the use of tele-ICU. The study included 2034 patients in the preintervention period (January 2003 to August 2005) and 2108 patients in the postintervention period (July 2004 to July 2006).\n\n\nMAIN OUTCOME MEASURES\nHospital and ICU mortality, complications, and hospital and ICU survivors' LOS, with outcomes adjusted for severity of illness.\n\n\nRESULTS\nLocal physicians delegated full treatment authority to the tele-ICU for 655 patients (31.1%) and authority to intervene only in life-threatening events for the remainder. Observed hospital mortality rates were 12.0% (95% confidence interval [CI], 10.6% to 13.5%) in the preintervention period and 9.9% (95% CI, 8.6% to 11.2%) in the postintervention period (preintervention to postintervention decrease, 2.1%; 95% CI, 0.2% to 4.1%; P = .03); observed ICU mortality rates were 9.2% (95% CI, 8.0% to 10.5%) in the preintervention period and 7.8% (95% CI, 6.7% to 9.0%) in the postintervention period (preintervention to postintervention decrease, 1.4%; 95% CI, -0.3% to 3.2%; P = .12). After adjustment for severity of illness, there were no significant differences associated with the telemedicine intervention for hospital mortality (relative risk, 0.85; 95% CI, 0.71 to 1.03) or for ICU mortality (relative risk, 0.88; 95% CI, 0.71 to 1.08). There was a significant interaction between the tele-ICU intervention and severity of illness (P < .001), in which tele-ICU was associated with improved survival in sicker patients but with no improvement or worse outcomes in less sick patients. There were no significant differences between the preintervention and postintervention periods for hospital or ICU LOS.\n\n\nCONCLUSION\nRemote monitoring of ICU patients was not associated with an overall improvement in mortality or LOS.", "corpus_id": 32070971, "score": 1 }, { "doc_id": "1469264", "title": "Intensive care unit telemedicine: Alternate paradigm for providing continuous intensivist care", "abstract": "ObjectiveIntensive care units (ICUs) account for an increasing percentage of hospital admissions and resource consumption. Adverse events are common in ICU patients and contribute to high mortality rates and costs. Although evidence demonstrates reduced complications and mortality when intensivists manage ICU patients, a dramatic national shortage of these specialists precludes most hospitals from implementing an around-the-clock, on-site intensivist care model. Alternate strategies are needed to bring expertise and proactive, continuous care to the critically ill. We evaluated the feasibility of using telemedicine as a means of achieving 24-hr intensivist oversight and improved clinical outcomes. DesignObservational time series triple cohort study. SettingA ten-bed surgical ICU in an academic-affiliated community hospital. PatientsAll patients whose entire ICU stay occurred within the study periods. InterventionsA 16-wk program of continuous intensivist oversight was instituted in a surgical ICU, where before the intervention, intensivist consultation was available but there were no on-site intensivists. Intensivists provided management during the intervention using remote monitoring methodologies (video conferencing and computer-based data transmission) to obtain clinical information and to communicate with on-site personnel. To assess the benefit of the remote management program, clinical and economic performance during the intervention were compared with two 16-wk periods within the year before the intervention. Measurements and Main ResultsICU and hospital mortality (observed and Acute Physiology and Chronic Health Evaluation III, severity-adjusted), ICU complications, ICU and hospital length-of-stay, and ICU and hospital costs were measured during the 3 study periods. Severity-adjusted ICU mortality decreased during the intervention period by 68% and 46%, compared with baseline periods one and two, respectively. Severity-adjusted hospital mortality decreased by 33% and 30%, and the incidence of ICU complications was decreased by 44% and 50%. ICU length of stay decreased by 34% and 30%, and ICU costs decreased by 33% and 36%, respectively. The cost savings were associated with a lower incidence of complications. ConclusionsTechnology-enabled remote care can be used to provide continuous ICU patient management and to achieve improved clinical and economic outcomes. This intervention’s success suggests that remote care programs may provide a means of improving quality of care and reducing costs when on-site intensivist coverage is not available.", "corpus_id": 1469264, "score": 1 }, { "doc_id": "23971850", "title": "Association of health information technology and teleintensivist coverage with decreased mortality and ventilator use in critically ill patients.", "abstract": "BACKGROUND\nLittle evidence exists to support implementing various health information technologies, such as telemedicine, in intensive care units.\n\n\nMETHODS\nA coordinated health information technology bundle (HITB) was implemented along with remote intensivist coverage (RIC) at a 727-bed academic community hospital. Critical care specialists provided bedside coverage during the day and RIC at night to achieve intensivist coverage 24 hours per day, 7 days per week. We evaluated the effect of HITB-RIC on mortality, ventilator and vasopressor use, and the intervention length of stay. We compared our results with those achieved at baseline.\n\n\nRESULTS\nA total of 954 control patients who received care for 16 months before the implementation of HITB-RIC and 959 study patients who received care for 10 months after the implementation were included in the analysis. Mortality for the control and intervention groups were 21.4% and 14.7%, respectively. In addition, the observed mortality for the intervention group was 75.8% (P < .001) of that predicted by the Acute Physiology and Chronic Health Evaluation IV hospital mortality equations, which was 29.5% lower relative to the control group. Regression results confirm that the hospital mortality of the intensive care unit patients was significantly lower after implementation of the intervention, controlling for predicted risk of mortality and do-not-resuscitate status. Overall, intervention patients also had significantly less (P = .001) use of mechanical ventilation, controlling for body-system diagnosis category and severity of illness.\n\n\nCONCLUSION\nThe use of HITB-RIC was associated with significantly lower mortality and less ventilator use in critically ill patients.", "corpus_id": 23971850, "score": 1 }, { "doc_id": "205538595", "title": "Clinical and economic outcomes of the electronic intensive care unit: Results from two community hospitals*", "abstract": "Objective:To determine the impact of a telemedicine system, the electronic intensive care unit (eICU), on ICU, and non-ICU mortality, total mortality, total and ICU-specific length of stay, and total hospital cost at two community hospitals. Design:Observational study with one baseline period and two comparison periods (eICU wave one and eICU wave two). Each time period was 4 months in duration. Setting:Four ICU from two community hospitals in the metropolitan Chicago area. Hospital one is a 610-bed teaching hospital with three adult ICU (ten-bed medical ICU, ten-bed cardiac ICU, and 14-bed surgical ICU). Hospital two is a 185-bed nonteaching hospital with a ten-bed mixed medical/surgical ICU. Patients:All patients 18 yrs or older with an ICU stay of at least 4 hrs during the specified time period were included. Interventions:The eICU was implemented at both hospitals in April 2003. Measurements and Main Results:Mortality, length of stay, and total cost were measured. Age, gender, race/ethnicity, trauma status, Acute Physiology and Chronic Health Evaluation III score, and physician utilization of the eICU were included as covariates.Included in the analysis were 4088 patients (1371 at baseline, 1287 in eICU wave one, and 1430 in eICU wave two). The eICU did not have a significant effect on ICU/non-ICU/total mortality or hospital length of stay. ICU length of stay increased over time and was associated with higher physician utilization of the eICU. Although total hospital costs increased over time, the rate of increase was steeper for those patients whose physicians permitted only a low level of eICU involvement. Conclusions:In our study of >4000 patients representing two community hospitals, we did not find a reduction in mortality, length of stay, or hospital cost attributable to the introduction of the eICU.", "corpus_id": 205538595, "score": 1 }, { "doc_id": "20021098", "title": "Impact of telemedicine intensive care unit coverage on patient outcomes: a systematic review and meta-analysis.", "abstract": "BACKGROUND\nAlthough remote intensive care unit (ICU) coverage is rapidly being adopted to enhance access to intensivists, its effect on patient outcomes is unclear. We conducted a meta-analysis to examine the impact of telemedicine ICU (tele-ICU) coverage on mortality and length of stay (LOS).\n\n\nMETHODS\nWe conducted a systematic review of studies published from January 1, 1950, through September 30, 2010, using PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Global Health, Web of Science, the Cochrane Library, and conference abstracts. We included studies that reported data on the primary outcomes of ICU and in-hospital mortality or on the secondary outcomes of ICU and hospital LOS.\n\n\nRESULTS\nWe identified 13 eligible studies involving 35 ICUs. All the studies used a before-and-after design. The studies included 41 374 patients (15 667 pre-tele-ICU and 25 707 post-tele-ICU patients). Tele-ICU coverage was associated with a reduction in ICU mortality (pooled odds ratio, 0.80; 95% confidence interval [CI], 0.66-0.97; P = .02) but not in-hospital mortality for patients admitted to an ICU (pooled odds ratio, 0.82; 95% CI, 0.65-1.03; P = .08). Similarly, tele-ICU coverage was associated with a reduction in ICU LOS (mean difference, -1.26 days; 95% CI, -2.21 to -0.30; P = .01) but not hospital LOS (mean difference, -0.64; 95% CI, -1.52 to 0.25; P = .16).\n\n\nCONCLUSION\nTele-ICU coverage is associated with lower ICU mortality and LOS but not with lower in-hospital mortality or hospital LOS.", "corpus_id": 20021098, "score": 0 }, { "doc_id": "22376760", "title": "[The clinical application of remote critical care network].", "abstract": "OBJECTIVE\nTo discuss and evaluate whether a remote critical care program network can improve clinical and economic performance across multiple intensive care units (ICUs).\n\n\nMETHODS\nThe consultative center composed of intensivists and physician extenders to provide remote consultations for the critical patients. Supporting software, including electronic data display and communication interface were available both in the ICU center and at the remote sites. Clinical and economic performance after 1 year application of the program was compared with the performance before the intervention.\n\n\nRESULTS\nDuring January 2008 to July 2009, there had been 63 hospitals in Zhejiang Province joined the network. A total of 1 617 patients had received remote critical care consultations. One hundred and seventy-three remote teaching ward rounds and 72 lectures had been conducted on the network during this period. The before-and after-data comparison for 23 hospitals which had joined the network for longer than 1 year showed that, the program had decreased ICUs raw mortality by 11.6% (12.9% vs. 14.6%), and reduced transfer rate by 38.3% (2.9% vs. 4.7%), and ICUs bed occupancy rate increased by 6.1% (83.4% vs. 78.6%).\n\n\nCONCLUSION\nThe application of a remote critical care program was associated with improved clinical outcomes of critically ill patients and hospital financial performance.", "corpus_id": 22376760, "score": 0 }, { "doc_id": "38976658", "title": "Use of telemedicine to provide pediatric critical care inpatient consultations to underserved rural Northern California.", "abstract": "OBJECTIVE\nTo report a novel application of telemedicine and to assess the resulting quality and satisfaction of care. Study design An existing telemedicine program was evaluated through the use of a nonconcurrent cohort design. Cohorts of patients were compared by means of the Pediatric Risk of Mortality, version III (PRISM III), to adjust for severity of illness and assess risk-adjusted mortality rates. Satisfaction and quality of care surveys administered to the pediatric patient's parents and providers were also analyzed.\n\n\nRESULTS\nTelemedicine consultations (n=70) were conducted on 47 patients during a 2-year period. Patients receiving telemedicine consultations were sicker than the average pediatric patient cared for in the adult intensive care unit (ICU) (n=180) and compared with historic control pediatric patients (n=116) (mean PRISM III score of 9.6 versus 7.7 and 7.5, respectively). PRISM III-standardized mortality ratios were consistent among the same cohorts of patients (0.24, 0.36, and 0.37, respectively). Overall satisfaction and perception of quality of care was high among parents and rural health care providers.\n\n\nCONCLUSIONS\nThis study demonstrates that a regional pediatric ICU-based telemedicine program providing live interactive consultations to a rural adult ICU can provide quality care that is considered highly satisfactory to a select group of critically ill pediatric patients.", "corpus_id": 38976658, "score": 0 }, { "doc_id": "5930715", "title": "Impact of an Intensive Care Unit Telemedicine Program on a Rural Health Care System", "abstract": "Abstract We evaluated the impact of a 15-hospital, rural, multi-state intensive care unit (ICU) telemedicine program. Acute Physiology, Age, and Chronic Health Evaluation (APACHE® III) scores, raw mortality rates, and actual-to-predicted length of stay (LOS) ratios and mortality ratios were used. Surveys evaluated program impact in smaller facilities and satisfaction of the physicians staffing the remote center. Smaller facilities' staff reported improvements in the quality of critical care services and reduced transfers. In regional hospitals, acuity scores increased (retention of sicker patients) while raw mortality was the same or lower. Length of stay ratios were reduced in these hospitals. In the tertiary hospital, actual-to-predicted ICU and hospital mortality and LOS ratios decreased.", "corpus_id": 5930715, "score": 0 }, { "doc_id": "79550924", "title": "The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses", "abstract": "Nonrandomised studies, including case-control and cohort studies, can be challenging to implement and conduct. Assessment of the quality of such studies is essential for a proper understanding of nonrandomised studies. The Newcastle-Ottawa Scale (NOS) is an ongoing collaboration between the Universities of Newcastle, Australia and Ottawa, Canada. It was developed to assess the quality of nonrandomised studies with its design, content and ease of use directed to the task of incorporating the quality assessments in the interpretation of meta-analytic results. A 'star system' has been developed in which a study is judged on three broad perspectives: the selection of the study groups; the comparability of the groups; and the ascertainment of either the exposure or outcome of interest for case-control or cohort studies respectively. The goal of this project is to develop an instrument providing an easy and convenient tool for quality assessment of nonrandomised studies to be used in a systematic review.", "corpus_id": 79550924, "score": 0 }, { "doc_id": "6319826", "title": "Quantifying heterogeneity in a meta-analysis.", "abstract": "The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity.", "corpus_id": 6319826, "score": 0 }, { "doc_id": "18492784", "title": "Measuring inconsistency in meta-analyses", "abstract": "Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice? \n\nSystematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.\n\nAssessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4\n\nTests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted?\n\nA test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …", "corpus_id": 18492784, "score": 0 }, { "doc_id": "45709820", "title": "The statistical basis of meta-analysis.", "abstract": "Two models for study-to-study variation in a meta-analysis are presented, critiqued and illustrated. One, the fixed effects model, takes the studies being analysed as the universe of interest; the other, the random effects model, takes these studies as representing a sample from a larger population of possible studies. With emphasis on clinical trials, this paper illustrates in some detail the application of both models to three summary measures of the effect of an experimental intervention versus a control: the standardized difference for comparing two means, and the relative risk and odds ratio for comparing two proportions.", "corpus_id": 45709820, "score": 0 }, { "doc_id": "38976658", "title": "Use of telemedicine to provide pediatric critical care inpatient consultations to underserved rural Northern California.", "abstract": "OBJECTIVE\nTo report a novel application of telemedicine and to assess the resulting quality and satisfaction of care. Study design An existing telemedicine program was evaluated through the use of a nonconcurrent cohort design. Cohorts of patients were compared by means of the Pediatric Risk of Mortality, version III (PRISM III), to adjust for severity of illness and assess risk-adjusted mortality rates. Satisfaction and quality of care surveys administered to the pediatric patient's parents and providers were also analyzed.\n\n\nRESULTS\nTelemedicine consultations (n=70) were conducted on 47 patients during a 2-year period. Patients receiving telemedicine consultations were sicker than the average pediatric patient cared for in the adult intensive care unit (ICU) (n=180) and compared with historic control pediatric patients (n=116) (mean PRISM III score of 9.6 versus 7.7 and 7.5, respectively). PRISM III-standardized mortality ratios were consistent among the same cohorts of patients (0.24, 0.36, and 0.37, respectively). Overall satisfaction and perception of quality of care was high among parents and rural health care providers.\n\n\nCONCLUSIONS\nThis study demonstrates that a regional pediatric ICU-based telemedicine program providing live interactive consultations to a rural adult ICU can provide quality care that is considered highly satisfactory to a select group of critically ill pediatric patients.", "corpus_id": 38976658, "score": 1 }, { "doc_id": "15976033", "title": "Intensive care unit robotic telepresence facilitates rapid physician response to unstable patients and decreased cost in neurointensive care.", "abstract": "BACKGROUND\nThe timely assessment and treatment of ICU patients is important for neurosurgeons and neurointensivists. We hypothesized that the use of RTP can improve physician rapid response to unstable ICU patients.\n\n\nMETHODS\nThis is a prospective study using a before-after, cohort-control design to test the effectiveness of RTP. Physicians used RTP to make rounds in the ICU in response to nursing pages. Data concerning several aspects of the RTP interaction including the latency of the response, the problem being treated, the intervention that was ordered, and the type of information gathered using the RTP were documented. The effect of RTP on ICU length of stay and cost was assessed.\n\n\nRESULTS\nThe use of RTP was associated with a reduction in latency of attending physician face-to-face response for routine and urgent pages compared to conventional care (RTP: 9.2 +/- 9.3 minutes vs conventional: 218 +/- 186 minutes). The response latencies to brain ischemia (7.8 +/- 2.8 vs 152 +/- 85 minutes) and elevated ICP (11 +/- 14 vs 108 +/- 55 minutes) were reduced (P < .001), as was the LOS for patients with SAH (2 days) and brain trauma (1 day). There was an increase in ICU occupancy by 11% compared with the prerobot era, and there was an ICU cost savings of $1.1 million attributable to the use of RTP.\n\n\nCONCLUSION\nThe use of RTP enabled rapid face-to-face attending physician response to ICU patients and resulted in decreased ICU cost and LOS.", "corpus_id": 15976033, "score": 1 }, { "doc_id": "3843614", "title": "Clinical outcomes after telemedicine intensive care unit implementation*", "abstract": "Objective: To examine clinical outcomes before and after implementation of a telemedicine program in the intensive care units of a five-hospital healthcare system. Design: Observational study with the baseline period of 1 yr before the start of a telemedicine intensive care unit program implementation at each of 5 hospitals. The post periods are 1, 2, and 3 yrs after telemedicine intensive care unit program implementation at each hospital. Setting: Ten adult intensive care units (114 beds) in five community hospitals in south Florida. A telemedicine intensive care unit program with remote 24/7 intensivist and critical care nurse electronic monitoring was implemented by a phased approach between December 2005 and July 2007. Measurements and Main Results: Records from 24,656 adult intensive care unit patients were analyzed. Hospital length of stay, intensive care unit length of stay, hospital mortality, and Case Mix Index were measured. Severity of illness using All Patient Refined-Diagnosis Related Groups scores was used as a covariate. From the baseline year to year 3 postimplementation, the severity-adjusted hospital length of stay was lowered from 11.86 days (95% confidence interval [CI] 11.55–12.21) to 10.16 days (95% CI 9.80−10.53; p < .001), severity-adjusted intensive care unit length of stay was lowered from 4.35 days (95% CI 4.22–4.49) to 3.80 days (95% CI 3.65–3.94; p < .001), and the relative risk of hospital mortality decreased to 0.77 (95% CI 0.69–0.87; p < .001). Conclusions: After 3 yrs of deployment of a telemedicine intensive care unit program, this retrospective observational study of mortality and length of stay outcomes included all cases admitted to an adult intensive care unit and found statistically significant decreases in severity-adjusted hospital length of stay of 14.2%, intensive care unit length of stay of 12.6%, and relative risk of hospital mortality of 23%, respectively, in a multihospital healthcare system.", "corpus_id": 3843614, "score": 1 }, { "doc_id": "12876080", "title": "A multifaceted intervention for quality improvement in a network of intensive care units: a cluster randomized trial.", "abstract": "CONTEXT\nEvidence-based practices improve intensive care unit (ICU) outcomes, but eligible patients may not receive them. Community hospitals treat most critically ill patients but may have few resources dedicated to quality improvement.\n\n\nOBJECTIVE\nTo determine the effectiveness of a multicenter quality improvement program to increase delivery of 6 evidence-based ICU practices.\n\n\nDESIGN, SETTING, AND PARTICIPANTS\nPragmatic cluster-randomized trial among 15 community hospital ICUs in Ontario, Canada. A total of 9269 admissions occurred during the trial (November 2005 to October 2006) and 7141 admissions during a decay-monitoring period (December 2006 to August 2007).\n\n\nINTERVENTION\nWe implemented a videoconference-based forum including audit and feedback, expert-led educational sessions, and dissemination of algorithms to sequentially improve delivery of 6 practices. We randomized ICUs into 2 groups. Each group received this intervention, targeting a new practice every 4 months, while acting as control for the other group, in which a different practice was targeted in the same period. MAIN MEASURE OUTCOMES: The primary outcome was the summary ratio of odds ratios (ORs) for improvement in adoption (determined by daily data collection) of all 6 practices during the trial in intervention vs control ICUs.\n\n\nRESULTS\nOverall, adoption of the targeted practices was greater in intervention ICUs than in controls (summary ratio of ORs, 2.79; 95% confidence interval [CI], 1.00-7.74). Improved delivery in intervention ICUs was greatest for semirecumbent positioning to prevent ventilator-associated pneumonia (90.0% of patient-days in last month vs 50.0% in first month; OR, 6.35; 95% CI, 1.85-21.79) and precautions to prevent catheter-related bloodstream infection (70.0% of patients receiving central lines vs 10.6%; OR, 30.06; 95% CI, 11.00-82.17). Adoption of other practices, many with high baseline adherence, changed little.\n\n\nCONCLUSION\nIn a collaborative network of community ICUs, a multifaceted quality improvement intervention improved adoption of care practices.\n\n\nTRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00332982.", "corpus_id": 12876080, "score": 0 }, { "doc_id": "25461996", "title": "Evaluation of the Impact of a tele-ICU Pharmacist on the Management of Sedation in Critically III Mechanically Ventilated Patients", "abstract": "Background: An organized and uniform approach to managing sedation in critically ill patients has been associated with improved outcomes, but the most effective means of optimizing sedative medication use in clinical practice has not been fully determined. Pharmacist interventions directed at improving sedation guideline compliance have been shown to reduce the duration of mechanical ventilation. Objective: To determine the impact that pharmacy staffing configurations that include a tele-ICU pharmacist have on compliance with an intensive care unit (ICU) sedation guideline in critically ill mechanically ventilated patients requiring continuous-infusion sedative medications. Methods: Compliance with an established ICU sedation guideline, the performance of daily sedative interruptions, and the number of sedative medication–related interventions were evaluated before and after expansion of the ICU pharmacist staffing model to include comprehensive off-hours pharmacist coverage supported with established tele-ICU resources. In both groups, sedation was managed by the primary ICU team. In the intervention group, a pharmacist working in the tele-ICU center performed electronic record audits and made sedative medication recommendations to the primary team. Results: The addition of third shift tele-ICU pharmacist support was associated with a significant increase in the percentage of patients who received a daily sedative interruption (45% vs 54%; p < 0.0001). This occurred in the context of significant increases in the total number of ICU pharmacist interventions (36 vs 49.4 per 100 patient days, p < 0.0001), the number of therapeutic interventions (20.4 vs 26.1 per 100 patient days, p < 0.001), and the number of sedative-related interventions (0.9 vs 4.4 per 100 patient days, p < 0.0001). Conclusions: Tele-ICU resources can be utilized to increase compliance with an established ICU sedation guideline and extend the benefits that daytime ICU clinical pharmacy services provide. Increased ICU pharmacist availability may have additional benefits not measured in this study.", "corpus_id": 25461996, "score": 0 }, { "doc_id": "19116352", "title": "Implementation of a Model of Robotic Tele-Presence (RTP) in the Neuro-ICU: Effect on Critical Care Nursing Team Satisfaction", "abstract": "IntroductionRobotic Tele-Presence (RTP) is a form of mobile telemedicine, which enables a direct face-to-face rapid response by the physician, instead of the traditional telephonic paradigm. We hypothesized that a model of RTP for after-hour ICU rounds and emergencies would be associated with improved ICU nurse satisfaction.MethodsWe implemented a prospective nighttime multidisciplinary ICU round time, using RTP at our Neuro-ICU. To test for critical ICU nurse team satisfaction, a questionnaire was implemented. The primary outcome was nurse satisfaction measured through a questionnaire with answers trichotomized into: agreement, disagreement, and no opinion. The occurrence of outcomes was compared between the groups by χ2 or Fisher exact tests for the difference in proportions (PD) with Bonferroni correction for multiple pairwise comparisons.ResultsIn total, 34 nurses completed the pre-survey and 40 nurses completed the post-survey. Night nurses were more likely to agree that RTP was associated with: ICU physicians being sufficiently available in the ICU (agreement 6–20 %, PD 14 %, p = 0.008), present during acute emergencies (agreement 44–65 %, PD 21 %, p = 0.007), and had enough time to get questions answered from the physician team (agreement 41–53 %, PD 11 %, p = NS).ConclusionsThis data suggest improvement in critical care nursing team satisfaction with a model of RTP in the Neuroscience ICU, particularly during nighttime hours. RTP is a tool that may enhance communication among components of the ICU team.", "corpus_id": 19116352, "score": 0 }, { "doc_id": "19498566", "title": "The research agenda in ICU telemedicine: a statement from the Critical Care Societies Collaborative.", "abstract": "ICU telemedicine uses audiovisual conferencing technology to provide critical care from a remote location. Research is needed to best define the optimal use of ICU telemedicine, but efforts are hindered by methodological challenges and the lack of an organized delivery approach. We convened an interdisciplinary working group to develop a research agenda in ICU telemedicine, addressing both methodological and knowledge gaps in the field. To best inform clinical decision-making and health policy, future research should be organized around a conceptual framework that enables consistent descriptions of both the study setting and the telemedicine intervention. The framework should include standardized methods for assessing the preimplementation ICU environment and describing the telemedicine program. This framework will facilitate comparisons across studies and improve generalizability by permitting context-specific interpretation. Research based on this framework should consider the multidisciplinary nature of ICU care and describe the specific program goals. Key topic areas to be addressed include the effect of ICU telemedicine on the structure, process, and outcome of critical care delivery. Ideally, future research should attempt to address causation instead of simply associations and elucidate the mechanism of action in order to determine exactly how ICU telemedicine achieves its effects. ICU telemedicine has significant potential to improve critical care delivery, but high-quality research is needed to best inform its use. We propose an agenda to advance the science of ICU telemedicine and generate research with the greatest potential to improve patient care.", "corpus_id": 19498566, "score": 0 }, { "doc_id": "22745062", "title": "Costs and effectiveness of tele-ICUs in reducing morbidity and mortality in intensive care units", "abstract": "A substantial amount of healthcare is delivered in intensive care units (ICUs); amounting to over 13 million ICU bed-days per year 1 . Intensive care is a costly and growing expense in the US healthcare system, with ICUs comprising between 5–10% of hospital beds, consuming 20–34% of all acute care resources, and a total of 1% of the US gross domestic product 2 . These costs are increasing due to more severely ill patients and new technologies 3 .", "corpus_id": 22745062, "score": 0 }, { "doc_id": "5573811", "title": "Systematic Review: Impact of Health Information Technology on Quality, Efficiency, and Costs of Medical Care", "abstract": "Key Summary Points Health information technology has been shown to improve quality by increasing adherence to guidelines, enhancing disease surveillance, and decreasing medication errors. Much of the evidence on quality improvement relates to primary and secondary preventive care. The major efficiency benefit has been decreased utilization of care. Effect on time utilization is mixed. Empirically measured cost data are limited and inconclusive. Most of the high-quality literature regarding multifunctional health information technology systems comes from 4 benchmark research institutions. Little evidence is available on the effect of multifunctional commercially developed systems. Little evidence is available on interoperability and consumer health information technology. A major limitation of the literature is its generalizability. Health care experts, policymakers, payers, and consumers consider health information technologies, such as electronic health records and computerized provider order entry, to be critical to transforming the health care industry (1-7). Information management is fundamental to health care delivery (8). Given the fragmented nature of health care, the large volume of transactions in the system, the need to integrate new scientific evidence into practice, and other complex information management activities, the limitations of paper-based information management are intuitively apparent. While the benefits of health information technology are clear in theory, adapting new information systems to health care has proven difficult and rates of use have been limited (9-11). Most information technology applications have centered on administrative and financial transactions rather than on delivering clinical care (12). The Agency for Healthcare Research and Quality asked us to systematically review evidence on the costs and benefits associated with use of health information technology and to identify gaps in the literature in order to provide organizations, policymakers, clinicians, and consumers an understanding of the effect of health information technology on clinical care (see evidence report at www.ahrq.gov). From among the many possible benefits and costs of implementing health information technology, we focus here on 3 important domains: the effects of health information technology on quality, efficiency, and costs. Methods Analytic Frameworks We used expert opinion and literature review to develop analytic frameworks (Table) that describe the components involved with implementing health information technology, types of health information technology systems, and the functional capabilities of a comprehensive health information technology system (13). We modified a framework for clinical benefits from the Institute of Medicine's 6 aims for care (2) and developed a framework for costs using expert consensus that included measures such as initial costs, ongoing operational and maintenance costs, fraction of health information technology penetration, and productivity gains. Financial benefits were divided into monetized benefits (that is, benefits expressed in dollar terms) and nonmonetized benefits (that is, benefits that could not be directly expressed in dollar terms but could be assigned dollar values). Table. Health Information Technology Frameworks Data Sources and Search Strategy We performed 2 searches (in November 2003 and January 2004) of the English-language literature indexed in MEDLINE (1995 to January 2004) using a broad set of terms to maximize sensitivity. (See the full list of search terms and sequence of queries in the full evidence report at www.ahrq.gov.) We also searched the Cochrane Central Register of Controlled Trials, the Cochrane Database of Abstracts of Reviews of Effects, and the Periodical Abstracts Database; hand-searched personal libraries kept by content experts and project staff; and mined bibliographies of articles and systematic reviews for citations. We asked content experts to identify unpublished literature. Finally, we asked content experts and peer reviewers to identify newly published articles up to April 2005. Study Selection and Classification Two reviewers independently selected for detailed review the following types of articles that addressed the workings or implementation of a health technology system: systematic reviews, including meta-analyses; descriptive qualitative reports that focused on exploration of barriers; and quantitative reports. We classified quantitative reports as hypothesis-testing if the investigators compared data between groups or across time periods and used statistical tests to assess differences. We further categorized hypothesis-testing studies (for example, randomized and nonrandomized, controlled trials, controlled before-and-after studies) according to whether a concurrent comparison group was used. Hypothesis-testing studies without a concurrent comparison group included those using simple prepost, time-series, and historical control designs. Remaining hypothesis-testing studies were classified as cross-sectional designs and other. We classified quantitative reports as a predictive analysis if they used methods such as statistical modeling or expert panel estimates to predict what might happen with implementation of health information technology rather than what has happened. These studies typically used hybrid methodsfrequently mixing primary data collection with secondary data collection plus expert opinion and assumptionsto make quantitative estimates for data that had otherwise not been empirically measured. Cost-effectiveness and cost-benefit studies generally fell into this group. Data Extraction and Synthesis Two reviewers independently appraised and extracted details of selected articles using standardized abstraction forms and resolved discrepancies by consensus. We then used narrative synthesis methods to integrate findings into descriptive summaries. Each institution that accounted for more than 5% of the total sample of 257 papers was designated as a benchmark research leader. We grouped syntheses by institution and by whether the systems were commercially or internally developed. Role of the Funding Sources This work was produced under Agency for Healthcare Research and Quality contract no. 2002. In addition to the Agency for Healthcare Research and Quality, this work was also funded by the Office of the Assistant Secretary for Planning and Evaluation, U.S. Department of Health and Human Services, and the Office of Disease Prevention and Health Promotion, U.S. Department of Health and Human Services. The funding sources had no role in the design, analysis, or interpretation of the study or in the decision to submit the manuscript for publication. Data Synthesis Literature Selection Overview Of 867 articles, we rejected 141 during initial screening: 124 for not having health information technology as the subject, 4 for not reporting relevant outcomes, and 13 for miscellaneous reasons (categories not mutually exclusive). Of the remaining 726 articles, we excluded 469 descriptive reports that did not examine barriers (Figure). We recorded details of and summarized each of the 257 articles that we did include in an interactive database (healthit.ahrq.gov/tools/rand) that serves as the evidence table for our report (14). Twenty-four percent of all studies came from the following 4 benchmark institutions: 1) the Regenstrief Institute, 2) Brigham and Women's Hospital/Partners Health Care, 3) the Department of Veterans Affairs, and 4) LDS Hospital/Intermountain Health Care. Figure. Search flow for health information technology ( HIT ) literature. Pediatrics Types and Functions of Technology Systems The reports addressed the following types of primary systems: decision support aimed at providers (63%), electronic health records (37%), and computerized provider order entry (13%). Specific functional capabilities of systems that were described in reports included electronic documentation (31%), order entry (22%), results management (19%), and administrative capabilities (18%). Only 8% of the described systems had specific consumer health capabilities, and only 1% had capabilities that allowed systems from different facilities to connect with each other and share data interoperably. Most studies (n= 125) assessed the effect of the systems in the outpatient setting. Of the 213 hypothesis-testing studies, 84 contained some data on costs. Several studies assessed interventions with limited functionality, such as stand-alone decision support systems (15-17). Such studies provide limited information about issues that today's decision makers face when selecting and implementing health information technology. Thus, we preferentially highlight in the following paragraphs studies that were conducted in the United States, that had empirically measured data on multifunctional systems, and that included health information and data storage in the form of electronic documentation or order-entry capabilities. Predictive analyses were excluded. Seventy-six studies met these criteria: 54 from the 4 benchmark leaders and 22 from other institutions. Data from Benchmark Institutions The health information technology systems evaluated by the benchmark leaders shared many characteristics. All the systems were multifunctional and included decision support, all were internally developed by research experts at the respective academic institutions, and all had capabilities added incrementally over several years. Furthermore, most reported studies of these systems used research designs with high internal validity (for example, randomized, controlled trials). Appendix Table 1 (18-71) provides a structured summary of each study from the 4 benchmark institutions. This table also includes studies that met inclusion criteria not highlighted in this synthesis (26, 27, 30, 39, 40, 53, 62, 65, 70, 71). The data supported 5 primary themes (3 directly r", "corpus_id": 5573811, "score": 0 }, { "doc_id": "17194990", "title": "Room for improvement? A survey of the methods used in systematic reviews of adverse effects", "abstract": "BackgroundAlthough the methods for conducting systematic reviews of efficacy are well established, there is much less guidance on how systematic reviews of adverse effects should be performed.MethodsIn order to determine where methodological research is most needed to improve systematic reviews of adverse effects of health care interventions, we conducted a descriptive analysis of systematic reviews published between 1994 and 2005. We searched the Database of Abstracts of Reviews of Effects (DARE) and The Cochrane Database of Systematic Reviews (CDSR) to identify systematic reviews in which the primary outcome was an adverse effect or effects. We then extracted data on many of the elements of the systematic review process including: types of interventions studied, adverse effects of interest, resources searched, search strategies, data sources included in reviews, quality assessment of primary data, nature of the data analysis, and source of funding.Results256 reviews were included in our analysis, of which the majority evaluated drug interventions and pre-specified the adverse effect or effects of interest. A median of 3 resources were searched for each review and very few reviews (13/256) provided sufficient information to reproduce their search strategies. Although more than three quarters (185/243) of the reviews sought to include data from sources other than randomised controlled trials, fewer than half (106/256) assessed the quality of the studies that were included. Data were pooled quantitatively in most of the reviews (165/256) but heterogeneity was not always considered. Less than half (123/256) of the reviews reported on the source of funding.ConclusionThere is an obvious need to improve the methodology and reporting of systematic reviews of adverse effects. The methodology around identification and quality assessment of primary data is the main concern.", "corpus_id": 17194990, "score": 0 }, { "doc_id": "207385682", "title": "Staff acceptance of tele-ICU coverage: a systematic review.", "abstract": "BACKGROUND\nRemote coverage of ICUs is increasing, but staff acceptance of this new technology is incompletely characterized. We conducted a systematic review to summarize existing research on acceptance of tele-ICU coverage among ICU staff.\n\n\nMETHODS\nWe searched for published articles pertaining to critical care telemedicine systems (aka, tele-ICU) between January 1950 and March 2010 using PubMed, Cumulative Index to Nursing and Allied Health Literature, Global Health, Web of Science, and the Cochrane Library and abstracts and presentations delivered at national conferences. Studies were included if they provided original qualitative or quantitative data on staff perceptions of tele-ICU coverage. Studies were imported into content analysis software and coded by tele-ICU configuration, methodology, participants, and findings (eg, positive and negative staff evaluations).\n\n\nRESULTS\nReview of 3,086 citations yielded 23 eligible studies. Findings were grouped into four categories of staff evaluation: overall acceptance level of tele-ICU coverage (measured in 70% of studies), impact on patient care (measured in 96%), impact on staff (measured in 100%), and organizational impact (measured in 48%). Overall acceptance was high, despite initial ambivalence. Favorable impact on patient care was perceived by > 82% of participants. Staff impact referenced enhanced collaboration, autonomy, and training, although scrutiny, malfunctions, and contradictory advice were cited as potential barriers. Staff perceived the organizational impact to vary. An important limitation of available studies was a lack of rigorous methodology and validated survey instruments in many studies.\n\n\nCONCLUSIONS\nInitial reports suggest high levels of staff acceptance of tele-ICU coverage, but more rigorous methodologic study is required.", "corpus_id": 207385682, "score": 0 } ]

{ "doc_id": "53116772", "title": "Ethnobotanical Survey of Dracaena cinnabari and Investigation of the Pharmacognostical Properties, Antifungal and Antioxidant Activity of Its Resin", "abstract": "Dracaena cinnabari Balf. f. (Dracaenaceae) is an important plant endemic to Soqotra Island, Yemen. Dragon’s blood (Dam Alakhwin) is the resin that exudes from the plant stem. The ethnobotanical survey was carried out by semi-structured questionnaires and open interviews to document the ethnobotanical data of the plant. According to the collected ethnobotanical data, the resin of D. cinnabari is widely used in the traditional folk medicine in Soqotra for treatment of dermal, dental, eye and gastrointestinal diseases in humans. The resin samples found on the local Yemeni markets were partly or totally substituted by different adulterants. Organoleptic properties, solubility and extractive value were demonstrated as preliminary methods to identify the authentic pure Soqotri resin as well as the adulterants. In addition, the resin extracts and its solution in methanol were investigated for their in vitro antifungal activities against six human pathogenic fungal strains by the agar diffusion method, for antioxidant activities using the DPPH assay and for cytotoxic activity using the neutral red uptake assay. The crude authentic resin dissolves completely in methanol. In comparison with different resin extracts, the methanolic solution of the whole resin showed the strongest biological activities. It showed strong antifungal activity, especially against Microsporum gypseum and Trichophyton mentagrophytes besides antioxidant activities and toxicity against FL-cells. These findings confirm and explain the traditional uses of the resin for the treatment of skin diseases and mouth fungal infections.", "corpus_id": 53116772 }

[ { "doc_id": "13537536", "title": "Raman spectroscopy of coloured resins used in antiquity: dragon's blood and related substances.", "abstract": "Dragon's blood is a deep red resin which has been used for centuries by many cultures and much prized for it's rarity, depth of colour and alchemical associations. The original source of dragon's blood resin is believed to be Dracaena cinnabari from Socotra in Africa, but since mediaeval times there have been several alternatives from different geographical locations from the Canary Islands to the East Indies. Here, the Raman spectra of dragon's blood resins from Dracaena draco Liliacae trees growing in several different locations bordering the Mediterranean and Middle East are compared with the resins from alternative botanical sources such as Daemonorops draco, Dracaena cinnabari and Eucalyptus terminalis, which all generically come under the description of dragon's blood. Key vibrational spectroscopic marker bands are identified in the Raman spectra of the resins, which are suggested for adoption as a protocol for the identification of the botanical and possible geographical sources of modern dragon's blood resins. The Raman spectra of materials, which are falsely attributed to dragon's blood resin are also shown for comparison and identification purposes. Changes in the Raman spectra of genuine dragon's blood resin specimens arising from simple processing treatment during the preparation of the resins for sale are also identified, which suggests a possible attribution characteristic for unknown samples.", "corpus_id": 13537536, "score": 1 }, { "doc_id": "45677202", "title": "Raman spectroscopic analysis of dragon's blood resins-basis for distinguishing between Dracaena(Convallariaceae), Daemonorops(Palmae) and Croton(Euphorbiaceae).", "abstract": "\"Dragon[prime or minute]s blood\" is the name applied to the deep-red coloured resin obtained from various plants. The original source in Roman times, used by many cultures and esteemed for its depth of colour and mystical association, was the dragon tree Dracaena cinnabari(Convallariaceae), found only on the Indian Ocean island of Socotra, (Yemen). Additional sources emerged later, including another species of Dracaena, D. draco, from the Canary Islands and Madeira, and species in the genera Daemonorops(Palmae) from South East Asia and Croton(Euphorbiaceae) from tropical parts of both the New and Old Worlds. In this study, examples of dragon's blood resins from the Economic Botany Collections at the Royal Botanic Gardens, Kew, dating from 1851 to 1993, have been analysed non-destructively using Raman spectroscopy. The Raman spectra of well-documented, provenanced specimens have been used to establish the source of specimens of questionable or unknown origin. It has also been possible from the Raman spectra to indicate whether processing of the resins has been undertaken in the preparation of the specimens before their deposition at Kew.", "corpus_id": 45677202, "score": 1 }, { "doc_id": "13267387", "title": "Identification and differentiation of dragon's blood in works of art using gas chromatography/mass spectrometry", "abstract": "AbstractDragon's blood is a common but non-specific name for red-coloured resins that are produced by various plants, particularly exudations from plant species belonging to the genera Dracaena and Daemonorops. Although dragon's blood is mentioned in historic sources as a colourant, it has hardly ever been identified in real artworks. This paper reports the identification and discrimination of dragon's blood produced by Dracaena cinnabari, Dracaena draco as well as Daemonorops draco and Daemonorops micracantha by means of gas chromatography/mass spectrometry (GC/MS) within the context of a routine analysis of binding media used in works of art. The detection of specific flavonoid marker compounds in both underivatised and methylated methanol extracts provided the first evidence for the use of dragon's blood from all four species in various works of art from the fifteenth to nineteenth centuries. Dragon's blood was mainly used as a red colourant in gold lacquers as well as translucent glazes and paints, e.g. in reverse-glass paintings (Hinterglasmalerei).\n FigureSplendid and colourful Hinterglasmalerei in the Amelierung technique with gold foils on two panels of the Corning House Altar, ca. 1560–1580, before restoration. The red paints contain dragon’s blood from Dae. draco. The width of the altar with closed wings is 19.5 cm. Photo: Simone Bretz, Oberau, © The Corning Museum of Glass, Corning (NY)", "corpus_id": 13267387, "score": 1 }, { "doc_id": "83405050", "title": "Ethnoflora of the Soqotra Archipelago", "abstract": "Ethnoflora of the Soqotra Archipelago is an attractive, user-friendly manual to the plants of this little-known but botanically important group of islands, situated off the Horn of Africa and governed by Yemen. Designed as a practical guide for conservationists and planners, as well as students, botanists and others interested in the plant life of the region, this comprehensive volume differs from a standard Flora in two significant ways.", "corpus_id": 83405050, "score": 1 }, { "doc_id": "31760782", "title": "Flavylium chromophores as species markers for dragon's blood resins from Dracaena and Daemonorops trees.", "abstract": "A simple and rapid liquid chromatographic method with diode-array UV-vis spectrophotometric detection has been developed for the authentication of dragon's blood resins from Dracaena and Daemonorops trees. Using this method it was discovered that the flavylium chromophores, which contribute to the red colour of these resins, differ among the species and could be used as markers to differentiate among species. A study of parameters, such as time of extraction, proportion of MeOH and pH, was undertaken to optimise the extraction of the flavyliums. This method was then used to make extracts from samples of dragon's blood resin obtained from material of known provenance. From the samples analysed 7,6-dihydroxy-5-methoxyflavylium (dracorhodin), 7,4'-dihydroxy-5-methoxyflavylium (dracoflavylium) and 7,4'-dihydroxyflavylium were selected as species markers for Daemonorops spp., Dracaena draco and Dracaena cinnabari, respectively. The chromatograms from these samples were used to build an HPLC-DAD database. The ability to discriminate among species of dragon's blood using the single marker compounds was compared with a principal components analysis of the chromatograms in the HPLC-DAD database. The results from the HPLC-DAD method based on the presence of these flavylium markers was unequivocal. The HPLC-DAD method was subsequently applied to 37 samples of dragon blood resins from the historical samples in the Economic Botany Collection, Royal Botanic Gardens, Kew. The method identified anomalies in how samples in this collection had been labelled. It is clear that the method can be used to evaluate the provenance of samples used in different areas of cultural heritage. It also could be used to monitor the trade of endangered species of dragon's blood and the species being used in complex formulations of traditional Chinese medicine.", "corpus_id": 31760782, "score": 0 }, { "doc_id": "26500377", "title": "Potential carcinogenicity of homoisoflavanoids and flavonoids from Resina sanguinis draconis (Dracaena cinnabari Balf.).", "abstract": "Polarographic behavior of three homoisoflavanoids and four flavanoids isolated from the dragon's blood (Resina sanguinis draconis. Dracaena cinnabari Balf.), collected at Sokotra, was investigated in aprotic solution and an index of potential carcinogenicity tg alpha was determined. Generally, homoisoflavanoids and flavanoids were reduced in two two-electron steps, the first being reversible and the second one irreversible. The parameter tg alpha values indicated that the majority of these compounds possesses no or only marginal potential carcinogenic activity. However, it was demonstrated that some structural modifications in basic flavonoid structure lead to changed electrochemical properties and a substantial increase of derivative potential carcinogenicity.", "corpus_id": 26500377, "score": 1 }, { "doc_id": "95738060", "title": "Damalachawin, a triflavonoid of a new structural type from dragon's blood of Dracaena cinnabari", "abstract": "A new triflavonoid, damalachawin, was isolated from dragon's blood of Dracaena cinnabari. Its structure was established mainly by NMR spectroscopy.", "corpus_id": 95738060, "score": 1 }, { "doc_id": "98381947", "title": "Flavonoids of dragon's blood from Dracaena cinnabari", "abstract": "Abstract In addition to 7-hydroxy-3-(4-hydroxybenzyl)-8-methoxychroman, 3-(4-hydroxybenzyl)-7,8-methylenedioxychroman, 7-hydroxy-3-(4-hydroxybenzyl)chroman, (±)-7,4′-dihydroxy-3′-methoxyflavan, (2 S )-7-hydroxyflavan, 4,4′-dihydroxy-2-methoxydihydrochalcone, 4,4′-dihydroxy-2′-methoxychalcone, 7,4′-dihydroxyflavone and (2 S )-7-hydroxyflavan-4-one, three new flavonoids have been isolated from the resin, called ‘dragon's blood’, of Dracaena cinnabari , the structures of which have been elucidated as 7-hydroxy-3-(3-hydroxy-4-methoxybenzyl)chroman, (2 S )-7,3′-dihydroxy-4′-methoxyflavan and 4-hydroxy-2-methoxydihydrochalcone.", "corpus_id": 98381947, "score": 0 }, { "doc_id": "95721607", "title": "Cinnabarone, a biflavonoid from dragon's blood of Dracaena cinnabari", "abstract": "Abstract A new biflavonoid, cinnabarone, was isolated from dragon's blood of Dracaena cinnabari . Its structure was established, mainly by NMR spectroscopy, as a dihydrochalcone linked by a carbon-carbon bond to a deoxotetrahydrochalcone.", "corpus_id": 95721607, "score": 0 }, { "doc_id": "8805822", "title": "Dracophane, a metacyclophane derivative from the resin of Dracaena cinnabari Balf.", "abstract": "Dracophane, a novel structural derivative of metacyclophane, was isolated from the resin of Dracaena cinnabari Balf. The structure of this compound was determined by spectroscopic methods to be 3,12,21-trihydroxy-1,10,19-tris(4-hydroxyphenyl)-5,14,23-trimethoxy[3.3.3]metacyclophane.", "corpus_id": 8805822, "score": 1 }, { "doc_id": "25175031", "title": "Chemoprotective potentials of homoisoflavonoids and chalcones of Dracaena cinnabari: modulations of drug‐metabolizing enzymes and antioxidant activity", "abstract": "A series of homoisoflavonoids and chalcones, isolated from the endemic tropical plant Dracaena cinnabari Balf. (Agavaceae), were tested for their potential to inhibit cytochrome P4501A (CYP1A) enzymes and Fe‐enhanced in vitro peroxidation of microsomal lipids in C57B1/6 mouse liver. The effects of the polyphenolic compounds were compared with those of prototypal flavonoid modulators of CYP1A and the well‐known antioxidant, butylated hydroxytoluene. 2‐Hydroxychalcone and partly 4,6‐dihydroxychalcone were found to be strong inhibitors of CYP1A‐dependent 7‐ethoxyresorufin O‐deethylase (EROD) activity in vitro comparable to the effects of quercetin and chrysin. The first screening of flavonoids and chalcones of Dracaena cinnabari for antioxidant activity was done in an in vitro microsomal peroxidation assay. While chalcones were shown to be poor antioxidants, 7,8‐methylenedioxy‐3(4‐hydroxybenzyl) chromane, as one of the tested homoisoflavonoids, exhibited a strong antioxidant activity comparable to that of the strongest flavonol antioxidant, quercetin. Copyright © 2001 John Wiley & Sons, Ltd.", "corpus_id": 25175031, "score": 0 }, { "doc_id": "44018248", "title": "Medical ethnobotany of the Yucatec Maya: Healers’ consensus as a quantitative criterion", "abstract": "Medical Ethnobotany of the Yucatec Maya: Healers’ Consensus as a Quantitative Criterion. Economic Botany 53(2):144–160, 1999. There is an urgent need to obtain information on the relative importance of a taxon used medicinally as compared to others within the same culture. This was achieved through a documentation of the current indigenous medical uses of 320 species in three Yucatec Maya communities during 18 months of fieldwork. The 1549 individual reports documented were divided into nine groups, which classify indigenous uses. The frequency of usage of the individual plants reported was employed in the analysis of the ethnobotanical importance of the respective taxa. Species cited more frequently in a group of indigenous uses are regarded to be of greater ethnobotanical importance than those cited only by a few informants. In order to obtain information on possible biological, pharmacological and toxicological effects of some particularly important species, the scientific literature on these taxa was evaluated systematically. The study is the basis for phytochemical and pharmacological evaluations of the traditional uses.ResumenSe considera esencial la documentación de la importancia relativa que un taxon de uso medicinal tiene, en comparación con otros taxones dentro de una misma cultura. Con este propósito se realizó un estudio etnobotánico de 18 meses, investigando el uso de 320 especies en très comunidades Mayas del Estado de Yucatán (México). Se documentaron 1549 usos indigenas, que se clasificaron en 9 grupos. Se utilizó el numero de usos indígenas para determinar la importancia relativa de cada especie; así, las especies medicinales que fueron citadas con mayor frecuencia se consideran las de mayor importancia, mientras que las especies citadas con menor frecuencia son las de menor importancia. Para evaluar los usos indigenas se obtuvo información sobre efectos biológicos, farmacológicos y toxicológicos de las especies, através de una revisión sistemática de la literatura científica. Este estudio es la base para la selección de plantas que se evaluarán en estudios fitoquímicos y farmacológicos.", "corpus_id": 44018248, "score": 0 }, { "doc_id": "2342330", "title": "Antimicrobial activity of some medicinal plants of the island Soqotra.", "abstract": "Twenty-five selected plants belonging to 19 families were collected from different localities of the island Soqotra, dried and extracted with the solvents chloroform, methanol and hot water to yield 80 extracts. The extracts were tested for their antimicrobial activity against several Gram-positive and Gram-negative bacteria and against one yeast species using agar diffusion method. Antibacterial activity was demonstrated especially against Gram-positive bacteria including multiresistant Staphylococcus strains. The greatest activity was exhibited by the methanolic extracts of Boswellia elongata, Boswellia ameero, Buxus hildebrandtii, Commiphora parvifolia, Jatropha unicostata, Kalanchoe farinacea, Pulicaria stephanocarpa, Punica protopunica, Withania adunensis and Withania riebeckii. Only the methanolic extract of Buxus hildebrandtii displayed significant antifungal activity.", "corpus_id": 2342330, "score": 0 }, { "doc_id": "28949446", "title": "Flavonoid dimers from the total phenolic extract of Chinese dragon's blood, the red resin of Dracaena cochinchinensis.", "abstract": "Eight new flavonoid dimers, named cochinchinenins I-M (1-5), including three pairs of enantiomers (1a/1b-3a/3b) and two optically pure flavonoid dimers (4-5), along with a known analogue (6), were isolated from total phenolic extract of the red resin of Dracaena cochinchinensis (Chinese dragon's blood). The planar structures of 1-5 were elucidated by extensive spectroscopic analysis including HRESIMS and 1D/2D NMR. Their absolute configurations were determined on the basis of experimental and calculated electronic circular dichroism (ECD) data. Compounds 4 and 5 exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated BV-2 microglial cells with IC50 value of 4.9±0.4 and 5.4±0.6μM, respectively.", "corpus_id": 28949446, "score": 0 }, { "doc_id": "83539968", "title": "Flavans of dragon’s blood from Dracaena draco and Dracaena tamaranae", "abstract": "Abstract Flavans of D. draco subsp. draco and subsp. ajgal and of D. tamaranae were isolated and identified for a chemotaxonomic survey. A major constituent of all taxa was (2 S )-4,7′-dihydroxy-8-methylflavan.", "corpus_id": 83539968, "score": 0 }, { "doc_id": "20817462", "title": "In vitro antifungal activity of dragon's blood from Croton urucurana against dermatophytes.", "abstract": "Based on ethnobotanical approach, the dragon's blood collected from Croton urucurana Baill. bark (Euphorbiaceae) was tested for antifungal activity against five dermatophytes by paper disk diffusion method. The minimal inhibitory concentration (MIC) showing no visible fungal growth was also determined, using tube dilution technique. The test dermatophytes were Tricophyton tonsurans, Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis and Epidermophyton floccossum. The dragon's blood (0.175-3.0 mg/ml) exhibited an inhibition zone range of 7.6-26.9 mm against all the tested fungi with minimal inhibitory concentrations of 1.25-2.5 mg/ml.", "corpus_id": 20817462, "score": 0 }, { "doc_id": "22536703", "title": "The useful plants of Tambopata, Peru: I. Statistical hypotheses tests with a new quantitative technique", "abstract": "This paper describes a new, simple, quantitative technique for evaluating the relative usefulness of plants to people. The technique is then compared to the quantitative approaches in ethnobotany that have been developed recently. Our technique is used to calculate the importance of over 600 species of woody plants to non-indigenous mestizo people in Tambopata, Amazonian Peru. Two general classes of hypotheses are formulated and tested statistically, concerning (1) the relative importance of different species, and (2) the importance of different families. The plant families are compared with respect to all uses, and with respect to five broad groups of uses. Palms, Annonaceae, and Lauraceae were found to be the most useful woody plant families. On average, the 20 largest woody plant families are most important to mestizos for subsistence construction materials, followed in descending order by commercial, edible, technological, and medicinal uses.ResumenEn éste estudio se describe una nueva técnica cuantitativa para la evaluation de la relativa utilidad de plantas a la gente. Esta técnica se compara con aquellas técnicas cuantitativas recientemente desarrolladas en etnobotánica. Con ésta técnica nosotros estimamos la importantia que las plantas lenosas, más de 600 especies, tienenpara los mestizos de Tambopata de la Amazonia del Peru. Estadisticamente, se prueban dos hipótesis generates concernientes a (1) la relativa importantia de especies diferentes, y a (2) la importantia de diferentes familias. Las familias de plantas son comparadas entre ellas en relation a todos los usos, y con respecto a cinco grupos amplios de usos. Se descubrió que lasfamilias leńosas mas útiles son las palmeras, Annonaceas, y Lauraceas. En término promedio, las 20 familias mas grandes de plantas leñosas tienen prioridad como materiales de constructión de subsistencia, seguidas en orden descendiente por sus usos comerciales, comestibles, tecnológicos, y medicinales.", "corpus_id": 22536703, "score": 0 }, { "doc_id": "3808056", "title": "Use of a Free Radical Method to Evaluate Antioxidant Activity", "abstract": "The antiradical activities of various antioxidants were determined using the free radical, 2,2-Diphenyl-1-picrylhydrazyl (DPPH*). In its radical form. DPPH* has an absorption band at 515 nm which dissappears upon reduction by an antiradical compound. Twenty compounds were reacted with the DPPH* and shown to follow one of three possible reaction kinetic types. Ascorbic acid, isoascorbic acid and isoeugenol reacted quickly with the DPPH* reaching a steady state immediately. Rosmarinic acid and δ-tocopherol reacted a little slower and reached a steady state within 30 min. The remaining compounds reacted more progressively with the DPPH* reaching a steady state from 1 to 6 h. Caffeic acid, gentisic acid and gallic acid showed the highest antiradical activities with a stoichiometry of 4 to 6 reduced DPPH* molecules per molecule of antioxidant. Vanillin, phenol, γ-resorcylic acid and vanillic acid were found to be poor antiradical compounds. The stoichiometry for the other 13 phenolic compounds varied from one to three reduced DPPH* molecules per molecule of antioxidant. Possible mechanisms are proposed to explain the experimental results.", "corpus_id": 3808056, "score": 0 } ]

{ "doc_id": "22591965", "title": "Non-lysosomal Degradation of Singly Phosphorylated Oligosaccharides Initiated by the Action of a Cytosolic Endo-β-N-acetylglucosaminidase*", "abstract": "Phosphorylated oligosaccharides (POSs) are produced by the degradation of dolichol-linked oligosaccharides (DLOs) by an unclarified mechanism in mammalian cells. Although POSs are exclusively found in the cytosol, their intracellular fates remain unclear. Our findings indicate that POSs are catabolized via a non-lysosomal glycan degradation pathway that involves a cytosolic endo-β-N-acetylglucosaminidase (ENGase). Quantitative and structural analyses of POSs revealed that ablation of the ENGase results in the significant accumulation of POSs with a hexasaccharide structure composed of Manα1,2Manα1,3(Manα1,6)Manβ1,4GlcNAcβ1,4GlcNAc. In vitro ENGase assays revealed that the presence of an α1,2-linked mannose residue facilitates the hydrolysis of POSs by the ENGase. Liquid chromatography-mass spectrometric analyses and fluorescent labeling experiments show that such POSs contain one phosphate group at the reducing end. These results indicate that ENGase efficiently hydrolyzes POSs that are larger than Man4GlcNAc2-P, generating GlcNAc-1-P and neutral Gn1-type free oligosaccharides. These results provide insight into important aspects of the generation and degradation of POSs.", "corpus_id": 22591965 }

[ { "doc_id": "205153162", "title": "Cotranslational and posttranslocational N-glycosylation of proteins in the endoplasmic reticulum.", "abstract": "Asparagine linked glycosylation of proteins is an essential protein modification reaction in most eukaryotic organisms. N-linked oligosaccharides are important for protein folding and stability, biosynthetic quality control, intracellular traffic and the physiological function of many N-glycosylated proteins. In metazoan organisms, the oligosaccharyltransferase is composed of a catalytic subunit (STT3A or STT3B) and a set of accessory subunits. Duplication of the catalytic subunit gene allowed cells to evolve OST complexes that act sequentially to maximize the glycosylation efficiency of the large number of proteins that are glycosylated in metazoan organisms. We will summarize recent progress in understanding the mechanism of (a) cotranslational glycosylation by the translocation channel associated STT3A complex, (b) the role of the STT3B complex in mediating cotranslational or posttranslocational glycosylation of acceptor sites that have been skipped by the STT3A complex, and (c) the role of the oxidoreductase MagT1 in STT3B-dependent glycosylation of cysteine-proximal acceptor sites.", "corpus_id": 205153162, "score": 0 }, { "doc_id": "24116675", "title": "An evolving view of the eukaryotic oligosaccharyltransferase.", "abstract": "Asparagine-linked glycosylation (ALG) is one of the most common protein modification reactions in eukaryotic cells, as many proteins that are translocated across or integrated into the rough endoplasmic reticulum (RER) carry N-linked oligosaccharides. Although the primary focus of this review will be the structure and function of the eukaryotic oligosaccharyltransferase (OST), key findings provided by the analysis of the archaebacterial and eubacterial OST homologues will be reviewed, particularly those that provide insight into the recognition of donor and acceptor substrates. Selection of the fully assembled donor substrate will be considered in the context of the family of human diseases known as congenital disorders of glycosylation (CDG). The yeast and vertebrate OST are surprisingly complex hetero-oligomeric proteins consisting of seven or eight subunits (Ost1p, Ost2p, Ost3p/Ost6p, Ost4p, Ost5p, Stt3p, Wbp1p, and Swp1p in yeast; ribophorin I, DAD1, N33/IAP, OST4, STT3A/STT3B, Ost48, and ribophorin II in mammals). Recent findings from several laboratories have provided overwhelming evidence that the STT3 subunit is critical for catalytic activity. Here, we will consider the evolution and assembly of the eukaryotic OST in light of recent genomic evidence concerning the subunit composition of the enzyme in diverse eukaryotes.", "corpus_id": 24116675, "score": 0 }, { "doc_id": "18544231", "title": "Generation and degradation of free asparagine-linked glycans", "abstract": "Asparagine (N)-linked protein glycosylation, which takes place in the eukaryotic endoplasmic reticulum (ER), is important for protein folding, quality control and the intracellular trafficking of secretory and membrane proteins. It is known that, during N-glycosylation, considerable amounts of lipid-linked oligosaccharides (LLOs), the glycan donor substrates for N-glycosylation, are hydrolyzed to form free N-glycans (FNGs) by unidentified mechanisms. FNGs are also generated in the cytosol by the enzymatic deglycosylation of misfolded glycoproteins during ER-associated degradation. FNGs derived from LLOs and misfolded glycoproteins are eventually merged into one pool in the cytosol and the various glycan structures are processed to a near homogenous glycoform. This article summarizes the current state of our knowledge concerning the formation and catabolism of FNGs.", "corpus_id": 18544231, "score": 1 }, { "doc_id": "24822944", "title": "Metabolically programmed quality control system for dolichol-linked oligosaccharides", "abstract": "Significance In mammals, asparagine (N)-linked glycosylation of nascent polypeptides synthesized in the endoplasmic reticulum regulates folding, degradation, and intracellular trafficking of the glycoproteins. The normal N-glycosylation requires the completely-assembled dolichol-linked oligosaccharide (DLO) as the optimal glycan donor substrate; however, a low-glucose environment causes arrest of the DLO assembly, which results in the synthesis of extensively truncated premature DLOs, thereby increasing a risk of abnormal N-glycosylation. Here, we report that under low-glucose conditions, the premature DLOs are efficiently degraded by unidentified pyrophosphatase, catabolizing them to singly phosphorylated oligosaccharides. Our results suggest that the pyrophosphatase-mediated degradation of premature DLOs functions as a quality control system to avoid abnormal N-glycosylation under conditions that impair efficient DLO biosynthesis. The glycolipid Glc3Man9GlcNAc2-pyrophosphate-dolichol serves as the precursor for asparagine (N)-linked protein glycosylation in mammals. The biosynthesis of dolichol-linked oligosaccharides (DLOs) is arrested in low-glucose environments via unknown mechanisms, resulting in abnormal N-glycosylation. Here, we show that under glucose deprivation, DLOs are prematurely degraded during the early stages of DLO biosynthesis by pyrophosphatase, leading to the release of singly phosphorylated oligosaccharides into the cytosol. We identified that the level of GDP-mannose (Man), which serves as a donor substrate for DLO biosynthesis, is substantially reduced under glucose deprivation. We provide evidence that the selective shutdown of the GDP-Man biosynthetic pathway is sufficient to induce the release of phosphorylated oligosaccharides. These results indicate that glucose-regulated metabolic changes in the GDP-Man biosynthetic pathway cause the biosynthetic arrest of DLOs and facilitate their premature degradation by pyrophosphatase. We propose that this degradation system may avoid abnormal N-glycosylation with premature oligosaccharides under conditions that impair efficient DLO biosynthesis.", "corpus_id": 24822944, "score": 1 }, { "doc_id": "23537324", "title": "Fate of oligosaccharide-lipid intermediates synthesized by resting rat-spleen lymphocytes.", "abstract": "Using conditions to avoid the utilization of labelled precursors by intracellular glycosyltransferases, experiments are described demonstrating that intact rat-spleen lymphocytes are capable of utilizing exogenous GDP-mannose and UDP-N-acetylglucosamine to synthesize dolichyl monophosphate mannose and dolichyl diphosphate oligosaccharides. Kinetic and chase experiments show that dolichyl diphosphate oligosaccharides are either utilized for the transfer of their carbohydrate moieties to protein acceptors or further degraded. Since glycosylation of proteins is limited in resting lymphocytes, the degradation pathway appears as a major event in the fate of the dolichyl diphosphate oligosaccharides synthesized in vitro. These dolichyl diphosphate oligosaccharides are degraded into phospho-oligosaccharides and oligosaccharides which are released in the medium. This enzymatic cleavage of the phosphodiester bond is inhibited by bacitracin. The phospho-oligosaccharides are susceptible to alkaline phosphatase giving neutral oligosaccharides and they are cleaved by endo-N-acetyl-beta-D-glucosaminidase H leaving N-acetylglucosamine 1-phosphate and neutral oligosaccharides. These data suggest that splitting of the phosphodiester bond of colichyl diphosphate oligosaccharides, dephosphorylation and/or endo-N-acetyl-beta-D-glucosaminidase hydrolysis of the phosphorylated oligosaccharides could represent the beginning of the catabolic pathway of dolichyl diphosphate oligosaccharides.", "corpus_id": 23537324, "score": 1 }, { "doc_id": "1542340", "title": "Identification of phosphorylated oligosaccharides in cells of patients with a congenital disorders of glycosylation (CDG-I).", "abstract": "Protein N-glycosylation is initiated by the dolichol cycle in which the oligosaccharide precursor Glc(3)Man(9)GlcNAc(2)-PP-dolichol is assembled in the endoplasmic reticulum (ER). One critical step in the dolichol cycle concerns the availability of Dol-P at the cytosolic face of the ER membrane. In RFT1 cells, the lipid-linked oligosaccharide (LLO) intermediate Man(5)GlcNAc(2)-PP-Dol accumulates at the cytosolic face of the ER membrane. Since Dol-P is a rate-limiting intermediate during protein N-glycosylation, continuous accumulation of Man(5)GlcNAc(2)-PP-Dol would block the dolichol cycle. Hence, we investigated the molecular mechanisms by which accumulating Man(5)GlcNAc(2)-PP-Dol could be catabolized in RFT1 cells. On the basis of metabolic labeling experiments and in comparison to human control cells, we identified phosphorylated oligosaccharides (POS), not found in human control cells and present evidence that they originate from the accumulating LLO intermediates. In addition, POS were also detected in other CDG patients' cells accumulating specific LLO intermediates at different cellular locations. Moreover, the enzymatic activity that hydrolyses oligosaccharide-PP-Dol into POS was identified in human microsomal membranes and required Mn(2+) for optimal activity. In CDG patients' cells, we thus identified and characterized POS that could result from the catabolism of accumulating LLO intermediates.", "corpus_id": 1542340, "score": 1 }, { "doc_id": "24470493", "title": "Eukaryotic Oligosaccharyltransferase Generates Free Oligosaccharides during N-Glycosylation*", "abstract": "Background: The enzyme generating free oligosaccharides (fOSs) in the lumen of the endoplasmic reticulum (ER) has been unidentified. Results: Oligosaccharyltransferase (OST), the N-glycosylating enzyme, hydrolyzes dolichol-linked oligosaccharides to release the fOSs. Conclusion: OST is responsible for the generation of fOSs in the ER lumen. Significance: This study provides a mechanistic insight into the formation of luminal fOSs in yeast. Asparagine (N)-linked glycosylation regulates numerous cellular activities, such as glycoprotein quality control, intracellular trafficking, and cell-cell communications. In eukaryotes, the glycosylation reaction is catalyzed by oligosaccharyltransferase (OST), a multimembrane protein complex that is localized in the endoplasmic reticulum (ER). During N-glycosylation in the ER, the protein-unbound form of oligosaccharides (free oligosaccharides; fOSs), which is structurally related to N-glycan, is released into the ER lumen. However, the enzyme responsible for this process remains unidentified. Here, we demonstrate that eukaryotic OST generates fOSs. Biochemical and genetic analyses using mutant strains of Saccharomyces cerevisiae revealed that the generation of fOSs is tightly correlated with the N-glycosylation activity of OST. Furthermore, we present evidence that the purified OST complex can generate fOSs by hydrolyzing dolichol-linked oligosaccharide, the glycan donor substrate for N-glycosylation. The heterologous expression of a single subunit of OST from the protozoan Leishmania major in S. cerevisiae demonstrated that this enzyme functions both in N-glycosylation and generation of fOSs. This study provides insight into the mechanism of PNGase-independent formation of fOSs.", "corpus_id": 24470493, "score": 1 }, { "doc_id": "5901524", "title": "Cytosolic-free oligosaccharides are predominantly generated by the degradation of dolichol-linked oligosaccharides in mammalian cells.", "abstract": "During asparagine (N)-linked protein glycosylation, eukaryotic cells generate considerable amounts of free oligosaccharides (fOSs) in the cytosol. It is generally assumed that such fOSs are produced by the deglycosylation of misfolded N-glycoproteins that are destined for proteasomal degradation or as the result of the degradation of dolichol-linked oligosaccharides (DLOs), which serve as glycan donor substrates in N-glycosylation reactions. The findings reported herein show that the majority of cytosolic fOSs are generated by a peptide:N-glycanase (PNGase) and an endo-β-N-acetylglucosaminidase (ENGase)-independent pathway in mammalian cells. The ablation of the cytosolic deglycosylating enzymes, PNGase and ENGase, in mouse embryonic fibroblasts had little effect on the amount of cytosolic fOSs generated. Quantitative analyses of fOSs using digitonin-permeabilized cells revealed that they are generated by the degradation of fully assembled Glc3Man9GlcNAc2-pyrophosphate-dolichol (PP-Dol) in the lumen of the endoplasmic reticulum. Because the degradation of Glc3Man9GlcNAc2-PP-Dol is greatly inhibited in the presence of an N-glycosylation acceptor peptide that is recognized by the oligosaccharyltransferase (OST), the OST-mediated hydrolysis of DLO is the most likely mechanism responsible for the production of a large fraction of the cytosolic fOSs.", "corpus_id": 5901524, "score": 0 }, { "doc_id": "2473178", "title": "The cytoplasmic peptide:N-glycanase (Ngly1)-basic science encounters a human genetic disorder.", "abstract": "Peptide:N-glycanase (PNGase) is a de-N-glycosylating enzyme that cleaves intact N-glycans from glycoproteins/glycopeptides. The activity of the cytoplasmic PNGase in several mammalian-derived cultured cells was first reported in 1993, and 7 years later, the gene encoding the enzyme was identified in budding yeast. Although the gene-PNG1 in budding yeast and NGLY1/Ngly1 in mammalian cells-appears to be well conserved throughout eukaryotes, the biological significance of this enzyme has remained elusive until recently. However, discovery of a human genetic disorder involving the NGLY1 gene clearly indicates that this enzyme plays a critical role in human biology. This review summarizes the research history of cytoplasmic PNGase. The importance of curiosity-driven, pure 'basic science' will also be discussed.", "corpus_id": 2473178, "score": 0 }, { "doc_id": "39722501", "title": "Physiological and molecular functions of the cytosolic peptide:N-glycanase.", "abstract": "Peptide:N-glycanase (PNGase) is a deglycosylating enzyme that acts on N-glycoproteins. A growing evidence exists to indicate that the cytosolic form of PNGase, which is ubiquitously distributed throughout eukaryotes, is not only implicated in the efficient degradation of misfolded glycoproteins destined for the proteasomal degradation but also in the generation of free oligosaccharides as the initial step in the non-lysosomal catabolism of N-glycans. This article summarizes the current state of our knowledge of the physiological and molecular functions of the cytosolic PNGase in a model organism, Saccharomyces cerevisiae, and also discusses the functional/structural diversities of this molecule within eukaryotes.", "corpus_id": 39722501, "score": 0 }, { "doc_id": "7428063", "title": "Identification of Roles for Peptide: N-Glycanase and Endo-β-N-Acetylglucosaminidase (Engase1p) during Protein N-Glycosylation in Human HepG2 Cells", "abstract": "Background During mammalian protein N-glycosylation, 20% of all dolichol-linked oligosaccharides (LLO) appear as free oligosaccharides (fOS) bearing the di-N-acetylchitobiose (fOSGN2), or a single N-acetylglucosamine (fOSGN), moiety at their reducing termini. After sequential trimming by cytosolic endo β-N-acetylglucosaminidase (ENGase) and Man2c1 mannosidase, cytosolic fOS are transported into lysosomes. Why mammalian cells generate such large quantities of fOS remains unexplored, but fOSGN2 could be liberated from LLO by oligosaccharyltransferase, or from glycoproteins by NGLY1-encoded Peptide-N-Glycanase (PNGase). Also, in addition to converting fOSGN2 to fOSGN, the ENGASE-encoded cytosolic ENGase of poorly defined function could potentially deglycosylate glycoproteins. Here, the roles of Ngly1p and Engase1p during fOS metabolism were investigated in HepG2 cells. Methods/Principal Findings During metabolic radiolabeling and chase incubations, RNAi-mediated Engase1p down regulation delays fOSGN2-to-fOSGN conversion, and it is shown that Engase1p and Man2c1p are necessary for efficient clearance of cytosolic fOS into lysosomes. Saccharomyces cerevisiae does not possess ENGase activity and expression of human Engase1p in the png1Δ deletion mutant, in which fOS are reduced by over 98%, partially restored fOS generation. In metabolically radiolabeled HepG2 cells evidence was obtained for a small but significant Engase1p-mediated generation of fOS in 1 h chase but not 30 min pulse incubations. Ngly1p down regulation revealed an Ngly1p-independent fOSGN2 pool comprising mainly Man8GlcNAc2, corresponding to ∼70% of total fOS, and an Ngly1p-dependent fOSGN2 pool enriched in Glc1Man9GlcNAc2 and Man9GlcNAc2 that corresponds to ∼30% of total fOS. Conclusions/Significance As the generation of the bulk of fOS is unaffected by co-down regulation of Ngly1p and Engase1p, alternative quantitatively important mechanisms must underlie the liberation of these fOS from either LLO or glycoproteins during protein N-glycosylation. The fully mannosylated structures that occur in the Ngly1p-dependent fOSGN2 pool indicate an ERAD process that does not require N-glycan trimming.", "corpus_id": 7428063, "score": 0 }, { "doc_id": "84285273", "title": "Man2C1, an α-mannosidase, is involved in the trimming of free oligosaccharides in the cytosol", "abstract": "The endoplasmic-reticulum-associated degradation of misfolded (glyco)proteins ensures that only functional, correctly folded proteins exit from the endoplasmic reticulum and that misfolded ones are degraded by the ubiquitin–proteasome system. During the degradation of misfolded glycoproteins, they are deglycosylated by the PNGase (peptide:N-glycanase). The free oligosaccharides released by PNGase are known to be further catabolized by a cytosolic α-mannosidase, although the gene encoding this enzyme has not been identified unequivocally. The findings in the present study demonstrate that an α-mannosidase, Man2C1, is involved in the processing of free oligosaccharides that are formed in the cytosol. When the human Man2C1 orthologue was expressed in HEK-293 cells, most of the enzyme was localized in the cytosol. Its activity was enhanced by Co2+, typical of other known cytosolic α-mannosidases so far characterized from animal cells. The down-regulation of Man2C1 activity by a small interfering RNA drastically changed the amount and structure of oligosaccharides accumulating in the cytosol, demonstrating that Man2C1 indeed is involved in free oligosaccharide processing in the cytosol. The oligosaccharide processing in the cytosol by PNGase, endo-β-N-acetylglucosaminidase and α-mannosidase may represent the common ‘non-lysosomal’ catabolic pathway for N-glycans in animal cells, although the molecular mechanism as well as the functional importance of such processes remains to be determined.", "corpus_id": 84285273, "score": 0 }, { "doc_id": "682277", "title": "Transfer of Free Polymannose-type Oligosaccharides from the Cytosol to Lysosomes in Cultured Human Hepatocellular Carcinoma HEPG2 Cells", "abstract": "Large, free polymannose oligosaccharides generated during glycoprotein biosynthesis rapidly appear in the cytosol of HepG2 cells where they undergo processing by a cytosolic endo H–like enzyme and a mannosidase to yield the linear isomer of Man5GlcNAc (Man[α1-2]Man[α1-2]Man[α1-3][Man α1-6]Man[β14]GlcNAc). Here we have examined the fate of these partially trimmed oligosaccharides in intact HepG2 cells. Subsequent to pulse–chase incubations with d-[2- 3H]mannose followed by permeabilization of cells with streptolysin O free oligosaccharides were isolated from the resulting cytosolic and membrane-bound compartments. Control pulse–chase experiments revealed that total cellular free oligosaccharides are lost from HepG2 cells with a half-life of 3–4 h. In contrast use of the vacuolar H+/ATPase inhibitor, concanamycin A, stabilized total cellular free oligosaccharides and enabled us to demonstrate a translocation of partially trimmed oligosaccharides from the cytosol into a membrane-bound compartment. This translocation process was unaffected by inhibitors of autophagy but inhibited if cells were treated with either 100 μM swainsonine, which provokes a cytosolic accumulation of large free oligosaccharides bearing 8-9 residues of mannose, or agents known to reduce cellular ATP levels which lead to the accumulation of the linear isomer of Man5GlcNAc in the cytosol. Subcellular fractionation studies on Percoll density gradients revealed that the cytosol-generated linear isomer of Man5GlcNAc is degraded in a membrane-bound compartment that cosediments with lysosomes.", "corpus_id": 682277, "score": 0 }, { "doc_id": "15591821", "title": "The Compartmentalisation of Phosphorylated Free Oligosaccharides in Cells from a CDG Ig Patient Reveals a Novel ER-to-Cytosol Translocation Process", "abstract": "Background Biosynthesis of the dolichol linked oligosaccharide (DLO) required for protein N-glycosylation starts on the cytoplasmic face of the ER to give Man5GlcNAc2-PP-dolichol, which then flips into the ER for further glycosylation yielding mature DLO (Glc3Man9GlcNAc2-PP-dolichol). After transfer of Glc3Man9GlcNAc2 onto protein, dolichol-PP is recycled to dolichol-P and reused for DLO biosynthesis. Because de novo dolichol synthesis is slow, dolichol recycling is rate limiting for protein glycosylation. Immature DLO intermediates may also be recycled by pyrophosphatase-mediated cleavage to yield dolichol-P and phosphorylated oligosaccharides (fOSGN2-P). Here, we examine fOSGN2-P generation in cells from patients with type I Congenital Disorders of Glycosylation (CDG I) in which defects in the dolichol cycle cause accumulation of immature DLO intermediates and protein hypoglycosylation. Methods and Principal Findings In EBV-transformed lymphoblastoid cells from CDG I patients and normal subjects a correlation exists between the quantities of metabolically radiolabeled fOSGN2-P and truncated DLO intermediates only when these two classes of compounds possess 7 or less hexose residues. Larger fOSGN2-P were difficult to detect despite an abundance of more fully mannosylated and glucosylated DLO. When CDG Ig cells, which accumulate Man7GlcNAc2-PP-dolichol, are permeabilised so that vesicular transport and protein synthesis are abolished, the DLO pool required for Man7GlcNAc2-P generation could be depleted by adding exogenous glycosylation acceptor peptide. Under conditions where a glycotripeptide and neutral free oligosaccharides remain predominantly in the lumen of the ER, Man7GlcNAc2-P appears in the cytosol without detectable generation of ER luminal Man7GlcNAc2-P. Conclusions and Significance The DLO pools required for N-glycosylation and fOSGN2-P generation are functionally linked and this substantiates the hypothesis that pyrophosphatase-mediated cleavage of DLO intermediates yields recyclable dolichol-P. The kinetics of cytosolic fOSGN2-P generation from a luminally-generated DLO intermediate demonstrate the presence of a previously undetected ER-to-cytosol translocation process for either fOSGN2-P or DLO.", "corpus_id": 15591821, "score": 1 }, { "doc_id": "7943451", "title": "Endo-β-N-acetylglucosaminidase forms N-GlcNAc protein aggregates during ER-associated degradation in Ngly1-defective cells", "abstract": "Significance In the endoplasmic reticulum (ER), N-glycans on glycoproteins play important roles in dictating the folding status of proteins by a sophisticated N-glycan–dependent protein quality control machinery. In this study we identified the dysregulation of ER-associated degradation (ERAD) in cells that were defective in the cytosolic deglycosylating enzyme, Ngly1. ERAD dysregulation was caused by an unexpected deglycosylating activity of endo-β-N-acetylglucosaminidase, another cytosolic deglycosylation enzyme, and this action resulted in the intracellular formation of protein aggregates. Our results clearly point to the critical role of N-glycans even in cytosolic events of the ERAD process by controlling the conformation/solubility of proteins. This study may also provide a potential mechanism for explaining the pathology of a human genetic disorder caused by mutations in the NGLY1 gene. The cytoplasmic peptide:N-glycanase (PNGase; Ngly1 in mice) is a deglycosylating enzyme involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) process. The precise role of Ngly1 in the ERAD process, however, remains unclear in mammals. The findings reported herein, using mouse embryonic fibroblast (MEF) cells, that the ablation of Ngly1 causes dysregulation of the ERAD process. Interestingly, not only delayed degradation but also the deglycosylation of a misfolded glycoprotein was observed in Ngly1−/− MEF cells. The unconventional deglycosylation reaction was found to be catalyzed by the cytosolic endo-β-N-acetylglucosaminidase (ENGase), generating aggregation-prone N-GlcNAc proteins. The ERAD dysregulation in cells lacking Ngly1 was restored by the additional knockout of ENGase gene. Thus, our study underscores the functional importance of Ngly1 in the ERAD process and provides a potential mechanism underlying the phenotypic consequences of a newly emerging genetic disorder caused by mutation of the human NGLY1 gene.", "corpus_id": 7943451, "score": 0 }, { "doc_id": "21257880", "title": "Establishment of a real-time analytical method for free oligosaccharide transport from the ER to the cytosol.", "abstract": "During N-glycosylation of proteins, significant amounts of free unconjugated glycans are also generated in the lumen of the endoplasmic reticulum (ER). These ER-derived free glycans are translocated into the cytosol by a putative transporter on the ER membrane for further processing. However, the molecular nature of the transporter remains to be determined. Here, we report the establishment of a novel assay method for free oligosaccharide transport from the ER lumen using chemically synthesized fluorescence-labeled N-glycan derivatives. In this method, fluorescence-labeled glycan substrates were encapsulated inside mouse liver microsomes, followed by incubation with the cytosol and a fluorescence-quenching agent (anti-fluorophore antibody). The rate of substrate efflux was then monitored in real time by the decrease in the fluorescence intensity. The present data clearly demonstrated that the oligosaccharide transport activity under the current assay conditions was both ATP and cytosol dependent. The transporter activity was also found to be glycan structure specific because free glucosylated glycans were unable to be transported out of the microsomes. This new assay method will be a useful tool for identifying the transporter protein on the ER membrane.", "corpus_id": 21257880, "score": 0 }, { "doc_id": "7633005", "title": "Free Oligosaccharides to Monitor Glycoprotein Endoplasmic Reticulum-associated Degradation in Saccharomyces cerevisiae*", "abstract": "In eukaryotic cells, N-glycosylation has been recognized as one of the most common and functionally important co- or post-translational modifications of proteins. “Free” forms of N-glycans accumulate in the cytosol of mammalian cells, but the precise mechanism for their formation and degradation remains unknown. Here, we report a method for the isolation of yeast free oligosaccharides (fOSs) using endo-β-1,6-glucanase digestion. fOSs were undetectable in cells lacking PNG1, coding the cytoplasmic peptide:N-glycanase gene, suggesting that almost all fOSs were formed from misfolded glycoproteins by Png1p. Structural studies revealed that the most abundant fOS was M8B, which is not recognized well by the endoplasmic reticulum-associated degradation (ERAD)-related lectin, Yos9p. In addition, we provide evidence that some of the ERAD substrates reached the Golgi apparatus prior to retrotranslocation to the cytosol. N-Glycan structures on misfolded glycoproteins in cells lacking the cytosol/vacuole α-mannosidase, Ams1p, was still quite diverse, indicating that processing of N-glycans on misfolded glycoproteins was more complex than currently envisaged. Under ER stress, an increase in fOSs was observed, whereas levels of M7C, a key glycan structure recognized by Yos9p, were unchanged. Our method can thus provide valuable information on the molecular mechanism of glycoprotein ERAD in Saccharomyces cerevisiae.", "corpus_id": 7633005, "score": 0 }, { "doc_id": "28380392", "title": "Dual-gradient high-performance liquid chromatography for identification of cytosolic high-mannose-type free glycans.", "abstract": "It has been shown that free oligosaccharides derived from N-linked glycans accumulate in the cytosol of animal cells. Most of the glycans have only a single GlcNAc at their reducing termini (Gn1 glycans), whereas the original N-glycans retain N,N'-diacetylchitobiose at their reducing termini (Gn2 glycans). Under the conditions of high-performance liquid chromatography (HPLC) mapping established for pyridylamine (PA)-labeled Gn2 N-glycans, Gn1 glycans are not well retained on reversed-phase HPLC, making simultaneous analysis of Gn1 and Gn2 glycans problematic. We introduced a dual gradient (i.e., pH and butanol gradient) for the separation of Gn1 and Gn2 glycans in a single reversed-phase HPLC. Determination of elution time for various standard Gn2 high-mannose-type glycans, as well as Gn1 glycans found in the cytosol of animal cells, showed that elution of Gn1 and Gn2 glycans could be separated. Sufficient separation for most of the structural isomers could be achieved for Gn1 and Gn2 glycans. This HPLC, therefore, is a powerful method for identification of the structures of PA-labeled glycans, especially Gn1-type glycans, isolated from the cytosol of animal cells.", "corpus_id": 28380392, "score": 1 }, { "doc_id": "36469323", "title": "Endo-β-N-acetylglucosaminidase, an enzyme involved in processing of free oligosaccharides in the cytosol", "abstract": "Formation of oligosaccharides occurs both in the cytosol and in the lumen of the endoplasmic reticulum (ER). Luminal oligosaccharides are transported into the cytosol to ensure that they do not interfere with proper functioning of the glycan-dependent quality control machinery in the lumen of the ER for newly synthesized glycoproteins. Once in the cytosol, free oligosaccharides are catabolized, possibly to maximize the reutilization of the component sugars. An endo-β-N-acetylglucosaminidase (ENGase) is a key enzyme involved in the processing of free oligosaccharides in the cytosol. This enzyme activity has been widely described in animal cells, but the gene encoding this enzyme activity has not been reported. Here, we report the identification of the gene encoding human cytosolic ENGase. After 11 steps, the enzyme was purified 150,000-fold to homogeneity from hen oviduct, and several internal amino acid sequences were analyzed. Based on the internal sequence and examination of expressed sequence tag (EST) databases, we identified the human orthologue of the purified protein. The human protein consists of 743 aa and has no apparent signal sequence, supporting the idea that this enzyme is localized in the cytosol. By expressing the cDNA of the putative human ENGase in COS-7 cells, the enzyme activity in the soluble fraction was enhanced 100-fold over the basal level, confirming that the human gene identified indeed encodes for ENGase. Careful gene database surveys revealed the occurrence of ENGase homologues in Drosophila melanogaster, Caenorhabditis elegans, and Arabidopsis thaliana, indicating the broad occurrence of ENGase in higher eukaryotes. This gene was expressed in a variety of human tissues, suggesting that this enzyme is involved in basic biological processes in eukaryotic cells.", "corpus_id": 36469323, "score": 0 }, { "doc_id": "136418", "title": "Generation of free oligosaccharides from bacterial protein N-linked glycosylation systems.", "abstract": "All Campylobacter species are capable of N-glycosylating their proteins and releasing the same oligosaccharides into the periplasm as free oligosaccharides (fOS). Previously, analysis of fOS production in Campylobacter required fOS derivatization or large culture volumes and several chromatography steps prior to fOS analysis. In this study, label-free fOS extraction and purification methods were developed and coupled with quantitative analysis techniques. Our method follows three simple steps: (1) fOS extraction from the periplasmic space, (2) fOS purification using silica gel chromatography followed by porous graphitized carbon purification and (3) fOS analysis and accurate quantitation using a combination of thin-layer chromatography, mass spectrometry, NMR, and high performance anion exchange chromatography with pulsed amperometric detection. We applied our techniques to analyze fOS from C. jejuni, C. lari, C. rectus, and C. fetus fetus that produce different fOS structures. We accurately quantified fOS in Campylobacter species that ranged from 7.80 (±0.84) to 49.82 (±0.46) nmoles per gram of wet cell pellet and determined that the C. jejuni fOS comprises 2.5% of the dry cell weight. In addition, a novel di-phosphorylated fOS species was identified in C. lari. This method provides a sensitive and quantitative method to investigate the genesis, biology and breakdown of fOS in the bacterial N-glycosylation systems.", "corpus_id": 136418, "score": 0 }, { "doc_id": "14606177", "title": "A comparative study of free oligosaccharides in the milk of domestic animals", "abstract": "The present study was conducted to obtain a comprehensive overview of oligosaccharides present in the milk of a variety of important domestic animals including cows, goats, sheep, pigs, horses and dromedary camels. Using an analytical workflow that included ultra-performance liquid chromatography–hydrophilic interaction liquid chromatography with fluorescence detection coupled to quadrupole time-of-flight MS, detailed oligosaccharide libraries were established. The partial or full characterisation of the neutral/fucosylated, phosphorylated and sialylated structures was facilitated by sequencing with linkage- and sugar-specific exoglycosidases. Relative peak quantification of the 2-aminobenzamide-labelled oligosaccharides provided additional information. Milk from domestic animals contained a much larger variety of complex oligosaccharides than was previously assumed, and thirteen of these structures have been identified previously in human milk. The direct comparison of the oligosaccharide mixtures reflects their role in the postnatal maturation of different types of gastrointestinal systems, which, in this way, are prepared for certain post-weaning diets. The potential value of animal milk for the commercial extraction of oligosaccharides to be used in human and animal health is highlighted.", "corpus_id": 14606177, "score": 0 }, { "doc_id": "11575482", "title": "Purification and characterization of endo-beta-N-acetylglucosaminidase from hen oviduct.", "abstract": "Endo-beta-N-acetylglucosaminidase from hen oviduct (Endo-HO) was purified to homogeneity by ammonium sulfate fractionation and then by column chromatographies on DEAE-Sephacel, hydroxyapatite, Octyl-Sepharose CL-4B, Co2+-chelating Sepharose FF, and YMC-Pack Diol-200G. Partial purification of the enzyme was reported previously [Tarentino, A.L. and Maley, F. (1976) J. Biol. Chem. 251, 6537-6543]. The molecular weight was 54,000 by gel filtration and 52,000 by SDS-PAGE in the presence of 2-mercaptoethanol, indicating that Endo-HO is composed of a single polypeptide chain. The optimum pH was 6.5, and the Km value was 25 microM when pyridylaminated Man6GlcNAc2 was used as a substrate. EDTA and metal cations tested, except Hg2+, had no effects on Endo-HO activity. Substrate specificity results using pyridylaminated N-linked sugar chains revealed that Endo-HO hydrolyzed oligomannose-type sugar chains faster than complex- and hybrid-type chains, and that sugar chains containing the Manalpha1-2Manalpha1-3Manbeta1-4GlcNAcbeta1-GlcN Ac structure were good substrates for the enzyme. These findings suggest that in cytosol the enzyme contributes to the production of a free oligosaccharide with one reducing end N-acetylglucosamine residue in cooperation with neutral alpha-mannosidase, an enzyme that specifically hydrolyzes oligosaccharides to Manalpha1-2Manalpha1-2Manalpha1-3(Manalpha1-6)++ +Manbeta1-4GlcNAc.", "corpus_id": 11575482, "score": 0 }, { "doc_id": "19411077", "title": "Cytosol-to-lysosome Transport of Free Polymannose-type Oligosaccharides", "abstract": "In hepatocellular carcinoma HepG2 cells, free polymannose-type oligosaccharides appearing in the cytosol during the biosynthesis and quality control of glycoproteins are rapidly translocated into lysosomes by an as yet poorly defined process (Saint-Pol, A., Bauvy, C., Codogno, P., and Moore, S. E. H. (1997)J. Cell Biol. 136, 45–59). Here, we demonstrate an ATP-dependent association of [2-3H]mannose-labeled Man5GlcNAc with isolated rat liver lysosomes. This association was only observed in the presence of swainsonine, a mannosidase inhibitor, which was required for the protection of sedimentable, but not nonsedimentable, Man5GlcNAc from degradation, indicating that oligosaccharides were transported into lysosomes. Saturable high affinity transport (K uptake, 22.3 μm, V max, 7.1 fmol/min/unit of β-hexosaminidase) was dependent upon the hydrolysis of ATP but independent of vacuolar H+/ATPase activity. Transport was inhibited strongly by NEM and weakly by vanadate but not by sodium azide, and, in addition, the sugar transport inhibitors phloretin, phloridzin, and cytochalasin B were without effect on transport. Oligosaccharide import did not show absolute specificity but was selective toward partially demannosylated and dephosphorylated oligosaccharides, and, furthermore, inhibition studies revealed that the free reducing GlcNAc residue of the oligosaccharide was of critical importance for its interaction with the transporter. These results demonstrate the presence of a novel lysosomal free oligosaccharide transporter that must work in concert with cytosolic hydrolases in order to clear the cytosol of endoplasmic reticulum-generated free oligosaccharides.", "corpus_id": 19411077, "score": 0 }, { "doc_id": "11867092", "title": "Basal Autophagy Is Required for the Efficient Catabolism of Sialyloligosaccharides*", "abstract": "Background: The role of autophagy in glycan catabolism remains to be clarified. Results: In Atg5−/− cells, defective in autophagosome formation, sialyloligosaccharides accumulate specifically in the cytosol. Conclusion: Basal autophagy is essential for lysosomal catabolism of sialyloligosaccharides. Significance: This result not only underscores the importance of autophagy in glycan catabolism but also suggests that basal autophagy is required for proper function of lysosomes. Macroautophagy is an essential, homeostatic process involving degradation of a cell's own components; it plays a role in catabolizing cellular components, such as protein or lipids, and damaged or excess organelles. Here, we show that in Atg5−/− cells, sialyloligosaccharides specifically accumulated in the cytosol. Accumulation of these glycans was observed under non-starved conditions, suggesting that non-induced, basal autophagy is essential for their catabolism. Interestingly, once accumulated in the cytosol, sialylglycans cannot be efficiently catabolized by resumption of the autophagic process, suggesting that functional autophagy is important for preventing sialyloligosaccharides from accumulating in the cytosol. Moreover, knockdown of sialin, a lysosomal transporter of sialic acids, resulted in a significant reduction of sialyloligosaccharides, implying that autophagy affects the substrate specificity of this transporter. This study thus provides a surprising link between basal autophagy and catabolism of N-linked glycans.", "corpus_id": 11867092, "score": 0 } ]

{ "doc_id": "4360985", "title": "Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas", "abstract": "In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.", "corpus_id": 4360985 }

[ { "doc_id": "45265", "title": "Genetics of adult glioma.", "abstract": "Gliomas make up approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. Despite the frequency of gliomas, the etiology of these tumors remains largely unknown. Diffuse gliomas, including astrocytomas and oligodendrogliomas, belong to a single pathologic class but have very different histologies and molecular etiologies. Recent genomic studies have identified separate molecular subtypes within the glioma classification that appear to correlate with biological etiology, prognosis, and response to therapy. The discovery of these subtypes suggests that molecular genetic tests are and will be useful, beyond classical histology, for the clinical classification of gliomas. While a familial susceptibility to glioma has been identified, only a small percentage of gliomas are thought to be due to single-gene hereditary cancer syndromes. Through the use of linkage studies and genome-wide association studies, multiple germline variants have been identified that are beginning to define the genetic susceptibility to glioma.", "corpus_id": 45265, "score": 0 }, { "doc_id": "14693017", "title": "Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma", "abstract": "Transformed stem cells have been isolated from some human cancers. We report that, unlike other brain cancers, the lethal glioblastoma multiforme contains neural precursors endowed with all of the critical features expected from neural stem cells. Similar, yet not identical, to their normal neural stem cell counterpart, these precursors emerge as unipotent (astroglial) in vivo and multipotent (neuronal-astroglial-oligodendroglial) in culture. More importantly, these cells can act as tumor-founding cells down to the clonal level and can establish tumors that closely resemble the main histologic, cytologic, and architectural features of the human disease, even when challenged through serial transplantation. Thus, cells possessing all of the characteristics expected from tumor neural stem cells seem to be involved in the growth and recurrence of adult human glioblastomas multiforme.", "corpus_id": 14693017, "score": 0 }, { "doc_id": "4430962", "title": "Identification of human brain tumour initiating cells", "abstract": "The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 105 CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.", "corpus_id": 4430962, "score": 0 }, { "doc_id": "3345100", "title": "The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary", "abstract": "The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M–mutant; RELA fusion–positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma—a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.", "corpus_id": 3345100, "score": 0 }, { "doc_id": "20356267", "title": "Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601)", "abstract": "Targeted therapies for cancer is a rapidly advancing field, but the identification of tumor-specific ligands has proven difficult. Chlorotoxin (CTX) is a small, 36 amino acid neurotoxin isolated from the venom of the Giant Yellow Israeli scorpion Leiurus Quinquestriatus. Interestingly, the peptide has been found to preferentially bind to a variety of human malignancies, but shows little or no binding to normal human tissues. A synthetic version of this peptide (TM-601) has been manufactured and covalently linked to iodine 131 (131I-TM-601) as a means of targeting radiation to tumor cells. Preclinical studies and Phase I clinical trials have been completed in patients with recurrent glioma, a type of malignant brain tumor. These studies demonstrated that intracavitary dosing of 131I-TM-601 appears safe, minimally toxic, and binds malignant glioma with high affinity and for long durations. A Phase II trial of this agent using higher doses of radioactivity and repeated local administrations is underway. In addition, enrolment has begun in a Phase I trial evaluating whether systemically delivered 131I-TM-601 can be used to image metastatic solid tumors and primary gliomas. Due to its small size, selective tumor binding properties, minimal toxicity and relative ease of manipulation, CTX represents a potentially important targeting agent for many cancers.", "corpus_id": 20356267, "score": 0 }, { "doc_id": "29217381", "title": "Primary brain tumours in adults", "abstract": "The most frequent primary brain tumours in adults are gliomas and primary CNS lymphomas. In gliomas, molecular genetic analysis plays an increasing part in classification and treatment planning, a feature well illustrated by the chemosensitive oligodendrogliomas. Unfortunately, management of glioblastoma is still mainly palliative. Incidence of primary CNS lymphoma has increased strikingly in the past 20 years; substantial progress has been achieved in patients who are immunocompetent with the addition of methotrexate-based chemotherapy to radiotherapy, but the potential neurotoxic effects of this combination in elderly patients is worrisome.", "corpus_id": 29217381, "score": 0 }, { "doc_id": "205269411", "title": "CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009.", "abstract": "T he objective of CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2005–2009 is to provide a current and comprehensive review of the descriptive epidemiology of primary brain and central nervous system (CNS) tumors in the United States population. CBTRUS has obtained data on all primary brain and CNS tumors from the Centers for Disease Control and Prevention, National Program of Cancer Registries (NPCR) and the National Cancer Institute, Surveillance, Epidemiology and End Results (SEER) program for diagnosis years 2005–2009. Incidence counts and rates of primary malignant and non-malignant brain and CNS tumors are documented by histology, gender, age, race, and Hispanic ethnicity.", "corpus_id": 205269411, "score": 0 }, { "doc_id": "11232699", "title": "Novel approaches to glioma drug design and drug screening", "abstract": "Introduction: Gliomas are considered the most malignant form of brain tumors, and ranked among the most aggressive human cancers. Despite advance standard therapy the prognosis for patients with gliomas remains poor. Chemotherapy has played an important role as an adjuvant in treating gliomas. The efficacy of the chemotherapeutic drug is limited due to poor drug delivery and the inherent chemo- and radio-resistance. Challenges of the brain cancer therapy in clinical settings are; i) to overcome the chemo- and radio-resistance, ii) to improve drug delivery to tumors and iii) the development of effective drug screening procedures. Areas covered: In this review, the authors discuss clinically important chemotherapeutic agents used for treating malignant gliomas along with novel drug design approaches. The authors, furthermore, discuss the in vitro and in vivo drug screening procedures for the development of novel drug candidates. Expert opinion: The development of novel and highly potent chemotherapeutic agents for both glioma and glioma stem cells (GSCs) is highly important for future brain cancer research. Thus, research efforts should be directed towards developing innovative molecularly targeted antiglioma agents in order to reduce the toxicity and drug resistance which are associated with current forms of therapy. Development of novel pre-clinical drug screening procedures is also very critical for the overall success of brain cancer therapies in clinical settings.", "corpus_id": 11232699, "score": 0 }, { "doc_id": "44445916", "title": "The Molecular and Genetic Basis of Neurological Tumours", "abstract": "There are no effective therapies for many tumours of the nervous system. This is, in part, a consequence of their location within relatively inaccessible tissues. It is also likely, however, that the unique characteristics of the cells that give rise to these tumours create a set of conditions that facilitate tumour development. Here, we consider recent advances in molecular genetics, the development of mouse models and developmental neurobiology as they relate to tumours of neuroectodermal origin. It is likely that these advances will provide insight into underlying mechanisms and provide a rational framework for the development of effective interventions.", "corpus_id": 44445916, "score": 0 }, { "doc_id": "39688", "title": "Recent advances in therapy for glioblastoma.", "abstract": "Glioblastoma is the most common primary malignant brain tumor in adults and is a challenging disease to treat. The current standard of care includes maximal safe surgical resection, followed by a combination of radiation and chemotherapy with temozolomide. Despite that, recurrence is quite common, and so we continue to search for more effective treatments both for initial therapy and at the time of recurrence. This article will review recent advances in therapy for glioblastoma, including surgery, radiotherapy, cytotoxic chemotherapies, molecularly targeted agents, and immunotherapy; the role of antiangiogenic agents in the treatment of glioblastoma is discussed in a separate article in this issue of the Archives.", "corpus_id": 39688, "score": 0 }, { "doc_id": "3262543", "title": "Proximal events in Wnt signal transduction", "abstract": "The Wnt family of secreted ligands act through many receptors to stimulate distinct intracellular signalling pathways in embryonic development, in adults and in disease processes. Binding of Wnt to the Frizzled family of receptors and to low density lipoprotein receptor-related protein 5 (LRP5) or LRP6 co-receptors stimulates the intracellular Wnt–β-catenin signalling pathway, which regulates β-catenin stability and context-dependent transcription. This signalling pathway controls many processes, such as cell fate determination, cell proliferation and self-renewal of stem and progenitor cells. Intriguingly, the transmembrane receptor Tyr kinases Ror2 and Ryk, as well as Frizzled receptors that act independently of LRP5 or LRP6, function as receptors for Wnt and activate β-catenin-independent pathways. This leads to changes in cell movement and polarity and to the antagonism of the β-catenin pathway.", "corpus_id": 3262543, "score": 0 }, { "doc_id": "21322621", "title": "Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2.", "abstract": "We describe the molecular cloning and expression of cDNAs encoding human PPAR gamma 1 and PPAR gamma 2. Our sequences are distinct from the published sequence at 3 positions, resulting in nonconservative amino acid substitutions. In humans, PPAR gamma mRNA is expressed in spleen, bone marrow, liver, testis, skeletal muscle and brain, in addition to fat. Three thiazolidinediones were found to 1) displace a radiolabeled thiazolidinedione from both receptors with essentially the same IC50s and 2) to transactivate both PPAR gamma isoforms with similar EC50s in transient cotransfection assays utilizing the adipocyte-specific aP2 promoter. Saturating concentrations of these 3 thiazolidinediones altered the conformation of in vitro synthesized PPAR gamma protein producing a 27 kDa protease-resistant fragment. These results indicate that the antidiabetic effects of thiazolidinediones in humans are likely to be mediated via binding to and transactivation of PPAR gamma 1 and gamma 2.", "corpus_id": 21322621, "score": 0 }, { "doc_id": "30643431", "title": "Identification of c-MYC as a target of the APC pathway.", "abstract": "The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.", "corpus_id": 30643431, "score": 0 }, { "doc_id": "6135804", "title": "The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway.", "abstract": "beta-Catenin plays a dual role in the cell: one in linking the cytoplasmic side of cadherin-mediated cell-cell contacts to the actin cytoskeleton and an additional role in signaling that involves transactivation in complex with transcription factors of the lymphoid enhancing factor (LEF-1) family. Elevated beta-catenin levels in colorectal cancer caused by mutations in beta-catenin or by the adenomatous polyposis coli molecule, which regulates beta-catenin degradation, result in the binding of beta-catenin to LEF-1 and increased transcriptional activation of mostly unknown target genes. Here, we show that the cyclin D1 gene is a direct target for transactivation by the beta-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter. Inhibitors of beta-catenin activation, wild-type adenomatous polyposis coli, axin, and the cytoplasmic tail of cadherin suppressed cyclin D1 promoter activity in colon cancer cells. Cyclin D1 protein levels were induced by beta-catenin overexpression and reduced in cells overexpressing the cadherin cytoplasmic domain. Increased beta-catenin levels may thus promote neoplastic conversion by triggering cyclin D1 gene expression and, consequently, uncontrolled progression into the cell cycle.", "corpus_id": 6135804, "score": 0 }, { "doc_id": "206824155", "title": "Genome-Wide Profiling of Peroxisome Proliferator-Activated Receptor γ in Primary Epididymal, Inguinal, and Brown Adipocytes Reveals Depot-Selective Binding Correlated with Gene Expression", "abstract": "ABSTRACT Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and function. We and others have previously mapped PPARγ binding at a genome-wide level in murine and human adipocyte cell lines and in primary human adipocytes. However, little is known about how binding patterns of PPARγ differ between brown and white adipocytes and among different types of white adipocytes. Here we have employed chromatin immunoprecipitation combined with deep sequencing to map and compare PPARγ binding in in vitro differentiated primary mouse adipocytes isolated from epididymal, inguinal, and brown adipose tissues. While these PPARγ binding profiles are overall similar, there are clear depot-selective binding sites. Most PPARγ binding sites previously mapped in 3T3-L1 adipocytes can also be detected in primary adipocytes, but there are a large number of PPARγ binding sites that are specific to the primary cells, and these tend to be located in closed chromatin regions in 3T3-L1 adipocytes. The depot-selective binding of PPARγ is associated with highly depot-specific gene expression. This indicates that PPARγ plays a role in the induction of genes characteristic of different adipocyte lineages and that preadipocytes from different depots are differentially preprogrammed to permit PPARγ lineage-specific recruitment even when differentiated in vitro.", "corpus_id": 206824155, "score": 0 }, { "doc_id": "13911866", "title": "Wnt/beta-Catenin Signaling in Glioma", "abstract": "Extensive data have shown that Wnt/beta-catenin signaling is associated with various disease pathologies, including an important role in tumorigenesis. Here, we review the regulation of Wnt/beta-catenin signaling in glioma, with particular focus on the expression signatures of the main components in Wnt/beta-catenin signaling, the role of key factors in Wnt/beta-catenin signaling, and crosstalk with other signaling pathways. Finally, we discuss the involvement of microRNAs in Wnt/beta-catenin signaling in glioma. This review reveals new insights into the role of Wnt/beta-catenin signaling in gliomagenesis, and highlights new therapeutic approaches for glioma, based on the modulation of the Wnt/beta-catenin pathway.", "corpus_id": 13911866, "score": 0 }, { "doc_id": "16727350", "title": "Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction", "abstract": "Circadian clock mechanisms are far-from-equilibrium dissipative structures. Peroxisome proliferator-activated receptors (PPAR alpha, beta/delta, and gamma) play a key role in metabolic regulatory processes, particularly in heart muscle. Links between circadian rhythms (CRs) and PPARs have been established. Mammalian CRs involve at least two critical transcription factors, CLOCK and BMAL1 (Gekakis et al., 1998; Hogenesch et al., 1998). PPAR gamma plays a major role in both glucose and lipid metabolisms and presents circadian properties which coordinate the interplay between metabolism and CRs. PPAR gamma is a major component of the vascular clock. Vascular PPAR gamma is a peripheral regulator of cardiovascular rhythms controlling circadian variations in blood pressure and heart rate through BMAL1. We focused our review on diseases with abnormalities of CRs and with primary or secondary cardiac dysfunction. Moreover, these diseases presented changes in the Wnt/beta-catenin pathway and PPARs, according to two opposed profiles. Profile 1 was defined as follows: inactivation of the Wnt/beta-catenin pathway with increased expression of PPAR gamma. Profile 2 was defined as follows: activation of the Wnt/beta-catenin pathway with decreased expression of PPAR gamma. A typical profile 1 disease is arrhythmogenic right ventricular cardiomyopathy, a genetic cardiac disease which presents mutations of the desmosomal proteins and is mainly characterized by fatty acid accumulation in adult cardiomyocytes mainly in the right ventricle. The link between PPAR gamma dysfunction and desmosomal genetic mutations occurs via inactivation of the Wnt/beta-catenin pathway presenting oscillatory properties. A typical profile 2 disease is type 2 diabetes, with activation of the Wnt/beta-catenin pathway and decreased expression of PPAR gamma. CRs abnormalities are present in numerous pathologies such as cardiovascular diseases, sympathetic/parasympathetic dysfunction, hypertension, diabetes, neurodegenerative diseases, cancer which are often closely inter-related.", "corpus_id": 16727350, "score": 0 }, { "doc_id": "34784842", "title": "Vasculogenesis and angiogenesis initiation under normoxic conditions through Wnt/β-catenin pathway in gliomas", "abstract": "Abstract The canonical Wnt/β-catenin pathway is up-regulated in gliomas and involved in proliferation, invasion, apoptosis, vasculogenesis and angiogenesis. Nuclear β-catenin accumulation correlates with malignancy. Hypoxia activates hypoxia-inducible factor (HIF)-1α by inhibiting HIF-1α prolyl hydroxylation, which promotes glycolytic energy metabolism, vasculogenesis and angiogenesis, whereas HIF-1α is degraded by the HIF prolyl hydroxylase under normoxic conditions. We focus this review on the links between the activated Wnt/β-catenin pathway and the mechanisms underlying vasculogenesis and angiogenesis through HIF-1α under normoxic conditions in gliomas. Wnt-induced epidermal growth factor receptor/phosphatidylinositol 3-kinase (PI3K)/Akt signaling, Wnt-induced signal transducers and activators of transcription 3 (STAT3) signaling, and Wnt/β-catenin target gene transduction (c-Myc) can activate HIF-1α in a hypoxia-independent manner. The PI3K/Akt/mammalian target of rapamycin pathway activates HIF-1α through eukaryotic translation initiation factor 4E-binding protein 1 and STAT3. The β-catenin/T-cell factor 4 complex directly binds to STAT3 and activates HIF-1α, which up-regulates the Wnt/β-catenin target genes cyclin D1 and c-Myc in a positive feedback loop. Phosphorylated STAT3 by interleukin-6 or leukemia inhibitory factor activates HIF-1α even under normoxic conditions. The activation of the Wnt/β-catenin pathway induces, via the Wnt target genes c-Myc and cyclin D1 or via HIF-1α, gene transactivation encoding aerobic glycolysis enzymes, such as glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production, as the primary alternative of ATP, at all oxygen levels, even in normoxic conditions. Lactate released by glioma cells via the monocarboxylate lactate transporter-1 up-regulated by HIF-1α and lactate anion activates HIF-1α in normoxic endothelial cells by inhibiting HIF-1α prolyl hydroxylation and preventing HIF labeling by the von Hippel-Lindau protein. Increased lactate with acid environment and HIF-1α overexpression induce the vascular endothelial growth factor (VEGF) pathway of vasculogenesis and angiogenesis under normoxic conditions. Hypoxia and acidic pH have no synergistic effect on VEGF transcription.", "corpus_id": 34784842, "score": 1 }, { "doc_id": "18074845", "title": "Thermodynamics in cancers: opposing interactions between PPAR gamma and the canonical WNT/beta-catenin pathway", "abstract": "Cancer cells are the site of numerous metabolic and thermodynamic abnormalities. We focus this review on the interactions between the canonical WNT/beta-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR gamma) in cancers and their implications from an energetic and metabolic point of view. In numerous tissues, PPAR gamma activation induces inhibition of beta-catenin pathway, while the activation of the canonical WNT/beta-catenin pathway inactivates PPAR gamma. In most cancers but not all, PPAR gamma is downregulated while the WNT/beta-catenin pathway is upregulated. In cancer cells, upregulation of the WNT/beta-catenin signaling induces dramatic changes in key metabolic enzymes that modify their thermodynamic behavior. This leads to activation of pyruvate dehydrogenase kinase1 (PDK-1) and monocarboxylate lactate transporter. Consequently, phosphorylation of PDK-1 inhibits the pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-coenzyme A (acetyl-CoA) in mitochondria and only a part of acetyl-CoA can enter the tricarboxylic acid cycle. This leads to aerobic glycolysis in spite of the availability of oxygen. This phenomenon is referred to as the Warburg effect. Cytoplasmic pyruvate is converted into lactate. The WNT/beta-catenin pathway induces the transcription of genes involved in cell proliferation, i.e., MYC and CYCLIN D1. This ultimately promotes the nucleotide, protein and lipid synthesis necessary for cell growth and multiplication. In cancer, activation of the PI3K-AKT pathway induces an increase of the aerobic glycolysis. Moreover, prostaglandin E2 by activating the canonical WNT pathway plays also a role in cancer. In addition in many cancer cells, PPAR gamma is downregulated. Moreover, PPAR gamma contributes to regulate some key circadian genes. In cancers, abnormalities in the regulation of circadian rhythms (CRs) are observed. CRs are dissipative structures which play a key-role in far-from-equilibrium thermodynamics. In cancers, metabolism, thermodynamics and CRs are intimately interrelated.", "corpus_id": 18074845, "score": 0 }, { "doc_id": "17688164", "title": "Interactions between PPAR Gamma and the Canonical Wnt/Beta-Catenin Pathway in Type 2 Diabetes and Colon Cancer", "abstract": "In both colon cancer and type 2 diabetes, metabolic changes induced by upregulation of the Wnt/beta-catenin signaling and downregulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) may help account for the frequent association of these two diseases. In both diseases, PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated. In colon cancer, upregulation of the canonical Wnt system induces activation of pyruvate dehydrogenase kinase and deactivation of the pyruvate dehydrogenase complex. As a result, a large part of cytosolic pyruvate is converted into lactate through activation of lactate dehydrogenase. Lactate is extruded out of the cell by means of activation of monocarboxylate lactate transporter-1. This phenomenon is called Warburg effect. PPAR gamma agonists induce beta-catenin inhibition, while inhibition of the canonical Wnt/beta-catenin pathway activates PPAR gamma.", "corpus_id": 17688164, "score": 0 }, { "doc_id": "17128575", "title": "Opposite Interplay between PPAR Gamma and Canonical Wnt/Beta-Catenin Pathway in Amyotrophic Lateral Sclerosis", "abstract": "The opposite interplay between peroxisome proliferator-activated receptor gamma (PPAR gamma) and Wnt/beta-catenin signaling has led to the categorization of neurodegenerative diseases (NDs) as either NDs in which PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated [amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease, multiple sclerosis, Friedreich’s ataxia] or NDs in which PPAR gamma is upregulated while the canonical Wnt/beta-catenin signaling is downregulated (bipolar disorder, schizophrenia, Alzheimer’s disease). ALS, a common adult-onset debilitating ND, is characterized by a chronic and progressive degeneration of upper and lower motor neurons resulting in muscular atrophy, paralysis, and ultimately death. The intent of this review is to provide an analysis of the integration of these two opposed systems, i.e., canonical Wnt/beta-catenin and PPAR gamma, in ALS. Understanding this integration may aid in the development of novel ALS therapies. Although the canonical Wnt/beta-catenin pathway is upregulated in ALS, riluzole, an enhancer of the canonical Wnt signaling, is classically prescribed in this disease in humans. However, studies carried out on ALS transgenic mice have shown beneficial effects after treatment by PPAR gamma agonists partly due to their anti-inflammatory effects.", "corpus_id": 17128575, "score": 0 }, { "doc_id": "13777024", "title": "Aerobic Glycolysis Hypothesis Through WNT/Beta-Catenin Pathway in Exudative Age-Related Macular Degeneration", "abstract": "Exudative age-related macular degeneration (AMD) is characterized by molecular mechanisms responsible for the initiation of choroidal neovascularization (CNV). Inflammatory processes are associated with upregulation of the canonical WNT/beta-catenin pathway in exudative AMD. We focus this review on the link between WNT/beta-catenin pathway activation and neovascular progression in exudative AMD through activation of aerobic glycolysis for production of angiogenic factors. Increased WNT/beta-catenin pathway involves hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). WNT/beta-catenin pathway stimulates PI3K/Akt pathway and then HIF-1alpha which activates glycolytic enzymes: glucose transporter (Glut), pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDH-A), and monocarboxylate lactate transporter (MCT-1). This phenomenon is called aerobic glycolysis or the Warburg effect. Consequently, phosphorylation of PDK-1 inhibits the pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and only a part of acetyl-CoA can enter the tricarboxylic acid cycle. Cytosolic pyruvate is converted into lactate through the action of LDH-A. In exudative AMD, high level of cytosolic lactate is correlated with increase of VEGF expression, the angiogenic factor of CNV. Photoreceptors in retina cells can metabolize glucose through aerobic glycolysis to protect them against oxidative damage, as cancer cells do.", "corpus_id": 13777024, "score": 0 }, { "doc_id": "206737822", "title": "PPARγ agonists: Potential treatments for exudative age-related macular degeneration.", "abstract": "Choroidal neovascularization (CNV) characterizes the progression of exudative age-related macular degeneration (AMD) with the deterioration in the central vision. Vascular inflammation, and overproduction of inflammatory cytokines, growth factors and aberrant endothelial cell migration, initiate defective blood vessel proliferation in exudative AMD. CNV formation is initiated by the interplay between inflammation, the hallmark of exudative AMD, and the activation of WNT/β-catenin pathway. Upregulation of WNT/β-catenin pathway involves activation of PI3K/Akt pathway and then the Warburg effect to produce lactate. Lactate production generates VEGF expression and then participates to the initiation of CNV in exudative AMD. WNT/β-catenin pathway and PPARγ act in an opposite manner in several diseases. We focus this review on the interplay between PPARγ and canonical WNT/β-catenin pathway and the anti-inflammatory role of PPARγ in exudative AMD. In exudative AMD, PPARγ agonists downregulate inflammation and the WNT/β-catenin pathway. PPARγ agonists can appear as promising treatment against the initiation and the progression of CNV in exudative AMD.", "corpus_id": 206737822, "score": 0 }, { "doc_id": "40701525", "title": "Glycogen: The forgotten cerebral energy store", "abstract": "The brain contains a significant amount of glycogen that is an order of magnitude smaller than that in muscle, but several‐fold higher than the cerebral glucose content. Although the precise role of brain glycogen to date is unknown, it seems affected by focal activation, neurotransmitters, and overall electrical activity and hormones. Based on its relatively low concentration, the role of brain glycogen as a significant energy store has been discounted. This work reviews recent experimental evidence that brain glycogen is an important reserve of glucose equivalents: (1) glial glycogen can provide the majority of the glucose supply deficit during hypoglycemia for more than 100 min, consistent with the proposal that glial lactate is a fuel for neurons; (2) glycogen concentrations may be as high as 10 μmol/g, substantially higher than was thought previously; (3) glucose cycling in and out of glycogen amounts to ∼1% of the cerebral metabolic rate of glucose (CMRglc) in human and rat brain, amounting to an effective stability of glycogen in the resting awake brain during euglycemia and hyperglycemia, (4) brain glycogen metabolism/concentrations are insulin/glucose sensitive; and (5) after a single episode of hypoglycemia, brain glycogen levels rebound to levels that exceed the pre‐hypoglycemic concentrations (supercompensation). This experimental evidence supports the proposal that brain glycogen may be involved in the development of diabetes complications, specifically impaired glucose sensing (hypoglycemia unawareness) observed clinically in some diabetes patients under insulin treatment. It is proposed further that brain glycogen becomes important in any metabolic state where supply transiently cannot meet demand, such conditions that could occur during prolonged focal activation, sleep deprivation, seizures, and mild hypoxia. © 2003 Wiley‐Liss, Inc.", "corpus_id": 40701525, "score": 0 }, { "doc_id": "19684581", "title": "Wnt meets Warburg: another piece in the puzzle?", "abstract": "One of the most common abnormalities of cancer cells is their predilection to engage in a high rate of glycolysis despite the continued availability of oxygen. First described by Otto Warburg, this phenomenon of aerobic glycolysis (or the Warburg effect) has recently been proposed to result from cancer‐associated alterations in signal transduction pathways. In this issue of The EMBO Journal, Pate et al provide further support for this hypothesis by demonstrating that Wnt signaling plays an important role in establishing aerobic glycolysis as a mechanism to support in vivo cancer cell proliferation.", "corpus_id": 19684581, "score": 0 }, { "doc_id": "29300457", "title": "The Organization, Promoter Analysis, and Expression of the Human PPARγ Gene*", "abstract": "PPARγ is a member of the PPAR subfamily of nuclear receptors. In this work, the structure of the human PPARγ cDNA and gene was determined, and its promoters and tissue-specific expression were functionally characterized. Similar to the mouse, two PPAR isoforms, PPARγ1 and PPARγ2, were detected in man. The relative expression of human PPARγ was studied by a newly developed and sensitive reverse transcriptase-competitive polymerase chain reaction method, which allowed us to distinguish between PPARγ1 and γ2 mRNA. In all tissues analyzed, PPARγ2 was much less abundant than PPARγ1. Adipose tissue and large intestine have the highest levels of PPARγ mRNA; kidney, liver, and small intestine have intermediate levels; whereas PPARγ is barely detectable in muscle. This high level expression of PPARγ in colon warrants further study in view of the well established role of fatty acid and arachidonic acid derivatives in colonic disease. Similarly as mouse PPARγs, the human PPARγs are activated by thiazolidinediones and prostaglandin J and bind with high affinity to a PPRE. The human PPARγ gene has nine exons and extends over more than 100 kilobases of genomic DNA. Alternate transcription start sites and alternate splicing generate the PPARγ1 and PPARγ2 mRNAs, which differ at their 5′-ends. PPARγ1 is encoded by eight exons, and PPARγ2 is encoded by seven exons. The 5′-untranslated sequence of PPARγ1 is comprised of exons A1 and A2, whereas that of PPARγ2 plus the additional PPARγ2-specific N-terminal amino acids are encoded by exon B, located between exons A2 and A1. The remaining six exons, termed 1 to 6, are common to the PPARγ1 and γ2. Knowledge of the gene structure will allow screening for PPARγ mutations in humans with metabolic disorders, whereas knowledge of its expression pattern and factors regulating its expression could be of major importance in understanding its biology.", "corpus_id": 29300457, "score": 0 }, { "doc_id": "7246740", "title": "β-Catenin Signalling in Glioblastoma Multiforme and Glioma-Initiating Cells", "abstract": "Glioblastoma multiforme (GBM) is a commonly occurring brain tumor with a poor prognosis. GBM can develop both “de novo” or evolve from a previous astrocytoma and is characterized by high proliferation and infiltration into the surrounding tissue. Following treatment (surgery, radiotherapy, and chemotherapy), tumors often reappear. Glioma-initiating cells (GICs) have been identified in GBM and are thought to be responsible for tumors initiation, their continued growth, and recurrence. β-catenin, a component of the cell-cell adhesion complex and of the canonical Wnt pathway, regulates proliferation, adhesion, and migration in different cell types. β-catenin and components of the Wnt canonical pathway are commonly overexpressed in GBM. Here, we review previous work on the role of Wnt/β-catenin signalling in glioma initiation, proliferation, and invasion. Understanding the molecular mechanisms regulating GIC biology and glioma progression may help in identifying novel therapeutic targets for GBM treatment.", "corpus_id": 7246740, "score": 1 }, { "doc_id": "2234299", "title": "Pyruvate Dehydrogenase Kinase as a Potential Therapeutic Target for Malignant Gliomas", "abstract": "Metabolic aberrations in the form of altered flux through key metabolic pathways are the major hallmarks of several life-threatening malignancies including malignant gliomas. These adaptations play an important role in the enhancement of the survival and proliferation of gliomas at the expense of the surrounding normal/healthy tissues. Recent studies in the field of neurooncology have directly targeted the altered metabolic pathways of malignant tumor cells for the development of anti-cancer drugs. Aerobic glycolysis due to elevated production of lactate from pyruvate regardless of oxygen availability is a common metabolic alteration in most malignancies. Aerobic glycolysis offers survival advantages in addition to generating substrates such as fatty acids, amino acids and nucleotides required for the rapid proliferation of cells. This review outlines the role of pyruvate dehydrogenase kinase (PDK) in gliomas as an inhibitor of pyruvate dehydrogenase that catalyzes the oxidative decarboxylation of pyruvate. An in-depth investigation on the key metabolic enzyme PDK may provide a novel therapeutic approach for the treatment of malignant gliomas.", "corpus_id": 2234299, "score": 0 }, { "doc_id": "14477577", "title": "Wnt/β-Catenin Signaling in Development and Disease", "abstract": "A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades. Wnt genes encode small secreted proteins that are found in all animal genomes. Wnt signaling is involved in virtually every aspect of embryonic development and also controls homeostatic self-renewal in a number of adult tissues. Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.", "corpus_id": 14477577, "score": 0 }, { "doc_id": "37346391", "title": "The promise and perils of Wnt signaling through beta-catenin.", "abstract": "Wnt pathways are involved in the control of gene expression, cell behavior, cell adhesion, and cell polarity. In addition, they often operate in combination with other signaling pathways. The Wnt/beta-catenin pathway is the best studied of the Wnt pathways and is highly conserved through evolution. In this pathway, Wnt signaling inhibits the degradation of beta-catenin, which can regulate transcription of a number of genes. Some of the genes regulated are those associated with cancer and other diseases (for example, colorectal cancer and melanomas). As a result, components of the Wnt/beta-catenin pathway are promising targets in the search for therapeutic agents. Information about Wnt pathways is available both in canonical terms and at the species level. In addition to the canonical Wnt/beta-catenin pathway, information is now available for Drosophila, Caenorhabditis elegans, and Xenopus. The STKE Connections Maps for these pathways provide an important tool in accessing this large body of complex information.", "corpus_id": 37346391, "score": 0 }, { "doc_id": "669448", "title": "Wnt signaling in disease and in development", "abstract": "ABSTRACTThe highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how Wnt signals work. The catalogue of Wnt signaling components has exploded. We now realize that multiple extracellular, cytoplasmic, and nuclear components modulate Wnt signaling. Moreover, receptor-ligand specificity and multiple feedback loops determine Wnt signaling outputs. It is also clear that Wnt signals are required for adult tissue maintenance. Perturbations in Wnt signaling cause human degenerative diseases as well as cancer.", "corpus_id": 669448, "score": 0 }, { "doc_id": "40792587", "title": "The Wnt inhibitory factor 1 (WIF1) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence.", "abstract": "Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by MDM2 and CDK4 identified Wnt inhibitory factor 1 (WIF1) as a candidate tumor suppressor gene in glioblastoma. WIF1 encodes a secreted Wnt antagonist and was strongly downregulated in most glioblastomas as compared with normal brain, implying deregulation of Wnt signaling, which is associated with cancer. WIF1 silencing was mediated by deletion (7/69, 10%) or epigenetic silencing by promoter hypermethylation (29/110, 26%). Co-amplification of MDM2 and CDK4 that is present in 10% of glioblastomas was associated in most cases with deletion of the whole genomic region enclosed, including the WIF1 locus. This interesting pathogenetic constellation targets the RB and p53 tumor suppressor pathways in tandem, while simultaneously activating oncogenic Wnt signaling. Ectopic expression of WIF1 in glioblastoma cell lines revealed a dose-dependent decrease of Wnt pathway activity. Furthermore, WIF1 expression inhibited cell proliferation in vitro, reduced anchorage-independent growth in soft agar, and completely abolished tumorigenicity in vivo. Interestingly, WIF1 overexpression in glioblastoma cells induced a senescence-like phenotype that was dose dependent. These results provide evidence that WIF1 has tumor suppressing properties. Downregulation of WIF1 in 75% of glioblastomas indicates frequent involvement of aberrant Wnt signaling and, hence, may render glioblastomas sensitive to inhibitors of Wnt signaling, potentially by diverting the tumor cells into a senescence-like state.", "corpus_id": 40792587, "score": 0 }, { "doc_id": "13517160", "title": "Turcot syndrome (glioma polyposis): a case report.", "abstract": "Turcot's syndrome (glioma-polyposis) is a rare hereditary disorder characterized by association of colonic polyposis with primary tumors of the central nervous system. We report a case of a 27-year-old male diagnosed with Turcot's syndrome after an autopsy. The patient survived for more than two decades after his initial presentation with medulloblastoma at the age of five years. Such a long survival is exceptional in patients with this syndrome. Based on the genetic mutations, the patients with Turcot's syndrome are classified into adenomatous polyposis coli (APC) group or hereditary non-polyposis colon cancer (HNPCC) group. The article highlights the contrasting features of the two groups.", "corpus_id": 13517160, "score": 0 }, { "doc_id": "6136692", "title": "Wnt inhibitory factor-1 regulates glioblastoma cell cycle and proliferation", "abstract": "Wnt proteins are powerful regulators of cell proliferation and differentiation, and activation of the Wnt signalling pathway is involved in the pathogenesis of several types of human tumours. Wnt inhibitory factor-1 (WIF-1) acts as a Wnt antagonist and tumour suppressor. Previous studies have shown that reducing expression of the WIF-1 gene aberrantly activates Wnt signalling and induces the development of certain types of cancers. In the present study, we examined the expression of WIF-1 in human primary glioblastoma multiforme (GBM) tumours. Studies using semiquantitative reverse transcription-polymerase chain reaction and immunohistochemical analysis revealed that WIF-1 expression is lower in human GBM than in normal brain tissue. To clarify the role of WIF-1, we transfected U251 human glioblastoma-derived cells, which do not express WIF-1, with the pcDNA3.1-WIF1 vector to restore WIF-1 expression. The results of cell proliferation, colony formation and apoptosis assays, as well as flow cytometry, indicate that exogenous WIF-1 has no effect on U251 cell apoptosis, but does arrest cells at the G(0)/G(1) phase and inhibit cell growth. Collectively, our data suggest that WIF-1 is a potent inhibitor of GBM growth.", "corpus_id": 6136692, "score": 0 }, { "doc_id": "7166440", "title": "Downregulation of WIF-1 by hypermethylation in astrocytomas.", "abstract": "Wnt inhibitory factor-1 (WIF-1) acts as a Wnt antagonist and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression of WIF-1 activate Wnt signaling aberrantly and induce the development of several human tumors. By using RT-PCR, immunohistochemistry and methylation-specific PCR, we analyzed the expression and methylation of WIF-1 in 4 normal brain tissues, 35 freshly resected astrocytoma tissues and 4 glioblastoma-derived cell lines. Significant downregulation of WIF-1 mRNA and protein expression levels was observed in astrocytoma tissues compared with normal brain tissues. Significant association between WIF-1 downregulation and pathological grade of astrocytomas was found. WIF-1 gene aberrant methylation was observed in 19 of 35 (54.29%) tumor samples. The promoter methylation tumors showed low WIF-1 protein and mRNA expression, whereas the promoter unmethylation tumors displayed high protein and mRNA expression levels. Moreover, complete absence of WIF-1 mRNA expression was observed in four cell lines, whereas treatment with demethylating agent, 5-aza-2'-deoxycytidine, restored WIF-1 expression. Our results suggested that the WIF-1 gene is frequently silenced in astrocytoma by aberrant promoter methylation. This may be an important mechanism in astrocytoma carcinogenesis.", "corpus_id": 7166440, "score": 0 }, { "doc_id": "30344019", "title": "Functional interaction between peroxisome proliferator-activated receptor gamma and beta-catenin.", "abstract": "Studies have demonstrated cross talk between beta-catenin and peroxisome proliferator-activated receptor gamma (PPARgamma) signaling pathways. Specifically, activation of PPARgamma induces the proteasomal degradation of beta-catenin in cells that express an adenomatous polyposis coli-containing destruction complex. In contrast, oncogenic beta-catenin is resistant to such degradation and inhibits the expression of PPARgamma target genes. In the present studies, we demonstrate a functional interaction between beta-catenin and PPARgamma that involves the T-cell factor (TCF)/lymphocyte enhancer factor (LEF) binding domain of beta-catenin and a catenin binding domain (CBD) within PPARgamma. Mutation of K312 and K435 in the TCF/LEF binding domain of an oncogenic beta-catenin (S37A) significantly reduces its ability to interact with and inhibit the activity of PPARgamma. Furthermore, these mutations render S37A beta-catenin susceptible to proteasomal degradation in response to activation of PPARgamma. Mutation of F372 within the CBD (helices 7 and 8) of PPARgamma disrupts its binding to beta-catenin and significantly reduces the ability of PPARgamma to induce the proteasomal degradation of beta-catenin. We suggest that in normal cells, PPARgamma can function to suppress tumorigenesis and/or Wnt signaling by targeting phosphorylated beta-catenin to the proteasome through a process involving its CBD. In contrast, oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain.", "corpus_id": 30344019, "score": 0 }, { "doc_id": "25054872", "title": "Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis.", "abstract": "The Wnt/beta-catenin signalling pathway appears to operate to maintain the undifferentiated state of preadipocytes by inhibiting adipogenic gene expression. To define the mechanisms regulating suppression of Wnt/beta-catenin signalling, we analysed the beta-catenin expression in response to activation of transcription factors that regulate adipogenesis. The results show an extensive down-regulation of nuclear beta-catenin that occurs during the first few days of differentiation of 3T3-L1 preadipocytes and coincides with the induction of the adipogenic transcription factors, C/EBPbeta (CCAAT-enhancer-binding protein) and PPARgamma (peroxisome-proliferator-activated receptor). To assess the role of each of these factors in this process, we conditionally overexpressed C/EBPbeta in Swiss mouse fibroblasts using the TET-off system. Abundant expression of C/EBPbeta alone had minimal effect on beta-catenin expression, whereas expression of C/EBPbeta, in the presence of dexamethasone, induced PPARgamma expression and caused a measurable decrease in beta-catenin. In addition, exposure of cells expressing both C/EBPbeta and PPARgamma to a potent PPARgamma ligand resulted in an even greater decrease in beta-catenin by mechanisms that involve the proteasome. Our studies also suggest a reciprocal relationship between PPARgamma activity and beta-catenin expression, since ectopic production of Wnt-1 in preadipocytes blocked the induction of PPARgamma gene expression. Moreover, by suppressing beta-catenin expression, ectopic expression of PPARgamma in Wnt-1-expressing preadipocytes rescued the block in adipogenesis after their exposure to the PPARgamma ligand, troglitazone.", "corpus_id": 25054872, "score": 0 }, { "doc_id": "24411854", "title": "Peroxisome proliferator-activated receptor gamma activation can regulate beta-catenin levels via a proteasome-mediated and adenomatous polyposis coli-independent pathway.", "abstract": "The transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to the family of nuclear hormone receptors and consists of two isotypes, PPARgamma1 and PPARgamma2. Our earlier studies have shown that troglitazone (TZD)-mediated activation of PPARgamma2 in hepatocytes inhibits growth and attenuates cyclin D1 transcription via modulating CREB levels. Because this process of growth inhibition was also associated with an inhibition of beta-catenin expression at a post-translational level, our aim was to elucidate the mechanism involved. beta-Catenin is a multifunctional protein, which can regulate cell-cell adhesion by interacting with E-cadherin and other cellular processes via regulating target gene transcription in association with TCF/LEF transcription factors. Two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways, one involving glycogen synthase kinase 3beta (GSK3beta) and the other involving p53-Siah-1, degrade excess beta-catenin in normal cells. Our immunofluorescence and Western blot studies indicated a TZD-dependent decrease in cytoplasmic and membrane-bound beta-catenin, indicating no increase in its membrane translocation. This was associated with a reduction in E-cadherin expression. PPARgamma2 activation inhibited GSK3beta kinase activity, and pharmacological inhibition of GSK3beta activity was unable to restore beta-catenin expression following PPARgamma2 activation. Additionally, this beta-catenin degradation pathway was operative in cells, with inactivating mutations of both APC and p53. Inhibition of the proteasomal pathway inhibited PPARgamma2-mediated degradation of beta-catenin, and incubation with TZD increased ubiquitination of beta-catenin. We conclude that PPARgamma2-mediated suppression of beta-catenin levels involves a novel APC/GSK3beta/p53-independent ubiquitination-mediated proteasomal degradation pathway.", "corpus_id": 24411854, "score": 1 }, { "doc_id": "24111328", "title": "Wnt signaling and forebrain development.", "abstract": "Components of the Wnt signaling pathway are expressed in a tightly regulated and spatially specific manner during development of the forebrain, and Wnts are key regulators of regional forebrain identity. Wnt signaling from the cortical hem regulates the expansion and cell-type specification of the adjacent neuroepithelium and, in conjunction with Bmp, Fgf, and Shh signaling, controls dorsal-ventral forebrain patterning. Subsequently, Wnt signaling dynamically regulates the behavior of cortical progenitor cells, initially promoting the expansion of radial glia progenitor cells and later inducing neurogenesis by promoting terminal differentiation of intermediate progenitor cells. A role for Wnt signaling in cell-type specification has also been proposed.", "corpus_id": 24111328, "score": 0 }, { "doc_id": "24480929", "title": "Wnt signaling: multiple functions in neural development", "abstract": "Abstract.Wnt signaling has proven to be essential for neural development at various stages and across species. Wnts are involved in morphogenesis and patterning, and their proliferation-promoting role is a key function in stem cell maintenance and the expansion of progenitor pools. Moreover, Wnt signaling is involved in differentiation processes and lineage decision events during both central and peripheral nervous system development. Additionally, several reports point to a role of Wnt signaling in axon guidance and neurite outgrowth. This article reviews and consolidates the existing evidence for the functions of Wnt signaling in neural development.", "corpus_id": 24480929, "score": 0 }, { "doc_id": "14838107", "title": "Wnts in adult brain: from synaptic plasticity to cognitive deficiencies", "abstract": "During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer’s disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts.", "corpus_id": 14838107, "score": 0 }, { "doc_id": "8743917", "title": "Wnt signaling in the vertebrate central nervous system: from axon guidance to synaptic function.", "abstract": "Regulation of cell signaling by Wnt proteins is critical for the formation of neuronal circuits. Wnts modulate axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnts activate diverse signaling pathways that lead to local changes on the cytoskeleton or global cellular changes involving nuclear function. Recently, a link between neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been uncovered. Indeed, neuronal activity regulates the release of Wnt and the localization of their receptors. Wnts mediate synaptic structural changes induced by neuronal activity or experience. New emerging evidence suggests that dysfunction in Wnt signaling contributes to neurological disorders. In this article, the attention is focused on the function of Wnt signaling in the formation of neuronal circuits in the vertebrate central nervous system.", "corpus_id": 8743917, "score": 0 }, { "doc_id": "3195846", "title": "Wnt/β-catenin and its Diverse Physiological Cell Signaling Pathways in Neurodegenerative and Neuropsychiatric Disorders", "abstract": "Wnt signaling is a fundamental pathway in embryogenesis which is evolutionary conserved from metazoans to humans. Much of our understanding of Wnt signaling events emerged from key developmental studies in drosophila, zebra fish, xenopus, and mice. Considerable data now exists on the role of Wnt signaling beyond these developmental processes and in particular its role in health and disease. The focus of this special issue is on Wnt/β-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders. This special issue is composed of six reviews and two original articles selected to highlight recent advances in the role of Wnt signaling in CNS embryonic development, in adult brain function, in neurodegenerative conditions such as Alzheimer’s disease, schizophrenia, NeuroAIDS, and in gliomas. The finding that β-catenin can translocate to the nucleus where it binds to TCF/LEF transcription factors to regulate target gene expression was a seminal observation that linked β-catenin/LEF to T cell development and differentiation. We also provide a nostalgic look on recent advances in role of Wnts in T cell development and maturation. These reviews highlight the extensive body of work in these thematic areas as well as identify knowledge gaps, where appropriate. Understanding Wnt function under healthy and diseased conditions may provide a therapeutic resource, albeit it a challenging one, in diseases where dysfunctional and/or diminished Wnt signaling is a prominent player in the disease process.", "corpus_id": 3195846, "score": 0 }, { "doc_id": "13920198", "title": "Wnt your brain be inflamed? Yes, it Wnt!", "abstract": "The roles of Wnts in neural development, synaptogenesis, and cancer are generally well characterized. Nonetheless, evidence exists that interactions between the immune and nervous systems control major brain regenerative processes ranging from physiological or pathological (reparative) regeneration to neurogenesis and synaptic plasticity. Recent studies describe deregulated Wnt-Fzd signaling in degenerative and inflammatory central nervous system (CNS) disorders, and the expression of Wnt signaling components in the immune system, and in immune-like cells of the mammalian CNS. This would suggest a likely involvement of Wnts in inflammation-driven brain damage and inflammation-directed brain repair. Here, we review how Wnts modulate neuroimmune interactions and offer a perspective on the most challenging therapeutic opportunities for those CNS diseases where injury-reactive Wnt-flavored inflammation precedes secondary neurodegeneration.", "corpus_id": 13920198, "score": 0 }, { "doc_id": "25504472", "title": "Functional Characterization of WNT7A Signaling in PC12 Cells", "abstract": "WNT factors represent key mediators of many processes in animal development and homeostasis and act through a receptor complex comprised of members of the Frizzled and low density lipoprotein-related receptors (LRP). In mammals, 19 genes encoding Wingless and Int-related factor (WNTs), 10 encoding Frizzled, and 2 encoding LRP proteins have been identified, but little is known of the identities of individual Frizzled-LRP combinations mediating the effects of specific WNT factors. Additionally, several secreted modulators of WNT signaling have been identified, including at least three members of the Dickkopf family. WNT7A is a WNT family member expressed in the vertebrate central nervous system capable of modulating aspects of neuronal plasticity. Gene knock-out models in the mouse have revealed that WNT7A plays a role in cerebellar maturation, although its function in the development of distal limb structures and of the reproductive tract have been more intensely studied. To identify a receptor complex for this WNT family member, we have analyzed the response of the rat pheochromocytoma cell line PC12 to WNT7A. We find that PC12 cells are capable of responding to WNT7A as measured by increased β-catenin stability and activation of a T-cell factor-based luciferase reporter construct and that these cells express three members of the Frizzled family (Frizzled-2, -5, and -7) and LRP6. Our functional analysis indicates that WNT7A can specifically act via a Frizzled-5·LRP6 receptor complex in PC12 cells and that this activity can be antagonized by Dickkopf-1 and Dickkopf-3.", "corpus_id": 25504472, "score": 0 }, { "doc_id": "24099578", "title": "DKK1 Antagonizes Wnt Signaling without Promotion of LRP6 Internalization and Degradation*", "abstract": "DKK1 is a secreted protein that antagonizes Wnt signaling and plays essential roles in vertebrate embryogenesis including head induction, skeletal development, and limb patterning. DKK1 is also implicated in osteoporosis, arthritis, and cancer and represents a potential therapeutic target for the treatment of these diseases. DKK1 is a high affinity antagonistic ligand for LRP6, which is a Wnt coreceptor that acts together with the Frizzled serpentine receptor to initiate Wnt signal transduction. Two different models have been proposed to account for the mechanism by which DKK1 antagonizes LRP6 function. One model suggests that DKK1 binding to LRP6 disrupts Wnt-induced Frizzled-LRP6 complex formation, whereas the other model proposes that DKK1 interaction with LRP6 promotes LRP6 internalization and degradation, thereby reducing the cell surface LRP6 level. To clarify the molecular basis of DKK1 action, we examined how DKK1 affects the endogenous LRP6 in several mammalian cell lines including mouse embryonic fibroblasts. Here we show that DKK1 inhibits Wnt signaling but induces neither LRP6 down-regulation from the cell surface nor reduction of total LRP6 protein level and that DKK1 has no effect on the rate of continuous internalization of LRP6 and the half-life (about 4.7 h) of LRP6. We conclude that DKK1 inhibition of LRP6 is independent of LRP6 internalization and degradation.", "corpus_id": 24099578, "score": 0 }, { "doc_id": "13935650", "title": "Secreted antagonists of the Wnt signalling pathway", "abstract": "The extracellular antagonists of the Wnt signalling pathway can be divided into two broad classes. Both classes of molecule prevent ligand-receptor interactions, but by different mechanisms: members of the first class, which include the sFRP (secreted Frizzled-related protein) family, WIF (Wnt inhibitory factor)-1 and Cerberus, primarily bind to Wnt proteins; the second class comprises certain members of the Dickkopf (Dkk) family, which bind to one subunit of the Wnt receptor complex. In addition, there are other protein interactions that contribute to Wnt antagonist function. Moreover, certain sFRPs and Dkks do not antagonise Wnt function, which suggests that these families have as-yet-undiscovered functions.", "corpus_id": 13935650, "score": 0 }, { "doc_id": "9300321", "title": "DKK1, a negative regulator of Wnt signaling, is a target of the β-catenin/TCF pathway", "abstract": "Wnt signaling plays an important role in embryonic development and tumorigenesis. These biological effects are exerted by activation of the β-catenin/TCF transcription complex and consequent regulation of a set of downstream genes. TCF-binding elements have been found in the promoter regions of many TCF target genes and characterized by a highly conserved consensus sequence. Utilizing this consensus sequence, we performed an in silico screening for new TCF target genes. Through computational screening and subsequent experimental analysis, we identified a novel TCF target gene, DKK1, which has been shown to be a potent inhibitor of Wnt signaling. Our finding suggests the existence of a novel feedback loop in Wnt signaling.", "corpus_id": 9300321, "score": 0 }, { "doc_id": "7459170", "title": "Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease", "abstract": "The secreted Frizzled-related proteins (SFRPs) are a family of soluble proteins that are structurally related to Frizzled (Fz) proteins, the serpentine receptors that mediate the extensively used cell-cell communication pathway involving Wnt signalling. Because of their homology with the Wnt-binding domain on the Fz receptors, SFRPs were immediately characterised as antagonists that bind to Wnt proteins to prevent signal activation. Since these initial studies, interest in the family of SFRPs has grown progressively, offering new perspectives on their function and mechanism of action in both development and disease. These studies indicate that SFRPs are not merely Wnt-binding proteins, but can also antagonise one another's activity, bind to Fz receptors and influence axon guidance, interfere with BMP signalling by acting as proteinase inhibitors, and interact with other receptors or matrix molecules. Furthermore, their expression is altered in different types of cancers, bone pathologies, retinal degeneration and hypophosphatemic diseases, indicating that their activity is fundamental for tissue homeostasis. Here we review some of the debated aspects of SFRP-Wnt interactions and discuss the new and emerging roles of SFRPs.", "corpus_id": 7459170, "score": 0 }, { "doc_id": "9561740", "title": "β‐catenin is a target for the ubiquitin–proteasome pathway", "abstract": "β‐catenin is a central component of the cadherin cell adhesion complex and plays an essential role in the Wingless/Wnt signaling pathway. In the current model of this pathway, the amount of β‐catenin (or its invertebrate homolog Armadillo) is tightly regulated and its steady‐state level outside the cadherin–catenin complex is low in the absence of Wingless/Wnt signal. Here we show that the ubiquitin‐dependent proteolysis system is involved in the regulation of β‐catenin turnover. β‐catenin, but not E‐cadherin, p120cas or α‐catenin, becomes stabilized when proteasome‐mediated proteolysis is inhibited and this leads to the accumulation of multi‐ubiquitinated forms of β‐catenin. Mutagenesis experiments demonstrate that substitution of the serine residues in the glycogen synthase kinase 3β (GSK3β) phosphorylation consensus motif of β‐catenin inhibits ubiquitination and results in stabilization of the protein. This motif in β‐catenin resembles a motif in IκB (inhibitor of NFκB) which is required for the phosphorylation‐dependent degradation of IκB via the ubiquitin–proteasome pathway. We show that ubiquitination of β‐catenin is greatly reduced in Wnt‐expressing cells, providing the first evidence that the ubiquitin–proteasome degradation pathway may act downstream of GSK3β in the regulation of β‐catenin.", "corpus_id": 9561740, "score": 0 }, { "doc_id": "15856518", "title": "The JNK- and AKT/GSK3β- Signaling Pathways Converge to Regulate Puma Induction and Neuronal Apoptosis Induced by Trophic Factor Deprivation", "abstract": "The AKT, GSK3 and JNK family kinases have been implicated in neuronal apoptosis associated with neuronal development and several neurodegenerative conditions. However, the mechanisms by which these kinase pathways regulate apoptosis remain unclear. In this study we have investigated the role of these kinases in neuronal cell death using an established model of trophic factor deprivation induced apoptosis in cerebellar granule neurons. BCL-2 family proteins are known to be central regulators of apoptosis and we have determined that the pro-apoptotic family member Puma is transcriptionally up-regulated in trophic factor deprived neurons and that Puma induction is required for apoptosis in vitro and in vivo. Importantly, we demonstrate that Puma induction is dependent on both JNK activation and AKT inactivation. AKT is known to regulate a number of downstream pathways, however we have determined that PI3K-AKT inactivation induces Puma expression through a GSK3β-dependent mechanism. Finally we demonstrate that the JNK and AKT/GSK3β pathways converge to regulate FoxO3a-mediated transcriptional activation of Puma. In summary we have identified a novel and critical link between the AKT, GSK3β and JNK kinases and the regulation of Puma induction and suggest that this may be pivotal to the regulation of neuronal apoptosis in neurodegenerative conditions.", "corpus_id": 15856518, "score": 0 }, { "doc_id": "13449245", "title": "GSK3 signalling in neural development", "abstract": "Recent evidence suggests that glycogen synthase kinase 3 (GSK3) proteins and their upstream and downstream regulators have key roles in many fundamental processes during neurodevelopment. Disruption of GSK3 signalling adversely affects brain development and is associated with several neurodevelopmental disorders. Here, we discuss the mechanisms by which GSK3 activity is regulated in the nervous system and provide an overview of the recent advances in the understanding of how GSK3 signalling controls neurogenesis, neuronal polarization and axon growth during brain development. These recent advances suggest that GSK3 is a crucial node that mediates various cellular processes that are controlled by multiple signalling molecules — for example, disrupted in schizophrenia 1 (DISC1), partitioning defective homologue 3 (PAR3), PAR6 and Wnt proteins — that regulate neurodevelopment.", "corpus_id": 13449245, "score": 0 }, { "doc_id": "33010159", "title": "GSK3: a multifaceted kinase in Wnt signaling.", "abstract": "GSK3 is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnts, hedgehog, growth factors, cytokines, and G protein-coupled ligands. Although the inhibition of GSK3-mediated beta-catenin phosphorylation is known to be the key event in Wnt-beta-catenin signaling, the mechanisms that underlie this event remain incompletely understood. The recent demonstration of GSK3 involvement in Wnt receptor phosphorylation illustrates the multifaceted roles that GSK3 plays in Wnt-beta-catenin signaling. In this review, we will summarize these recent results and offer explanations, hypotheses, and models to reconcile some of these observations.", "corpus_id": 33010159, "score": 0 }, { "doc_id": "20847300", "title": "Mechanisms regulating glioma invasion.", "abstract": "Glioblastoma (GBM) is the most aggressive, deadliest, and most common brain malignancy in adults. Despite the advances made in surgical techniques, radiotherapy and chemotherapy, the median survival for GBM patients has remained at a mere 14 months. GBM poses several unique challenges to currently available treatments for the disease. For example, GBM cells have the propensity to aggressively infiltrate/invade into the normal brain tissues and along the vascular tracks, which prevents complete resection of all malignant cells and limits the effect of localized radiotherapy while sparing normal tissue. Although anti-angiogenic treatment exerts anti-edematic effect in GBM, unfortunately, tumors progress with acquired increased invasiveness. Therefore, it is an important task to gain a deeper understanding of the intrinsic and post-treatment invasive phenotypes of GBM in hopes that the gained knowledge would lead to novel GBM treatments that are more effective and less toxic. This review will give an overview of some of the signaling pathways that have been shown to positively and negatively regulate GBM invasion, including, the PI3K/Akt, Wnt, sonic hedgehog-GLI1, and microRNAs. The review will also discuss several approaches to cancer therapies potentially altering GBM invasiveness.", "corpus_id": 20847300, "score": 1 }, { "doc_id": "12632351", "title": "PPAR Regulation of Inflammatory Signaling in CNS Diseases", "abstract": "Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPARα, γ, and δ isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-κB and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.", "corpus_id": 12632351, "score": 0 }, { "doc_id": "21812924", "title": "Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.", "abstract": "Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved in lipid metabolism and also play a role in adipocyte differentiation. We present the expression patterns of the PPAR subtypes in the adult rat, determined by in situ hybridization using specific probes for PPAR-alpha, -beta and -gamma, and by immunohistochemistry using a polyclonal antibody that recognizes the three rat PPAR subtypes. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, with relative levels varying between them from one cell type to the other. PPAR-alpha is highly expressed in hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPAR-beta is expressed ubiquitously and often at higher levels than PPAR-alpha and -gamma. PPAR-gamma is expressed predominantly in adipose tissue and the immune system. Our results suggest new potential directions to investigate the functions of the different PPAR subtypes.", "corpus_id": 21812924, "score": 0 }, { "doc_id": "38820927", "title": "Peroxisome proliferator-activated receptor gamma in diabetes and metabolism.", "abstract": "The peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been the focus of intense research during the past decade because ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of type 2 diabetes. Recent advances include the discovery of novel genes that are regulated by PPAR-gamma, which helps explain how activation of this adipocyte-predominant transcription factor regulates glucose and lipid homeostasis. Increased levels of circulating free fatty acids and lipid accumulation in non-adipose tissue have been implicated in the development of insulin resistance. This situation is improved by PPAR-gamma ligands, which promote fatty acid storage in fat depots and regulate the expression of adipocyte-secreted hormones that impact on glucose homeostasis. The net result of the pleiotropic effects of PPAR-gamma ligands is improvement of insulin sensitivity, although undesired side-effects limit the utility of this therapy. It might be possible to dissociate the anti-diabetic and adverse effects through selective modulation of PPAR-gamma activity.", "corpus_id": 38820927, "score": 0 }, { "doc_id": "44539527", "title": "PPAR(gamma) and glucose homeostasis.", "abstract": "Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor involved in the control of metabolism. Research on PPARgamma is oriented towards understanding its role in insulin sensitization, which was inspired by the discovery that antidiabetic agents, the thiazolidinediones, were agonists for PPARgamma. PPARgamma stimulation improves glucose tolerance and insulin sensitivity in type 2 diabetic patients and in animal models of insulin resistance through mechanisms that are incompletely understood. Upon activation, PPARgamma heterodimerizes with retinoid X receptor, recruits specific cofactors, and binds to responsive DNA elements, thereby stimulating the transcription of target genes. Because PPARgamma is highly enriched in adipose tissue and because of its major role in adipocyte differentiation, it is thought that the effects of PPARgamma in adipose tissue are crucial to explain its role in insulin sensitization, but recent studies have highlighted the contribution of other tissues as well. Although relatively potent for their insulin-sensitizing action, currently marketed PPARgamma activators have some important undesirable side effects. These concerns led to the discovery of new ligands with potent antidiabetic properties but devoid of certain of these side effects. Data from human genetic studies and from PPARgamma heterozygous knockout mice indicate that a reduction in PPARgamma activity could paradoxically improve insulin sensitivity. These findings suggest that modulation of PPARgamma activity by partial agonists or compounds that affect cofactor recruitment might hold promise for the treatment of insulin resistance.", "corpus_id": 44539527, "score": 0 }, { "doc_id": "7228505", "title": "PPARs, Cardiovascular Metabolism, and Function: Near- or Far-from-Equilibrium Pathways", "abstract": "Peroxisome proliferator-activated receptors (PPAR α, β/δ and γ) play a key role in metabolic regulatory processes and gene regulation of cellular metabolism, particularly in the cardiovascular system. Moreover, PPARs have various extra metabolic roles, in circadian rhythms, inflammation and oxidative stress. In this review, we focus mainly on the effects of PPARs on some thermodynamic processes, which can behave either near equilibrium, or far-from-equilibrium. New functions of PPARs are reported in the arrhythmogenic right ventricular cardiomyopathy, a human genetic heart disease. It is now possible to link the genetic desmosomal abnormalitiy to the presence of fat in the right ventricle, partly due to an overexpression of PPARγ. Moreover, PPARs are directly or indirectly involved in cellular oscillatory processes such as the Wnt-b-catenin pathway, circadian rhythms of arterial blood pressure and cardiac frequency and glycolysis metabolic pathway. Dysfunction of clock genes and PPARγ may lead to hyperphagia, obesity, metabolic syndrome, myocardial infarction and sudden cardiac death, In pathological conditions, regulatory processes of the cardiovascular system may bifurcate towards new states, such as those encountered in hypertension, type 2 diabetes, and heart failure. Numerous of these oscillatory mechanisms, organized in time and space, behave far from equilibrium and are “dissipative structures”.", "corpus_id": 7228505, "score": 0 }, { "doc_id": "13794944", "title": "Vascular PPARgamma controls circadian variation in blood pressure and heart rate through Bmal1.", "abstract": "Thiazolidinediones (TZDs) are PPARgamma activators that exhibit vasculoprotective properties. To determine the vascular function of PPARgamma, we analyzed Tie2Cre/flox and SM22Cre/flox mice. Unexpectedly, both knockout strains exhibited a significant reduction of circadian variations in blood pressure and heart rate in parallel with diminished variations in urinary norepinephrine/epinephrine excretion and impaired rhythmicity of the canonical clock genes, including Bmal1. PPARgamma expression in the aorta exhibited a robust rhythmicity with a more than 20-fold change during the light/dark cycle. Rosiglitazone treatment induced aortic expression of Bmal1 mRNA, and ChIP and promoter assays revealed that Bmal1 is a direct PPARgamma target gene. These studies have uncovered a role for vascular PPARgamma as a peripheral factor participating in regulation of cardiovascular rhythms.", "corpus_id": 13794944, "score": 0 }, { "doc_id": "39979939", "title": "PPARs and molecular mechanisms of transrepression.", "abstract": "In the last few years, PPARs have emerged as key regulators of inflammatory and immune responses. However, the mechanistic basis of the anti-inflammatory effects of peroxisome proliferator-activated receptors (PPARs) remains poorly understood. Accumulating evidence suggests that these effects result from inhibition of signal-dependent transcription factors that mediate inflammatory programs of gene activation. Several mechanisms underlying negative regulation of gene expression by PPARs have been described. Recent studies, using siRNA, microarray analysis and macrophage-specific knockout mice, have highlighted PPARs molecular transrepression mechanism in macrophages. Identification of their mechanism of action should help promote the understanding of the physiologic roles that PPARs play in immunity and contribute to the development of new therapeutic agents.", "corpus_id": 39979939, "score": 0 }, { "doc_id": "22974645", "title": "Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy.", "abstract": "Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC. We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state. Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC. These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.", "corpus_id": 22974645, "score": 1 }, { "doc_id": "44608772", "title": "The Wnt/beta-catenin signaling pathway targets PPARgamma activity in colon cancer cells.", "abstract": "Control of colon cell fate in adenocarcinomas is disrupted, in part, due to aberrant Wnt/beta-catenin signaling. The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) has been implicated in the development of colon cancers. In the adenomatous polyposis coli multiple intestinal neoplasia (APCMin) mouse cancer model, PPARgamma expression in the colonic mucosa is markedly altered. In addition, PPARgamma protein levels are elevated, possibly through sequestration by activated beta-catenin in colon cancer cell lines. Induction of the Wnt/beta-catenin pathway by LiCl also elevated PPARgamma levels and induced PPARgamma-dependent reporter and endogenous target genes. Mechanistically, PPARgamma, through interactions with beta-catenin and T cell transcription factor (Tcf)-4, may be a determinant of cell fate and is likely a target of the Wnt pathway in cancer cells.", "corpus_id": 44608772, "score": 0 }, { "doc_id": "32318159", "title": "Gene expression profile of adipocyte differentiation and its regulation by peroxisome proliferator-activated receptor-gamma agonists.", "abstract": "PPAR gamma is an adipocyte-specific nuclear hormone receptor. Agonists of PPAR gamma, such as thiazolidinediones (TZDs), promote adipocyte differentiation and have insulin-sensitizing effects in animals and diabetic patients. Affymetrix oligonucleotide arrays representing 6347 genes were employed to profile the gene expression responses of mature 3T3-L1 adipocytes and differentiating preadipocytes to a TZD PPAR gamma agonist in vitro. The expression of 579 genes was significantly up- or down-regulated by more than 1.5-fold during differentiation and/or by treatment with TZD, and these genes were organized into 32 clusters that demonstrated concerted changes in expression of genes controlling cell growth or lipid metabolism. Quantitative PCR was employed to further characterize gene expression and led to the identification of beta-catenin as a new PPAR gamma target gene. Both mRNA and protein levels for beta-catenin were down-regulated in 3T3-L1 adipocytes compared with fibroblasts and were further decreased by treatment of adipocytes with PPAR gamma agonists. Treatment of db/db mice with a PPAR gamma agonist also resulted in reduction of beta-catenin mRNA levels in adipose tissue. These results suggest that beta-catenin plays an important role in the regulation of adipogenesis. Thus, the transcriptional patterns revealed in this study further the understanding of adipogenesis process and the function of PPAR gamma activation.", "corpus_id": 32318159, "score": 0 }, { "doc_id": "20540231", "title": "Thermodynamic Aspects and Reprogramming Cellular Energy Metabolism during the Fibrosis Process", "abstract": "Fibrosis is characterized by fibroblast proliferation and fibroblast differentiation into myofibroblasts, which generate a relaxation-free contraction mechanism associated with excessive collagen synthesis in the extracellular matrix, which promotes irreversible tissue retraction evolving towards fibrosis. From a thermodynamic point of view, the mechanisms leading to fibrosis are irreversible processes that can occur through changing the entropy production rate. The thermodynamic behaviors of metabolic enzymes involved in fibrosis are modified by the dysregulation of both transforming growth factor β (TGF-β) signaling and the canonical WNT/β-catenin pathway, leading to aerobic glycolysis, called the Warburg effect. Molecular signaling pathways leading to fibrosis are considered dissipative structures that exchange energy or matter with their environment far from the thermodynamic equilibrium. The myofibroblastic cells arise from exergonic processes by switching the core metabolism from oxidative phosphorylation to glycolysis, which generates energy and reprograms cellular energy metabolism to induce the process of myofibroblast differentiation. Circadian rhythms are far-from-equilibrium thermodynamic processes. They directly participate in regulating the TGF-β and WNT/β-catenin pathways involved in energetic dysregulation and enabling fibrosis. The present review focusses on the thermodynamic implications of the reprogramming of cellular energy metabolism, leading to fibroblast differentiation into myofibroblasts through the positive interplay between TGF-β and WNT/β-catenin pathways underlying in fibrosis.", "corpus_id": 20540231, "score": 0 }, { "doc_id": "42712152", "title": "The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway", "abstract": "Myofibroblasts are non-muscular contractile cells that occur physiologically in organs such as in stem villi of the human placenta during normal pregnancies. They have the ability to contract and relax in response to changes in the volume of the intervillous chamber. Myofibroblasts are also found in many pathological states, and are involved in wound healing and fibrosis processes in several organs such as liver, lung, kidney, and heart. During fibrosis, the contractile phenomenon is a relaxation-free mechanism, associated with the synthesis of collagen in the extracellular matrix (ECM), which leads to irreversible fibrosis, tissue retraction and finally apoptosis of the myofibroblasts. The molecular motor of myofibroblasts is the non-muscle myosin type II (NMII). Differentiation of fibroblasts into myofibroblast is largely regulated by the Transforming Growth Factor-β1 (TGF-β1). This system regulates the canonical WNT/β-catenin pathway in a positive manner and PPARγ in a negative manner. WNT/β-catenin promotes fibrosis while PPARγ prevents fibrosis. This review focuses on the contractile properties of myofibroblasts and on the TGF-β1 conductor which regulates the antagonism between PPARγ and the canonical WNT/β-catenin pathway.", "corpus_id": 42712152, "score": 0 }, { "doc_id": "18512446", "title": "A potential link between peroxisome proliferator-activated receptor signalling and the pathogenesis of arrhythmogenic right ventricular cardiomyopathy.", "abstract": "AIMS\nArrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by major fibro-fatty replacement of the right ventricle (RV). We hypothesized that changes in peroxisome proliferator-activated receptor (PPAR) signalling contributed to myocardium fatty accumulation and contractile dysfunction in ARVC.\n\n\nMETHODS AND RESULTS\nReal-time quantitative reverse transcriptase-polymerase chain reaction and western blotting were used to assess cardiac expression of PPARalpha and gamma and two of their downstream target genes--medium-chain acyl-CoA dehydrogenase (MCAD) and phosphoenolpyruvate carboxykinase (PEPCK)--in both RV and left ventricle (LV) from five controls and five ARVC patients. In vitro motility assays were used to analyse functional properties of myosin. In the RV, sliding velocity was nearly two-fold lower in ARVC than in controls, whereas a 10% reduction in velocity values was noted between ARVC and non-failing myocardium in the LV. In controls, PPARalpha and MCAD mRNA and protein levels were higher in the RV compared with the LV. In ARVC, the expression of PPARalpha and MCAD mRNA and/or proteins was decreased in both RV and LV. RV from ARVC was also characterized by a dramatic activation of the PPARgamma pathway, as attested by the increase in PPARgamma mRNA and protein (500 and 270%, respectively, each P < 0.001) and by the induction of PEPCK gene. In contrast, the LV of ARVC heart exhibited no changes in the expression of the PPARgamma regulatory pathway compared with control.\n\n\nCONCLUSION\nARVC is associated with major disturbances in the PPARalpha and PPARgamma signalling pathway in the RV that may contribute to intracellular lipid overload and severe myosin dysfunction.", "corpus_id": 18512446, "score": 0 }, { "doc_id": "2277031", "title": "Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer.", "abstract": "Plakoglobin and beta-catenin are homologous proteins functioning in cell adhesion and transactivation. Their activities are controlled by three types of interactions: those with cadherins in adherens junctions, linking them to the actin cytoskeleton; interactions in the nucleus, where they bind to transcription factors and stimulate gene expression; interactions of free cytoplasmic beta-catenin with axin and adenomatous polyposis coli (APC) protein which target it for degradation. Studies in the past year have demonstrated the complex interplay between these three types of interactions and the different behavior of beta-catenin and plakoglobin in their involvement in morphogenesis and tumorigenesis strongly suggesting that catenins play key roles in adhesion-mediated signaling.", "corpus_id": 2277031, "score": 0 }, { "doc_id": "43456478", "title": "Differential Mechanisms of LEF/TCF Family-Dependent Transcriptional Activation by β-Catenin and Plakoglobin", "abstract": "ABSTRACT β-Catenin and plakoglobin are highly homologous components of cell-cell adherens junctions linking cadherin receptors to the actin cytoskeleton. β-Catenin, in addition, activates transcription by forming a complex with LEF/TCF family transcription factors in the nucleus. Plakoglobin can also bind to LEF-1 and, when overexpressed in mammalian cells, enhances LEF-1-directed transcription. Plakoglobin overexpression, however, results in the elevation and nuclear translocation of endogenous β-catenin. We show here, by DNA mobility shift analysis, that the formation of a plakoglobin-LEF/TCF-DNA complex in vitro is very inefficient compared to a complex containing β-catenin-LEF-DNA. Moreover, in plakoglobin-transfected cells plakoglobin-LEF/TCF-DNA complexes were not formed; rather, the endogenous β-catenin, whose level is elevated by plakoglobin transfection, formed a β-catenin–LEF–DNA complex. Removal of the N- and C-terminal domains of both β-catenin and plakoglobin (leaving the armadillo repeat domain intact) induced plakoglobin-LEF-DNA complex formation and also enhanced β-catenin–LEF–DNA complexing, both with in vitro-translated components and in transfected cells. Transfection with these truncated catenins increased endogenous β-catenin levels, but the truncated catenins acted as dominant-negative inhibitors of β-catenin-driven transcription by forming transcriptionally inactive complexes with LEF-1. When these catenin mutants were prevented from entering the nucleus, by their fusion to the connexin transmembrane domain, they indirectly activated transcription by increasing endogenous β-catenin levels. These results suggest that overexpression of plakoglobin does not directly activate transcription and that formation of catenin-LEF-DNA complexes is negatively regulated by the catenin N- and C-terminal domains.", "corpus_id": 43456478, "score": 0 }, { "doc_id": "20163877", "title": "Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study.", "abstract": "OBJECTIVES\nThe aim of the present investigation was to redefine the clinicopathologic profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), with special reference to disease progression and left ventricular (LV) involvement.\n\n\nBACKGROUND\nLong-term follow-up data from clinical studies indicate that ARVC is a progressive heart muscle disease that with time may lead to more diffuse right ventricular (RV) involvement and LV abnormalities and culminate in heart failure.\n\n\nMETHODS\nForty-two patients (27 male, 15 female; 9 to 65 years old, mean [+/-SD] age 29.6 +/- 18) from six collaborative medical centers, with a pathologic diagnosis of ARVC at autopsy or heart transplantation, and with the whole heart available, were studied according to a specific clinicomorphologic protocol.\n\n\nRESULTS\nThirty-four patients died suddenly (16 during effort); 4 underwent heart transplantation; 2 died as a result of advanced heart failure; and 2 died of other causes. Sudden death was the first sign of disease in 12 patients; the other 30 had palpitations, with syncope in 11, heart failure in 8 and stroke in 3. Twenty-seven patients experienced ventricular arrhythmias (ventricular tachycardia in 17), and 5 received a pacemaker. Ten patients had isolated RV involvement (group A); the remaining 32 (76%) also had fibrofatty LV involvement that was observed histologically only in 15 (group B) and histologically and macroscopically in 17 (group C). Patients in group C were significantly older than those in groups A and B (39 +/- 15 years vs. 20 +/- 8.8 and 25 +/- 9.7 years, respectively), had significantly longer clinical follow-up (9.3 +/- 7.3 years vs. 1.2 +/- 2.1 and 3.4 +/- 2.2 years, respectively) and developed heart failure significantly more often (47% vs. 0 and 0, respectively). Patients in groups B and C had warning symptoms (80% and 87%, respectively, vs. 30%) and clinical ventricular arrhythmias (73% and 82%, respectively, vs. 20%) significantly more often than patients in group A. Hearts from patients in group C weighed significantly more than those from patients in groups A and B (500 +/- 150 g vs. 328 +/- 40 and 380 +/- 95 g, respectively), whereas hearts from both group B and C patients had severe RV thinning (87% and 71%, respectively, vs. 20%) and inflammatory infiltrates (73% and 88%, respectively, vs. 30%) significantly more often than those from group A patients.\n\n\nCONCLUSIONS\nLV involvement was found in 76% of hearts with ARVC, was age dependent and was associated with clinical arrhythmic events, more severe cardiomegaly, inflammatory infiltrates and heart failure. ARVC can no longer be regarded as an isolated disease of the right ventricle.", "corpus_id": 20163877, "score": 0 }, { "doc_id": "23431148", "title": "WNT/β-catenin Signaling Pathway and Downstream Modulators in Low- and High-grade Glioma.", "abstract": "BACKGROUND\nAberrant activation of the canonical Wingless-type MMTV integration site family (WNT)/β-catenin signaling pathway is critical for gliomas.\n\n\nMATERIALS AND METHODS\nIn 74 gliomas of different histological grade and in 24 glioblastoma cell lines, protein expression of WNT member 3a (WNT3a), β-catenin and transcription factor 4 (TCF4) was investigated by immunohistochemistry, western blotting, immunofluorescence and immunocytochemistry. In tumors and cell lines, WNT3A expression was assessed at the mRNA level by quantitative real-time polymerase chain reaction.\n\n\nRESULTS\nWNT3a was overexpressed at the protein and mRNA levels in malignant astrocytic tumors and cell lines. Cytoplasmic expression of β-catenin was detected in high-grade gliomas and cell lines, with evidence of nuclear translocation on fractionated protein extracts. Activating mutations in the β-catenin encoding gene (CTNNB1) were excluded by direct sequencing. TCF4 was statistically correlated with Ki-67/MIB-1 and cyclin D1 labeling indices.\n\n\nCONCLUSION\nExpression of WNT3a, cytoplasmic β-catenin and TCF4 was significantly associated with the histological malignancy grade and with a worse prognosis for patients with glioma.", "corpus_id": 23431148, "score": 0 }, { "doc_id": "39211681", "title": "Wnt/beta-Catenin pathway in human glioma: expression pattern and clinical/prognostic correlations", "abstract": "Gliomas are the most common primary intracranial tumors. Understanding the molecular basis of gliomas’ progression is required to develop more effective therapies. The Wnt/β-catenin signaling cascade is an important signal transduction pathway in human cancers. Although, overactivation of this pathway is a hallmark of several forms of cancer, little is known about its role in human gliomas. Here, we aimed to determine the clinical significance of Wnt/β-catenin pathway components in gliomas. Immunohistochemical staining was performed to detect the expression patterns of Wnt1, β-catenin and Cyclin D1 in the biopsies from 96 patients with primary gliomas. Kaplan–Meier survival and Cox regression analyses were performed to evaluate the prognosis of patients. Cytoplasmic staining pattern of Wnt1, membranous, cytoplasmic and nuclear accumulation of β-catenin, and nuclear localization of Cyclin D1 were demonstrated by immunohistochemical staining. The Wnt1 expression significantly correlated with the expression of Cyclin D1 (P < 0.0001). The ratio of tumors with a cytoplasmic–nuclear pattern or a cytoplasmic pattern of β-catenin was significantly higher in Wnt1-positive (P < 0.01) and Cyclin D1-positive (P < 0.01) tumors than in Wnt1-negative and Cyclin D1-negative tumors, respectively. The protein expression levels of Wnt1, β-catenin and Cyclin D1 were all positively correlated with the Karnofsky performance scale (KPS) score and World Health Organization (WHO) grades of patients with gliomas. Furthermore, Wnt1, cytoplasmic–nuclear β-catenin and Cyclin D1 status were all the independent prognostic factors for glioma patients (P = 0.01, 0.007 and 0.005, respectively). These results provide convincing evidence that the Wnt/β-catenin pathway correlated closely with the progression of gliomas and might be a novel prognostic marker for this neoplasm.", "corpus_id": 39211681, "score": 1 }, { "doc_id": "2360593", "title": "Activation of Wnt/β-catenin/Tcf signaling pathway in human astrocytomas", "abstract": "Astrocytomas are the most common form of primary brain tumors. Understanding the molecular basis of development and progression of astrocytomas is required to develop more effective therapies. Although, over activation of Wnt/beta-catenin/Tcf pathway is a hallmark of several forms of cancer, little is known about its role in human astrocytomas. Here, we report the evidence that Wnt/beta-catenin/Tcf signaling pathway is constitutively activated in astrocytic tumors. In the present study, human astrocytic tumors with different clinical grades were analyzed for mRNA expression of Dvl-1, Dvl-2, Dvl-3, beta-catenin, c-myc and cyclin D1 and protein levels of beta-catenin, Lef1, Tcf4, c-Myc, N-Myc, c-jun and cyclin D1. RT-PCR analysis demonstrated the overexpression of Dvl-3, beta-catenin, c-myc and cyclin D1 in astrocytomas. Western blotting revealed upregulation of beta-catenin, Lef1, Tcf4 and their target proteins in the core tumor tissues in comparison to peritumor and normal brain tissues. The protein and mRNA levels were positively correlated with the histological malignancy. Cytoplasmic and nuclear accumulation of beta-catenin, nuclear localization of Lef1, Tcf4, c-Myc, N-Myc, c-jun and cyclin D1 were demonstrated by immunohistochemical staining. Our studies tend to suggest that Wnt/beta-catenin/Tcf signaling pathway is implicated in malignancy of astrocytomas.", "corpus_id": 2360593, "score": 1 }, { "doc_id": "39825460", "title": "Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition.", "abstract": "Here we show that activation of the canonical WNT/β-catenin pathway increases the expression of stem cell genes and promotes the migratory and invasive capacity of glioblastoma. Modulation of WNT signaling alters the expression of epithelial-to-mesenchymal transition activators, suggesting a role of this process in the regulation of glioma motility. Using immunohistochemistry in patient-derived glioblastoma samples we showed higher numbers of cells with intranuclear signal for β-catenin in the infiltrating edge of tumor compared to central tumor parenchyma. These findings suggest that canonical WNT/β-catenin pathway is a critical regulator of GBM invasion and may represent a potential therapeutic target.", "corpus_id": 39825460, "score": 0 }, { "doc_id": "25365463", "title": "β-catenin and Gli1 are prognostic markers in glioblastoma", "abstract": "Glioblastomas (GBMs), the most common primary malignancies of the central nervous system, are highly aggressive and heterogeneous, and remain a dramatic therapeutic challenge. Markers mirroring the complex molecular profile of GBMs that are predictive of patient outcomes are needed to define novel multi-targeted treatment strategies. Resistance to current GBM therapies is partly due to a subpopulation of stem-like and other self-renewing cells (hereafter called glioma stem-like cancer cells, GSCC), which are therefore of key interest as therapeutic entry points. Wnt and Hedgehog are among the main pathways involved in GSCC renewal. β-catenin and Gli1 are markers of Wnt and Hedgehog activation respectively and both pathways are known to be altered in gliomas. To date, there are no investigations of Gli1 protein expression in GBM tissue, and recently a high expression of β-catenin has been found to have a poor prognostic impact in GBM patients in a study. We have therefore quantified the positivity for β-catenin, Gli1, as well as Ki-67, p53, and EGFR proteins on immunohistochemically-stained GBM sections from 106 patients in an investigation for potential predictive biomarkers. Correlation between these markers and survival was evaluated by pair-wise Pearson correlation coefficient and by bi-dimensional hierarchical clustering, followed by survival estimations using linear regression models and classification trees. We demonstrated that both β-catenin and, for the first time, Gli1 proteins are highly predictive markers of short survival, being found in 75 and 90% of the highly predictive trees, respectively, whereas Ki-67, p53 and EGFR were under 30% and thus, not considered as predictive. Our results indicate a role of β-catenin and Gli1 in GBM malignant behaviour, and suggest that inhibiting members of Wnt and Hedgehog pathways could be a valuable therapeutic strategy for GBM patients. See commentary: A magnifying glass on glioblastoma stem cell signaling pathways", "corpus_id": 25365463, "score": 0 }, { "doc_id": "206537328", "title": "PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas.", "abstract": "A hallmark feature of glioblastoma is its strong self-renewal potential and immature differentiation state, which contributes to its plasticity and therapeutic resistance. Here, integrated genomic and biological analyses identified PLAGL2 as a potent protooncogene targeted for amplification/gain in malignant gliomas. Enhanced PLAGL2 expression strongly suppresses neural stem cell (NSC) and glioma-initiating cell differentiation while promoting their self-renewal capacity upon differentiation induction. Transcriptome analysis revealed that these differentiation-suppressive activities are attributable in part to PLAGL2 modulation of Wnt/beta-catenin signaling. Inhibition of Wnt signaling partially restores PLAGL2-expressing NSC differentiation capacity. The identification of PLAGL2 as a glioma oncogene highlights the importance of a growing class of cancer genes functioning to impart stem cell-like characteristics in malignant cells.", "corpus_id": 206537328, "score": 0 }, { "doc_id": "2944241", "title": "Temozolomide downregulates P-glycoprotein expression in glioblastoma stem cells by interfering with the Wnt3a/glycogen synthase-3 kinase/β-catenin pathway.", "abstract": "BACKGROUND\nGlioblastoma multiforme stem cells display a highly chemoresistant phenotype, whose molecular basis is poorly known. We aim to clarify this issue and to investigate the effects of temozolomide on chemoresistant stem cells.\n\n\nMETHODS\nA panel of human glioblastoma cultures, grown as stem cells (neurospheres) and adherent cells, was used.\n\n\nRESULTS\nNeurospheres had a multidrug resistant phenotype compared with adherent cells. Such chemoresistance was overcome by apparently noncytotoxic doses of temozolomide, which chemosensitized glioblastoma cells to doxorubicin, vinblastine, and etoposide. This effect was selective for P-glycoprotein (Pgp) substrates and for stem cells, leading to an investigation of whether there was a correlation between the expression of Pgp and the activity of typical stemness pathways. We found that Wnt3a and ABCB1, which encodes for Pgp, were both highly expressed in glioblastoma stem cells and reduced by temozolomide. Temozolomide-treated cells had increased methylation of the cytosine-phosphate-guanine islands in the Wnt3a gene promoter, decreased expression of Wnt3a, disrupted glycogen synthase-3 kinase/β-catenin axis, reduced transcriptional activation of ABCB1, and a lower amount and activity of Pgp. Wnt3a overexpression was sufficient to transform adherent cells into neurospheres and to simultaneously increase proliferation and ABCB1 expression. On the contrary, glioblastoma stem cells silenced for Wnt3a lost the ability to form neurospheres and reduced at the same time the proliferation rate and ABCB1 levels.\n\n\nCONCLUSIONS\nOur work suggests that Wnt3a is an autocrine mediator of stemness, proliferation, and chemoresistance in human glioblastoma and that temozolomide may chemosensitize the stem cell population by downregulating Wnt3a signaling.", "corpus_id": 2944241, "score": 0 }, { "doc_id": "12749295", "title": "FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis.", "abstract": "Wnt/β-catenin signaling is essential for stem cell regulation and tumorigenesis, but its molecular mechanisms are not fully understood. Here, we report that FoxM1 is a downstream component of Wnt signaling and is critical for β-catenin transcriptional function in tumor cells. Wnt3a increases the level and nuclear translocation of FoxM1, which binds directly to β-catenin and enhances β-catenin nuclear localization and transcriptional activity. Genetic deletion of FoxM1 in immortalized neural stem cells abolishes β-catenin nuclear localization. FoxM1 mutations that disrupt the FoxM1-β-catenin interaction or FoxM1 nuclear import prevent β-catenin nuclear accumulation in tumor cells. FoxM1-β-catenin interaction controls Wnt target gene expression, is required for glioma formation, and represents a mechanism for canonical Wnt signaling during tumorigenesis.", "corpus_id": 12749295, "score": 0 }, { "doc_id": "34801495", "title": "Wnt3a mediated activation of Wnt/β-catenin signaling promotes tumor progression in glioblastoma", "abstract": "Presence of a distinct population of cells that drives tumor progression supports the hierarchical model of tumor development in Glioblastoma (GBM) and substantiates the cancer stem cell hypothesis. Amongst the various developmental signaling pathways that are aberrantly activated, we here show that activated Wnt/β-catenin signaling pathway plays a critical role in malignant transformation and tumor progression in gliomas. We demonstrate that Wnt ligands - Wnt1 and Wnt3a are expressed in a graded manner in these tumors as well as over-expressed in glioma stem cell-lines. A selective inhibition of Wnt signaling pathway by selective knock-down of its ligands Wnt1 and Wnt3a in glioma-derived stem-like cells led to decreased cell proliferation, cell migration and chemo-resistance. Furthermore, Wnt silencing in glioma cells reduced the capacity to form intra-cranial tumors in vivo. Taken together, our study indicates Wnt/β-catenin signaling pathway as an essential driver of glioma tumorigenesis, recognizing role of Wnt3a as an oncogene and thereby offering novel therapeutic strategies for management of these tumors.", "corpus_id": 34801495, "score": 0 }, { "doc_id": "3136582", "title": "Downregulation of Wnt2 and β-catenin by siRNA suppresses malignant glioma cell growth", "abstract": "Increasing evidence suggests that aberrant activation of Wnt signaling is involved in tumor development and progression. Our earlier study on gene expression profile in human gliomas by microarray found that some members of Wnt family were overexpressed. To further investigate the involvement of Wnt signaling in gliomas, the expression of core components of Wnt signaling cascade in 45 astrocytic glioma specimens with different tumor grades was examined by reverse transcription-PCR and immunohistochemistry. Wnt2, Wnt5a, frizzled2 and β-catenin were overexpressed in gliomas. Knockdown of Wnt2 and its key mediator β-catenin in the canonical Wnt pathway by siRNA in human U251 glioma cells inhibited cell proliferation and invasive ability, and induced apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous U251 gliomas with siRNA targeting Wnt2 and β-catenin intratumorally also delayed the tumor growth. In both in vitro and in vivo studies, downregulation of Wnt2 and β-catenin was associated with the decrease of PI3K/p-AKT expression, indicating the interplay between Wnt/β-catenin and PI3K/AKT signaling cascades. In conclusion, the canonical Wnt pathway is of critical importance in the gliomagenesis and intervention of this pathway may provide a new therapeutic approach for malignant gliomas.", "corpus_id": 3136582, "score": 0 }, { "doc_id": "21333323", "title": "Role of Wnt5a in the proliferation of human glioblastoma cells.", "abstract": "Wnt5a operates as either a tumor suppressor or a tumor stimulator, according to tumor type. The functions of Wnt5a in human glioblastoma (GBM) have yet to be determined. We initially evaluated the expression of Wnt5a in human glioma. The results of immunohistochemical analyses have revealed that Wnt5a expression was higher in human GBM than in normal brain tissue and low-grade astrocytoma. In order to assess the role of Wnt5a on proliferation in human glioblastoma cells, we employed U87MG and GBM-05, a newly established GBM cell line. GBM-05 was established from a patient diagnosed with GBM. GBM-05 cells were shown to express Nestin, but did not express GFAP and Map2ab. GBM-05 cells formed infiltrating brain tumors after being intracerebrally transplanted into nude mice, and xenotransplanted GBM-05 cells were observed to differentiate into neuronal and astrocyte lineages. Wnt5a expression in the xenotransplanted tumors was higher than that detected in the surrounding brain tissues. The overexpression of Wnt5a increased the proliferation of GBM-05 and U87MG in vitro. By way of contrast, the downregulation of Wnt5a expression as the result of RNA interference reduced proliferation from GBM-05 and U87MG cells in vitro, and reduced tumorigenicity in vivo. Our data indicate that Wnt5a signaling is an important regulator in the proliferation of human glioma cells.", "corpus_id": 21333323, "score": 0 }, { "doc_id": "20626131", "title": "Relationship between the Expression of E-, N-cadherins and beta-catenin and Tumor Grade in Astrocytomas", "abstract": "Cadherins are cell-surface glycoproteins that mediate Ca2+-dependent, homophilic cell–cell adhesion. The classical cadherins, E- and N-cadherins, connect to beta-catenin, the lining protein. There appears to be a relationship between their dysfunction and tumor invasion and metastasis. The aim of our study was to examine the possibility of a relationship between alterations in the E- and N-cadherin and catenin expression and malignancy in astrocytomas. Forty-five astrocytomas (18 glioblastomas, 16 anaplastic astrocytomas, and 11 diffuse astrocytomas) were collected and stained immunohistochemically for cadherins and beta-catenin. None of the astrocytomas were immunoreactive for E-cadherin. N-cadherin and beta-catenin were present at cell–cell borders in 61% of glioblastomas and 31% of anaplastic astrocytomas. The incidence of immunoreactivity for N-cadherin and beta-catenin increased significantly with the histological grade of astrocytomas (p=0.001, by Kruskal–Wallis test). Moreover, in anaplastic astrocytomas and glioblastomas, the Ki-67 labeling indices in both N-cadherin-positive and beta-catenin-positive cases were higher than that in negative cases (p=0.05 and 0.03, respectively, by Fisher's exact test). These results suggest that the expression of N-cadherin or beta-catenin may be related to the biological behavior of astrocytomas.", "corpus_id": 20626131, "score": 0 }, { "doc_id": "38311104", "title": "Proteomic analysis of β‐catenin activation in mouse liver by DIGE analysis identifies glucose metabolism as a new target of the Wnt pathway", "abstract": "The Wnt/β‐catenin signaling pathway has been increasingly implicated in liver development and physiology. Aberrant activation of this pathway is one of the major genetic events observed during the process of human HCC development. To gain insight into the mechanism underlying β‐catenin action in the liver, we conducted a quantitative differential proteomic analysis using 2‐D DIGE combined with MS, in mice with liver‐specific deletion of Apc resulting in acute activation of β‐catenin signaling (ApcKOliv mice). We identified 94 protein spots showing differential expression between mutant ApcKOliv and control mice, corresponding to 56 individual proteins. Most of the proteins identified were associated with metabolic pathways, such as ammonia and glucose metabolism. Our analysis showed an increase in lactate dehydrogenase activity together with a downregulation of two mitochondrial ATPase subunits (ATP5a1 and ATP5b). These observations indicate that β‐catenin signaling may induce a shift in the glucose metabolism from oxidative phosphorylation to glycolysis, known as the “Warburg effect”. Imaging with 18F‐fluoro‐2‐deoxy‐D‐glucose‐positron emission tomography suggests that the specific metabolic reprogramming induced by β‐catenin in the liver does not imply the first step of glycolysis. This observation may explain why some HCCs are difficult to assess by fluoro‐2‐deoxy‐D‐glucose‐positron emission tomography imaging.", "corpus_id": 38311104, "score": 0 }, { "doc_id": "7200927", "title": "Rethinking the Warburg effect with Myc micromanaging glutamine metabolism.", "abstract": "The MYC oncogene, which is frequently deregulated in human cancers, encodes a master transcription factor c-Myc (herein termed Myc) that integrates cell proliferation with metabolism through its regulation of thousands of genes including microRNAs (miRNA). In addition to its known function in regulating the cell cycle and glucose metabolism, recent studies document a role for Myc in stimulating glutamine catabolism, in part through the repression of miRNAs miR-23a and miR-23b. These observations suggest an additional level of complexity in tumor metabolism, which includes the commensal metabolic relationship between hypoxic and nonhypoxic regions of tumors as well as the surrounding stroma. Thus, a reevaluation of cancer metabolism considering glutamine catabolism with a better understanding of the tumor histological complexity is needed before cancer metabolism can be effectively targeted in therapy.", "corpus_id": 7200927, "score": 0 }, { "doc_id": "14302639", "title": "Mitotic and mitogenic Wnt signalling", "abstract": "Canonical Wnt signalling plays an important role in development, tissue homeostasis, and cancer. At the cellular level, canonical Wnt signalling acts by regulating cell fate, cell growth, and cell proliferation. With regard to proliferation, there is increasing evidence for a complex interaction between canonical Wnt signalling and the cell cycle. Mitogenic Wnt signalling regulates cell proliferation by promoting G1 phase. In mitosis, components of the Wnt signalling cascade function directly in spindle formation. Moreover, Wnt signalling is strongly activated in mitosis, suggesting that ‘mitotic Wnt signalling’ plays an important role to orchestrate a cell division program. Here, we review the complex interplay between Wnt signalling and the cell cycle.", "corpus_id": 14302639, "score": 0 }, { "doc_id": "8168438", "title": "Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction", "abstract": "Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are used as building blocks during anabolic macromolecular synthesis. Investigations of phosphoinositol 3-kinase (PI3K) and its downstream effector AKT have confirmed that these oncogenes play a direct role in stimulating glucose uptake and metabolism, rendering the transformed cell addicted to glucose for the maintenance of survival. In contrast, less is known about the regulation of glutamine uptake and metabolism. Here, we report that the transcriptional regulatory properties of the oncogene Myc coordinate the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis. A consequence of this Myc-dependent glutaminolysis is the reprogramming of mitochondrial metabolism to depend on glutamine catabolism to sustain cellular viability and TCA cycle anapleurosis. The ability of Myc-expressing cells to engage in glutaminolysis does not depend on concomitant activation of PI3K or AKT. The stimulation of mitochondrial glutamine metabolism resulted in reduced glucose carbon entering the TCA cycle and a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids. These data suggest that oncogenic levels of Myc induce a transcriptional program that promotes glutaminolysis and triggers cellular addiction to glutamine as a bioenergetic substrate.", "corpus_id": 8168438, "score": 0 }, { "doc_id": "20655189", "title": "Deregulation of Glucose Transporter 1 and Glycolytic Gene Expression by c-Myc*", "abstract": "Unlike normal mammalian cells, which use oxygen to generate energy, cancer cells rely on glycolysis for energy and are therefore less dependent on oxygen. We previously observed that the c-Myc oncogenic transcription factor regulates lactate dehydrogenase A and induces lactate overproduction. We, therefore, sought to determine whether c-Myc controls other genes regulating glucose metabolism. In Rat1a fibroblasts and murine livers overexpressing c-Myc, the mRNA levels of the glucose transporter GLUT1, phosphoglucose isomerase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase were elevated. c-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.", "corpus_id": 20655189, "score": 0 }, { "doc_id": "24455208", "title": "Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms.", "abstract": "The mammalian pyruvate dehydrogenase complex (PDC) plays central and strategic roles in the control of the use of glucose-linked substrates as sources of oxidative energy or as precursors in the biosynthesis of fatty acids. The activity of this mitochondrial complex is regulated by the continuous operation of competing pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) reactions. The resulting interconversion cycle determines the fraction of active (nonphosphorylated) pyruvate dehydrogenase (E1) component. Tissue-specific and metabolic state-specific control is achieved by the selective expression and distinct regulatory properties of at least four PDK isozymes and two PDP isozymes. The PDK isoforms are members of a family of serine kinases that are not structurally related to cytoplasmic Ser/Thr/Tyr kinases. The catalytic subunits of the PDP isoforms are Mg2+-dependent members of the phosphatase 2C family that has binuclear metal-binding sites within the active site. The dihydrolipoyl acetyltransferase (E2) and the dihydrolipoyl dehydrogenase-binding protein (E3BP) are multidomain proteins that form the oligomeric core of the complex. One or more of their three lipoyl domains (two in E2) selectively bind each PDK and PDP1. These adaptive interactions predominantly influence the catalytic efficiencies and effector control of these regulatory enzymes. When fatty acids are the preferred source of acetyl-CoA and NADH, feedback inactivation of PDC is accomplished by the activity of certain kinase isoforms being stimulated upon preferentially binding a lipoyl domain containing a reductively acetylated lipoyl group. PDC activity is increased in Ca2+-sensitive tissues by elevating PDP1 activity via the Ca2+-dependent binding of PDP1 to a lipoyl domain of E2. During starvation, the irrecoverable loss of glucose carbons is restricted by minimizing PDC activity due to high kinase activity that results from the overexpression of specific kinase isoforms. Overexpression of the same PDK isoforms deleteriously hinders glucose consumption in unregulated diabetes.", "corpus_id": 24455208, "score": 0 }, { "doc_id": "20108952", "title": "Enzymes involved in l-lactate metabolism in humans.", "abstract": "l-lactate formation occurs via the reduction of pyruvate catalyzed by lactate dehydrogenase. l-lactate removal takes place via its oxidation into pyruvate, which may be oxidized or converted into glucose. Pyruvate oxidation involves the cooperative effort of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondrial respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. In addition, pyruvate may undergo reversible transamination to alanine by alanine aminotransferase. Enzymes involved in l-lactate metabolism are crucial to diabetes pathophysiology and therapy. Elevated plasma alanine aminotransferase concentration has been associated with insulin resistance. Polymorphisms in the G6PC2 gene have been associated with fasting glucose concentration and insulin secretion. In diabetes patients, pyruvate dehydrogenase is down-regulated and the activity of pyruvate carboxylase is diminished in the pancreatic islets. Inhibitors of fructose 1,6-bisphosphatase are being investigated as potential therapy for type 2 diabetes. In addition, enzymes implicated in l-lactate metabolism have revealed to be important in cancer cell homeostasis. Many human tumors have higher LDH5 levels than normal tissues. The LDHC gene is expressed in a broad range of tumors. The activation of PDH is a potential mediator in the body response that protects against cancer and PDH activation has been observed to reduce glioblastoma growth. The expression of PDK1 may serve as a biomarker of poor prognosis in gastric cancer. Mitochondrial DNA mutations have been detected in a number of human cancers. Genes encoding succinate dehydrogenase have tumor suppressor functions and consequently mutations in these genes may cause a variety of tumors.", "corpus_id": 20108952, "score": 0 }, { "doc_id": "23093679", "title": "Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells*", "abstract": "High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase α (PDHα) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1α (HIF-1α) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDHα phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1α expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.", "corpus_id": 23093679, "score": 0 }, { "doc_id": "36759050", "title": "Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer", "abstract": "Most solid tumors are characterized by a metabolic shift from glucose oxidation to glycolysis, in part due to actively suppressed mitochondrial function, a state that favors resistance to apoptosis. Suppressed mitochondrial function may also contribute to the activation of hypoxia-inducible factor 1α (HIF1α) and angiogenesis. We have previously shown that the inhibitor of pyruvate dehydrogenase kinase (PDK) dichloroacetate (DCA) activates glucose oxidation and induces apoptosis in cancer cells in vitro and in vivo. We hypothesized that DCA will also reverse the ‘pseudohypoxic’ mitochondrial signals that lead to HIF1α activation in cancer, even in the absence of hypoxia and inhibit cancer angiogenesis. We show that inhibition of PDKII inhibits HIF1α in cancer cells using several techniques, including HIF1α luciferase reporter assays. Using pharmacologic and molecular approaches that suppress the prolyl-hydroxylase (PHD)-mediated inhibition of HIF1α, we show that DCA inhibits HIF1α by both a PHD-dependent mechanism (that involves a DCA-induced increase in the production of mitochondria-derived α-ketoglutarate) and a PHD-independent mechanism, involving activation of p53 via mitochondrial-derived H2O2, as well as activation of GSK3β. Effective inhibition of HIF1α is shown by a decrease in the expression of several HIF1α regulated gene products as well as inhibition of angiogenesis in vitro in matrigel assays. More importantly, in rat xenotransplant models of non-small cell lung cancer and breast cancer, we show effective inhibition of angiogenesis and tumor perfusion in vivo, assessed by contrast-enhanced ultrasonography, nuclear imaging techniques and histology. This work suggests that mitochondria-targeting metabolic modulators that increase pyruvate dehydrogenase activity, in addition to the recently described pro-apoptotic and anti-proliferative effects, suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1α activation in solid tumors.", "corpus_id": 36759050, "score": 0 }, { "doc_id": "3133925", "title": "Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer", "abstract": "Much of the mechanism by which Wnt signaling drives proliferation during oncogenesis is attributed to its regulation of the cell cycle. Here, we show how Wnt/β‐catenin signaling directs another hallmark of tumorigenesis, namely Warburg metabolism. Using biochemical assays and fluorescence lifetime imaging microscopy (FLIM) to probe metabolism in vitro and in living tumors, we observe that interference with Wnt signaling in colon cancer cells reduces glycolytic metabolism and results in small, poorly perfused tumors. We identify pyruvate dehydrogenase kinase 1 (PDK1) as an important direct target within a larger gene program for metabolism. PDK1 inhibits pyruvate flux to mitochondrial respiration and a rescue of its expression in Wnt‐inhibited cancer cells rescues glycolysis as well as vessel growth in the tumor microenvironment. Thus, we identify an important mechanism by which Wnt‐driven Warburg metabolism directs the use of glucose for cancer cell proliferation and links it to vessel delivery of oxygen and nutrients.", "corpus_id": 3133925, "score": 0 }, { "doc_id": "12280721", "title": "Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis*", "abstract": "Cancer cells display high rates of aerobic glycolysis, a phenomenon known historically as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are highly produced by cancer cells even in the presence of oxygen. Hypoxia-induced gene expression in cancer cells has been linked to malignant transformation. Here we provide evidence that lactate and pyruvate regulate hypoxia-inducible gene expression independently of hypoxia by stimulating the accumulation of hypoxia-inducible Factor 1α (HIF-1α). In human gliomas and other cancer cell lines, the accumulation of HIF-1α protein under aerobic conditions requires the metabolism of glucose to pyruvate that prevents the aerobic degradation of HIF-1α protein, activates HIF-1 DNA binding activity, and enhances the expression of several HIF-1-activated genes including erythropoietin, vascular endothelial growth factor, glucose transporter 3, and aldolase A. Our findings support a novel role for pyruvate in metabolic signaling and suggest a mechanism by which high rates of aerobic glycolysis can promote the malignant transformation and survival of cancer cells.", "corpus_id": 12280721, "score": 0 }, { "doc_id": "22959752", "title": "Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues", "abstract": "Expression of monocarboxylate transporter MCT1 was studied in archival tissues from human CNS using antibodies to the carboxyl-terminal end of MCT1. Sections of neocortex, hippocampus and cerebellum of brains from 10 adult autopsy patients who died from other than CNS disease, and from archival surgical biopsy specimens of 83 primary CNS and eight non-CNS tumors were studied. MCT1 immunoreactivity was present in microvessels and, ependymocytes of normal CNS tissues similar to that reported for MCT1 expression in rat brains. MCT1 immunoreactivity was strongest in ependymomas, hemangioblastomas and high grade glial neoplasms, and weakest in low grade gliomas. Increased MCT1 expression in high grade glial neoplasms may provide a potential therapeutic target for treatment of some CNS neoplasms.", "corpus_id": 22959752, "score": 0 }, { "doc_id": "30958881", "title": "MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1.", "abstract": "The invasive behavior of glioblastoma multiforme (GBM) cells is one of the most important reasons for the poor prognosis of this cancer. For invasion, tumor cells must acquire an ability to digest the extracellular matrix and infiltrate the normal tissue bordering the tumor. Preventing this by altering effector molecules can significantly improve a patient's prognosis. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. The expression levels of miR-218 correlate with the invasive potential of GBM cells. In this study, we found that miR-218 expression was low in glioma tissues, especially in GBM. The data showed an inverse correlation in 60 GBM tissues between the levels of miR-218 and MMP mRNAs (MMP-2, -7 and -9). Additionally, ectopic expression of miR-218 suppressed the invasion of GBM cells whereas inhibition of miR-218 expression enhanced the invasive ability. Numerous members of the MMP family are downstream effectors of the Wnt/LEF1 pathway. Target prediction databases and luciferase data showed that LEF1 is a new direct target of miR-218. Importantly, western blot assays demonstrated that miR-218 can reduce protein levels of LEF1 and MMP-9. We, therefore, hypothesize that miR-218 directly targets LEF1, resulting in reduced synthesis of MMP-9. Results suggest that miR-218 is involved in the invasive behavior of GBM cells and by targeting LEF1 and blocking the invasive axis, miR-218-LEF1-MMPs, it may be useful for developing potential clinical strategies.", "corpus_id": 30958881, "score": 0 }, { "doc_id": "11087034", "title": "Mechanisms of glioma cell invasion.", "abstract": "Invasive growth is one of the characteristics of gliomas--local infiltration into the surrounding nerve tissue decisively restricts all treatment strategies. Particularly the merit of all local treatment modalities is queried. The question whether a glioma represents a diffuse disease of the CNS or a local disturbance with unrestrained expansion tendency is still at issue. Understanding of the invasion mechanisms is of importance inasmuch as biologically reasonable and effective strategies of limiting and suppressing glioma invasion can only hence be derived. The affinity of glioma cells towards certain structures of the extracellular matrix as well as taking advantage of tumour vascularisation with regard to extension play a decisive role. Still not fully understood are tumour host interactions. Future thinking will have to take into account these interactions as well as evidence to be derived from development neurobiology and regeneration capacity of the CNS. The present review is meant to give a short overview and disclose many questions.", "corpus_id": 11087034, "score": 0 }, { "doc_id": "23674090", "title": "Elevated levels of M(r) 92,000 type IV collagenase in human brain tumors.", "abstract": "Local invasive growth is one of the key features of primary malignant brain tumors accompanied by remodeling of the vasculature and destruction of normal brain tissue. Tissue invasiveness is an essential biological function used by a tumor to overcome the various barriers to its progression. The expression of metalloproteases has been shown to play a critical role in the invasive process in a number of tumors; however, their expression in human brain tumors has not been previously reported. In this study we showed metalloprotease activities at M(r) 240,000, 123,000, 92,000, 72,000, and 67,000 in brain tumor extracts. These enzyme activities were inhibited by EDTA, an inhibitor of metalloproteases. Significant increases in levels of protease bands at M(r) 92,000, 123,000, and 240,000 were observed in glioblastoma and metastatic lung tumors. Enzymatic inhibition and Western blotting with M(r) 92,000 type IV collagenase antibody confirmed the presence of M(r) 92,000 type IV collagenase in all samples. Quantitative analysis by densitometry showed 8-10-fold and 6-8-fold increases in M(r) 92,000 type IV collagenase activity in glioblastoma and metastatic lung carcinoma samples, respectively, when compared with normal brain, meningioma, astrocytoma, metastatic colon, and breast carcinoma samples. These findings provide evidence for elevated levels of metalloproteases in glioblastomas and suggest a therapeutic target for minimizing the invasive propensity of gliomas using protease inhibitors.", "corpus_id": 23674090, "score": 0 }, { "doc_id": "31527442", "title": "Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomas", "abstract": "Aberrant activation of wingless (Wnt) signaling is involved in the pathogenesis of various cancers. Recent studies suggested a role of Wnt signaling in gliomas, the most common primary brain tumors. We investigated 70 gliomas of different malignancy grades for promoter hypermethylation in 8 genes encoding members of the secreted frizzled‐related protein (SFRP1, SFRP2, SFRP4, SFRP5), dickkopf (DKK1, DKK3) and naked (NKD1, NKD2) families of Wnt pathway inhibitors. All tumors were additionally analyzed for mutations in exon 3 of the β‐catenin gene (CTNNB1). While none of the tumors carried CTNNB1 mutations, we found frequent promoter hypermethylation of Wnt pathway inhibitor genes, with at least one of these genes being hypermethylated in 6 of 16 diffuse astrocytomas (38%), 4 of 14 anaplastic astrocytomas (29%), 7 of 10 secondary glioblastomas (70%) and 23 of 30 primary glioblastomas (77%). Glioblastomas often demonstrated hypermethylation of 2 or more analyzed genes. Hypermethylation of SFRP1, SFRP2 and NKD2 each occurred in more than 40% of the primary glioblastomas, while DKK1 hypermethylation was found in 50% of secondary glioblastomas. Treatment of SFRP1‐, SFRP5‐, DKK1‐, DKK3‐, NKD1‐ and NKD2‐hypermethylated U87‐MG glioblastoma cells with 5‐aza‐2′‐deoxycytidine and trichostatin A resulted in increased expression of each gene. Furthermore, SFRP1‐hypermethylated gliomas showed significantly lower expression of the respective transcripts when compared with unmethylated tumors. Taken together, our results suggest an important role of epigenetic silencing of Wnt pathway inhibitor genes in astrocytic gliomas, in particular, in glioblastomas, with distinct patterns of hypermethylated genes distinguishing primary from secondary glioblastomas.", "corpus_id": 31527442, "score": 0 }, { "doc_id": "31335282", "title": "The oncogenic activation of beta-catenin.", "abstract": "The activation of beta-catenin to an oncogenic state can result from the inactivation of the tumor suppressor adenomatous polyposis coli (APC), by direct mutation in the beta-catenin gene, or by the activation of wnt receptors. Once activated, beta-catenin most likely promotes tumor progression through its persistent interaction with one or more of its numerous downstream targets.", "corpus_id": 31335282, "score": 0 }, { "doc_id": "10721630", "title": "Promoter methylation of WNT inhibitory factor-1 and expression pattern of WNT/β-catenin pathway in human astrocytoma: pathologic and prognostic correlations", "abstract": "WNT inhibitory factor-1 (WIF1) is an antagonist of the WNT signaling pathway. We investigated the relationship between WIF1 promoter methylation and regulation of the WNT/β-catenin signaling pathway, tumor grade, and survival in patients with astrocytoma. This study included 86 cases of astrocytoma, comprising 20 diffuse astrocytomas and 66 glioblastomas. In addition, 17 temporal lobectomy specimens from patients with epilepsy were included as controls. The ratio of methylated DNA to total methylated and unmethylated DNA (% methylation) was measured by methylation- and unmethylation-specific PCR. Representative tumor tissue was immunostained for WIF1, β-catenin, cyclin D1, c-myc, and isocitrate dehydrogenase 1. Levels of WIF1 promoter methylation, mRNA expression, and protein expression in a glioblastoma cell line were compared before and after demethylation treatment. The mean percent methylation of the WIF1 promoter in astrocytomas was higher than that in control brain tissue. WIF1 protein expression was lower in the tumor group with >5% methylation than in the group with <5% methylation. Cytoplasmic β-catenin staining was more frequently observed in tumors with a low WIF1 protein expression level. Demethylation treatment of a glioblastoma cell line increased WIF1 mRNA and protein expression. Increased WIF1 promoter methylation and decreased WIF1 protein expression were not related to patient survival. In conclusion, WIF1 expression is downregulated by promoter methylation and is an important mechanism of aberrant WNT/β-catenin pathway activation in astrocytoma pathogenesis.", "corpus_id": 10721630, "score": 0 }, { "doc_id": "27937045", "title": "PPAR delta: a dagger in the heart of the metabolic syndrome.", "abstract": "Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis.", "corpus_id": 27937045, "score": 0 }, { "doc_id": "25843121", "title": "Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding.", "abstract": "PPARs are members of the nuclear hormone receptor superfamily and are primarily involved in lipid metabolism. The expression patterns of all 3 PPAR isotypes in 22 adult rat organs were analyzed by a quantitative ribonuclease protection assay. The data obtained allowed comparison of the expression of each isotype to the others and provided new insight into the less studied PPAR beta (NR1C2) expression and function. This isotype shows a ubiquitous expression pattern and is the most abundant of the three PPARs in all analyzed tissues except adipose tissue. Its expression is especially high in the digestive tract, in addition to kidney, heart, diaphragm, and esophagus. After an overnight fast, PPAR beta mRNA levels are dramatically down-regulated in liver and kidney by up to 80% and are rapidly restored to control levels upon refeeding. This tight nutritional regulation is independent of the circulating glucocorticoid levels and the presence of PPAR alpha, whose activity is markedly up-regulated in the liver and small intestine during fasting. Finally, PPAR gamma 2 mRNA levels are decreased by 50% during fasting in both white and brown adipose tissue. In conclusion, fasting can strongly influence PPAR expression, but in only a few selected tissues.", "corpus_id": 25843121, "score": 0 }, { "doc_id": "40485523", "title": "Neuronal differentiation of embryonic midbrain cells by upregulation of peroxisome proliferator-activated receptor-gamma via the JNK-dependent pathway.", "abstract": "Our previous study showed that the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist 15-deoxy-PGJ(2) has the promoting ability to differentiate neuronal PC12 cells. To expand our study, the effect of 15-deoxy-PGJ(2) on the differentiation of embryonic midbrain cells into dopaminergic neuronal cells was investigated in this study. The relationship between cell differentiation with activation of PPAR-gamma and the possible signal pathway were also investigated. 15-Deoxy-PGJ(2) increased neurite extension, a typical characteristic of the differentiation of embryonic midbrain cells isolated from 12-day rat embryos in a dose-dependent manner. The expression of differentiation markers, neurofilament, tyrosine hydroxylase, and nestin, was also increased by the treatment of 15-deoxy-PGJ(2). Consistent with the increasing effect on cell differentiation, 15-deoxy-PGJ(2) increased the expression and transcriptional activity of PPAR-gamma in cultured embryonic midbrain cells. In addition, the expression of PPAR-gamma and NeuN in the differentiated neuron of fetus (17 days) and adult rat brain was co-localized. Furthermore, treatment of PPAR-gamma antagonist bisphenol A diglycidyl ether blocked 15-deoxy-PGJ(2)-induced neuronal differentiation of embryonic midbrain cells and expression of PPAR-gamma. To elucidate the possible signal pathway, the activation of mitogenic-activated protein (MAP) kinase family was determined. 15-Deoxy-PGJ(2) (0.5 microM) increased activation of Jun N-terminal kinase (JNK) and p38 kinase but not extra-signal response kinase (ERK). In addition, NGF (50 ng/ml) further increased the 15-deoxy-PGJ(2)-induced JNK activation. Moreover, pretreatment of specific inhibitor of JNK SP600125 blocked the 15-deoxy-PGJ(2)-induced JNK activation. This inhibition correlated well with the inhibition of neurite extension and expression of PPAR-gamma induced by 15-deoxy-PGJ(2). The present results therefore indicate that 15-deoxy-PGJ(2) stimulates differentiation of embryonic midbrain cells into dopaminergic neuronal cells, and its effect may be PPAR-gamma and JNK signal pathway dependent.", "corpus_id": 40485523, "score": 0 }, { "doc_id": "37172824", "title": "Terminal differentiation of human breast cancer through PPAR gamma.", "abstract": "We have previously demonstrated that PPAR gamma stimulates the terminal differentiation of adipocyte precursors when activated by synthetic ligands, such as the antidiabetic thiazolidinedione (TZD) drugs. We show here that PPAR gamma is expressed at significant levels in human primary and metastatic breast adenocarcinomas. Ligand activation of this receptor in cultured breast cancer cells causes extensive lipid accumulation, changes in breast epithelial gene expression associated with a more differentiated, less malignant state, and a reduction in growth rate and clonogenic capacity of the cells. Inhibition of MAP kinase, shown previously to be a powerful negative regulator of PPAR gamma, improves the TZD ligand sensitivity of nonresponsive cells. These data suggest that the PPAR gamma transcriptional pathway can induce terminal differentiation of malignant breast epithelial cells and thus may provide a novel, nontoxic therapy for human breast cancer.", "corpus_id": 37172824, "score": 0 }, { "doc_id": "10712853", "title": "Loss-of-function mutations in PPAR gamma associated with human colon cancer.", "abstract": "The gamma isoform of the peroxisome proliferator-activated receptor, PPAR gamma, regulates adipocyte differentiation and has recently been shown to be expressed in neoplasia of the colon and other tissues. We have found four somatic PPAR gamma mutations among 55 sporadic colon cancers: one nonsense, one frameshift, and two missense mutations. Each greatly impaired the function of the protein. c.472delA results in deletion of the entire ligand binding domain. Q286P and K319X retain a total or partial ligand binding domain but lose the ability to activate transcription through a failure to bind to ligands. R288H showed a normal response to synthetic ligands but greatly decreased transcription and binding when exposed to natural ligands. These data indicate that colon cancer in humans is associated with loss-of-function mutations in PPAR gamma.", "corpus_id": 10712853, "score": 0 }, { "doc_id": "22466491", "title": "Peroxisome Proliferator-Activated Receptor Agonists and Bladder Cancer: Lessons from Animal Studies", "abstract": "This article reviews available animal studies on the possible link between the use of peroxisome proliferator-activated receptor (PPAR) agonists and bladder cancer, with further discussion on the possible implications to humans. Carcinogenicity studies suggest that the PPARγ agonist pioglitazone and dual PPARα/γ agonists such as ragaglitazar, muraglitazar, and naveglitazar may increase the risk of bladder cancer in a dose-responsive pattern in rats. It is interesting that bladder cancer related to PPAR agonists shows remarkable species- and sex-specificity and has a predilection to occur in the ventral dome of bladder in rodents. While male rats treated with pioglitazone or muraglitazar have a higher propensity to develop bladder cancer than female rats, mice of both sexes do not develop bladder cancer even when exposed to very high doses. Direct genotoxicity or cytotoxicity of PPAR agonists is unlikely to be the mode of action because most of the parent compounds or their metabolites of the PPAR agonists are neither mutagenic nor genotoxic, and they are rarely excreted in the urine; but a receptor-mediated PPAR effect cannot be excluded. Some suggest a “urolithiasis hypothesis” referring to the formation of urinary solids and calculi, which subsequently causes bladder necrosis, regenerative proliferation, hypertrophy, and cancer. However, whether these animal findings could have human relevance is not yet fully understood. Some argue that the urolithiasis-induced bladder cancer might be rat-specific and would probably not be applicable to humans. An effect of increased urinary growth factors induced by PPAR agonists has also been proposed, but this requires more investigations. Before fully clarified, a balance between the risks and benefits of the use of pioglitazone, an approved oral antidiabetic agent that has recently been linked to an increased but not yet confirmed risk of bladder cancer in humans, should be justified for individual use.", "corpus_id": 22466491, "score": 0 }, { "doc_id": "20205987", "title": "Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-gamma agonists through induction of apoptosis.", "abstract": "Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptors superfamily, have an important regulatory role in adipogenesis and inflammation. PPAR-gamma ligands induce terminal differentiation and growth inhibition of human breast cancer cells and prostatic cancer cells. In this study, we demonstrated that PPAR-gamma, but not PPAR-alpha, was expressed in human lung cancer cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. We also found that the synthetic PPAR-gamma agonist thiazolidinedione compounds (troglitazone) and the endogenous PPAR-gamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), inhibited the growth of human lung cancer cells through the induction of apoptosis. However, PPAR-alpha agonist (bezafibrate) and other prostanoids (PGE(2), PGF(2alpha)) did not induce apoptosis. These findings suggest that PPAR-gamma may play an important role in the pathogenesis of lung cancer and that PPAR-gamma agonist may be useful therapeutic agents in the treatment of human lung cancer.", "corpus_id": 20205987, "score": 0 }, { "doc_id": "45779977", "title": "A novel PPAR alpha/gamma dual agonist inhibits cell growth and induces apoptosis in human glioblastoma T98G cells.", "abstract": "AIM\nTo examine the effect of a novel peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist TZD18 on cell proliferation and apoptosis in human glioblastoma T98G cells and its possible mechanism.\n\n\nMETHODS\nRT-PCR, MTT, TUNEL, Flow cytometry, and Western blot analysis were employed.\n\n\nRESULTS\nTZD18 inhibited the growth of T98G cells in a concentration-dependent manner, which was associated with a G1 to S cell cycle arrest. Besides, significant apoptosis was induced after treatment with a non-toxic dose of TZD18. During the process, the expression of Bcl-2 protein was down-regulated, while that of Bax and p27kip proteins was up-regulated, and the activity of caspase-3 was elevated. However, this effect appeared to be PPARalpha and PPARgamma independent since their antagonists could not reverse this effect.\n\n\nCONCLUSIONS\nTZD18, a novel PPARalpha/gamma dual agonist, inhibited cell growth and induce apoptosis in human glioblastoma T98G cells in vitro, indicating a therapeutic potential for TZD18 in the treatment of glioblastoma.", "corpus_id": 45779977, "score": 0 }, { "doc_id": "8380120", "title": "Ligands for PPARγ and RAR Cause Induction of Growth Inhibition and Apoptosis in Human Glioblastomas", "abstract": "High-grade gliomas are characterized by a rapid proliferation rate, invasiveness and angiogenesis. Our previous data indicated that the combination of ligands for peroxisome proliferator-activated receptor γ (PPARγ) and retinoic acid receptor (RAR) induces apoptosis of breast cancer cells in vitro and in a murine model. In this study, we have shown that 11 glioblastoma cell lines and nine fresh glioblastoma tissue samples from patients expressed high-levels of PPARγ. In contrast, glia from nine healthy human brains expressed very low levels of PPARγ. No mutations or polymorphisms of the PPARγ gene were observed in these cell lines. The effect of the PPARγ ligand Pioglitazone (PGZ) either in the absence or in the presence of a RAR ligand [all-trans retinoic acid (ATRA)] on the proliferation and apoptosis of glioblastoma cells was examined using two glioblastoma cell lines (N39 and DBTRG05MG). PGZ and/or ATRA inhibited significantly the proliferation of both cell lines. Flow cytometry analysis showed that G1 cell cycle arrest was induced by these ligands. In addition, apoptosis occurred in both cell lines treated with either PGZ or ATRA, which was associated with a downregulation of bcl-2 and an upregulation of bax proteins. An enhanced effect was observed when PGZ and ATRA were combined. Furthermore, treatment of fresh glioblastoma tissue from patients with PGZ, either alone or in combination with ATRA, induced a significant level of tumor cell apoptosis together with a downregulation of bcl-2 protein level as compared with untreated control brain tissue. Taken together, our data demonstrated that PGZ, either alone or in combination with ATRA, induced apoptosis and inhibited proliferation of glioblastoma cells, and more interestingly, induced apoptosis of fresh glioblastoma cells from patients. Therefore, we conclude that these ligands may possess adjuvant therapeutic potential for patients with glioblastoma.", "corpus_id": 8380120, "score": 0 }, { "doc_id": "28241081", "title": "Peroxisome proliferator-activated receptor γ agonist pioglitazone inhibits β-catenin-mediated glioma cell growth and invasion", "abstract": "Gliomas are the most common primary tumors of the central nervous system. Rapid proliferation and diffuse brain invasion of these tumors are likely to determine the unfavorable prognosis. Recent studies have shown that ligand activation of peroxisome proliferator-activated receptor γ (PPARγ) can induce differentiation and inhibit proliferation of several cancer cells. In this study, we identified pioglitazone, one PPARγ ligand in particular, suppressed human glioma cells proliferation, migration, and induced glioma cells apoptosis. Concomitantly, expression level of β-catenin protein, a key molecule in carcinogenesis, was decreased in glioma cells treated with pioglitazone. Noteworthy, knockdown of β-catenin expression using siRNA technology mimicked the anti-neoplastic potency of pioglitazone. These results indicate that β-catenin is one of the mediators for pioglitazone to suppress glioma cells growth and invasion. Due to its capacity to counteract β-catenin and glioma cell proliferation and migration, pioglitazone represents a promising drug for adjuvant therapy of glioma and other highly migratory tumor entities.", "corpus_id": 28241081, "score": 1 }, { "doc_id": "384819", "title": "Inhibition of in Vivo Glioma Growth and Invasion by Peroxisome Proliferator-Activated Receptor γ Agonist Treatment", "abstract": "The peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear hormone receptor family, represents a possible new target in glioma therapy. Because PPARγ plays a crucial role in regulation of insulin sensitivity, synthetic agonists are already in clinical use for type II diabetes treatment. Beyond these metabolic effects, PPARγ agonists exhibit antineoplastic effects. In this study, we investigated the antineoplastic effects of the PPARγ agonist pioglitazone in glioma cells. Pioglitazone reduced cellular viability of rat, human, and PPARγ-overexpressing glioma cells in vitro in a time- and concentration-dependent manner. No antineoplastic effects were induced by pioglitazone in glioma cells overexpressing a PPARγ mutant. Furthermore, proliferation was reduced by pioglitazone, as measured by Ki-67 immunoreactivity, in vitro. Continuous intracerebral infusion of pioglitazone into gliomas induced by intrastriatal injection of C6 cells reduced tumor volumes by 83%. Oral administration of pioglitazone reduced tumor volumes by 76.9%. Subsequent brain tissue analysis revealed induction of apoptotic cell death. Ki-67 expression and BrdU incorporation revealed a reduction of proliferation in vivo. Reduced invasion of C6 cells and lower matrix metalloproteinase 9 levels in vivo indicate pioglitazone-mediated reduction of invasion. Together, these data indicate that pioglitazone may be of potential use in treatment of malignant gliomas.", "corpus_id": 384819, "score": 0 }, { "doc_id": "24734604", "title": "PPARγ and RXRγ ligands act synergistically as potent antineoplastic agents in vitro and in vivo glioma models", "abstract": "Glioblastoma represent the most common primary brain tumor in adults and are currently considered incurable. We investigated antiproliferative and anti‐invasive mechanisms of 6‐OH‐11‐O‐hydroxyfenantrene (IIF), a retinoid X receptor ligand, and pioglitazone (PGZ), a peroxisome proliferator‐activated receptor γ activator, in three different glioblastoma cell lines. A dose‐dependent reduction of tumor invasion and strong decrease of matrix metalloproteinases 2 and 9 expression was observed, especially when a combination therapy of IIF and PGZ was administered. Combined treatment also markedly reduced proliferation and induced apoptosis in all glioma cell lines tested. This was in particular accompanied by decrease of antiapoptotic proteins Bcl2 and p53, while simultaneously pro‐apoptotic cytochrome c, cleaved caspase 3, Bax and Bad levels increased. These in vitro findings were further substantiated in a murine glioma model in vivo, where oral administration of PGZ and IIF resulted in significantly reduced tumor volume and proliferation. Of note, treatment with nuclear receptor ligands was not only effective when the treatment was initiated shortly after the intraparenchymal seeding of the glioma cells, but even when initiated in the last third of the observation period. Collectively, our results demonstrate the effectiveness of a combined treatment of ligands of proliferator‐activated receptor and retinoid X receptor against glioblastoma.", "corpus_id": 24734604, "score": 0 }, { "doc_id": "16492284", "title": "Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma?", "abstract": "Glioblastoma multiforme (GBM) represents one of the most frequent malignant brain tumors. Current therapies do not provide real solutions to this pathology. Their failure can be ascribed to a cell subpopulation with stem-like properties called glioma stem cells (GSCs). Therefore, new therapeutic strategies GSC-targeted are needed. PPARγ, a nuclear receptor involved in lipid metabolism, has already been indicated as a promising target for antineoplastic therapies. Recent studies have reported that synthetic PPARγ agonists, already in clinical use for the treatment of type II diabetes, exhibit antineoplastic effects in a wide range of malignant tumor cells, including glioma cells. We investigated the effect of the synthetic PPARγ agonist Pioglitazone on viability, proliferation, morphology, and differentiation in six GSC lines isolated from GBM patients. We also analyzed Pioglitazone-induced changes in transcriptional levels of Wnt/β catenin related genes. Results showed that response to Pioglitazone was heterogeneous inducing an evident decrease of cell viability and proliferation only in a subset of GSC lines. We did not find any sign of cell differentiation neither observing cell morphology nor analyzing the expression of stemness and differentiation markers. Moreover, Wnt/β signaling pathway was only mildly affected from a transcriptional point of view after Pioglitazone exposure.", "corpus_id": 16492284, "score": 0 }, { "doc_id": "7555466", "title": "β-Catenin overexpression in malignant glioma and its role in proliferation and apoptosis in glioblastma cells", "abstract": "Abstractβ-Catenin, a core component of Wnt/β-catenin signaling, has been shown to be a crucial factor in a broad range of tumors, while its role in glioma is not well understood. In this study, the expression of β-catenin in astrocytic glioma tissues with different grade and human normal cerebral tissues was examined using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. We found a higher expression level of β-catenin in astrocytic glioma patients with high grade in comparison with the normal controls. Additionally, siRNA was transfected into human U251 glioblastoma cells by liposome after the design of siRNA was confirmed to effectively inhibit the expression of β-catenin by RT-PCR. Compared to the control siRNA group, siRNA-mediated knockdown of β-catenin in human U251 cells inhibited cell proliferation, resulted in cell apoptosis, and arrested cell cycle in G0/G1. Additionally, downregulation of β-catenin decreased the expression level of cyclin D1, c-Myc and c-jun. Taken together, these results indicate that overexpression of β-catenin may be an important contributing factor to glioma progression.", "corpus_id": 7555466, "score": 0 }, { "doc_id": "215214010", "title": "Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy", "abstract": "Prognosis for patients suffering from malignant glioma has not substantially improved. Specific immunotherapy as a novel treatment concept critically depends on target antigens, which are highly overexpressed in the majority of gliomas, but the number of such antigens is still very limited. SOX2 was identified by screening an expression database for transcripts that are overexpressed in malignant glioma, but display minimal expression in normal tissues. Expression of SOX2 mRNA was further investigated in tumour and normal tissues by real-time PCR. Compared to cDNA from pooled normal brain, SOX2 was overexpressed in almost all (9 out of 10) malignant glioma samples, whereas expression in other, non-malignant tissues was almost negligible. SOX2 protein expression in glioma cell lines and tumour tissues was verified by Western blot and immunofluorescence. Immunohistochemistry demonstrated SOX2 protein expression in all malignant glioma tissues investigated ranging from 6 to 66% stained tumour cells. Human leucocyte antigen-A*0201-restricted SOX2-derived peptides were tested for the activation of glioma-reactive CD8 þ cytotoxic T lymphocytes (CTLs). Specific CTLs were raised against the peptide TLMKKDKYTL and were capable of lysing glioma cells. The abundant and glioma-restricted overexpression of SOX2 and the generation of SOX2-specific and tumour-reactive CTLs may recommend this antigen as target for T-cell-based immunotherapy of glioma. Malignant glioma represents the most common type of primary brain tumours in the United States (Hofman et al, 2006). Despite aggressive treatment with surgical resection followed by radio-therapy and chemotherapy, these tumours ultimately recur (Butowski et al, 2006). The median survival of patients suffering from glioblastoma multiforme (GBM), the highest-grade malignant astrocytoma, has not improved significantly over the past decades, remaining at about 12 months (Legler et al, 1999). The infiltrative nature of the tumour, the impracticality of optimal resection and the comparative intolerance of the normal brain for cytotoxic therapies together lead to a 5-year survival rate that is below 2% (Surawicz et al, 1998). This extraordinary high morbidity has triggered a desperate search for novel and more specific therapeutic approaches. The use of either antibody-based or T-cell-mediated immu-notherapy to selectively kill remnant glioma cells that could not be completely removed by surgery because of the infiltration of the tumour into the surrounding brain tissue has received increasing attention. Several animal models suggested that GBM may be amenable to immune therapeutic approaches (Sampson et al, 1996; Okada et al, 1998) and the identification of humoral as well as cellular immune responses in brain tumour patients …", "corpus_id": 215214010, "score": 0 }, { "doc_id": "42231118", "title": "Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma.", "abstract": "Malignant astrocytomas are among the most common brain tumours and few therapeutic options exist. It has recently been recognized that the ligand-activated nuclear receptor PPARgamma can regulate cellular proliferation and induce apoptosis in different malignant cells. We report the effect of three structurally different PPARgamma agonists inducing apoptosis in human (U87MG and A172) and rat (C6) glioma cells. The PPARgamma agonists ciglitazone, LY171 833 and prostaglandin-J2, but not the PPARalpha agonist WY14643, inhibited proliferation and induced cell death. PPARgamma agonist-induced cell death was characterized by DNA fragmentation and nuclear condensation, as well as inhibited by the synthetic receptor-antagonist bisphenol A diglycidyl ether (BADGE). In contrast, primary murine astrocytes were not affected by PPARgamma agonist treatment. The apoptotic death in the glioma cell lines treated with PPARgamma agonists was correlated with the transient up-regulation of Bax and Bad protein levels. Furthermore, inhibition of Bax expression by specific antisense oligonucleotides protected glioma cells against PPARgamma-mediated apoptosis, indicating an essential role of Bax in PPARgamma-induced apoptosis. However, PPARgamma agonists not only induced apoptosis but also caused redifferentiation as indicated by outgrowth of long processes and expression of the redifferentiation marker N-cadherin in response to PPARgamma agonists. Taken together, treatment of glioma cells with PPARgamma agonists may hold therapeutic potential for the treatment of gliomas.", "corpus_id": 42231118, "score": 0 }, { "doc_id": "8546416", "title": "PPARγ Agonists Promote Oligodendrocyte Differentiation of Neural Stem Cells by Modulating Stemness and Differentiation Genes", "abstract": "Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPARγ agonist ciglitazone or 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3–7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal β-III tubulin and astrocyte-specific GFAP in NSCs in 3–7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases.", "corpus_id": 8546416, "score": 0 }, { "doc_id": "14108864", "title": "PPARγ agonists regulate the expression of stemness and differentiation genes in brain tumour stem cells", "abstract": "Background:Brain tumour stem cells (BTSCs) are a small population of cancer cells that exhibit self-renewal, multi-drug resistance, and recurrence properties. We have shown earlier that peroxisome proliferator-activated receptor gamma (PPARγ) agonists inhibit the expansion of BTSCs in T98G and U87MG glioma. In this study, we analysed the influence of PPARγ agonists on the expression of stemness and differentiation genes in BTSCs.Methods:The BTSCs were isolated from T98G and DB29 glioma cells, and cultured in neurobasal medium with epidermal growth factor+basic fibroblast growth factor. Proliferation was measured by WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2 H-5-tetrazolio]-1,3-benzene disulphonate) and 3H thymidine uptake assays, and gene expression was analysed by quantitative reverse--transcription PCR and Taqman array. The expression of CD133, SRY box 2, and nanog homeobox (Nanog) was also evaluated by western blotting, immunostaining, and flow cytometry.Results:We found that PPARγ agonists, ciglitazone and 15-deoxy-Δ12,14-ProstaglandinJ2, inhibited cell viability and proliferation of T98G- and DB29-BTSCs. The PPARγ agonists reduced the expansion of CD133+ BTSCs and altered the expression of stemness and differentiation genes. They also inhibited Sox2 while enhancing Nanog expression in BTSCs.Conclusion:These findings highlight that PPARγ agonists inhibit BTSC proliferation in association with altered expression of Sox2, Nanog, and other stemness genes. Therefore, targeting stemness genes in BTSCs could be a novel strategy in the treatment of glioblastoma.", "corpus_id": 14108864, "score": 0 }, { "doc_id": "16461463", "title": "Differential activation of catalase expression and activity by PPAR agonists: Implications for astrocyte protection in anti-glioma therapy☆", "abstract": "Glioma survival is dismal, in part, due to an imbalance in antioxidant expression and activity. Peroxisome proliferator-activated receptor (PPAR) agonists have antineoplastic properties which present new redox-dependent targets for glioma anticancer therapies. Herein, we demonstrate that treatment of primary cultures of normal rat astrocytes with PPAR agonists increased the expression of catalase mRNA protein, and enzymatic activity. In contrast, these same agonists had no effect on catalase expression and activity in malignant rat glioma cells. The increase in steady-state catalase mRNA observed in normal rat astrocytes was due, in part, to de novo mRNA synthesis as opposed to increased catalase mRNA stability. Moreover, pioglitazone-mediated induction of catalase activity in normal rat astrocytes was completely blocked by transfection with a PPARγ-dominant negative plasmid. These data suggest that defects in PPAR-mediated signaling and gene expression may represent a block to normal catalase expression and induction in malignant glioma. The ability of PPAR agonists to differentially increase catalase expression and activity in normal astrocytes but not glioma cells suggests that these compounds might represent novel adjuvant therapeutic agents for the treatment of gliomas.", "corpus_id": 16461463, "score": 0 }, { "doc_id": "14326218", "title": "LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways", "abstract": "Lysophosphatidic acid (LPA) plays a critical role in the proliferation and migration of colon cancer cells; however, the downstream signaling events underlying these processes remain poorly characterized. The aim of this study was to investigate the signaling pathways triggered by LPA to regulate the mechanisms involved in the progression of colorectal cancer (CRC). We have used three cell line models of CRC, and initially analyzed the expression profile of LPA receptors (LPAR). Then, we treated the cells with LPA and events related to their tumorigenic potential, such as migration, invasion, anchorage-independent growth, proliferation as well as apoptosis and cell cycle were evaluated. We used the Chip array technique to analyze the global gene expression profiling that occurs after LPA treatment, and we identified cell signaling pathways related to the cell cycle. The inhibition of these pathways verified the conclusions of the transcriptomic analysis. We found that the cell lines expressed LPAR1, -2 and -3 in a differential manner and that 10 μM LPA did not affect cell migration, invasion and anchorage-independent growth, but it did induce proliferation and cell cycle progression in HCT-116 cells. Although LPA in this concentration did not induce transcriptional activity of β-catenin, it promoted the activation of Rho and STAT-3. Moreover, ROCK and STAT-3 inhibitors prevented LPA-induced proliferation, but ROCK inhibition did not prevent STAT-3 activation. Finally, we observed that LPA regulates the expression of genes related to the cell cycle and that the combined inhibition of ROCK and STAT-3 prevented cell cycle progression and increased the LPA-induced expression of cyclins E1, A2 and B1 to a greater degree than either inhibitor alone. Overall, these results demonstrate that LPA increases the proliferative potential of colon adenocarcinoma HCT-116 cells through a mechanism involving cooperation between the Rho-ROCK and STAT3 pathways involved in cell cycle control.", "corpus_id": 14326218, "score": 0 }, { "doc_id": "34587801", "title": "STAT3 inhibition by WP1066 suppresses the growth and invasiveness of bladder cancer cells.", "abstract": "Signal transducer and activator of transcription 3 (STAT3) regulates the expression of genes mediating cell survival, proliferation and angiogenesis and is aberrantly activated in various types of malignancies, including bladder cancer. We examined whether it could be a novel therapeutic target for bladder cancer using the STAT3 inhibitor WP1066. In T24 and UMUC-3 bladder cancer cells, 5 µM WP1066 prevented the phosphorylation of STAT3 and 2.5 µM WP1066 decreased cell survival and proliferation significantly (P<0.01). WP1066 also induced apoptosis accompanied by the suppression of the expression of Bcl-2 and Bcl-xL in T24 cells. Moreover, the covered area in a wound and the number of cells invading through a Matrigel chamber decreased significantly (P<0.01) when cells were treated with WP1066. The activities of MMP-2 and MMP-9 were also decreased by treatment with 10 µM WP1066. Our results revealed that using WP1066 to inhibit the STAT3 signaling pathway suppressed the viability and invasiveness of bladder cancer cells effectively and could be a novel therapeutic strategy against bladder cancer.", "corpus_id": 34587801, "score": 0 }, { "doc_id": "7379450", "title": "STAT3 Oligonucleotide Inhibits Tumor Angiogenesis in Preclinical Models of Squamous Cell Carcinoma", "abstract": "Purpose Signal transducer and activator of transcription 3 (STAT3) has shown to play a critical role in head and neck squamous cell carcinoma (HNSCC) and we have recently completed clinical trials of STAT3 decoy oligonucleotide in patients with recurrent or metastatic HNSCC. However, there is limited understanding of the role of STAT3 in modulating other aspects of tumorigenesis such as angiogenesis. In this study, we aimed to examine the effects of STAT3 decoy oligonucleotide on tumor angiogenesis. Experimental Design A STAT3 decoy oligonucleotide and small interfering RNA (siRNA) were used to inhibit STAT3 in endothelial cells in vitro and in vivo. The biochemical effects of STAT3 inhibition were examined in conjunction with the consequences on proliferation, migration, apoptotic staining, and tubule formation. Additionally, we assessed the effects of STAT3 inhibition on tumor angiogenesis using murine xenograft models. Results STAT3 decoy oligonucleotide decreased proliferation, induces apoptosis, decreased migration, and decreased tubule formation of endothelial cells in vitro. The STAT3 decoy oligonucleotide also inhibited tumor angiogenesis in murine tumor xenografts. Lastly, our data suggest that the antiangiogenic effects of STAT3 decoy oligonucleotide were mediatedthrough the inhibition of both STAT3 and STAT1. Conclusions The STAT3 decoy oligonucleotidewas found to be an effective antiangiogenic agent, which is likely to contribute to the overall antitumor effects of this agent in solid tumors.Taken together with the previously demonstrated antitumor activity of this agent, STAT3 decoy oligonucleotide represents a promising single agent approach to targeting both the tumor and vascular compartments in various malignancies.", "corpus_id": 7379450, "score": 0 }, { "doc_id": "45228451", "title": "STAT3 is essential for the maintenance of neurosphere‐initiating tumor cells in patients with glioblastomas: A potential for targeted therapy?", "abstract": "Glioblastoma (GBM), the highest‐grade form of gliomas, is the most frequent and the most aggressive. Recently, a subpopulation of cells with stem cells characteristics, commonly named “tumor‐initiating stem cells” (TISCs) or “cancer stem cells” (CSCs) were identified in GBM. These cells were shown to be highly resistant to chemotherapeutic drugs and to ionizing radiations. Consequently, the knowledge of the signals that regulate the functions and survival of TISCs is crucial. In our work, we describe a neurosphere‐initiating cell (NS‐IC) assay to quantify TISC/CSCs from patients with GBM and show that these cells are tumorigenic in vivo. We demonstrate that the intracellular signal transducer and activator of transcription STAT3 is constitutively activated by phosphorylation preferentially on serine 727 in these cells. Moreover, we demonstrate that the selective inhibition of STAT3 by the chemical compound Stattic or by siRNA STAT3 abrogates TISC/CSC proliferation and NS‐IC suggesting that self‐renewal of GBM “stem‐like” cells depends on the presence of STAT3 for their maintenance. Finally, we show that inhibition of STAT3 by Stattic sensitizes TISC/CSCs to the inhibitory action of Temozolomide with a strong synergistic effect of both drugs. Overall, these results suggest that strategies focused on STAT3 inhibition are efficient at the level of “stem‐like” cells and could be of interest for therapeutic purposes in patients with malignant GBM.", "corpus_id": 45228451, "score": 0 }, { "doc_id": "8685570", "title": "STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications", "abstract": "Signal transducer and activator of transcription 3 (STAT3) is a potent regulator of gliomagenesis through its induction of angiogenesis, host immunosuppression, and tumor invasion. Gain of function mutations result in constitutive activation of STAT3 in glioma cells, making STAT3 an attractive target for inhibition in cancer therapy. Nevertheless, some studies show that STAT3 also participates in terminal differentiation and apoptosis of various cell lines and in glioma with phosphatase and tensin homolog (PTEN)-deficient genetic backgrounds. In light of these findings, the utility of STAT3 as a prognostic indicator and as a target of drug therapies will be contingent on a more nuanced understanding of its pro- and anti-tumorigenic effects.", "corpus_id": 8685570, "score": 0 }, { "doc_id": "40477299", "title": "The Jak/STAT pathway.", "abstract": "The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway mediates cellular responses to cytokines (e.g., IL-6) and growth factors (e.g., EGF).", "corpus_id": 40477299, "score": 0 }, { "doc_id": "16552365", "title": "Transcription Factor STAT3 as a Novel Molecular Target for Cancer Prevention", "abstract": "Signal Transducers and Activators of Transcription (STATs) are a family of transcription factors that regulate cell proliferation, differentiation, apoptosis, immune and inflammatory responses, and angiogenesis. Cumulative evidence has established that STAT3 has a critical role in the development of multiple cancer types. Because it is constitutively activated during disease progression and metastasis in a variety of cancers, STAT3 has promise as a drug target for cancer therapeutics. Recently, STAT3 was found to have an important role in maintaining cancer stem cells in vitro and in mouse tumor models, suggesting STAT3 is integrally involved in tumor initiation, progression and maintenance. STAT3 has been traditionally considered as nontargetable or undruggable, and the lag in developing effective STAT3 inhibitors contributes to the current lack of FDA-approved STAT3 inhibitors. Recent advances in cancer biology and drug discovery efforts have shed light on targeting STAT3 globally and/or specifically for cancer therapy. In this review, we summarize current literature and discuss the potential importance of STAT3 as a novel target for cancer prevention and of STAT3 inhibitors as effective chemopreventive agents.", "corpus_id": 16552365, "score": 0 }, { "doc_id": "42017989", "title": "Activated STAT3 Regulates Hypoxia-Induced Angiogenesis and Cell Migration in Human Glioblastoma", "abstract": "BACKGROUND:Glioblastoma is the most common primary brain tumor, with typical histopathologic findings, pseudopalisading necrosis, and microvascular proliferation, all of which are associated with a poor prognosis. Hypoxia is known to affect these morphological features, but the underlying molecular mechanism has been poorly understood. OBJECTIVE:To determine the role of signal transducer and activator of transcription 3 (STAT3) in the malignant progression of glioblastoma under hypoxic conditions. METHODS:We studied STAT3 activation by hypoxic stress and its effect on hypoxia-induced angiogenesis and cell migration using U87, A172, T98, and U373 human glioblastoma cell lines. RESULTS:All four glioblastoma cells analyzed expressed detectable levels of STAT3 phosphorylation. Hypoxic stress markedly increased phosphorylated STAT3 level in a time-dependent fashion, and activated STAT3 was translocated into the nucleus. Hypoxic conditions led to a 30-50% increase in angiogenesis and cell migration, but these effects were significantly attenuated by small interfering ribonucleic acid-mediated knockdown of STAT3. Furthermore, STAT3 activation was associated with an elevated expression of hypoxic inducible factor-1, vascular endothelial growth factor, matrix metalloproteinase 2, and TWIST messenger ribonucleic acid and protein, which may play a critical role in hypoxia-induced angiogenesis and migration. CONCLUSION:STAT3 plays an important role in glioblastoma angiogenesis and migration triggered by hypoxia. Therefore, STAT3 might be a target for control of pseudopalisading necrosis and angiogenesis in glioblastoma.", "corpus_id": 42017989, "score": 0 }, { "doc_id": "2794399", "title": "Knockdown of STAT3 expression by RNAi suppresses growth and induces apoptosis and differentiation in glioblastoma stem cells.", "abstract": "Glioblastoma is a highly lethal brain tumor of the human primary nervous system tumors. Previous studies demonstrated that glioblastoma stem cells were able to initiate and reform the original cancer. In this study, we found that there were expression and activation of STAT3, a key signal transduction factor and oncoprotein, in human glioblastoma stem cells (GSCs). STAT3 plays a key role in proliferation, apoptosis and differentiation in embryonic stem cells and several cancer types. To investigate the effects of STAT3 on human GSCs, the expression and activation of STAT3 were suppressed by RNAi mediated with lentivirus. We demonstrated that siRNA of STAT3 significantly suppressed STAT3 expression and activation and resulted in inhibition of cell growth in GSCs. Knockdown of STAT3 induces apoptosis and reduces significantly expression of Bcl-2 and cyclin-D in human primary GSCs, whereas no significance was achieved in BAX and caspase-3 expression. Inhibition of STAT3 expression is associated not only with decreasing of CD133+ cell proportion and increasing of GFAP and MBP expression, but also with decrease of the capacity to initiate a tumor in human primary GSCs. Together, these studies suggest that STAT3 is an important target for human GSCs in regulation of GSCs growth, apoptosis, differentiation and tumorigenic potential.", "corpus_id": 2794399, "score": 0 }, { "doc_id": "24328427", "title": "STAT3 Is Required for Proliferation and Maintenance of Multipotency in Glioblastoma Stem Cells", "abstract": "Signal transducer and activator of transcription 3 (STAT3) regulates diverse cellular processes, including cell growth, differentiation, and apoptosis, and is frequently activated during tumorigenesis. Recently, putative glioblastoma stem cells (GBM‐SCs) were isolated and characterized. These cells can self‐renew indefinitely in culture, are highly tumorigenic, and retain the ability to differentiate in culture. We have found that treatment of GBM‐SCs with two chemically distinct small molecule inhibitors of STAT3 DNA‐binding inhibits cell proliferation and the formation of new neurospheres from single cells. Genetic knockdown of STAT3 using a short hairpin RNA also inhibits GBM‐SC proliferation and neurosphere formation, confirming that these effects are specific to STAT3. Although STAT3 inhibition can induce apoptosis in serum‐derived GBM cell lines, this effect was not observed in GBM‐SCs grown in stem cell medium. Markers of neural stem cell multipotency also decrease upon STAT3 inhibition, suggesting that STAT3 is required for maintenance of the stem‐like characteristics of these cells. Strikingly, even a transient inhibition of STAT3 leads to irreversible growth arrest and inhibition of neurosphere formation. These data suggest that STAT3 regulates the growth and self‐renewal of GBM‐SCs and is thus a potential target for cancer stem cell‐directed therapy of glioblastoma multiforme. STEM CELLS 2009;27:2383–2392", "corpus_id": 24328427, "score": 0 }, { "doc_id": "39134544", "title": "On-target JAK2/STAT3 inhibition slows disease progression in orthotopic xenografts of human glioblastoma brain tumor stem cells.", "abstract": "BACKGROUND\nGlioblastoma multiforme (GBM) is characterized by an aggressive clinical course, therapeutic resistance, and striking molecular heterogeneity. GBM-derived brain tumor stem cells (BTSCs) closely model this molecular heterogeneity and likely have a key role in tumor recurrence and therapeutic resistance. Emerging evidence indicates that Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 is an important mediator of tumor cell survival, growth, and invasion in a large group of GBM. Here, we used a large set of molecularly heterogeneous BTSCs to evaluate the translational potential of JAK2/STAT3 therapeutics.\n\n\nMETHODS\nBTSCs were cultured from GBM patients and MGMT promoter methylation, and the mutation statuses of EGFR, PTEN, and TP53 were determined. Endogenous JAK2/STAT3 activity was assessed in human GBM tissue, BTSCs, and orthotopic xenografts by immunohistochemistry and Western blotting. STAT3 short hairpin (sh)RNA, cucurbitacin-I, and WP1066 were used to inhibit JAK2/STAT3 activity in vitro and in vivo.\n\n\nRESULTS\nThe JAK2/STAT3 pathway was demonstrated to be highly activated in human GBM, molecularly heterogeneous BTSCs derived from these tumors, and BTSC xenografts. STAT3 shRNA knockdown or cucurbitacin-I and WP1066 administration resulted in on-target JAK2/STAT3 inhibition and dramatically reduced BTSC survival regardless of endogenous MGMT promoter methylation or EGFR, PTEN, and TP53 mutational status. BTSC orthotopic xenografts maintained the high levels of activated JAK2/STAT3 seen in their parent human tumors. Intraperitoneal WP1066 reduced intratumoral JAK2/STAT3 activity and prolonged animal survival.\n\n\nCONCLUSION\nOur study demonstrates the in vitro and in vivo efficacy of on-target JAK2/STAT3 inhibition in heterogeneous BTSC lines that closely emulate the genomic and tumorigenic characteristics of human GBM.", "corpus_id": 39134544, "score": 0 }, { "doc_id": "25419506", "title": "15d-PGJ2 and Rosiglitazone Suppress Janus Kinase-STAT Inflammatory Signaling through Induction of Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 in Glia*", "abstract": "Peroxisome proliferator-activated receptor (PPAR)-γ agonists are now emerging as therapeutic drugs for various inflammatory diseases. However, their molecular mechanism of action remains to be elucidated. Here we report a novel mechanism that underlies the PPAR-γ agonist-mediated suppression of brain inflammation. We show that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and rosiglitazone reduce the phosphorylation of STAT1 and STAT3 as well as Janus kinase 1 (JAK1) and JAK2 in activated astrocytes and microglia. The PPAR-γ agonist-mediated reduction in phosphorylation leads to the suppression of JAK-STAT-dependent inflammatory responses. The effects of 15d-PGJ2 and rosiglitazone are not mediated by activation of PPAR-γ. 15d-PGJ2 and rosiglitazone rapidly induce the transcription of suppressor of cytokine signaling (SOCS) 1 and 3, which in turn inhibit JAK activity in activated glial cells. In addition, Src homology 2 domain-containing protein phosphatase 2 (SHP2), another negative regulator of JAK activity, is also involved in their anti-inflammatory action. Our data suggest that 15d-PGJ2 and rosiglitazone suppress the initiation of JAK-STAT inflammatory signaling independently of PPAR-γ, thus attenuating brain inflammation.", "corpus_id": 25419506, "score": 0 }, { "doc_id": "35011892", "title": "Interruption of β-catenin suppresses the EGFR pathway by blocking multiple oncogenic targets in human glioma cells", "abstract": "Malignant gliomas are the most common type of intrinsic central nervous system (CNS) tumors with high mortality and morbidity. β-catenin is overexpressed in human glioblastoma and knockdown of β-catenin inhibits glioblastoma cell proliferation and invasive ability, and induces apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous LN229 gliomas with siRNA targeting β-catenin intratumorally also delayed the tumor growth. However, the mechanisms of down-regulation of β-catenin that represses glioblastoma malignancy behavior remain to be elucidated. We utilized text-mining of MEDLINE abstracts with natural language processing to establish the β-catenin biologic association network, and identified several interactions of this network with the EGFR pathway. In both in vitro and in vivo studies, our results confirmed down-regulation of β-catenin induced reduced expression of EGFR, STAT3 and AKT1 mRNA and protein, besides, the level of phosphorylated Akt also decreased. A similar reduction in expression of CyclinD1, MMP2 and MMP9, downstream genes of the EGFR pathway, was observed. These results suggest that the Wnt/β-catenin pathway regulates glioma cell proliferation and invasion, in part via the EGFR pathway.", "corpus_id": 35011892, "score": 0 }, { "doc_id": "24824552", "title": "beta-Catenin/TCF pathway upregulates STAT3 expression in human esophageal squamous cell carcinoma.", "abstract": "Precise roles of beta-catenin/TCF pathway involved in esophageal tumorigenesis remain elusive. Here we found STAT3 overexpression in esophageal cancer cells and tissues, and its overexpression in esophageal squamous cell carcinoma (ESCC) tissues correlated with beta-catenin cytoplasmic/nuclear accumulation. A functional TCF binding element was detected in STAT3 promoter which specifically bound to TCF4. Transfected beta-catenin induced STAT3 transcriptional activity dose-dependently, and also enhanced STAT3 mRNA and protein levels. These inductions were specifically abolished by dominant-negative TCF4. These results suggest that STAT3 is a target of beta-catenin/TCF pathway and might participate in esophageal tumorigenesis.", "corpus_id": 24824552, "score": 0 }, { "doc_id": "12542738", "title": "New perspectives in glioblastoma antiangiogenic therapy", "abstract": "Glioblastoma (GB) is highly vascularised tumour, known to exhibit enhanced infiltrative potential. One of the characteristics of glioblastoma is microvascular proliferation surrounding necrotic areas, as a response to a hypoxic environment, which in turn increases the expression of angiogenic factors and their signalling pathways (RAS/RAF/ERK/MAPK pathway, PI3K/Akt signalling pathway and WTN signalling cascade). Currently, a small number of anti-angiogenic drugs, extending glioblastoma patients survival, are available for clinical use. Most medications are ineffective in clinical therapy of glioblastoma due to acquired malignant cells or intrinsic resistance, angiogenic receptors cross-activation and redundant intracellular signalling, or the inability of the drug to cross the blood-brain barrier and to reach its target in vivo. Researchers have also observed that GB tumours are different in many aspects, even when they derive from the same tissue, which is the reason for personalised therapy. An understanding of the molecular mechanisms regulating glioblastoma angiogenesis and invasion may be important in the future development of curative therapeutic approaches for the treatment of this devastating disease.", "corpus_id": 12542738, "score": 0 }, { "doc_id": "1866452", "title": "Aberrant Signaling Pathways in Glioma", "abstract": "Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies.", "corpus_id": 1866452, "score": 0 }, { "doc_id": "24806543", "title": "The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: a review of preclinical and correlative clinical data.", "abstract": "PURPOSE\nThe epidermal growth factor receptor (EGFR) pathway is frequently upregulated in high-grade gliomas via gene amplification and by specific mutations that render EGFR constitutively active (EGFRvIII).\n\n\nMETHODS AND MATERIALS\nThis review highlights EGFR's role in mediating radiation resistance in gliomas: underlying molecular mechanisms, with discussion of relevant preclinical and clinical correlative data.\n\n\nRESULTS\nPreclinical and emerging clinical data suggest that EGFR signaling plays a potentially important role in mediating radiation resistance in human gliomas.\n\n\nCONCLUSIONS\nTargeting EGFR alone, or in combination with its downstream mediators, represents a promising new approach for the management of glioma patients.", "corpus_id": 24806543, "score": 0 }, { "doc_id": "26029604", "title": "Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.", "abstract": "BACKGROUND\nThe epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown.\n\n\nMETHODS\nWe sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro.\n\n\nRESULTS\nOf 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib.\n\n\nCONCLUSIONS\nCoexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.", "corpus_id": 26029604, "score": 0 }, { "doc_id": "207485732", "title": "Targeting the EGFR signaling pathway in cancer therapy", "abstract": "Introduction: Cancer is a devastating disease; however, several therapeutic advances have recently been made, wherein EGFR and its family members have emerged as useful biomarkers and therapeutic targets. EGFR, a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation. Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts. Areas covered: This review covers the basic mechanism of EGFR activation and the role of EGFR signaling in cancer progression. Furthermore, current developments made toward targeting the EGFR signaling pathway for the treatment of epithelial cancers and a summary of the various anti-EGFR therapeutic agents that are currently in use are also presented in this review. Expert opinion: EGFR signaling is a part of a complex network that has been the target of effective cancer therapies. However, a further understanding of the system is required to develop an effective anticancer regimen. A combination therapy that comprises an anti-EGFR and a chemotherapeutic/chemopreventive agent will exhibit a multi-pronged approach that can be developed into a highly attractive and specific molecular oriented remedy.", "corpus_id": 207485732, "score": 0 }, { "doc_id": "3069078", "title": "PI3K and STAT3: a new alliance.", "abstract": "UNLABELLED\nRecent proteomic data have uncovered an interdependence of PI3K and STAT3. In PI3K-tranformed murine cells, STAT3 is phosphorylated on Y705 and activated in a PI3K-dependent manner. Dominant negative STAT3 interferes with PI3K-induced oncogenic transformation. Phosphorylation of STAT3 in PI3K-transformed murine cells is mediated by the TEC kinase BMX. Observations on glioblastoma stem cells reveal similar critical roles for STAT3 and BMX. The new data document an important role of STAT3 in PI3K-driven oncogenic transformation and mark BMX as a promising therapeutic target that could enhance the effectiveness of PI3K inhibitors.\n\n\nSIGNIFICANCE\nThe PI3K–TOR and STAT3 signaling pathways represent two distinct regulatory networks. The discovery of a functional link between these pathways is significant for our understanding of PI3K- and STAT3-driven oncogenic mechanisms and identifies the TEC kinase BMX as a new cancer target.", "corpus_id": 3069078, "score": 0 }, { "doc_id": "29321530", "title": "PI3K and cancer: lessons, challenges and opportunities", "abstract": "The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K–AKT–mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.", "corpus_id": 29321530, "score": 0 }, { "doc_id": "18072294", "title": "Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding", "abstract": "Glioblastoma multiforme (GBM) is a grade IV astrocytoma with a median survival of 12 months despite current multi-modal treatment options. GBM is distinguished clinicopathologically into primary and secondary subtypes. Mutations of phosphatase and tensin homolog, and subsequent upregulation of the downstream protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway, are commonly seen in primary GBM and less predominantly in secondary GBM. While investigations into targeted treatments of mTOR have been attempted, feedback regulation within the mTOR signaling pathway may account for therapeutic resistance. Currently, rapamycin analogs, dual-targeted mTOR complex 1 and 2 agents as well as dual mTOR and phosphatidylinositol-3 kinase-targeted agents are being investigated experimentally and in clinical trials. This review will discuss the experimental potential of these agents in the treatment of GBM and their current stage in the GBM drug pipeline. Knowledge obtained from the application of these agents can help in understanding the pathogenesis of GBM as well as delineating subsequent treatment strategies.", "corpus_id": 18072294, "score": 0 }, { "doc_id": "2982680", "title": "Circulating endothelial progenitor cells are involved in VEGFR-2-related endothelial differentiation in glioma.", "abstract": "Endothelial progenitor cells (EPCs) play important roles in maintaining endothelial integrity and tumor vascularization. However, the differentiation of EPCs in the neoangiogenesis of gliomas has not yet been fully elucidated. The purpose in this study was to investigate the profile of EPC differentiation in rat C6 glioma using magnetic resonance imaging (MRI), a non-invasive monitoring assay. To achieve this goal, we isolated EPCs from rat bone marrow and identified them by detecting CD34, CD133, and VEGFR-2, the markers of EPCs. Coexpression of Ac-LDL and UEA-1 in EPCs was also determined. To dynamically monitor the migration of circulating cells, the EPCs were labeled with ultrasmall superparamagnetic iron oxide (USPIO) and injected by tail vein into rats bearing C6 glioma. MRI was performed at 24, 48, and 96 h after injection. The distribution and differentiation of EPCs were confirmed by histology. We found that the USPIO-labeled EPCs appeared at the tumor periphery where a large number of CD105-positive cells appeared at 24 h after injection by using MRI scanning. Ninety-six hours after injection, immunohistochemistry and Prussian blue staining were used to observe the labeled EPCs in the tumor tissue. We found that many of the labeled EPCs were overlapped with VEGFR-2-positive endothelial cells, but not CD105- or CD34-positive cells. These results suggest that EPCs can cross the blood-brain barrier from peripheral blood and home to tumors, where they differentiate into endothelial cells, including VEGFR-2-positive endothelial cells. MRI is a useful method for dynamically tracking the migration of USPIO-labeled EPCs.", "corpus_id": 2982680, "score": 0 }, { "doc_id": "31412828", "title": "Nuclear factor-κB in glioblastoma: insights into regulators and targeted therapy.", "abstract": "Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that regulates multiple aspects of cancer formation, growth, and treatment response. Glioblastoma (GBM), the most common primary malignant tumor of the central nervous system, is characterized by molecular heterogeneity, resistance to therapy, and high NF-κB activity. In this review, we examine the mechanisms by which oncogenic pathways active in GBM impinge on the NF-κB system, discuss the role of NF-κB signaling in regulating the phenotypic properties that promote GBM and, finally, review the components of the NF-κB pathway that have been targeted for treatment in both preclinical studies and clinical trials. While a direct role for NF-κB in gliomagenesis has not been reported, the importance of this transcription factor in the overall malignant phenotype suggests that more rational and specific targeting of NF-κB-dependent pathways can make a significant contribution to the management of GBM.", "corpus_id": 31412828, "score": 0 }, { "doc_id": "10051014", "title": "NF-κB and STAT3 in glioblastoma: therapeutic targets coming of age", "abstract": "Since we last addressed the roles of NF-κB and JAK/STAT3 signaling in glioblastoma (GBM) 5 years ago, tremendous strides have been made in the understanding of these two pathways in glioma biology. Contributing to prosurvival mechanisms, cancer stem cell maintenance and treatment resistance, both NF-κB and STAT3 have been characterized as major drivers of GBM. In this review, we address general improvements in the molecular understanding of GBM, the structure of NF-κB and STAT3 signaling, the ways in which these pathways contribute to GBM and advances in preclinical and clinical targeting of these two signaling cascades.", "corpus_id": 10051014, "score": 1 }, { "doc_id": "21592324", "title": "The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis.", "abstract": "Mammalian cells are believed to have a cell-intrinsic ability to increase glucose metabolism in response to hypoxia. Here we show that the ability of hematopoietic cells to up-regulate anaerobic glycolysis in response to hypoxia is dependent on receptor-mediated signal transduction. In the absence of growth factor signaling, hematopoietic cells fail to express hypoxia-inducible transcription factor (Hif-1alpha) mRNA. Growth factor-deprived hematopoietic cells do not engage in glucose-dependent anabolic synthesis and neither express Hif-1alpha mRNA nor require HIF-1alpha protein to regulate cell survival in response to hypoxia. However, HIF-1alpha is adaptive for the survival of growth factor-stimulated cells, as suppression of HIF-1alpha results in death when growing cells are exposed to hypoxia. Growth factor-dependent HIF-1alpha expression reprograms the intracellular fate of glucose, resulting in decreased glucose-dependent anabolic synthesis and increased lactate production, an effect that is enhanced when HIF-1alpha protein is stabilized by hypoxia. Together, these data suggest that HIF-1alpha contributes to the regulation of growth factor-stimulated glucose metabolism even in the absence of hypoxia.", "corpus_id": 21592324, "score": 0 }, { "doc_id": "205243417", "title": "Metabolic regulation of hematopoietic stem cells in the hypoxic niche.", "abstract": "Tissue homeostasis over the life of an organism relies on both self-renewal and multipotent differentiation of stem cells. Hematopoietic stem cells (HSCs) reside in a hypoxic bone marrow environment, and their metabolic status is distinct from that of their differentiated progeny. HSCs generate energy mainly via anaerobic metabolism by maintaining a high rate of glycolysis. This metabolic balance promotes HSC maintenance by limiting the production of reactive oxygen species, but leaves HSCs susceptible to changes in redox status. In this review, we discuss the importance of oxygen homeostasis and energy metabolism for maintenance of HSC function and long-term self-renewal.", "corpus_id": 205243417, "score": 0 }, { "doc_id": "23123229", "title": "Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth.", "abstract": "Most tumor cells take up more glucose than normal cells but metabolize glucose via glycolysis even in the presence of normal levels of oxygen, a phenomenon known as the Warburg effect. Tumor cells commonly express the embryonic M2 isoform of pyruvate kinase (PKM2) that may contribute to the metabolism shift from oxidative phosphorylation to aerobic glycolysis and tumorigenesis. Here we show that PKM2 is acetylated on lysine 305 and that this acetylation is stimulated by high glucose concentration. PKM2 K305 acetylation decreases PKM2 enzyme activity and promotes its lysosomal-dependent degradation via chaperone-mediated autophagy (CMA). Acetylation increases PKM2 interaction with HSC70, a chaperone for CMA, and association with lysosomes. Ectopic expression of an acetylation mimetic K305Q mutant accumulates glycolytic intermediates and promotes cell proliferation and tumor growth. These results reveal an acetylation regulation of pyruvate kinase and the link between lysine acetylation and CMA.", "corpus_id": 23123229, "score": 0 }, { "doc_id": "27912091", "title": "PKM2 promotes glucose metabolism and cell growth in gliomas through a mechanism involving a let-7a/c-Myc/hnRNPA1 feedback loop", "abstract": "Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than non-tumor cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let-7a/c-Myc/hnRNPA1/PKM2 signaling in glioma cell glucose metabolism. PKM2 depletion via siRNA inhibits cell proliferation and aerobic glycolysis in glioma cells. C-Myc promotes up-regulation of hnRNPA1 expression, hnRNPA1 binding to PKM pre-mRNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let-7a, which functionally targets c-Myc, whereas hnRNPA1 blocks the biogenesis of let-7a to counteract its ability to downregulate the c-Myc/hnRNPA1/PKM2 signaling pathway. The down-regulation of c-Myc/hnRNPA1/PKM2 by let-7a is verified using a glioma xenograft model. These results suggest that let-7a, c-Myc and hnRNPA1 from a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of glioma cells. These findings elucidate a new pathway mediating aerobic glycolysis in gliomas and provide an attractive potential target for therapeutic intervention.", "corpus_id": 27912091, "score": 0 }, { "doc_id": "8872564", "title": "β-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas", "abstract": "Astrocytes are the most abundant cell of the CNS and demonstrate contact inhibition in which a nonproliferative, nonmotile cellular state is achieved once stable intercellular contacts are formed between mature cells. Cellular injury disrupts these intercellular contacts, causing a loss of contact inhibition and the rapid initiation of healing. Dysregulation of the molecular pathways involved in this process is thought to lead to an aggressive cellular state associated with neoplasia. We investigated whether a comparable correlation exists between the response of astrocytes to injury and the malignant phenotype of astrocytomas. We discovered that the loss of contact inhibition plays a critical role in the initiation and regulation of reactive astrocytes in the healing of wounds. In particular, injury of the astrocytes interrupts and destabilizes the cadherin-catenin complexes at the cell membrane leading to nuclear translocation of β-catenin and characteristic changes associated with the activation of astrocytes. Similar signaling pathways are found to be active—but dysregulated—in astrocytomas. Inhibition of β-catenin signaling diminished both the response of astrocytes to injury and induction of the malignant phenotype of astrocytomas. The findings shed light on a unique mechanism associated with the pathogenesis of astrocytomas and provide a model for the loss of contact inhibition that may broadly apply to understanding the mechanisms of tissue repair and tumorigenesis in the brain.", "corpus_id": 8872564, "score": 0 }, { "doc_id": "7194806", "title": "Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth", "abstract": "Tyrosine phosphorylation of pyruvate kinase M2 gives tumor cells a metabolic advantage. A Malignant Metabolic Switch Cancer cells show aberrant metabolism, consuming more glucose than do healthy cells and producing lactate even in the presence of abundant oxygen, rather than shifting to oxidative phosphorylation. This phenomenon is called the Warburg effect, after Otto Warburg, who described it many years ago. Building on recent research implicating inhibition of the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) by phosphotyrosine binding as critical to the Warburg effect—and tumorigenesis—Hitosugi et al. explored the role of signaling from oncogenic forms of the fibroblast growth factor receptor type 1 (FGFR1) in mediating this metabolic switch. They found that FGFR1, a receptor tyrosine kinase, phosphorylated a tyrosine residue (Y105) on PKM2 itself. Further analysis revealed that this tyrosine residue was commonly phosphorylated in human cancers and that a mutant form of PKM2 lacking this tyrosine residue inhibited both “Warburg metabolism” and tumor growth. They thus propose that phosphorylation of PKM2 by oncogenic tyrosine kinases provides the very phosphotyrosine that binds to and inhibits PKM2 to induce the Warburg effect and promote tumor growth. The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. To better understand how tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect, we performed phosphoproteomic studies. We found that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y105). This inhibits the formation of active, tetrameric PKM2 by disrupting binding of the PKM2 cofactor fructose-1,6-bisphosphate. Furthermore, we found that phosphorylation of PKM2 Y105 is common in human cancers. The presence of a PKM2 mutant in which phenylalanine is substituted for Y105 (Y105F) in cancer cells leads to decreased cell proliferation under hypoxic conditions, increased oxidative phosphorylation with reduced lactate production, and reduced tumor growth in xenografts in nude mice. Our findings suggest that tyrosine phosphorylation regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth.", "corpus_id": 7194806, "score": 0 }, { "doc_id": "14191904", "title": "VEGF Promotes Proliferation of Human Glioblastoma Multiforme Stem-Like Cells through VEGF Receptor 2", "abstract": "Cancer stem-like cells, which have been described as tumor-initiating cells or tumor-propagating cells, play a crucial role in our fundamental understanding of glioblastoma multiforme (GBM) and its recurrence. GBM is a lethal cancer, characterized by florid vascularization and aberrantly elevated vascular endothelial growth factor (VEGF). VEGF promotes tumorigenesis and angiogenesis of human GBM stem-like cells (GBSCs). However, whether and how VEGF contributes to GBSCs proliferation remain largely uncertain. In this study, human GBSCs were isolated from surgical specimens of glioblastoma and cultured in medium favored for stem cell growth. Neural Colony-Forming Cell Assay and ATP assay were performed to measure GBSC proliferation under normoxia (20% O2) and hypoxia (1% O2). Our observations demonstrate that exogenous VEGF stimulates GBSC proliferation in a dose-dependent manner via VEGF Receptor 2 (VEGFR2); while VEGF Receptor 1 (VEGFR1) has a negative feedback effect on VEGFR2 when cells were exposed to higher concentration of VEGF. These results suggest that suppressing VEGFR2-dependent GBSC proliferation is a potentially therapeutic strategy in GBM.", "corpus_id": 14191904, "score": 0 }, { "doc_id": "23481028", "title": "Inactivation of PI3K/AKT signaling inhibits glioma cell growth through modulation of β-catenin-mediated transcription", "abstract": "Aberrant Wnt/β-catenin signaling contributes to the development of many cancers, including glial tumorigenesis. While cross talk between the Wnt/β-catenin and PI3K/AKT signaling pathways has been proposed, the impact of PI3K/AKT inhibition on β-catenin signaling in glioma remains unknown. In the present study, we report decreased cell proliferation and invasive ability upon the LY294002-induced inhibition of PI3K in both U251 and LN229 human glioblastoma cells in vitro. Pharmacologic inhibition of PI3K resulted in the downregulation of several members of the β-catenin pathway, including Fra-1, c-Myc, and cyclin D1. Downregulation impacted β-catenin-mediated transcription, as LY294002 decreased β-catenin/TCF transcriptional activity, determined by the reporter assay. Similar results were observed in vivo, as intratumoral injection of LY294002 downregulated the expression of the components of the β-catenin pathway and delayed tumor growth in nude mice harboring subcutaneous LN229 xenografts. These results suggest that the PI3K/AKT signaling pathway regulates glioma cell proliferation, in part via repression of the Wnt/β-catenin pathway.", "corpus_id": 23481028, "score": 0 }, { "doc_id": "638930", "title": "The antiproliferative effect of indomethacin-loaded lipid-core nanocapsules in glioma cells is mediated by cell cycle regulation, differentiation, and the inhibition of survival pathways", "abstract": "Despite recent advances in radiotherapy, chemotherapy, and surgical techniques, glioblastoma multiforme (GBM) prognosis remains dismal. There is an urgent need for new therapeutic strategies. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intense interest in recent years because they can provide sustained, controlled, and targeted delivery. Here, we investigate the mechanisms involved in the antiproliferative effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNC) in glioma cells. IndOH-LNC were able to reduce cell viability by inducing apoptotic cell death in C6 and U138-MG glioma cell lines. Interestingly, IndOH-LNC did not affect the viability of primary astrocytes, suggesting that this formulation selectively targeted transformed cells. Mechanistically, IndOH-LNC induced inhibition of cell growth and cell-cycle arrest to be correlated with the inactivation of AKT and β-catenin and the activation of GSK-3β. IndOH-LNC also induced G0/G1 and/or G2/M phase arrest, which was accompanied by a decrease in the levels of cyclin D1, cyclin B1, pRb, and pcdc2 and an increase in the levels of Wee1 CDK inhibitor p21WAF1. Additionally, IndOH-LNC promoted GBM cell differentiation, observed as upregulation of glial fibrillary acidic protein (GFAP) protein and downregulation of nestin and CD133. Taken together, the crosstalk among antiproliferative effects, cell-cycle arrest, apoptosis, and cell differentiation should be considered when tailoring pharmacological interventions aimed at reducing glioma growth by using formulations with multiples targets, such as IndOH-LNC.", "corpus_id": 638930, "score": 0 }, { "doc_id": "24590496", "title": "High β-catenin/Tcf-4 activity confers glioma progression via direct regulation of AKT2 gene expression.", "abstract": "Recent data suggest that the β-catenin/Tcf-4 signaling pathway plays an important role in human cancer tumorigenesis. However, the mechanism of β-catenin/Tcf-4 signaling in tumorigenesis is poorly understood. In this study, we show that Tcf-4 protein levels were significantly elevated in high-grade gliomas in comparison with low-grade gliomas and that Tcf-4 levels correlated with levels of AKT2. Reduction of β-catenin/Tcf-4 activity inhibited glioma cell proliferation and invasion in vitro and tumor growth in vivo. This effect of β-catenin/Tcf-4 activity was mediated by AKT2, and in vivo binding of β-catenin/Tcf-4 to the AKT2 promoter was validated using the chromatin immunoprecipitation assay and luciferase reporter assays. Taken together, we have demonstrated that Tcf-4 is associated with glioma progression and that AKT2 is a new member of the genes that are regulated by β-catenin/Tcf-4.", "corpus_id": 24590496, "score": 0 }, { "doc_id": "21438599", "title": "Differentiation of SWO-38 glioma cells induced by CDA-2 is mediated by peroxisome proliferator-activated receptor γ", "abstract": "Glioma remains one of the most lethal human tumors in spite of the progress in radiotherapy, chemotherapy, and surgical techniques. Cell differentiation agent-2 (CDA-2) is an extraction from healthy human urine consisting of primary organic acids and peptides, and it has been demonstrated to inhibit growth and induce differentiation in glioma and other cell lines. However, the mechanism remains unclear. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptors (NHRs) which are involved in cellular differentiation and proliferation. In this study, we investigated if CDA-2 induced differentiation of SWO-38 glioma cells is mediated by PPARγ. CDA-2 induced differentiation of SWO-38 cells was characterized by typical morphological changes, increased expression of GFAP, inhibition of proliferation and G0/G1 cell cycle arrest. CDA-2 also triggered up-regulation of PPARγ, GFAP and PTEN protein and a reduction of COX-2 protein. However, the effects of CDA-2 on SWO-38 cells could be partly reversed by GW9662, an irreversible PPARγ antagonist. Our investigation demonstrated that CDA-2 could be a potential drug for tumor differentiation therapy, and activation of the PPARγ pathway might be a crucial factor in glioma differentiation induced by CDA-2.", "corpus_id": 21438599, "score": 0 }, { "doc_id": "3449415", "title": "Cyclooxygenase-2 in glioblastoma multiforme.", "abstract": "Glioblastoma multiforme (GBM) represents the most prevalent brain primary tumor, yet there is a lack of effective treatment. With current therapies, fewer than 5% of patients with GBM survive more than 5 years after diagnosis. Mounting evidence from epidemiological studies reveals that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is correlated with reduced incidence of GBM, suggesting that cyclooxygenase-2 (COX-2) and its major product within the brain, prostaglandin E2 (PGE2), are involved in the development and progression of GBM. Here, we highlight our current understanding of COX-2 in GBM proliferation, apoptosis, invasion, angiogenesis, and immunosuppression by focusing on recent in vitro and in vivo experimental data. We also discuss the feasibility of COX-2 as a therapeutic target for GBM in light of the latest human studies.", "corpus_id": 3449415, "score": 0 }, { "doc_id": "8019067", "title": "Aberrantly activated Cox-2 and Wnt signaling interact to maintain cancer stem cells in glioblastoma.", "abstract": "Glioblastoma recurrence after aggressive therapy typically occurs within six months, and patients inevitably succumb to their disease. Tumor recurrence is driven by a subpopulation of cancer stem cells in glioblastoma (glioblastoma stem-like cells, GSCs), which exhibit resistance to cytotoxic therapies, compared to their non-stem-cell counterparts. Here, we show that the Cox-2 and Wnt signaling pathways are aberrantly activated in GSCs and interact to maintain the cancer stem cell identity. Cox-2 stimulates GSC self-renewal and proliferation through prostaglandin E2 (PGE2), which in turn activates the Wnt signaling pathway. Wnt signaling underlies PGE2-induced GSC self-renewal and independently directs GSC self-renewal and proliferation. Inhibition of PGE2 enhances the effect of temozolomide on GSCs, but affords only a modest survival advantage in a xenograft model in the setting of COX-independent Wnt activation. Our findings uncover an aberrant positive feedback interaction between the Cox-2/PGE2 and Wnt pathways that mediates the stem-like state in glioblastoma.", "corpus_id": 8019067, "score": 0 }, { "doc_id": "17565615", "title": "NSAIDs Inhibit Tumorigenesis, but How?", "abstract": "Numerous epidemiologic studies have reported that the long-term use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with a significant decrease in cancer incidence and delayed progression of malignant disease. The use of NSAIDs has also been linked with reduced risk from cancer-related mortality and distant metastasis. Certain prescription-strength NSAIDs, such as sulindac, have been shown to cause regression of precancerous lesions. Unfortunately, the extended use of NSAIDs for chemoprevention results in potentially fatal side effects related to their COX-inhibitory activity and suppression of prostaglandin synthesis. Although the basis for the tumor growth–inhibitory activity of NSAIDs likely involves multiple effects on tumor cells and their microenvironment, numerous investigators have concluded that the underlying mechanism is not completely explained by COX inhibition. It may therefore be possible to develop safer and more efficacious drugs by targeting such COX-independent mechanisms. NSAID derivatives or metabolites that lack COX-inhibitory activity, but retain or have improved anticancer activity, support this possibility. Experimental studies suggest that apoptosis induction and suppression of β-catenin–dependent transcription are important aspects of their antineoplastic activity. Studies show that the latter involves phosphodiesterase inhibition and the elevation of intracellular cyclic GMP levels. Here, we review the evidence for COX-independent mechanisms and discuss progress toward identifying alternative targets and developing NSAID derivatives that lack COX-inhibitory activity but have improved antineoplastic properties. Clin Cancer Res; 20(5); 1104–13. ©2013 AACR.", "corpus_id": 17565615, "score": 0 }, { "doc_id": "37115465", "title": "Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin.", "abstract": "Sulindac sulfone (exisulind), although a nonsteroidal anti-inflammatory drug derivative, induces apoptosis in tumor cells by a mechanism that does not involve cyclooxygenase inhibition. SW480 colon tumor cells contain guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) isoforms of the PDE5 and PDE2 gene families that are inhibited by exisulind and new synthetic analogues. The analogues maintain rank order of potency for PDE inhibition, apoptosis induction, and growth inhibition. A novel mechanism for exisulind to induce apoptosis is studied involving sustained increases in cGMP levels and cGMP-dependent protein kinase (PKG) induction not found with selective PDE5 or most other PDE inhibitors. Accumulated beta-catenin, shown to be a substrate for PKG, is decreased by exisulind, suggesting a mechanism to explain apoptosis induction in neoplastic cells harboring adenomatous polyposis coli gene mutations.", "corpus_id": 37115465, "score": 0 }, { "doc_id": "9308546", "title": "Sulindac and its metabolites inhibit invasion of glioblastoma cells via down‐regulation of Akt/PKB and MMP‐2", "abstract": "Non‐steroidal anti‐inflammatory drug (NSAID), sulindac has chemopreventive and anti‐tumorigenic properties, however, the molecular mechanism of this inhibitory action has not been clearly defined. The Akt/protein kinase B, serine/threonine kinase is well known as an important mediator of many cell survival signaling pathways. In the present study, we demonstrate that down‐regulation of Akt is a major effect of anti‐invasiveness property of sulindac and its metabolites in glioblastoma cells. Myristoylated Akt (MyrAkt) transfected U87MG glioblastoma cells showed increase invasiveness, whereas DN‐Akt transfected cells showed decrease invasiveness indicating that Akt potently promoted glioblastoma cell invasion. MMP‐2 promoter and enzyme activity were up‐regulated in Akt kinase activity dependent manner. Sulindac and its metabolites down‐regulated Akt phosphorylation, inhibited MMP‐2 production, and significantly inhibited invasiveness of human glioblastoma cells. In addition, sulindac and LY294002, a selective inhibitor of phosphoinositide 3‐kinase (PI3K), synergistically inhibited the invasion of glioblastoma cells. Furthermore, only celecoxib showed Akt phosphorylation reduction and an anti‐invasivness in glioblastoma cells, whereas aspirin, ketoprofen, ketorolac, and naproxen did not. In conclusion, our results provide evidence that down‐regulation of Akt pathway and MMP‐2 may be one of the mechanisms by which sulindac and its metabolites inhibit glioblastoma cell invasion. © 2004 Wiley‐Liss, Inc.", "corpus_id": 9308546, "score": 0 }, { "doc_id": "23242667", "title": "Eicosanoids and cancer", "abstract": "Eicosanoids, including prostaglandins and leukotrienes, are biologically active lipids that have been implicated in various pathological processes, such as inflammation and cancer. This Review highlights our understanding of the intricate roles of eicosanoids in epithelial-derived tumours and their microenvironment. The knowledge of how these lipids orchestrate the complex interactions between transformed epithelial cells and the surrounding stromal cells is crucial for understanding tumour evolution, progression and metastasis. Understanding the molecular mechanisms underlying the role of prostaglandins and other eicosanoids in cancer progression will help to develop more effective cancer chemopreventive and/or therapeutic agents.", "corpus_id": 23242667, "score": 0 }, { "doc_id": "26518480", "title": "Low-Dose Chemotherapy in Combination with COX-2 Inhibitors and PPAR-Gamma Agonists in Recurrent High-Grade Gliomas – A Phase II Study", "abstract": "Objectives: Combined treatment approaches targeting tumor as well as other cells contributing to tumor progression may control chemorefractory malignancies. Methods: A phase II trial was initiated to analyze the activity of continuously administered pioglitazone and rofecoxib combined with low-dose chemotherapy (capecitabine or temozolomide) in patients with high-grade gliomas (glioblastoma or anaplastic glioma). Results: Fourteen patients were evaluable for response and toxicity. Major side effects were palmoplantar erythema, edema and motor neuropathy grade 3. Disease stabilizations lasting longer than 3 months were noted in 4 of 14 patients (29%). Clinical responses did not correspond to immunohistochemical staining for cyclooxygenase 2, peroxisome proliferator-activated receptor-γ and CD31. Discussion: The study demonstrates that this novel regimen is moderately active and well tolerated in patients with high-grade gliomas. As a comparably small proportion of patients responded, the regimen might only be suitable for a subset of highly selected patients.", "corpus_id": 26518480, "score": 0 }, { "doc_id": "22591210", "title": "Inhibition of PDE5 by Sulindac Sulfide Selectively Induces Apoptosis and Attenuates Oncogenic Wnt/β-Catenin–Mediated Transcription in Human Breast Tumor Cells", "abstract": "Nonsteroidal anti-inflammatory drugs (NSAID) such as sulindac sulfide (SS) display promising antineoplastic properties, but toxicities resulting from COX inhibition limit their clinical use. Although COX inhibition is responsible for the anti-inflammatory activity of SS, recent studies suggest that phosphodiesterase (PDE) 5 inhibition and activation of cyclic guanosine monophosphate (cGMP) signaling are closely associated with its ability to induce apoptosis of tumor cells. However, the underlying mechanisms responsible for apoptosis induction, factors that influence sensitivity of tumor cells to SS, and the importance of PDE5 for breast tumor cell growth have not been established. Here we show that SS can induce apoptosis of breast tumor cells, which predominantly rely on PDE5 for cGMP hydrolysis but not normal mammary epithelial cells, which rely on PDE isozymes other than PDE5 for cGMP hydrolysis. Inhibition of PDE5 and activation of protein kinase G (PKG) by SS was associated with increased β-catenin phosphorylation, decreased β-catenin mRNA and protein levels, reduced β-catenin nuclear localization, decreased T-cell factor/lymphoid enhancer factor (Tcf/Lef) promoter activity, and decreased expression of Wnt/β-catenin–regulated proteins. Suppression of PDE5 with siRNA or known PDE5 inhibitors was sufficient to selectively induce apoptosis and attenuate β-catenin–mediated transcription in breast tumor cells with minimal effects on normal mammary epithelial cells. These findings provide evidence that SS induces apoptosis of breast tumor cells through a mechanism involving inhibition of PDE5 and attenuation of oncogenic Wnt/β-catenin–mediated transcription. We conclude that PDE5 represents a novel molecular target for the discovery of safer and more efficacious drugs for breast cancer chemoprevention. Cancer Prev Res; 4(8); 1275–84. ©2011 AACR.", "corpus_id": 22591210, "score": 0 }, { "doc_id": "46719630", "title": "New NSAID targets and derivatives for colorectal cancer chemoprevention.", "abstract": "Clinical and preclinical studies provide strong evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent numerous types of cancers, especially colorectal cancer. Unfortunately, the depletion of physiologically important prostaglandins due to cyclooxygenase (COX) inhibition results in potentially fatal toxicities that preclude the long-term use of NSAIDs for cancer chemoprevention. While studies have shown an involvement of COX-2 in colorectal tumorigenesis, other studies suggest that a COX-independent target may be at least partially responsible for the antineoplastic activity of NSAIDs. For example, certain NSAID derivatives have been identified that do not inhibit COX-2 but have demonstrated efficacy to suppress carcinogenesis with potential for reduced toxicity. A number of alternative targets have also been reported to account for the tumor cell growth inhibitory activity of NSAIDs, including the inhibition of cyclic guanosine monophosphate phosphodiesterases (cGMP PDEs), generation of reactive oxygen species (ROS), the suppression of the apoptosis inhibitor protein, survivin, and others. Here, we review several promising mechanisms that are being targeted to develop safer and more efficacious NSAID derivatives for colon cancer chemoprevention.", "corpus_id": 46719630, "score": 0 }, { "doc_id": "10701409", "title": "New insights into the role of COX 2 in inflammation", "abstract": "Cyclo-oxygenase (COX) is responsible for the synthesis of bioactive prostanoids, the inhibition of which serves as the basis for the mode of action of clinically used nonsteroidal anti-inflammatory drugs. While there were suggestions as early as the 1970s that an inducible isoform of COX exists, it was only in the early 1990s that COX 2 was identified, cloned and sequenced. Not surprisingly, this new isoform was expressed at sites of inflammation and reported to contribute to the inflammatory response. Recently, however, evidence is emerging to suggest that COX 2 also has anti-inflammatory properties. In this review, the two faces of COX 2 are examined, with emphasis on its role in regulating inflammatory resolution, including possible mechanisms of action", "corpus_id": 10701409, "score": 0 }, { "doc_id": "1039962", "title": "Mechanisms of peroxisome proliferator activated receptor γ regulation by non-steroidal anti-inflammatory drugs", "abstract": "Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation.", "corpus_id": 1039962, "score": 0 }, { "doc_id": "13908566", "title": "Systematic review: interactions between aspirin, and other nonsteroidal anti-inflammatory drugs, and polymorphisms in relation to colorectal cancer", "abstract": "Nonsteroidal anti‐inflammatory drugs (NSAIDs) include aspirin (acetylsalicylic acid, ASA). Long‐term use of NSAIDs has been associated with lowered risk of colorectal cancer (CRC), but the use is hampered by adverse effects. Also, the anti‐carcinogenic effects of NSAIDs are incompletely understood. Understanding biological effects of NSAIDs may help developing new preventive medical strategies.", "corpus_id": 13908566, "score": 0 }, { "doc_id": "7531081", "title": "Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research.", "abstract": "Curcuma longa (turmeric) has a long history of use in Ayurvedic medicine as a treatment for inflammatory conditions. Turmeric constituents include the three curcuminoids: curcumin (diferuloylmethane; the primary constituent and the one responsible for its vibrant yellow color), demethoxycurcumin, and bisdemethoxycurcumin, as well as volatile oils (tumerone, atlantone, and zingiberone), sugars, proteins, and resins. While numerous pharmacological activities, including antioxidant and antimicrobial properties, have been attributed to curcumin, this article focuses on curcumin's anti-inflammatory properties and its use for inflammatory conditions. Curcumin's effect on cancer (from an anti-inflammatory perspective) will also be discussed; however, an exhaustive review of its many anticancer mechanisms is outside the scope of this article. Research has shown curcumin to be a highly pleiotropic molecule capable of interacting with numerous molecular targets involved in inflammation. Based on early cell culture and animal research, clinical trials indicate curcumin may have potential as a therapeutic agent in diseases such as inflammatory bowel disease, pancreatitis, arthritis, and chronic anterior uveitis, as well as certain types of cancer. Because of curcumin's rapid plasma clearance and conjugation, its therapeutic usefulness has been somewhat limited, leading researchers to investigate the benefits of complexing curcumin with other substances to increase systemic bioavailability. Numerous in-progress clinical trials should provide an even deeper understanding of the mechanisms and therapeutic potential of curcumin.", "corpus_id": 7531081, "score": 0 }, { "doc_id": "34093108", "title": "Investigating the therapeutic role and molecular biology of curcumin as a treatment for glioblastoma", "abstract": "Objectives: Despite the aggressive standard of care for patients with glioblastoma multiforme, survival rates typically do not exceed 2 years. Therefore, current research is focusing on discovering new therapeutics or rediscovering older medications that may increase the overall survival of patients with glioblastoma. Curcumin, a component of the Indian natural spice, turmeric, also known for its antioxidant and anti-inflammatory properties, has been found to be an effective inhibitor of proliferation and inducer of apoptosis in many cancers. The goal of this study was to investigate the expanded utility of curcumin as an antiglioma agent. Methods: Using the PubMed MeSH database, we conducted a systematic review of the literature to include pertinent studies on the growth inhibitory effects of curcumin on glioblastoma cell lines based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 19 in vitro and five in vivo studies were analyzed. All of the studies indicated that curcumin decreased glioblastoma cell viability through various pathways (i.e. decrease in prosurvival proteins such as nuclear factor κB, activator protein 1, and phosphoinositide 3 kinase, and upregulation of apoptotic pathways like p21, p53, and executor caspase 3). Curcumin treatment also increased animal survival compared with control groups. Conclusions: Curcumin inhibits proliferation and induces apoptosis in certain subpopulations of glioblastoma tumors, and its ability to target multiple signaling pathways involved in cell death makes it an attractive therapeutic agent. As such, it should be considered as a potent anticancer treatment. Further experiments are warranted to elucidate the use of a bioavailable form of curcumin in clinical trials.", "corpus_id": 34093108, "score": 0 }, { "doc_id": "38046255", "title": "The targets of curcumin.", "abstract": "Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-kB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here.", "corpus_id": 38046255, "score": 0 }, { "doc_id": "22212970", "title": "Curcumin for the Treatment of Glioblastoma.", "abstract": "Glioblastoma multiforme is a highly aggressive primary cancer of the brain associated with a poor prognosis. Modest increases in survival can sometimes be achieved with the use of temozolomide and radiation therapy after surgery, but second-line therapy after recurrence has a limited efficacy. Curcumin has demonstrated promising results against this form of cancer in experimental models. The reported activity of curcumin against cancer stem cells, a major cause of glioblastoma resistance to therapy, and its ability to augment the apoptotic effects of ceramides, suggest it would have a synergistic effect with cytotoxic chemotherapy agents currently used in second-line therapy, such as lomustine.", "corpus_id": 22212970, "score": 0 }, { "doc_id": "4833922", "title": "Prospective of curcumin, a pleiotropic signalling molecule from Curcuma longa in the treatment of Glioblastoma.", "abstract": "GBM (Glioblastoma) is the most malignant human brain tumor with median survival of one year. The treatment involves surgery, radiotherapy and adjuvant chemotherapy mostly with the alkylation agents such as temozolomide (TMZ). Dietary polyphenol curcumin, isolated from the rhizome of the Curcuma longa (turmeric), has emerged as remarkable anti-cancer agent in the treatment of various peripheral cancers such as blood, lymphomas, multiple myeloma, melanoma as well as skin, lung, prostate, breast, ovarian, bladder, liver, gastrointestinal tract, pancreatic and colorectal epithelial cancers with a pleiotropic mode of action and also showed promise in alleviation of GBM. In this review, the mechanism of anticancer effect of curcumin in GBM has been discussed extensively. The clinical safety and pharmacokinetics of curcumin has been scrutinized to combat the challenges for the treatment of GBM.", "corpus_id": 4833922, "score": 0 }, { "doc_id": "37610640", "title": "Biological Properties of Curcumin-Cellular and Molecular Mechanisms of Action", "abstract": "Curcuminoids, a group of phenolic compounds isolated from the roots of Curcuma longa (Zingiberaceae), exhibit a variety of beneficial effects on health and on events that help in preventing certain diseases. A vast majority of these studies were carried out with curcumin (diferuloyl methane), which is a major curcuminoid. The most detailed studies using curcumin include anti-inflammatory, antioxidant, anticarcinogenic, antiviral, and antiinfectious activities. In addition, the wound healing and detoxifying properties of curcumin have also received considerable attention. As a result of extensive research on the therapeutic properties of curcumin, some understanding on the cellular, molecular, and biochemical mechanism of action of curcumin is emerging. These findings are summarized in this review.", "corpus_id": 37610640, "score": 0 }, { "doc_id": "20549194", "title": "Antioxidant and anti-inflammatory properties of curcumin.", "abstract": "Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and is commonly used as a spice and food-coloring agent. It is also used as a cosmetic and in some medical preparations. The desirable preventive or putative therapeutic properties of curcumin have also been considered to be associated with its antioxidant and anti-inflammatory properties. Because free-radical-mediated peroxidation of membrane lipids and oxidative damage of DNA and proteins are believed to be associated with a variety of chronic pathological complications such as cancer, atherosclerosis, and neurodegenerative diseases, curcumin is thought to play a vital role against these pathological conditions. The anti-inflammatory effect of curcumin is most likely mediated through its ability to inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). COX-2, LOX, and iNOS are important enzymes that mediate inflammatory processes. Improper upregulation of COX-2 and/or iNOS has been associated with the pathophysiology of certain types of human cancer as well as inflammatory disorders. Because inflammation is closely linked to tumor promotion, curcumin with its potent anti-inflammatory property is anticipated to exert chemopreventive effects on carcinogenesis. Hence, the past few decades have witnessed intense research devoted to the antioxidant and anti-inflammatory properties of curcumin. In this review, we describe both antioxidant and anti-inflammatory properties of curcumin, the mode of action of curcumin, and its therapeutic usage against different pathological conditions.", "corpus_id": 20549194, "score": 0 }, { "doc_id": "15787606", "title": "Dietary Curcumin Attenuates Glioma Growth in a Syngeneic Mouse Model by Inhibition of the JAK1,2/STAT3 Signaling Pathway", "abstract": "Purpose: Glioblastomas are the most common and most deadly primary brain tumors. Here, we evaluated the chemotherapeutic effect of the natural polyphenol curcumin on glioma cells in vitro and in vivo using an immunocompetent orthotopic mouse model. Experimental Design: Curcumin's effects on proliferation, cell cycle, migration, invasion, JAK/STAT3 signaling, STAT3 target gene expression, and STAT3C rescue experiments were determined in murine glioma cell lines in vitro. Therapeutic effects of curcumin in vivo were evaluated in tumor-bearing mice fed a Western-type diet fortified with curcumin (0.05%, w/w) and in control animals. Tumor growth patterns and survival were evaluated by immunohistochemistry, morphometric analyses, and Kaplan–Meier plots. Results: In vitro, curcumin inhibited JAK1,2/STAT3 tyrosine-phosphorylation in a dose-dependent fashion in murine glioma cell lines. Real-time RT-PCR revealed that curcumin downregulated transcription of the STAT3 target genes c-Myc, MMP-9, Snail, and Twist, and of the proliferation marker Ki67. Curcumin dose-dependently suppressed cell proliferation by inducing a G2/M phase arrest. In wound healing and Matrigel invasion assays, curcumin treatment resulted in a dose-dependent attenuation of the glioma cells' migratory and invasive behavior, which could be rescued by constitutively active STAT3C. In vivo, curcumin intake reduced the growth and midline crossing of intracranially implanted tumors and proliferation of tumor cells ensuing in significant long-term survival compared with control diet. Conclusion: This preclinical study shows that curcumin is capable of suppressing malignant glioma growth in vitro and in vivo. Our data suggest that the pharmacologically safe agent curcumin holds promise for clinical application in glioma therapy. Clin Cancer Res; 16(23); 5781–95. ©2010 AACR.", "corpus_id": 15787606, "score": 0 }, { "doc_id": "25608220", "title": "Activation of PPAR{gamma} by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR.", "abstract": "Colorectal cancer is a leading cause of cancer-related morbidity and mortality in the United States. Curcumin, the yellow pigment in turmeric, possesses inhibitory effects on growth of a variety of tumor cells by reducing cell proliferation and inducing apoptosis. Effects of the peroxisome proliferator-activated receptor-gamma (PPARgamma) on stimulating cell differentiation and on inducing cell cycle arrest have attracted attention from the perspective of treatment and prevention of cancer. The aim of this study was to elucidate the mechanisms by which curcumin inhibits colon cancer cell growth. In the present report, we observed that curcumin, in a dose-dependent manner, inhibited the growth of Moser cells, a human colon cancer-derived cell line, and stimulated the trans-activating activity of PPARgamma. Further studies demonstrated that activation of PPARgamma was required for curcumin to inhibit Moser cell growth. Activation of PPARgamma mediated curcumin suppression of the expression of cyclin D1, a critical protein in the cell cycle, in Moser cells. In addition, curcumin blocked EGF signaling by inhibiting EGF receptor (EGFR) tyrosine phosphorylation and suppressing the gene expression of EGFR mediated by activation of PPARgamma. In addition to curcumin reduction of the level of phosphorylated PPARgamma, inhibition of cyclin D1 expression played a major and significant role in curcumin stimulation of PPARgamma activity in Moser cells. Taken together, our results demonstrated for the first time that curcumin activation of PPARgamma inhibited Moser cell growth and mediated the suppression of the gene expression of cyclin D1 and EGFR. These results provided a novel insight into the roles and mechanisms of curcumin in inhibition of colon cancer cell growth and potential therapeutic strategies for treatment of colon cancer.", "corpus_id": 25608220, "score": 0 }, { "doc_id": "24538297", "title": "Curcumin suppresses cell proliferation through inhibition of the Wnt/β-catenin signaling pathway in medulloblastoma.", "abstract": "Recently, the survival rate of medulloblastoma patients has greatly improved; yet, patients undergoing current treatment regimes suffer from serious therapy-related side-effects. The aim of the present study was to investigate the anticancer effects of curcumin on medulloblastoma cells by testing its capacity to suppress proliferation and regulate the Wnt/β-catenin pathway. In the present study, cell proliferation was determined by MTT assay. Cell cycle was observed by flow cytometry. The changes in the Wnt/β-catenin pathway were analyzed by immunofluorescence, western blot analysis and RT-PCR. Curcumin treatment resulted in a dose- and time-dependent inhibition of proliferation in the medulloblastoma cell line. Curcumin treatment arrested the cell-cycle at the G2/M phase. Furthermore, curcumin treatment led to activation of GSK-3β, reduced expression of β-catenin and its downstream target cyclin D1. The attenuation of the Wnt/β‑catenin pathway was due to the loss of nuclear β-catenin. In conclusion, curcumin can inhibit cell growth by suppressing the Wnt/β-catenin signaling pathway, and it has the potential to be developed as a therapeutic agent for medulloblastoma.", "corpus_id": 24538297, "score": 0 }, { "doc_id": "45848514", "title": "Roles of the Akt/mTOR/p70S6K and ERK1/2 Signaling Pathways in Curcumin-Induced Autophagy", "abstract": "Curcumin has a potent anticancer effect and is a promising new therapeutic strategy. We previously demonstrated that curcumin induced non-apoptotic autophagic cell death in malignant glioma cells in vitro and in vivo. This compound inhibited the Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase pathway and activated the extracellular signal-regulated kinases 1/2 thereby inducing autophagy. Interestingly, activation of the first pathway inhibited curcumin-induced autophagy and cytotoxicity, whereas inhibition of the latter pathway inhibited curcumin-induced autophagy and induced apoptosis, thus augmenting the cytotoxicity of curcumin. These results imply that these two autophagic pathways have opposite effects on curcumin’s cytotoxicity. However, inhibition of nuclear factor κB, which is the main target of curcumin for its anticancer effect, was not observed in malignant glioma cells. These results suggest that autophagy but not nuclear factor κB plays a central role in curcumin anticancer therapy and warrant further investigation toward application in patients with malignant gliomas. Here, we discuss the therapeutic role of two autophagic pathways influenced by curcumin. Addendum to: Evidence That Curcumin Suppresses the Growth of Malignant Gliomas in Vitro and in Vivo through Induction of Autophagy: Role of Akt and Extracellular Signal-Regulated Kinase Signaling Pathways H. Aoki, Y. Takada, S. Kondo, R. Sawaya, B. B. Aggarwal and Y. Kondo Mol Pharmacol 2007; 72:29-39", "corpus_id": 45848514, "score": 0 }, { "doc_id": "8849967", "title": "Developments in antipsychotic therapy with regard to hypotheses for schizophrenia", "abstract": "The typical antipsychotic drugs like chlorpromazine and haloperidol were discovered by serendipity in the 1950s. A number of so-called “me too” drugs with similar chemical structures and modes of action were marketed in the subsequent years. The first atypical antipsychotic, clozapine, was an exception because it lacked some of the pharmacological properties of the typical antipsychotics related to the extrapyrimidal motor system. This unique feature of clozapine significantly broadened understanding of the mode of action of antipsychotics, and created new hypotheses for schizophrenia. Hypothesis-orientated development of new drugs was only recently initiated. Abnormalities of the immune system in schizophrenia are being increasingly discussed: shifts in the levels of T helper cells subsets 1 and 2 (Th1 and Th2) have been observed, and studies with risperidone and the cyclooxengenase (COX2) inhibitor celecoxib as an add-on therapy have provided very promising results. The glutamate N-methyl-D-aspartate (NMDA) receptors have also been investigated in relation to neuropathological abnormalities in prefrontal areas of the brain of patients with schizophrenia. This may lead to new technologies like artificial networks related to the glutamate NMDA receptor system. New molecular biological techniques used in pharmacogenomics and proteomics offer new and exciting directions for future drug developments.", "corpus_id": 8849967, "score": 0 }, { "doc_id": "34971773", "title": "Cytotoxic effects of antipsychotic drugs implicate cholesterol homeostasis as a novel chemotherapeutic target", "abstract": "The reported reduction in cancer risk in those suffering from schizophrenia may be because antipsychotic medications have antineoplastic effects. In this study, 6 antipsychotic agents with a range of structural and pharmacological properties (reserpine, chlorpromazine, haloperidol, pimozide, risperidone and olanzapine), were screened for their effect on the viability of cell lines derived from lymphoblastoma, neuroblastoma, non‐small cell lung cancer and breast adenocarcinoma. We aimed to determine if antipsychotic drugs in general possess cancer‐specific cytotoxic potential, and whether it can be attributed to a common mode of action. With the exception of risperidone, all drugs tested displayed selective inhibition of the viability of cancer cell lines compared with normal cells. Using Affymetrix expression microarrays and quantitative real‐time polymerase chain reaction, we found that for the antipsychotic drugs, olanzapine and pimozide, cytotoxicity appeared to be mediated via effects on cholesterol homeostasis. The role of cholesterol metabolism in the selective cytotoxicity of these drugs was supported by demonstration of their increased lethality when coadministered with a cholesterol synthesis inhibitor, mevastatin. Also, pimozide and olanzapine showed accelerating cytotoxic effects from 12 to 48 hr in time course studies, mirroring the time‐dependent onset of cytotoxicity induced by the amphiphile, U18666A. On the basis of these results, we concluded that the Class II cationic amphiphilic properties of antipsychotic drugs contribute to their cytotoxic effects by acting on cholesterol homeostasis and altering the biophysical properties of cellular membranes, and that drugs affecting membrane‐related cholesterol pathways warrant further investigation as potential augmentors of standard cancer chemotherapy.", "corpus_id": 34971773, "score": 0 }, { "doc_id": "19658185", "title": "Olanzapine inhibits the proliferation and induces the differentiation of glioma stem-like cells through modulating the Wnt signaling pathway in vitro.", "abstract": "OBJECTIVE\nOlanzapine, a D2/5-HT2 antagonist, is often used as an atypical antipsychotic drug in clinical. Previous research has found its new pharmacological influence on enhancing the differentiation of neural stem cells (NSCs) to oligodendrocyte-like cells (ODLCs). Glioblastomas are associated with poor prognoses owing to the glioma stem-like cells (GSLCs), which have a great many of similarities with adult NSCs. Hence, in this article, we aim to study the effects and associated mechanisms of olanzapine on GSLCs derived from human U87MG glioblastoma cell lines.\n\n\nMATERIALS AND METHODS\nThe methyl thiazolyl tetrazolium (MTT) colorimetric assay was conducted to investigate the effects of olanzapine on cell viability of GSLCs. Flow cytometric analysis was applied to study the cell cycle dynamics of GSLCs and Cell Counting Kit-8 (CCK-8) was used to further investigate the proliferation of GSLCs after treated with olanzapine or dimethyl sulfoxide (DMSO) for 48 h. Cell differentiation assay was carried out to study the differentiation of GSLCs and then Image-Pro Plus image analysis was used to measure the protrusion length of the differentiated cells. Furthermore, the confocal [Ca2+]c measurement was conducted to observe the influence of olanzapine on the opening function of Ca2+ channel. After the application of olanzapine for 48 h, RT-PCR was conducted to measure mRNA levels of calcium-sensing receptor (CaSR) and stromal interaction molecule 1 (STIM1), and Western blotting analysis was carried out to examine the expression of myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), CaSR protein, STIM1 protein and β-catenin protein.\n\n\nRESULTS\nOur results demonstrated that olanzapine inhibited the proliferation of GSLCs by arresting cell cycle in G0/G1 phase and facilitated the differentiation of such cells to ODLCs. After treated with olanzapine for 48 h, cells were very sensitive to 100 mM K+ stimulation, with increased spontaneous calcium wave. We also found olanzapine increased the protein expression of MBP and GFAP. In addition, the mRNA transcription and protein expression of CaSR and STIM1 were enhanced after treated with olanzapine for 48h, while the protein expression of β-catenin was suppressed.\n\n\nCONCLUSIONS\nOur results suggest that olanzapine modulates the Wnt signaling pathway through activating the Ca2+ pathway and restraining the β-catenin pathway, leading to the differentiation of GSLCs to ODLCs. It provides exciting prospects that olanzapine might be a new novel chemotherapeutic modality targeting GSLCs for the treatment of glioblastomas.", "corpus_id": 19658185, "score": 0 }, { "doc_id": "3893654", "title": "Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma", "abstract": "As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma.", "corpus_id": 3893654, "score": 0 }, { "doc_id": "24876214", "title": "Adipokines in inflammation and metabolic disease", "abstract": "The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.", "corpus_id": 24876214, "score": 0 }, { "doc_id": "4755176", "title": "Adiponectin: Regulation of its production and its role in human diseases", "abstract": "Adiponectin is a white and brown adipose tissue hormone, also known as gelatin-binding protein-28 (GBP28), AdipoQ, adipocyte complement-related protein (ACRP30), or apM1. Adiponectin circulates in the bloodstream in trimeric, hexameric, and high-molecular-mass species, while different forms of adiponectin have been found to play distinct roles in the balance of energy homoeostasis. Adiponectin is an insulin sensitizing hormone that exerts its action through its receptors AdipoR1, AdipoR2, and T-cadherin. AdipoR1 is expressed abundantly in muscle, whereas AdipoR2 is predominantly expressed in the liver. Adiponectin is inversely proportional to obesity, diabetes, and other insulin-resistant states. In this review we present the current findings regarding the regulation of its production and several new findings pertaining to its biological effects. Adiponectin enhances AMPK and the PPARα pathway in the liver and skeletal muscle. Adiponectin increases fatty acids oxidation, which lowers circulating free fatty acids and prevents insulin resistance. Adiponectin has been reported to exert an antiatherosclerotic effect. It inhibits macrophage activation and foam cell accumulation, while it also augments endothelial nitrous oxide production and protects the vasculature by reducing platelet aggregation and vasodilation. Apart from causing metabolic dysfunction, adiponectin deficiency may also contribute to coronary heart disease, steatohepatitis, insulin resistance, nonalcoholic fatty liver disease, and a wide array of cancers. In this study, we present ample evidence that adiponectin mediates multiple molecular pathways. We therefore support the concept that it shows distinct potential for being of therapeutic value in the treatment of obesity related diseases, ranging from metabolic syndrome to malignancies.", "corpus_id": 4755176, "score": 0 }, { "doc_id": "23902904", "title": "Adiponectin in inflammatory and immune-mediated diseases.", "abstract": "Circulating levels of adiponectin (APN) are reduced in obesity and associated comorbidities, with inflammation playing an important role in downregulating APN production. In contrast to obesity and metabolic disease, elevated systemic and local levels of APN are present in patients with inflammatory and immune-mediated diseases, including autoimmune and pulmonary conditions, heart and kidney failure, viral hepatitis, organ transplantation and perhaps critical illness. A positive association between inflammation and APN is usually reported in inflammatory/immune pathologies, in contrast with the negative correlation typical of metabolic disease. This review discusses the role of APN in modulation of inflammation and immunity and the potential mechanisms leading to increased levels of APN in inflammatory/immune diseases, including modification of adipose tissue physiology; relative contribution of different tissues and adipose depots; hormonal, pharmacological, nutritional and life style factors; the potential contribution of the microbiota as well as the role of altered APN clearance and release from T-cadherin-associated tissue reservoirs. Potential reasons for some of the apparently contradictory findings on the role of APN as a modulator of immunity and inflammation are also discussed, including a comparison of types of recombinant APN used for in vitro studies and strain-dependent differences in the phenotype of APN KO mice.", "corpus_id": 23902904, "score": 0 }, { "doc_id": "46449088", "title": "Leptin promotes metastasis by inducing an epithelial-mesenchymal transition in A549 lung cancer cells.", "abstract": "Leptin, an adipocyte-derived cytokine associated with obesity, has been reported to participate in carcinogenesis. Epithelial-mesenchymal transition (EMT) is also considered as a key event in tumor metastasis. The aim of this study is to investigate the mechanism of leptin in the promotion of EMT leading to metastasis in A549 lung cancer cells. We investigated the effect of leptin on migration of A549 cells using wound healing and transwell assays. The incidence of EMT in A549 cells was examined by real-time PCR and immunofluorescence staining. The expression of TGF-β in A549 cells was detected by real-time PCR, and blocking of TGF-β in A549 cells was achieved by siRNA techniques. Additional work was performed using 100 patient samples, which included samples from 50 patients diagnosed with lung cancer and an additional 50 patients diagnosed with lung cancer with metastatic bone lesions. Leptin expression was measured using immunohistochemistry techniques. We demonstrated that leptin can effectively enhance the metastasis of human lung cancer A549 cell line using both wound healing and transwell assays. We also found the incidence of EMT in A549 cells after leptin exposure. Furthermore, we detected the expression of TGF-β in A549 cells, which had been reported to play an important role in inducing EMT. We showed that leptin can significantly upregulate TGF-β at both the mRNA and protein levels in A549 cells. Using siRNA to block the expression of TGF-β in A549 cells, we confirmed the role of TGF-β in the promotion of metastasis and induction of EMT. Furthermore, we found that in patient samples leptin was present at higher levels in samples associated with diagnosis of lung cancer bone metastases tissue than lung cancer tissue. Our results indicated that leptin promoted the metastasis of A549 human lung cancer cell lines by inducing EMT in a TGF-β-dependent manner.", "corpus_id": 46449088, "score": 0 }, { "doc_id": "3879405", "title": "Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence.", "abstract": "Adiponectin, an adipocyte-secreted hormone that plays an important role in diabetes and cardiovascular disease, may also be of importance in the development and progression of several malignancies. Circulating adiponectin concentrations, which are determined mainly by genetic factors, nutrition, and adiposity, are lower in patients with breast, endometrial, prostate, and colon cancer. It has thus been proposed that adiponectin may be a biological link between obesity (especially central obesity) and increased cancer risk. Adiponectin may influence cancer risk through its well-recognized effects on insulin resistance, but it is also plausible that adiponectin acts on tumor cells directly. Several cancer cell types express adiponectin receptors that may mediate the effects of adiponectin on cellular proliferation. Herein, we review recent evidence supporting a role of serum adiponectin concentrations as a novel risk factor and possible diagnostic marker for obesity-related malignancies, including cancers of the breast, endometrium, colon, and prostate. Further studies are needed to fully elucidate the potential role of adiponectin in cancer diagnostics and therapeutics.", "corpus_id": 3879405, "score": 0 }, { "doc_id": "23427199", "title": "Adiponectin inhibits Wnt co-receptor, Lrp6, phosphorylation and β-catenin signaling.", "abstract": "Adiponectin is a pleiotropic adipokine implicated in obesity, metabolic syndrome and cardiovascular disease. Recent studies have identified adiponectin as a negative regulator of tissue fibrosis. Wnt/β-catenin signaling has also been implicated in metabolic syndrome and can promote tissue fibrosis, but the extent to which adiponectin cross-regulates Wnt/β-catenin signaling is unknown. Using primary human dermal fibroblasts and recombinant purified proteins, we show that adiponectin can limit β-catenin accumulation and downstream gene activation by inhibiting Lrp6 phosphorylation, a key activation step in canonical Wnt signaling. Inhibition of Wnt3a-mediated Lrp6 phospho-activation is relatively rapid (e.g., by 30 min), and is not dependent on established adiponectin G-protein coupled receptors, AdipoR1 and R2, suggesting a more direct relationship to Lrp6 signaling. In contrast, the ability of adiponectin to limit Wnt-induced and baseline collagen production in fibroblasts requires AdipoR1/R2. These results suggest the possibility that the pleiotropic effects of adiponectin may be mediated through distinct cell surface receptor complexes. Accordingly, we propose that the anti-fibrotic activity of adiponectin may be mediated through AdipoR1/R2 receptors, while the ability of adiponectin to inhibit Lrp6 phospho-activation may be relevant to other recently established roles for Lrp6 signaling in glucose metabolism and metabolic syndrome.", "corpus_id": 23427199, "score": 0 }, { "doc_id": "22959182", "title": "Adiponectin as Novel Regulator of Cell Proliferation in Human Glioblastoma", "abstract": "Adiponectin (Acrp30) is an adipocyte‐secreted hormone with pleiotropic metabolic effects, whose reduced levels were related to development and progression of several malignancies. We looked at the presence of Acrp30 receptors in human glioblastomas (GBM), hypothesizing a role for Acrp30 also in this untreatable cancer. Here we demonstrate that human GBM express Acrp30 receptors (AdipoR1 and AdipoR2), which are often co‐expressed in GBM samples (70% of the analyzed tumors). To investigate the effects of Acrp30 on GBM growth, we used human GBM cell lines U87‐MG and U251, expressing both AdipoR1 and AdipoR2 receptors. In these cells, Acrp30 treatment inhibits DNA synthesis and cell proliferation rate, inducing arrest in G1 phase of the cell cycle. These effects were correlated to a sustained activation of ERK1/2 and Akt kinases, upon Acrp30 treatment. Our results suggest that Acrp30 may represent a novel endogenous negative regulator of GBM cell proliferation, to be evaluated for the possible development of novel pharmacological approaches. J. Cell. Physiol. 229: 1444–1454, 2014. © 2014 Wiley Periodicals, Inc.", "corpus_id": 22959182, "score": 0 }, { "doc_id": "21333144", "title": "Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer.", "abstract": "Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.", "corpus_id": 21333144, "score": 0 }, { "doc_id": "6824218", "title": "Molecular Pathways: Adiponectin and Leptin Signaling in Cancer", "abstract": "The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiologic studies have highlighted associations between increased serum leptin levels and increased tumor growth, whereas adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify the areas of intervention and facilitate advancement in the field. Clin Cancer Res; 19(8); 1926–32. ©2013 AACR.", "corpus_id": 6824218, "score": 0 }, { "doc_id": "25494657", "title": "Improved therapeutic effect on malignant glioma with adenoviral suicide gene therapy combined with temozolomide", "abstract": "Malignant gliomas (MGs) are cancers with poor prognosis and limited therapeutic options. Herpes Simplex virus-1 thymidine kinase expressed from adenoviruses with prodrug ganciclovir (TK/GCV) is the best-characterized suicide gene therapy, whereas temozolomide (TMZ) is the first-line chemotherapy for MG. However, the potential of their combination has not been studied thoroughly. The aim of this study was to evaluate the therapeutic response of this combination and to study whether addition of valproic acid (VPA) could benefit the treatment outcome. Efficacies of different treatments were first studied in vitro in BT4C rat MG cells. Therapeutic assessment in vivo was done in an immunocompetent rat MG model for treatment efficacy and toxicity. In vitro, VPA was able to significantly enhance cytotoxicity and increase adenovirus-mediated transduction efficiency up to sevenfold. In vivo, rats receiving TK/GCV+TMZ had notably smaller tumors and enhanced survival (P<0.001) in comparison with control rats. However, VPA was not able to further enhance the treatment response in vivo. Leukocytopenia and thrombocytopenia were the major side effects. We conclude that careful optimization of the treatment schedules and doses of individual therapies are necessary to achieve an optimal therapeutic effect with TK/GCV+TMZ combination. No further in vivo benefit with VPA was observed.", "corpus_id": 25494657, "score": 0 }, { "doc_id": "206424803", "title": "Synergistic inhibitory effect of sulforaphane and 5‐fluorouracil in high and low metastasis cell lines of salivary gland adenoid cystic carcinoma", "abstract": "The present study aimed to evaluate the growth‐inhibitory effect of sulforaphane (SFN) and a traditional chemotherapy agent, 5‐fluorouracil (5‐Fu), against the proliferation of salivary gland adenoid cystic carcinoma high metastatic cell line (ACC‐M) and low metastasis cell line (ACC‐2). Furthermore, the expression of nuclear factor kappa B (NF‐κB) which induces resistance to anticancer chemotherapeutic agents was also detected. The combination effect of SFN and 5‐Fu was quantitatively determined using the method of median effect principle and the combination index. The nuclear NF‐κB p65 expression after treatment with the SFN‐5‐Fu combination was also evaluated by western blot analysis. The ACC‐M and ACC‐2 cells exhibited relative resistant to 5‐Fu. Treatment ACCs cells with SFN and 5‐Fu in combination, led to synergistic inhibition on cell growth and a decreased expression in nuclear NF‐κB p65 protein. This synergistic inhibitory effect was more significant in ACC‐M cells, which is associated with the greatly decreased expression of NF‐κB p65 (almost 5‐fold) after the combination treatment. Our results demonstrate synergism between SFN and 5‐Fu at higher doses against the ACC‐M and ACC‐2 cells, which was associated with the decreased expression of nuclear NF‐κB p65 protein. Copyright © 2008 John Wiley & Sons, Ltd.", "corpus_id": 206424803, "score": 0 }, { "doc_id": "7026004", "title": "Hypoxia-Inducible Factor-1 Inhibition in Combination with Temozolomide Treatment Exhibits Robust Antitumor Efficacy In vivo", "abstract": "Purpose: Inhibiting hypoxia-inducible factor-1 (HIF-1) represents a unique mechanism for cancer therapy. It is conceived that HIF-1 inhibitors may synergize with many classes of cancer therapeutic agents, such as angiogenesis inhibitors and cytotoxic drugs, to achieve a more robust tumor response. However, these hypotheses have not been rigorously tested in tumor models in vivo. The present study was carried out to evaluate the antitumor efficacy of combining HIF-1 inhibition with angiogenesis inhibitors or cytotoxic agents. Experimental Design: Using a D54MG-derived tumor model that allows knockdown of HIF-1α on doxycycline treatment, we examined the tumor responses to chemotherapeutic agents, including the angiogenesis inhibitor ABT-869 and cytotoxic agents 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide, in the presence or absence of an intact HIF-1 pathway. Results: Surprisingly, inhibiting HIF-1 in tumors treated with the angiogenesis inhibitor ABT-869 did not produce much added benefit compared with ABT-869 treatment alone, suggesting that the combination of an angiogenesis inhibitor with a HIF-1 inhibitor may not be a robust therapeutic regimen. In contrast, the cytotoxic drug temozolomide, when used in combination with HIF-1α knockdown, exhibited a superadditive and likely synergistic therapeutic effect compared with the monotherapy of either treatment alone in the D54MG glioma model. Conclusions: Our results show that the DNA alkylating agent temozolomide exhibits robust antitumor efficacy when used in combination with HIF-1 inhibition in D54MG-derived tumors, suggesting that the combination of temozolomide with HIF-1 inhibitors might be an effective regimen for cancer therapy. In addition, our results also show that the RNA interference–based inducible knockdown model can be a valuable platform for further evaluation of the combination treatment of other cancer therapeutics with HIF-1 inhibition.", "corpus_id": 7026004, "score": 0 }, { "doc_id": "23646947", "title": "Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model.", "abstract": "PURPOSE\nThe aims of the present work were to investigate the in vitro and in vivo antiangiogenic effects of chronic temozolomide treatment on various glioma models and to demonstrate whether bevacizumab (Avastin) increased the therapeutic benefits contributed by temozolomide in glioma.\n\n\nEXPERIMENTAL DESIGN\nThe expression levels of various antiangiogenic factors in four glioma cell lines were evaluated after chronic in vitro treatment with temozolomide by Western blot. Proliferation and migration assays were performed on human endothelial cells incubated with supernatants of glioma cells treated with and without temozolomide. Orthotopic glioma models were used to evaluate the antiangiogenic effects of temozolomide in vivo and the therapeutic benefits of different temozolomide treatment schedules used alone or in combination with bevacizumab.\n\n\nRESULTS\nTemozolomide, a proautophagic and proapoptotic drug, decreased the expression levels of HIF-1alpha, ID-1, ID-2, and cMyc in the glioma models investigated, all of which playing major roles in angiogenesis and the switch to hypoxic metabolism. These changes could be, at least partly, responsible for the impairment of angiogenesis observed in vitro and in vivo. Moreover, combining bevacizumab with temozolomide increased the survival of glioma-bearing mice in comparison to each compound administered alone.\n\n\nCONCLUSIONS\nIn addition to the numerous mechanisms of action already identified for temozolomide, we report here that it also exerts antitumor effects by impairing angiogenic processes. We further emphasize that bevacizumab, which is an antiangiogenic drug with a different mechanism of action, could be useful in combination with temozolomide to increase the latter's therapeutic benefit in glioma patients.", "corpus_id": 23646947, "score": 0 }, { "doc_id": "44439019", "title": "Resveratrol Enhances the Antitumor Effects of Temozolomide in Glioblastoma via ROS‐dependent AMPK‐TSC‐mTOR Signaling Pathway", "abstract": "Resveratrol has been regarded as a promising candidate for cancer prevention and treatment. The present study was to investigate the impact of resveratrol on the antitumor effects of temozolomide (TMZ), a standard treatment regiment of glioblastoma (GBM), in vitro and in vivo.", "corpus_id": 44439019, "score": 0 }, { "doc_id": "24528738", "title": "Inhibition of Bevacizumab-induced Epithelial-Mesenchymal Transition by BATF2 Overexpression Involves the Suppression of Wnt/β-Catenin Signaling in Glioblastoma Cells.", "abstract": "BACKGROUND/AIM\nBevacizumab (BV) has been used for the treatment of recurrent glioblastoma. However, it also induces epithelial-mesenchymal transition (EMT) in glioblastoma cells, which compromises its efficacy. BATF2 (basic leucine zipper ATF-like transcription factor 2), a multi-target transcriptional repressor, has been found to suppress cancer development partly through inhibition of Wnt/β-catenin singling. The roles of BATF2 and Wnt/β-catenin signaling in BV-induced EMT in glioblastoma cells were investigated in this study.\n\n\nMATERIALS AND METHODS\nBV was used to treat U87MG cells, and TOP/FOP FLASH luciferase reporters were employed to determine the activity of Wnt/β-catenin signaling. EMT markers were detected with quantitative reverse transcription-PCR and western blotting. Immunofluorescence (IF) was used to determine the compartmentation of β-catenin. Wound-healing, TransWell and ECIS assays were used to analyze cell adhesion, invasion and migration.\n\n\nRESULTS\nBV induced EMT phenotype in U87MG cells, and BATF2 overexpression significantly inhibited BV-induced EMT with suppression of Wnt/β-catenin signaling.\n\n\nCONCLUSION\nOur findings expanded the understanding of the role of BATF2 in tumors, and also suggested a potential of using BATF2 as a therapeutic target to hinder bevacizumab induced EMT in glioblastoma.", "corpus_id": 24528738, "score": 1 }, { "doc_id": "8360534", "title": "miR-125b inhibitor enhance the chemosensitivity of glioblastoma stem cells to temozolomide by targeting Bak1", "abstract": "Temozolomide (TMZ) is a promising chemotherapeutic agent for treating glioblastomas. However, resistance develops quickly with a high frequency. Glioblastoma stem cells (GSCs) causing resistance to drug therapy were considered to be one of key factors. The mechanisms underlying GSCs resistance to TMZ are not fully understood. MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance. Previous study showed that miR-125b was necessary for GSCs fission and for making stem cells insensitive to chemotherapy. Thus, exploring the functions and mechanisms of miR-125b action on TMZ-treated GSCs would be valuable. In this study, we found that miR-125b was up-regulated in TMZ-resistant cells, inhibition of which caused a marked increase of TMZ-induced cytotoxicity and apoptosis and a subsequent decrease in the resistance to TMZ in GSCs. Moreover, we demonstrated that the pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) was a direct target of miR-125b. Down-regulation of Bak1 inhibited TMZ-induced apoptosis and led to an increased resistance to TMZ. Restoring Bak1 expression recovered TMZ sensitivity on GSCs. Taken together; our data strongly support an important role for miR-125b on conferring TMZ resistance through targeting Bak1 expression.", "corpus_id": 8360534, "score": 0 }, { "doc_id": "3948589", "title": "ICAT inhibits glioblastoma cell proliferation by suppressing Wnt/β-catenin activity.", "abstract": "Inhibitor of β-catenin and T-cell factor (ICAT) is a key component of Wnt/β-catenin signaling. ICAT blocks the formation of the β-catenin/TCF complex and has been demonstrated to be involved in embryonic development and carcinogenesis. As an inhibitor of canonical Wnt signaling, ICAT was presumed to be a tumor-suppressor gene. However, the ICAT functions in human glioma remain unknown. In this study, we evaluated the expression of ICAT in 305 human glioma tissues and found that negative ICAT expression correlated with higher grade glioma and poor survival in patients with glioma. Then we transfected glioma cells with ICAT plasmid. Western blotting showed an increased ICAT protein expression level in glioma cells. MTT assay, flow cytometry and cell invasion assay were used to detect cell proliferation, cell cycle distribution, apoptosis and invasion. Our studies confirmed that ICAT inhibits glioma cell proliferation and invasion, and it induces cell apoptosis and cell cycle progression arrest. Besides, ICAT slowed down tumor growth in a glioblastoma xenograft model. Therefore, our study demonstrates that ICAT may serve as a tumor-suppressor in human glioma suggesting a promising direction for targeting therapy in glioma.", "corpus_id": 3948589, "score": 0 }, { "doc_id": "522028", "title": "STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression", "abstract": "Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA-alkylating agent temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-induced DNA damage due to elevated expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Here, we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (IL)-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P < 0.001, r = 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM. Mol Cancer Ther; 11(6); 1289–99. ©2012 AACR.", "corpus_id": 522028, "score": 0 }, { "doc_id": "14074940", "title": "Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast.", "abstract": "Consumers of higher levels of Brassica vegetables, particularly those of the genus Brassica (broccoli, Brussels sprouts and cabbage), reduce their susceptibility to cancer at a variety of organ sites. Brassica vegetables contain high concentrations of glucosinolates that can be hydrolyzed by the plant enzyme, myrosinase, or intestinal microflora to isothiocyanates, potent inducers of cytoprotective enzymes and inhibitors of carcinogenesis. Oral administration of either the isothiocyanate, sulforaphane, or its glucosinolate precursor, glucoraphanin, inhibits mammary carcinogenesis in rats treated with 7,12-dimethylbenz[a]anthracene. In this study, we sought to determine whether sulforaphane exerts a direct chemopreventive action on animal and human mammary tissue. The pharmacokinetics and pharmacodynamics of a single 150 mumol oral dose of sulforaphane were evaluated in the rat mammary gland. We detected sulforaphane metabolites at concentrations known to alter gene expression in cell culture. Elevated cytoprotective NAD(P)H:quinone oxidoreductase (NQO1) and heme oxygenase-1 (HO-1) gene transcripts were measured using quantitative real-time polymerase chain reaction. An observed 3-fold increase in NQO1 enzymatic activity, as well as 4-fold elevated immunostaining of HO-1 in rat mammary epithelium, provides strong evidence of a pronounced pharmacodynamic action of sulforaphane. In a subsequent pilot study, eight healthy women undergoing reduction mammoplasty were given a single dose of a broccoli sprout preparation containing 200 mumol of sulforaphane. Following oral dosing, sulforaphane metabolites were readily measurable in human breast tissue enriched for epithelial cells. These findings provide a strong rationale for evaluating the protective effects of a broccoli sprout preparation in clinical trials of women at risk for breast cancer.", "corpus_id": 14074940, "score": 0 }, { "doc_id": "10143146", "title": "Chemoprevention of prostate cancer by d,l-sulforaphane is augmented by pharmacological inhibition of autophagy.", "abstract": "There is a preclinical evidence that the oral administration of d,l-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer [prostatic intraepithelial neoplasia (PIN)] and well-differentiated cancer (WDC) but not late-stage poorly differentiated cancer (PDC). Because SFN treatment induces cytoprotective autophagy in cultured human prostate cancer cells, the present study tested the hypothesis that chemopreventive efficacy of SFN could be augmented by the pharmacologic inhibition of autophagy using chloroquine (CQ). Incidence of PDC characterized by prostate weight of more than 1 g was significantly lower in the SFN + CQ group than in control (P = 0.004), CQ group (P = 0.026), or SFN group (P = 0.002 by Fisher exact test). Average size of the metastatic lymph node was lower by about 42% in the SFN + CQ group than in control (P = 0.043 by Wilcoxon test). On the other hand, the SFN + CQ combination was not superior to SFN alone with respect to inhibition of incidence or burden of microscopic PIN or WDC. SFN treatment caused in vivo autophagy as evidenced by transmission electron microscopy. Mechanistic studies showed that prevention of prostate cancer and metastasis by the SFN + CQ combination was associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial-mesenchymal transition. Plasma proteomics identified protein expression signature that may serve as biomarker of SFN + CQ exposure/response. This study offers a novel combination regimen for future clinical investigations for prevention of prostate cancer in humans.", "corpus_id": 10143146, "score": 0 }, { "doc_id": "21329536", "title": "Sulforaphane as a promising molecule for fighting cancer.", "abstract": "Cancer is a complex disease characterized by multiple genetic and molecular alterations involving transformation, deregulation of apoptosis, proliferation, invasion, angiogenesis, and metastasis. To grow, invade, and metastasize, tumors need host components and primary dysfunction in the tumor microenvironment, in addition to cell dysfunction, can be crucial for carcinogenesis. A great variety of phytochemicals have been shown to be potentially capable of inhibiting and modulating several relevant targets simultaneously and is therefore non-specific. Because of the enormous biological diversity of cancer, this pleiotropism might constitute an advantage. Phytochemicals, in particular diet-derived compounds, have therefore been proposed and applied in clinical trials as cancer chemopreventive/chemotherapeutic agents. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables. SFN has proved to be an effective chemoprotective agent in cell culture, in carcinogen-induced and genetic animal cancer models, as well as in xenograft models of cancer. It promoted potent cytostatic and cytotoxic effects orchestrated by the modulation of different molecular targets. Cell vulnerability to SFN-mediated apoptosis was subject to regulation by cell-cycle-dependent mechanisms but was independent of a mutated p53 status. Moreover, combination of SFN with cytotoxic therapy potentiated the cytotoxic effect mediated by chemotherapy in vitro, thus suggesting its potential therapeutic benefit in clinical settings. Overall, SFN appears to be an effective and safe chemopreventive molecule and a promising tool to fight cancer.", "corpus_id": 21329536, "score": 0 }, { "doc_id": "24780825", "title": "Sulforaphane enhances temozolomide‐induced apoptosis because of down‐regulation of miR‐21 via Wnt/β‐catenin signaling in glioblastoma", "abstract": "Temozolomide (TMZ) has been widely used in the treatment of glioblastoma (GBM), although inherent or acquired resistance restricts the application. This study was aimed to evaluate the efficacy of sulforaphane (SFN) to TMZ‐induced apoptosis in GBM cells and the potential mechanism. Biochemical assays and subcutaneous tumor establishment were used to characterize the function of SFN in TMZ‐induced apoptosis. Our results revealed that β‐catenin and miR‐21 were concordantly expressed in GBM cell lines, and SFN significantly reduced miR‐21 expression through inhibiting the Wnt/β‐catenin/TCF4 pathway. Furthermore, down‐regulation of miR‐21 enhanced the pro‐apoptotic efficacy of TMZ in GBM cells. Finally, we observed that SFN strengthened TMZ‐mediated apoptosis in a miR‐21‐dependent manner. In conclusion, SFN effectively enhances TMZ‐induced apoptosis by inhibiting miR‐21 via Wnt/β‐catenin signaling in GBM cells. These findings support the use of SFN for potential therapeutic approach to overcome TMZ resistance in GBM treatment.", "corpus_id": 24780825, "score": 0 }, { "doc_id": "5135376", "title": "Sulforaphane induces differential modulation of mitochondrial biogenesis and dynamics in normal cells and tumor cells.", "abstract": "Antioxidant-based chemotherapy has been intensely debated. Herein, we show that sulforaphane (SFN) induced mitochondrial biogenesis followed by mitochondrial fusion in a kidney cell line commonly used in nephroprotective models. At the same concentration and exposure time, SFN induced cell death in prostate cancer cells accompanied by mitochondrial biogenesis and fragmentation. Stabilization of the nuclear factor E2-related factor-2 (Nrf2) could be associated with these effects in the tumor cell line. An increase in the peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) level and a decrease in the hypoxia-inducible factor-1α (HIF1α) level would suggest a possible metabolic shift. The knockdown in the nuclear respiratory factor-1 (NRF1) attenuated the SFN-induced effect on prostate cancer cells demonstrating that mitochondrial biogenesis plays an important role in cell death for this kind of tumor cells. This evidence supports SFN as a potential antineoplastic agent that could inhibit tumor development and could protect normal tissues by modulating common processes.", "corpus_id": 5135376, "score": 0 }, { "doc_id": "3082779", "title": "SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin", "abstract": "SARI, also called as BATF2, belongs to the BATF family and has been implicated in cancer cell growth inhibition. However, the role and mechanism of SARI in tumour angiogenesis are elusive. Here we demonstrate that SARI deficiency facilitates AOM/DSS-induced colonic tumorigenesis in mice. We show that SARI is a novel inhibitor of colon tumour growth and angiogenesis in mice. Antibody array and HUVEC-related assays indicate that VEGF has an essential role in SARI-controlled inhibition of angiogenesis. Furthermore, Co-IP/PAGE/mass spectrometry indicates that SARI directly targets ceruloplasmin (Cp), and induces protease degradation of Cp, thereby inhibiting the activity of the HIF-1α/VEGF axis. Tissue microarray results indicate that SARI expression inversely correlates with poor clinical outcomes in colon cancer patients. Collectively, our results indicate that SARI is a potential target for therapy by inhibiting angiogenesis through the reduction of VEGF expression and is a prognostic indicator for patients with colon cancer.", "corpus_id": 3082779, "score": 0 }, { "doc_id": "205531655", "title": "Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1", "abstract": "Enhanced expression of the CCN family of secretory integrin-binding proteins correlates with many essential components of the cancerous state, including tumor cell adhesion, proliferation, invasion and migration. Consequently, CCN1 expression is elevated in various cancers, including breast cancer, and its expression directly correlates with poor patient prognosis. Using subtraction–hybridization, combined with induction of cancer cell terminal differentiation, we cloned SARI (suppressor of activator protein (AP)-1, regulated by interferon (IFN)), an IFN-β-inducible, potent tumor suppressor gene that exerts cancer-selective growth inhibitory effects. Forced expression of SARI using an adenovirus (Ad.SARI) inhibits AP-1 function and downregulates CCN1 expression in multiple cancer lineages, resulting in a profound inhibition in anchorage-independent cell growth and tumor cell invasion. Overexpression of SARI reduces CCN1-promoter activity through inhibition of AP-1 binding. Accordingly, SARI selectively blocks expression of the transformed state in rat embryo fibroblast cells that stably overexpress c-Jun. These results illustrate that SARI inhibits AP-1 transactivating factor binding to the cis-element of the CCN1 promoter, possibly through its interaction with c-Jun. Overall, SARI can directly inhibit CCN1-induced transformation by inhibiting the transcription of CCN1, as well as indirectly by inhibiting the expression of c-Jun (and hence blocking AP-1 activity). In these contexts, transformed cells ‘addicted’ to AP-1 activity are rendered susceptible to SARI-mediated inhibition of expression of the transformed phenotype.", "corpus_id": 205531655, "score": 0 } ]

{ "doc_id": "29946700", "title": "Immunization in Alzheimer's disease: naïve hope or realistic clinical potential?", "abstract": "There has been considerable recent interest in vaccination of patients by immunotherapy as a potentially clinically useful methodology for combating histopathological changes in Alzheimer's disease (AD). The focus of the majority of this research has been on (1) active immunotherapy using the pre-aggregated synthetic β-amyloid (Aβ) 42 preparation AN1792 vaccine (QS-21), or (2) passive immunization using injections of already prepared polyclonal anti-Aβ antibodies (intravenous immunoglobulin). These two clinical approaches to the treatment of patients with AD represent the focus of this review. We conclude here that, with certain caveats, immunization offers further potential as a technique for the treatment (and possible prevention) of AD. New studies are seeking to develop and apply safer vaccines that do not result in toxicity and neuroinflammation. Nevertheless, caution is warranted, and future clinical investigations are required to tackle key outstanding issues. These include the need to demonstrate efficacy in humans as well as animal models (especially with respect to the potentially toxic side effects of immunotherapy), and fine-tuning in safely guiding the immune response. The issue of defining necessary and sufficient criteria for determining clinical efficacy remains an additional important issue for future immunization trials. The vaccination methodology appears to offer substantial current promise for clearing both soluble and aggregated amyloid in AD. However, it remains to be determined whether this approach will help to repair already damaged neural systems in the disease, and the extent to which vaccination-driven amyloid clearance will impact beneficially on patients' neurocognitive capacity and their functional status. The outcomes of future studies will be important both clinically and scientifically: an important further test of the validity of the amyloid hypothesis of AD is to evaluate the impact of an effective anti-amyloid strategy on the functional status of patients with this disease.", "corpus_id": 29946700 }

[ { "doc_id": "20156799", "title": "Current pharmacotherapy for Alzheimer's disease.", "abstract": "Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 4.5 million people in the United States. The mainstays of current pharmacotherapy for AD are compounds aimed at increasing the levels of acetylcholine in the brain, thereby facilitating cholinergic neurotransmission through inhibition of the cholinesterases. These drugs, known as acetylcholinesterase inhibitors (AChEIs), were first approved by the U.S. Food and Drug Administration (FDA) in 1995 based on clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. In 2004 the FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in moderate to severe AD cases. In clinical practice, memantine may be co-administered with an AChEI, although neither drug individually or in combination affects the underlying pathophysiology of dementia. Dementia in AD results from progressive synaptic loss and neuronal death. As knowledge of the mechanisms responsible for neurodegeneration in AD increases, it is anticipated that neuroprotective drugs to slow or prevent neuronal dysfunction and death will be developed to complement current symptomatic treatments.", "corpus_id": 20156799, "score": 0 }, { "doc_id": "15150253", "title": "The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics", "abstract": "It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.", "corpus_id": 15150253, "score": 0 }, { "doc_id": "10478592", "title": "Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics", "abstract": "Rapid progress towards understanding the molecular underpinnings of neurodegenerative disorders such as Alzheimer's disease is revolutionizing drug discovery for these conditions. Furthermore, the development of models for these disorders is accelerating efforts to translate insights related to neurodegenerative mechanisms into disease-modifying therapies. However, there is an urgent need for biomarkers to diagnose neurodegenerative disorders early in their course, when therapy is likely to be most effective, and to monitor responses of patients to new therapies. As research related to this need is currently most advanced for Alzheimer's disease, this Review focuses on progress in the development and validation of biomarkers to improve the diagnosis and treatment of Alzheimer's disease and related disorders.", "corpus_id": 10478592, "score": 0 }, { "doc_id": "36647451", "title": "Toward a Comprehensive Theory for Alzheimer's Disease. Hypothesis: Alzheimer's Disease Is Caused by the Cerebral Accumulation and Cytotoxicity of Amyloid β‐Protein", "abstract": "Abstract: A central challenge of research on Alzheimer's disease (AD) is to assemble the enormous body of scientific observations about the disorder, some of them seemingly in conflict with others, into a coherent and credible mechanism of pathogenesis. In this article, I attempt to synthesize the disparate findings on AD into a unified sequence that essentially begins with alterations in the production or clearance of the amyloid β‐protein (Aβ). Mounting evidence from many laboratories supports an Aβ accumulation in limbic and association cortices as the fundamental initiator of the disease, with attendant therapeutic implications.", "corpus_id": 36647451, "score": 0 }, { "doc_id": "10165633", "title": "Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients.", "abstract": "The defective clearance of amyloid-beta (Abeta) in the brain of Alzheimer's disease (AD) patients is unexplained. The immunohistochemical studies of the frontal lobe and hippocampus show perivascular and intraplaque infiltration by blood-borne macrophages containing intracellular Abeta but only inefficient clearance of beta deposits. Neurons and neuronal nuclei, respectively, express interleukin-1beta and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology ofbeta clearance, we examined Abeta phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls. Control monocytes display excellent differentiation into macrophages and intracellular phagocytosis of Abeta followed by beta degradation or export. AD monocytes show poor differentiation and only surface uptake of Abeta and suffer apoptosis. HLA DR and cyclooxygenase-2 are abnormally expressed on neutrophils and monocytes of AD patients. AD patients have higher levels of intracellular cytokines compared to controls. Thus Abeta clearance is not restricted to brain microglia and involves systemic innate immune responses. In AD, however, macrophage phagocytosis is defective, which may elicit compensatory response by the adaptive immune system.", "corpus_id": 10165633, "score": 0 }, { "doc_id": "38571933", "title": "General risk factors for dementia: A systematic evidence review", "abstract": "This review identifies and quantifies general (ie, nongenetic) risk factors for all‐cause dementia, Alzheimer's disease, and vascular dementia specifically.", "corpus_id": 38571933, "score": 0 }, { "doc_id": "26080281", "title": "Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease", "abstract": "High fat diets and sedentary lifestyles are becoming major concerns for Western countries. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and a condition known as the insulin-resistance syndrome or metabolic syndrome. These health conditions are well known to develop along with, or be precursors to atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of Alzheimer's disease (AD). To complicate matters, possession of one or more apolipoprotein E ɛ4 (APOE ɛ4) alleles further increases the risk or severity of many of these conditions, including AD. ApoE has roles in cholesterol metabolism and Aβ clearance, both of which are thought to be significant in AD pathogenesis. The apparent inadequacies of ApoE ɛ4 in these roles may explain the increased risk of AD in subjects carrying one or more APOE ɛ4 alleles. This review describes some of the physiological and biochemical changes that the above conditions cause, and how they are related to the risk of AD. A diversity of topics is covered, including cholesterol metabolism, glucose regulation, diabetes, insulin, ApoE function, amyloid precursor protein metabolism, and in particular their relevance to AD. It can be seen that abnormal lipid, cholesterol and glucose metabolism are consistently indicated as central in the pathophysiology, and possibly the pathogenesis of AD. As diagnosis of mild cognitive impairment and early AD are becoming more reliable, and as evidence is accumulating that health conditions such as diabetes, obesity, and coronary artery disease are risk factors for AD, appropriate changes to diets and lifestyles will likely reduce AD risk, and also improve the prognosis for people already suffering from such conditions.", "corpus_id": 26080281, "score": 0 }, { "doc_id": "39846558", "title": "Risk and protective factors for sporadic Alzheimer's disease.", "abstract": "Alzheimer's disease (AD) is the most common form of senile dementia. There are 24.3 million people suffering from this progressive neurodegenerative disorder worldwide. A century ago, AD was characterized with regard to the clinical manifestations and pathology for the first time. Up till now, there is a lack of full understanding of the underlying causes and molecular mechanisms leading to this progressive form of dementia. The majority of AD cases occur sporadically, what suggested that they could arise through interactions among various genetic and environmental factors. Current epidemiological investigations show that midlife hypertension, cardiovascular diseases, hypercholesterolemia, diabetes, obesity, inflammation, and viral infections can significantly contribute to the development and progression of AD, whereas active engagement in social, mental and physical activities may delay the onset of the disease. Apolipoprotein E (ApoE) is considered as the main genetic risk factor in the sporadic AD that is closely connected to lipid metabolism. Other genes involved in the disease pathways related to AD pathology in addition to cholesterol metabolism, neuroinflammation, amyloid and tau cascade, neuronal signalling, and plasticity are under investigation. In spite of the significant progress achieved, it is still not clear how genetic vulnerability and environmental exposures may contribute to the susceptibility of the disease. Therefore, understanding the role of disease-related risk factors for AD pathogenesis may help to identify specific modifiable risk factors that could provide possibility for the prevention of Alzheimer's dementia.", "corpus_id": 39846558, "score": 0 }, { "doc_id": "4418088", "title": "Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse", "abstract": "Amyloid-β peptide (Aβ) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes,. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Aβ42), which is the predominant form found in the amyloid plaques of Alzheimer's disease,. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner,. In the present study, transgenic animals were immunized with Aβ42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-β deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of β-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-β may be effective in preventing and treating Alzheimer's disease.", "corpus_id": 4418088, "score": 0 }, { "doc_id": "39249375", "title": "A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease.", "abstract": "Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species.", "corpus_id": 39249375, "score": 0 }, { "doc_id": "21422356", "title": "A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.", "abstract": "Vaccinations with amyloid-beta peptide (A beta) can dramatically reduce amyloid deposition in a transgenic mouse model of Alzheimer's disease. To determine if the vaccinations had deleterious or beneficial functional consequences, we tested eight months of A beta vaccination in a different transgenic model for Alzheimer's disease in which mice develop learning deficits as amyloid accumulates. Here we show that vaccination with A beta protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease. During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory. Later, at an age when untreated transgenic mice show memory deficits, the A beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice. The A beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study. This therapeutic approach may thus prevent and, possibly, treat Alzheimer's dementia.", "corpus_id": 21422356, "score": 0 }, { "doc_id": "21579664", "title": "Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease.", "abstract": "Active immunization with the amyloid beta (A beta) peptide has been shown to decrease brain A beta deposition in transgenic mouse models of Alzheimer's disease and certain peripherally administered anti-A beta antibodies were shown to mimic this effect. In exploring factors that alter A beta metabolism and clearance, we found that a monoclonal antibody (m266) directed against the central domain of A beta was able to bind and completely sequester plasma A beta. Peripheral administration of m266 to PDAPP transgenic mice, in which A beta is generated specifically within the central nervous system (CNS), results in a rapid 1,000-fold increase in plasma A beta, due, in part, to a change in A beta equilibrium between the CNS and plasma. Although peripheral administration of m266 to PDAPP mice markedly reduces A beta deposition, m266 did not bind to A beta deposits in the brain. Thus, m266 appears to reduce brain A beta burden by altering CNS and plasma A beta clearance.", "corpus_id": 21579664, "score": 0 }, { "doc_id": "5701343", "title": "Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis.", "abstract": "Immunization of transgenic mouse models of Alzheimer disease using amyloid-beta peptide (Abeta) reduces both the Alzheimer disease-like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Abeta42 in humans was discontinued because a few patients developed significant meningo-encephalitic cellular inflammatory reactions. Here we show that beneficial effects in mice arise from antibodies selectively directed against residues 4-10 of Abeta42, and that these antibodies inhibit both Abeta fibrillogenesis and cytotoxicity without eliciting an inflammatory response. These findings provide the basis for improved immunization antigens as well as attempts to design small-molecule mimics as alternative therapies.", "corpus_id": 5701343, "score": 0 }, { "doc_id": "12850827", "title": "Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice.", "abstract": "Neuritic plaques are a defining feature of Alzheimer disease (AD) pathology. These structures are composed of extracellular accumulations of amyloid-beta peptide (Abeta) and other plaque-associated proteins, surrounded by large, swollen axons and dendrites (dystrophic neurites) and activated glia. Dystrophic neurites are thought to disrupt neuronal function, but whether this damage is static, dynamic, or reversible is unknown. To address this, we monitored neuritic plaques in the brains of living PDAPP;Thy-1:YFP transgenic mice, a model that develops AD-like pathology and also stably expresses yellow fluorescent protein (YFP) in a subset of neurons in the brain. Using multiphoton microscopy, we observed and monitored amyloid through cranial windows in PDAPP;Thy-1:YFP double-transgenic mice using the in vivo amyloid-imaging fluorophore methoxy-X04, and individual YFP-labeled dystrophic neurites by their inherent fluorescence. In vivo studies using this system suggest that amyloid-associated dystrophic neurites are relatively stable structures in PDAPP;Thy-1:YFP transgenic mice over several days. However, a significant reduction in the number and size of dystrophic neurites was seen 3 days after Abeta deposits were cleared by anti-Abeta antibody treatment. This analysis suggests that ongoing axonal and dendritic damage is secondary to Abeta and is, in part, rapidly reversible.", "corpus_id": 12850827, "score": 0 }, { "doc_id": "23965747", "title": "Current Concepts and Future Prospects for Alzheimer Disease Vaccines", "abstract": "Alzheimer disease (AD) is the most prevalent form of dementia worldwide and is characterized by the progressive accumulation of the 42-residue amyloid β protein (Aβ) in brain regions serving memory and cognition. Only a few years ago, the proposition that AD may be amenable to any kind of therapy would have met with considerable skepticism. Yet, recent, exciting developments appear to suggest that immunizing against Aβ may bear some potential for arresting or even curing AD. However, a clinical trial of vaccination with synthetic human Aβ in AD patients was halted because of the development of meningoencephalitis in some patients. Further studies aimed at elucidating the mechanism of Aβ clearance upon Aβ immunization are needed. Such knowledge might facilitate the design of specific vaccination regimens, allowing exclusive targeting of Aβ plaques without inducing detrimental side effects.", "corpus_id": 23965747, "score": 0 }, { "doc_id": "43409846", "title": "The Memory Deficits in Alzheimer-Type Dementia: A Review", "abstract": "This review is an account of recent experimental studies of memory deficits at the early stages of Alzheimer-type dementia, evaluating these studies in relation to current theories of memory functioning in humans. Whilst memory deficits are found to be widespread, some aspects are more resilient to impairment than others. For example, the processes associated with articulatory rehearsal in working memory are unimpaired despite a reduction in performance on most tests of primary memory. The “implicit” aspects of secondary memory appear to remain unimpaired, in contrast to a marked decline in “explicit” or “episodic” memory. In addition, there is evidence that the rate of forgetting from secondary memory is normal. Some aspects of episodic and semantic memory are found to be impaired as a consequence of a decline in the efficient organisation and processing of verbal material at encoding or retrieval. It is concluded that the deficits share particular features found in organic amnesia, but with additional deficits which relate to impairments in other domains of functioning.", "corpus_id": 43409846, "score": 0 }, { "doc_id": "10535941", "title": "Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease", "abstract": "Background: Alzheimer disease (AD) is characterized by progressive cerebral atrophy that may be measured using MRI. Reported are MRI findings of a Phase IIa immunotherapy trial in AD prematurely terminated owing to meningoencephalitis in a subset of patients. Objective: To assess cerebral volume changes in patients immunized with AN1792 (β-amyloid [Aβ] 1 to 42) who were antibody responders (anti-AN1792 IgG titer of ≥1:2,200) compared with placebo patients. Methods: This randomized, multicenter, placebo-controlled, double-blind trial of AN1792 225 μg plus QS-21 50 μg included 372 patients with probable AD. Patients received one to three injections of AN1792/QS-21 or saline and were assessed for 12 months. Volumetric MRI was performed pre dose and at month 12 or early termination. Brain, ventricular, and hippocampal volume changes were measured from registered scan pairs. Results: Two hundred eighty-eight patients had paired scans (mean interval 10.9 months). Antibody responders (n = 45) had greater brain volume decrease (3.12 ± 1.98 vs 2.04 ± 1.74%; p = 0.007), greater ventricular enlargement as a percentage of baseline brain volume (1.10 ± 0.75 vs 0.48 ± 0.40%; p < 0.001), and a nonsignificant greater hippocampal volume decrease (3.78 ± 2.63 vs 2.86 ± 3.19%; p = 0.124) than placebo patients (n = 57). Increased losses in brain volume were not reflected in worsening cognitive performance; a composite z score across a Neuropsychological Test Battery showed differences favoring antibody responders over placebo (0.03 ± 0.39 vs −0.24 ± 0.45; p = 0.008). Conclusions: A dissociation between brain volume loss and cognitive function was observed in AN1792/QS-21 antibody responders. The reasons for this remain unclear but include the possibility that volume changes were due to amyloid removal and associated cerebral fluid shifts.", "corpus_id": 10535941, "score": 1 }, { "doc_id": "19875625", "title": "Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report", "abstract": "Amyloid-β peptide (Aβ) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Aβ in a transgenic mouse model of AD reduces both age-related accumulation of Aβ in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Aβ (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Aβ plaques; (ii) those areas of cortex that were devoid of Aβ plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Aβ-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)–(iii) strongly resemble the changes seen after Aβ immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Aβ plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7–9).", "corpus_id": 19875625, "score": 1 }, { "doc_id": "25336770", "title": "Neuropathology and Pathogenesis of Encephalitis following Amyloid β Immunization in Alzheimer's Disease", "abstract": "Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop β‐amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non treated transgenic animals im‐munization with amyloid β peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of menigoencephalitis following immunization with amyloid‐β peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation‐ with amyliod deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense(collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Aβ42and Aβ40, in addition to severe small cerebral blood Reduced amyloid burden was accompanied by low amyloid‐associated oxidative stress responses (reduced superoxide dismutase‐1:SOD‐1 expression) and by local inhibition of the stress‐activated protein kinase/c‐Jun N‐terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau in neurofibrillary tangles and β‐amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28α/β inductor, and of LMP7, LMP2 and MECL1 subunits of the immunopro‐teasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells.Immunoproteasome subunit expression was accompanied by local presentation of MHC class molecules. Release of antigenic peptides derived from β‐amyloid processing may enhance T‐cell inflammatory responses accounting for the meningoencephalitis following amyloid‐β peptide immunization", "corpus_id": 25336770, "score": 1 }, { "doc_id": "22930840", "title": "Lessons from the AN 1792 Alzheimer vaccine: lest we forget", "abstract": "Recent clinical and neuropathological data show that the AN 1792 vaccine enhanced the production of Abeta antibodies in the sera of Alzheimer's disease (AD) patients, but it appears to have been ineffective at stimulating the removal of Abeta deposits from the brain or at slowing the rate of cognitive decline. The 19 cases of meningoencephalitis were not linked in an obvious way to serum antibody titre, but they may have been linked to infiltration of the brain by antibodies and/or T-cells. Brain imaging indicated that oedema associated with the neuroinflammation did not reflect the typical distribution of neuritic plaques in AD. These outcomes were not anticipated by experiments on transgenic mice because compared to humans, these mice have less genetic variability, and their plaques have a different chemical composition, making them far more soluble and easier to remove. Furthermore, the consequences of vaccination are different. Vaccination of transgenic mice removes superfluous human Abeta while leaving endogenous mouse Abeta intact, whereas in humans the immune response is directed against an endogenous target that occurs naturally and is present in healthy brain tissue. The most important lesson to be learned from the AN 1792 trials is that new strategies for treating AD should not be tested on humans until they have been extensively tested on non-murine species.", "corpus_id": 22930840, "score": 1 }, { "doc_id": "6905030", "title": "Generation of antibodies specific for β-amyloid by vaccination of patients with Alzheimer disease", "abstract": "To characterize antibodies produced in humans in response to Aβ42 vaccination, we carried out immunohistochemical examinations of the brains of both transgenic mice and human patients with β-amyloid pathology. We collected sera from patients with Alzheimer disease who received a primary injection of pre-aggregated Aβ42 followed by one booster injection in a placebo-controlled study. Antibodies in immune sera recognized β-amyloid plaques, diffuse Aβ deposits and vascular β-amyloid in brain blood vessels. The antibodies did not cross-react with native full-length β-amyloid precursor protein or its physiological derivatives, including soluble Aβ42. These findings indicate that vaccination of AD patients with Aβ42 induces antibodies that have a high degree of selectivity for the pathogenic target structures. Whether vaccination to produce antibodies against β-amyloid will halt the cognitive decline in AD will depend upon clinical assessments over time.", "corpus_id": 6905030, "score": 1 }, { "doc_id": "19339379", "title": "Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease.", "abstract": "To test whether antibodies against beta-amyloid are effective in slowing progression of Alzheimer's disease, we assessed cognitive functions in 30 patients who received a prime and a booster immunization of aggregated Abeta(42) over a 1 year period in a placebo-controlled, randomized trial. Twenty patients generated antibodies against beta-amyloid, as determined by tissue amyloid plaque immunoreactivity assay. Patients who generated such antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, as indicated by the Mini Mental State Examination, the Disability Assessment for Dementia, and the Visual Paired Associates Test of delayed recall from the Wechsler Memory Scale, as compared to patients without such antibodies. These beneficial clinical effects were also present in two of three patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis. Our results establish that antibodies against beta-amyloid plaques can slow cognitive decline in patients with Alzheimer's disease.", "corpus_id": 19339379, "score": 1 }, { "doc_id": "35177297", "title": "Combination Therapy of Donepezil and Vitamin E in Alzheimer Disease", "abstract": "&NA; A retrospective chart review was performed on 130 patients from the Ohio State University Memory Disorders Clinic to examine the long‐term effects of combination therapy with donepezil and vitamin E on patients with Alzheimer disease. Subjects were included if they met National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer disease, had taken at least 5 mg donepezil and at least 1000 U vitamin E daily, had at least a 1‐year follow‐up while continuing these medications, and had a Mini‐Mental State Examination score of 10–24. The Mini‐Mental State Examination was then recorded annually thereafter. These data were compared with the Consortium to Establish a Registry for Alzheimer's Disease database for patients collected prior to the availability of these treatment options. Patients declined at a significantly lower rate as compared with the Consortium to Establish a Registry for Alzheimer's Disease data. The long‐term combination therapy of donepezil and vitamin E appears beneficial for patients with Alzheimer disease. Future prospective studies would be needed to compare combination treatment to vitamin E and donepezil alone.", "corpus_id": 35177297, "score": 0 }, { "doc_id": "26120821", "title": "A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD", "abstract": "Objective: To evaluate the long-term clinical efficacy and safety of donepezil versus placebo over 1 year in patients with mild to moderate AD. Methods: Patients (n = 286; mean age, 72.5 years) with possible or probable AD from five Northern European countries were randomized to receive either donepezil (n = 142; 5 mg/day for 28 days, followed by 10 mg/day) or placebo (n = 144) for 1 year. Results: The study was completed by 66.9% of the donepezil- and 67.4% of the placebo-treated patients. The benefit of donepezil over placebo was demonstrated by the Gottfries-Bråne-Steen (a global assessment for rating dementia symptoms) total score at weeks 24, 36, and 52 (p < 0.05) and at the study end point (week 52, last observation carried forward; p = 0.054). Advantages of donepezil over placebo were also observed in cognition and activities of daily living (ADL) assessed by the Mini-Mental State Examination at weeks 24, 36, and 52, and the end point (p < 0.02) and by the Progressive Deterioration Scale at week 52 and the end point (p < 0.05). Adverse events (AE) were recorded for 81.7% of donepezil- and 75.7% of placebo-treated patients, with 7% of donepezil- and 6.3% of placebo-treated patients discontinuing because of AE. Treatment response to donepezil was not predicted by APOE genotype or sex in this population. Conclusion: As the first 1-year, multinational, double-blinded, placebo-controlled study of a cholinesterase inhibitor in AD, these data support donepezil as a well tolerated and effective long-term treatment for patients with AD, with benefits over placebo on global assessment, cognition, and ADL.", "corpus_id": 26120821, "score": 0 }, { "doc_id": "18340153", "title": "Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial", "abstract": "BACKGROUND\nImmunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (Abeta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between Abeta(42) immune response, degree of plaque removal, and long-term clinical outcomes.\n\n\nMETHODS\nIn June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Abeta(42) (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Abeta immunostaining (Abeta load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model.\n\n\nFINDINGS\n20 participants--15 in the AN1792 group, five in the placebo group--died before follow-up started. A further 22 patients--19 in the AN1792 group, three in the placebo group--died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Abeta load was lower than in an unimmunised control group that was matched for age at death (2.1% [SE 0.7] in treated participants vs 5.1% [0.9] in controls; mean difference 3.0%, 95% CI 0.6-5.4; p=0.02). Although there was considerable variation in Abeta load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0.93, 95% CI 0.43-3.11; p=0.86) or of an improvement in the time to severe dementia (1.18, 0.45-3.11; p=0.73) in the AN1792 group versus the placebo group.\n\n\nINTERPRETATION\nAlthough immunisation with Abeta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.", "corpus_id": 18340153, "score": 0 }, { "doc_id": "28895177", "title": "Copolymer 1 reduces relapse rate and improves disability in relapsing‐remitting multiple sclerosis", "abstract": "we studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 ± 0.13 for patients receiving copolymer 1 and 1.68 ± 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by ≥1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo. This reaction was characterized by flushing or chest tightness with palpitations, anxiety, or dyspnea and commonly lasted for 30 seconds to 30 minutes. This rigorous study confirmed the findings of a previous pilot trial and demonstrated that copolymer 1 treatment can significantly and beneficially alter the course of relapsing-remitting MS in a well-tolerated fashion.", "corpus_id": 28895177, "score": 0 }, { "doc_id": "45614988", "title": "Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease.", "abstract": "Amyloid beta-peptide (Abeta) appears to play a key pathogenic role in Alzheimer disease (AD). Immune therapy in mouse models of AD via Abeta immunization or passive administration of Abeta antibodies markedly reduces Abeta levels and reverses behavioral impairment. However, a human trial of Abeta immunization led to meningoencephalitis in some patients and was discontinued. Here we show that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans plus glatiramer acetate, an FDA-approved synthetic copolymer used to treat multiple sclerosis, potently decreases Abeta plaques in an AD mouse model. This effect did not require the presence of antibody, as it was observed in B cell-deficient (Ig mu-null) mice. Vaccinated animals developed activated microglia that colocalized with Abeta fibrils, and the extent of microglial activation correlated strongly with the decrease in Abeta fibrils. Activation of microglia and clearing of Abeta occurred with the adjuvant alone, although to a lesser degree. Our results identify a novel approach to immune therapy for AD that involves clearing of Abeta through the utilization of compounds that have been safely tested on or are currently in use in humans.", "corpus_id": 45614988, "score": 0 }, { "doc_id": "21593244", "title": "Prototype Alzheimer’s Disease Vaccine Using the Immunodominant B Cell Epitope from β-Amyloid and Promiscuous T Cell Epitope Pan HLA DR-Binding Peptide1", "abstract": "Immunization of amyloid precursor protein transgenic mice with fibrillar β-amyloid (Aβ) prevents Alzheimer’s disease (AD)-like neuropathology. The first immunotherapy clinical trial used fibrillar Aβ, containing the B and T cell self epitopes of Aβ, as the immunogen formulated with QS21 as the adjuvant in the vaccine. Unfortunately, the clinical trial was halted during the phase II stage when 6% of the participants developed meningoencephalitis. The cause of the meningoencephalitis in the patients that received the vaccine has not been definitively determined; however, analysis of two case reports from the AN-1792 vaccine trial suggest that the meningoencephalitis may have been caused by a T cell-mediated autoimmune response, whereas production of anti-Aβ Abs may have been therapeutic to the AD patients. Therefore, to reduce the risk of an adverse T cell-mediated immune response to Aβ immunotherapy we have designed a prototype epitope vaccine that contains the immunodominant B cell epitope of Aβ in tandem with the synthetic universal Th cell pan HLA DR epitope, pan HLA DR-binding peptide (PADRE). Importantly, the PADRE-Aβ1–15 sequence lacks the T cell epitope of Aβ. Immunization of BALB/c mice with the PADRE-Aβ1–15 epitope vaccine produced high titers of anti-Aβ Abs. Splenocytes from immunized mice showed robust T cell stimulation in response to peptides containing PADRE. However, splenocytes from immunized mice were not reactivated by the Aβ peptide. New preclinical trials in amyloid precursor protein transgenic mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse events that occurred in the first clinical trial.", "corpus_id": 21593244, "score": 0 }, { "doc_id": "24200961", "title": "Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-beta peptide.", "abstract": "Intravenous immunoglobulin (IVIg), a purified immunoglobulin fraction manufactured from the blood of healthy humans, is an FDA-approved treatment for many immune and inflammatory diseases. Recent studies have demonstrated that IVIg therapy has several positive effects on patients with Alzheimer's disease (AD). These include improving cognitive functions and lowering the level of soluble amyloid-beta peptide (AbetaP) in the brain. Nonetheless, the mechanism by which IVIg mediates the clearance of AbetaP from the AD brain currently remains unknown. In this study we investigated the molecular basis for the direct and indirect effects of IVIg on AbetaP clearance using the BV-2 cellular microglia line. Specifically, we show that IVIg dissolves preformed AbetaP fibrils in vitro. Moreover, IVIg increases cellular tolerance to AbetaP, enhances microglial migration toward AbetaP deposits, and mediates phagocytosis of AbetaP. Thus, several mechanisms can be considered when examining the effects of IVIg. Our work supports the hypothesis that IVIg interferes by more than one mechanism in clearing AbetaP from the brains of Alzheimer's patients.", "corpus_id": 24200961, "score": 0 }, { "doc_id": "12920580", "title": "Antibodies against beta-amyloid reduce Abeta oligomers, glycogen synthase kinase-3beta activation and tau phosphorylation in vivo and in vitro.", "abstract": "Although active and passive immunization against the beta-amyloid peptide (Abeta) of amyloid plaque-bearing transgenic mice markedly reduces amyloid plaque deposition and improves cognition, the mechanisms of neuroprotection and impact on toxic oligomer species are not understood. We demonstrate that compared to control IgG2b, passive immunization with intracerebroventricular (icv) anti-Abeta (1-15) antibody into the AD HuAPPsw (Tg2576) transgenic mouse model reduced specific oligomeric forms of Abeta, including the dodecamers that correlate with cognitive decline. Interestingly, the reduction of soluble Abeta oligomers, but not insoluble Abeta, significantly correlated with reduced tau phosphorylation by glycogen synthase kinase-3beta (GSK-3beta), a major tau kinase implicated previously in mediating Abeta toxicity. A conformationally-directed antibody against amyloid oligomers (larger than tetramer) also reduced Abeta oligomer-induced activation of GSK3beta and protected human neuronal SH-SY5Y cells from Abeta oligomer-induced neurotoxicity, supporting a role for Abeta oligomers in human tau kinase activation. These data suggest that antibodies that are highly specific for toxic oligomer subspecies may reduce toxicity via reduction of GSK-3beta, which could be an important strategy for Alzheimer's disease (AD) therapeutics.", "corpus_id": 12920580, "score": 0 }, { "doc_id": "27815828", "title": "Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy", "abstract": "Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy", "corpus_id": 27815828, "score": 0 }, { "doc_id": "25255471", "title": "Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease", "abstract": "One hallmark of Alzheimer disease is the accumulation of amyloid β-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid β precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid β-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid β-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid β-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood–brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.", "corpus_id": 25255471, "score": 0 }, { "doc_id": "7788624", "title": "Intravenous immunoglobulins containing antibodies against β-amyloid for the treatment of Alzheimer’s disease", "abstract": "Objective: Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer’s disease (AD). Recently, it has been shown that antibodies against β-amyloid (Aβ) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of Aβ. This study reports the results from a pilot study using IVIgG in patients with AD. Methods: Five patients with AD were enrolled and received monthly IVIgG over a 6 month period. Efficacy assessment included total Aβ/Aβ1–42 measured in the CSF/serum as well as effects on cognition (ADAS-cog; CERAD) at baseline and at 6 months following IVIgG. Results: Following IVIgG, total Aβ levels in the CSF decreased by 30.1% (17.3–43.5%) compared to baseline (p<0.05). Total Aβ increased in the serum by 233% (p<0.05). No significant change was found in Aβ1–42 levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7±2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline. Conclusion: Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.", "corpus_id": 7788624, "score": 0 }, { "doc_id": "31018114", "title": "Amyloid beta peptide as a vaccine for Alzheimer's disease involves receptor-mediated transport at the blood-brain barrier.", "abstract": "Much research is now focused on a potential vaccine for Alzheimer's disease (AD). Current studies involve administering the amyloid beta peptide (Abeta) in Freund's complete adjuvant, which cannot be used in humans. Our studies show that the immune complex of Abeta is taken up by a receptor-mediated process at the blood-brain barrier (BBB). The success of immunization for AD, therefore, may be critically dependent on circulating Abeta levels which are lower in AD patients compared to AD transgenic mice. Moreover, we have found that modifying the antibody with polyamine increases its BBB permeability and may provide a better approach to passive immunization for Alzheimer's disease.", "corpus_id": 31018114, "score": 0 }, { "doc_id": "42802255", "title": "Anti-amyloid beta protein antibody passage across the blood–brain barrier in the SAMP8 mouse model of Alzheimer's disease: An age-related selective uptake with reversal of learning impairment", "abstract": "Amyloid beta protein (Abeta) levels are elevated in the brain of Alzheimer's disease patients. Anti-Abeta antibodies can reverse the histologic and cognitive impairments in mice which overexpress Abeta. Passive immunization appears safer than vaccination and treatment of patients will likely require human rather than xenogenic antibodies. Effective treatment will likely require antibody to cross the blood-brain barrier (BBB). Unfortunately, antibodies typically cross the BBB very poorly and accumulate less well in brain than even albumin, a substance nearly totally excluded from the brain. We compared the ability of two anti-Abeta human monoclonal IgM antibodies, L11.3 and HyL5, to cross the BBB of young CD-1 mice to that of young and aged SAMP8 mice. The SAMP8 mouse has a spontaneous mutation that induces an age-related, Abeta-dependent cognitive deficit. There was preferential uptake of intravenously administered L11.3 in comparison to HyL5, albumin, and a control human monoclonal IgM (RF), especially by hippocampus and olfactory bulb in aged SAMP8 mice. Injection of L11.3 into the brains of aged SAMP8 mice reversed both learning and memory impairments in aged SAMP8 mice, whereas IgG and IgM controls were ineffective. Pharmacokinetic analysis predicted that an intravenous dose 1000 times higher than the brain injection dose would reverse cognitive impairments. This predicted intravenous dose reversed the impairment in learning, but not memory, in aged SAMP8 mice. In conclusion, an IgM antibody was produced that crosses the BBB to reverse cognitive impairment in a murine model of Alzheimer's disease.", "corpus_id": 42802255, "score": 0 }, { "doc_id": "25585741", "title": "Passive Immunization against β-Amyloid Peptide Protects Central Nervous System (CNS) Neurons from Increased Vulnerability Associated with an Alzheimer's Disease-causing Mutation*", "abstract": "To characterize the effects of the familial Alzheimer's disease-causing Swedish mutations of amyloid precursor protein (SwAPP) on the vulnerability of central nervous system neurons, we induced epileptic seizures in transgenic mice expressing SwAPP. The transgene expression did not change the seizure threshold, but consistently more neurons degenerated in brains of SwAPP mice as compared with wild-type littermates. The degenerating neurons were stained both by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and by Gallyas silver impregnation. A susceptible population of neurons accumulated intracellular Aβ and immunoreacted with antibodies against activated caspase-3. To demonstrate that increased Aβ levels mediated the increased vulnerability, we infused antibodies against Aβ and found a significant reduction in neuronal loss that was paralleled by decreased brain levels of Aβ. Because the SwAPP mice exhibited no amyloid plaques at the age of these experiments, transgenic overproduction of Aβ in brain rendered neurons susceptible to damage much earlier than the onset of amyloid plaque formation. Our data underscore the possibility that Aβ is toxic, that it increases the vulnerability of neurons to excitotoxic events produced by seizures, and that lowering Aβ by passive immunization can protect neurons from Aβ-related toxicity.", "corpus_id": 25585741, "score": 0 }, { "doc_id": "23543249", "title": "Modulation of microglial activation state following passive immunization in amyloid depositing transgenic mice", "abstract": "Alzheimer's disease is a large and growing health problem. Several lines of transgenic mice overexpressing the amyloid precursor protein (APP) develop both diffuse and compacted amyloid deposits which increase in size and number with age. In the vicinity of compacted deposits, these mice develop neuritic dystrophy and activation of glia. Ultimately, these mice also develop memory deficits. Immunotherapy against the Abeta peptide has been effective in both clearing amyloid deposits from the brain, and improving the mnemonic performance of the transgenic mice. Associated with these actions, are changes in the expression of microglial markers. In some cases, the glial activation markers decline, consistent with reduced provocation from amyloid deposits. However, in a time course study, we found that some markers of microglial activation increase transiently once the immunotherapy is initiated. Still another marker continues to rise for up to 3 months of treatment, and remains elevated even after the parenchymal amyloid deposits are largely removed. These changes are consistent with a shift in the microglial phenotype, transitioning from a condition associated with inflammation and ineffective in clearing Abeta deposits to one with reduced inflammation, and capable of clearing deposited amyloid.", "corpus_id": 23543249, "score": 0 }, { "doc_id": "38365675", "title": "Human monoclonal antibodies against amyloid-beta from healthy adults", "abstract": "Two anti-amyloid-beta human antibody-producing cell lines were established from amyloid-beta (Abeta)-selected lymphocytes from peripheral blood of healthy adults. ELISA and Western blot analysis showed that the monoclonal antibodies bound with high affinity to the 43 amino acid-long amyloid-beta peptide. The antigen epitope of these antibodies encountered within amino acids 1-16 of the amyloid-beta peptide. The antibodies did not bind to several immunoglobulin light chain amyloids (AL) and amylin. One of the monoclonals was tested by immunohistochemistry for the binding to frozen sections of brains derived from patients with Alzheimer's disease. It specifically and intensively stained diffuse and core amyloid-beta plaques; whereas, sections from normal brains were not stained. Concomitant staining with a commercial mouse anti-amyloid-beta monoclonal antibody co-localized with that of the human antibody. Simultaneous staining with the human antibody and Congo red implied that the antibody binds primarily to an early immature form of beta-amyloid. Human monoclonal antibodies, which resemble physiologically normal non-pathogenic and possibly protective antibodies in healthy adults, might be attractive candidates for immune therapy of Alzheimer's disease.", "corpus_id": 38365675, "score": 0 }, { "doc_id": "46290628", "title": "The F(ab)'2 fragment of an Abeta-specific monoclonal antibody reduces Abeta deposits in the brain.", "abstract": "This work examines whether administering the F(ab' )2 fragment of an IgG1 monoclonal antibody (mAb) targeting the N-terminal 1-13 amino acids of the beta-amyloid peptide (Abeta mAb) reduces amyloid deposition in Alzheimer's disease (AD). The F(ab')2 fragment was injected intraperitoneally or intracranially into Tg2576 mice, a murine model of human AD. Both routes of administration significantly reduced Abeta plaque formation in the brain, as determined immunohistochemically and by monitoring levels of Abeta1-40 and Abeta1-42 peptide. Use of the F(ab')2 fragment significantly reduced phagocytic infiltration in the CNS when compared to intact mAb. Since IgG1 Abs do not fix complement, these findings suggest that effective in vivo clearance of amyloid deposits can be achieved without stimulation of FcR-reactive phagocytes or activation of the complement cascade.", "corpus_id": 46290628, "score": 0 }, { "doc_id": "23569553", "title": "Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice.", "abstract": "Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid-beta peptide (Abeta) levels and improves cognitive function. To specifically address the role of Abeta oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order Abeta structures but not full-length amyloid-beta precursor protein or C-terminal amyloid-beta precursor protein fragments. NAB61 also recognized a subset of brain Abeta deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated Abeta oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.", "corpus_id": 23569553, "score": 0 }, { "doc_id": "20419987", "title": "In vivo targeting of antibody fragments to the nervous system for Alzheimer’s disease immunotherapy and molecular imaging of amyloid plaques", "abstract": "Targeting therapeutic or diagnostic proteins to the nervous system is limited by the presence of the blood–brain barrier. We report that a F(ab′)2 fragment of a monoclonal antibody against fibrillar human Aβ42 that is polyamine (p)‐modified has increased permeability at the blood–brain barrier, comparable binding to the antigen, and comparable in vitro binding to amyloid plaques in Alzheimer’s disease (AD) transgenic mouse brain sections. Intravenous injection of the pF(ab′)24.1 in the AD transgenic mouse demonstrated efficient targeting to amyloid plaques throughout the brain, whereas the unmodified fragment did not. Removal of the Fc portion of this antibody derivative will minimize the inflammatory response and cerebral hemorrhaging associated with passive immunization and provide increased therapeutic potential for treating AD. Coupling contrast agents/radioisotopes might facilitate the molecular imaging of amyloid plaques with magnetic resonance imaging/positron emission tomography. The efficient delivery of immunoglobulin G fragments may also have important applications to other neurodegenerative disorders or for the generalized targeting of nervous system antigens.", "corpus_id": 20419987, "score": 0 }, { "doc_id": "45540538", "title": "Monoclonal antibodies that target pathological assemblies of Aβ", "abstract": "Amyloid beta (Aβ) immunotherapy for Alzheimer's disease has shown initial success in mouse models of Alzheimer's disease and in human patients. However, because of meningoencephalitis in clinical trials of active vaccination, approaches using therapeutic antibodies may be preferred. As a novel antigen to generate monoclonal antibodies, the current study has used Aβ oligomers (amyloid β‐derived diffusible ligands, ADDLs), pathological assemblies known to accumulate in Alzheimer's disease brain. Clones were selected for the ability to discriminate Alzheimer's disease from control brains in extracts and tissue sections. These antibodies recognized Aβ oligomers and fibrils but not the physiologically prevalent Aβ monomer. Discrimination derived from an epitope found in assemblies of Aβ1–28 and ADDLs but not in other sequences, including Aβ1–40. Immunoneutralization experiments showed that toxicity and attachment of ADDLs to synapses in culture could be prevented. ADDL‐induced reactive oxygen species (ROS) generation was also inhibited, establishing this response to be oligomer‐dependent. Inhibition occurred whether ADDLs were prepared in vitro or obtained from Alzheimer's disease brain. As conformationally sensitive monoclonal antibodies that selectively immunoneutralize binding and function of pathological Aβ assemblies, these antibodies provide tools by which pathological Aβ assemblies from Alzheimer's disease brain might be isolated and evaluated, as well as offering a valuable prototype for new antibodies useful for Alzheimer's disease therapeutics.", "corpus_id": 45540538, "score": 0 }, { "doc_id": "6501823", "title": "Meningoencephalitis associated with passive immunization of a transgenic murine model of Alzheimer's amyloidosis", "abstract": "Immunization against the Aβ peptide reverses the pathologic and behavioral manifestations of Alzheimer's disease in murine models. Since active immunization is associated with an autoimmune meningoencephalitis in a subset of humans, passive transfer of anti‐Aβ immunoglobulin is being pursued as a potentially safer alternative. We have identified cases of meningoencephalitis subsequent to peripheral and intracerebral passive immunization of Tg2576 mice. The vasocentric mononuclear infiltrate localized only to brain regions affected by Aβ amyloid deposits suggesting that the inflammatory reaction was Aβ specific. This report indicates that current passive immunization in humans should proceed with careful regard for autoimmune complications.", "corpus_id": 6501823, "score": 0 }, { "doc_id": "453000", "title": "HSV amplicon-mediated Aβ vaccination in Tg2576 mice: differential antigen-specific immune responses", "abstract": "Given the participation of amyloid beta (Abeta) in Alzheimer's disease (AD) pathogenesis the derivation of experimental therapeutics to prevent Abeta fibrillogenesis and/or enhance removal of parenchymal amyloid deposits represent viable disease-modifying approaches. Active Abeta-based immunotherapies have shown promise in mouse AD models, but application in human trials was accompanied by moderate brain inflammation in a subset of patients. Immune-shaping vaccine platforms may mitigate adverse effects. Herein, we describe the use of herpes simplex virus (HSV)-derived amplicons to elicit distinctive immune responses against Abeta. Two vaccine vectors were constructed: one expressing Abeta1-42 alone (HSVAbeta), and a second expressing Abeta1-42 fused with the molecular adjuvant tetanus toxin Fragment C (HSVAbeta/TtxFC). Peripheral administration of these vaccines augmented humoral responses to Abeta and reduced CNS Abeta deposition in Tg2576 AD mice. Interestingly and unexpectedly, HSVAbeta vaccination was uniquely toxic and incited the expression of pro-inflammatory molecule transcripts within the hippocampi of Tg2576 mice, suggesting that this paradigm may serve as a relevant model to study Abeta vaccine-elicited CNS inflammatory syndromes.", "corpus_id": 453000, "score": 0 }, { "doc_id": "619427", "title": "Is there a future for vaccination as a treatment for Alzheimer’s disease?", "abstract": "Vaccination of APP transgenic mice with Abeta has been shown to prevent amyloid deposits. A clinical trial of Abeta vaccination in Alzheimer's disease (AD) was halted due to serious neurological complications developing in some patients. Such complications were not observed in transgenic mice. Since human APP is not a mouse self-protein, vaccination of mice with Abeta should not produce an autoimmune reaction although this would be anticipated in AD. Moreover, mouse C1q poorly recognizes human Abeta so complement activation is much weaker in transgenic mice than in AD. Vaccination will increase complement activation through formation of antigen-antibody complexes. In mice this will enhance phagocytosis. But in AD, where complement is already overactivated, and where the senile plaques are relatively insoluble, this stimulation should increase production of the membrane attack complex, adding to the autodestruction of neurons. The future of vaccination as a therapy for AD will require surmounting the problems of autoimmune reactions generally and autotoxic complement activation specifically.", "corpus_id": 619427, "score": 0 }, { "doc_id": "14004286", "title": "Research criteria for the diagnosis of Alzheimer's disease: genetic risk factors, blood biomarkers and olfactory dysfunction", "abstract": "We note with interest the recently proposed new diagnostic framework published in Lancet Neurology entitled “Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria” by Dubois et al. (2007).", "corpus_id": 14004286, "score": 0 } ]

{ "doc_id": "54794998", "title": "Flocking Control of Multiple Mobile Agents with the Rules of Avoiding Collision", "abstract": "This paper investigates the flocking and the coordinative control problems of multiple mobile agents with the rules of avoiding collision. We propose a set of control laws using hysteresis in adding new links and applying new potential function to guarantee that the fragmentation of the network can be avoided, under which all agents approach a common velocity vector, and asymptotically converge to a fixed value of interagent distances and collisions between agents can be avoided throughout the motion. Furthermore, we extend the flocking algorithm to solve the flocking situation of the group with a virtual leader agent. The laws can make all agents asymptotically approach the virtual leader and collisions can be avoided between agents in the motion evolution. Finally, some numerical simulations are showed to illustrate the theoretical results.", "corpus_id": 54794998 }

[ { "doc_id": "5462808", "title": "Robust connectivity of networked vehicles", "abstract": "We present a simple geometric analysis of wireless connectivity in vehicle networks. We introduce a localized notion of connectedness, and construct a function that measures the robustness of this local connectedness to variations in position. Under a mild feasibility hypothesis, this function provides a sufficient condition for global connectedness of the network. Further, it is distributed, in the sense that both the function and its gradients can be calculated using only neighbor-to-neighbor communications. It can thus form the basis for distributed motion-control algorithms which respect connectivity constraints. We conclude with two simple examples of target applications.", "corpus_id": 5462808, "score": 0 }, { "doc_id": "546350", "title": "Flocks, herds and schools: A distributed behavioral model", "abstract": "The aggregate motion of a flock of birds, a herd of land animals, or a school of fish is a beautiful and familiar part of the natural world. But this type of complex motion is rarely seen in computer animation. This paper explores an approach based on simulation as an alternative to scripting the paths of each bird individually. The simulated flock is an elaboration of a particle systems, with the simulated birds being the particles. The aggregate motion of the simulated flock is created by a distributed behavioral model much like that at work in a natural flock; the birds choose their own course. Each simulated bird is implemented as an independent actor that navigates according to its local perception of the dynamic environment, the laws of simulated physics that rule its motion, and a set of behaviors programmed into it by the \"animator.\" The aggregate motion of the simulated flock is the result of the dense interaction of the relatively simple behaviors of the individual simulated birds.", "corpus_id": 546350, "score": 1 }, { "doc_id": "517188", "title": "Flocking for multi-agent dynamic systems: algorithms and theory", "abstract": "In this paper, we present a theoretical framework for design and analysis of distributed flocking algorithms. Two cases of flocking in free-space and presence of multiple obstacles are considered. We present three flocking algorithms: two for free-flocking and one for constrained flocking. A comprehensive analysis of the first two algorithms is provided. We demonstrate the first algorithm embodies all three rules of Reynolds. This is a formal approach to extraction of interaction rules that lead to the emergence of collective behavior. We show that the first algorithm generically leads to regular fragmentation, whereas the second and third algorithms both lead to flocking. A systematic method is provided for construction of cost functions (or collective potentials) for flocking. These collective potentials penalize deviation from a class of lattice-shape objects called /spl alpha/-lattices. We use a multi-species framework for construction of collective potentials that consist of flock-members, or /spl alpha/-agents, and virtual agents associated with /spl alpha/-agents called /spl beta/- and /spl gamma/-agents. We show that migration of flocks can be performed using a peer-to-peer network of agents, i.e., \"flocks need no leaders.\" A \"universal\" definition of flocking for particle systems with similarities to Lyapunov stability is given. Several simulation results are provided that demonstrate performing 2-D and 3-D flocking, split/rejoin maneuver, and squeezing maneuver for hundreds of agents using the proposed algorithms.", "corpus_id": 517188, "score": 0 }, { "doc_id": "17498886", "title": "Second-order consensus of multiple agents with coupling delay", "abstract": "In this paper, we investigate two kinds of second-order consensus algorithms for multiple agents with coupling delay under general fixed directed information topology. Stability analysis is performed based on Lyapunov-Krasovskii functional method. Delay-dependent asymptotical stability condition in terms of linear matrix inequalities (LMIs) is derived for the second-order consensus algorithm of delayed dynamical networks. Both delay-independent and delay-dependent asymptotical stabilities conditions in terms of LMIs are derived for the second-order consensus algorithm with information feedback.", "corpus_id": 17498886, "score": 0 }, { "doc_id": "46606090", "title": "Adaptive second-order consensus of networked mobile agents with nonlinear dynamics", "abstract": "We investigate second-order consensus of multiple nonlinear dynamical mobile agents with a virtual leader in a dynamic proximity network. We assume that only a small fraction of agents in the group have access to the information about the position and velocity of the virtual leader through, for example, certain pre-designed communication mechanism such as wireless broadcasting or sensing. To avoid fragmentation, we propose a connectivity-preserving second-order consensus algorithm. Under the assumption that the initial network is connected, we introduce local adaptation strategies for both the weights on the velocity navigational feedback and the velocity coupling strengths that enable all agents to synchronize with the virtual leader even when only one agent is informed, without requiring any knowledge of the agent dynamics. We finally provide some convincing simulation results to illustrate the theoretical results.", "corpus_id": 46606090, "score": 0 }, { "doc_id": "3626767", "title": "Neural-Network-Based Adaptive Leader-Following Control for Multiagent Systems With Uncertainties", "abstract": "A neural-network-based adaptive approach is proposed for the leader-following control of multiagent systems. The neural network is used to approximate the agent's uncertain dynamics, and the approximation error and external disturbances are counteracted by employing the robust signal. When there is no control input constraint, it can be proved that all the following agents can track the leader's time-varying state with the tracking error as small as desired. Compared with the related work in the literature, the uncertainty in the agent's dynamics is taken into account; the leader's state could be time-varying; and the proposed algorithm for each following agent is only dependent on the information of its neighbor agents. Finally, the satisfactory performance of the proposed method is illustrated by simulation examples.", "corpus_id": 3626767, "score": 0 }, { "doc_id": "120992826", "title": "Path tracking control of Lagrange systems with obstacle avoidance", "abstract": "This paper addresses a path tracking problem with obstacle avoidance for Lagrange systems. The proposed method is based on field potential methods in combination with navigation functions for obstacle avoidance. First, it is shown that a simple combination of the navigation function with the conventional path tracking controller does not work. Therefore, in order to cope with this problem, a new feedback law is proposed for a path parameter which characterizes the reference path. It is proved that the proposed controller achieves both path following and collision avoidance. Moreover, since the method adopts bounded navigation functions, the proposed controllers generate bounded input signals even when target systems approach obstacles. Finally, an experimental evaluation is performed with a two-link manipulator to illustrate the effectiveness of the proposed method.", "corpus_id": 120992826, "score": 1 }, { "doc_id": "121113483", "title": "Adaptive flocking with a virtual leader of multiple agents governed by locally Lipschitz nonlinearity", "abstract": "Abstract This paper investigates adaptive flocking of multi-agent systems (MASs) with a virtual leader. All agents and the virtual leader share the same intrinsic nonlinear dynamics, which satisfies a locally Lipschitz condition and depends on both position and velocity information for the agent itself. Under the assumption that the initial network is connected, an approach to preserving the connectivity of the network is proposed. On the basis of the Lyapunov stability theory, an adaptive flocking control law is derived, for making the MASs track the virtual leader without collision. Finally, a numerical example is presented to illustrate the effectiveness of the theoretical results.", "corpus_id": 121113483, "score": 0 }, { "doc_id": "62778473", "title": "On consensus algorithms for double-integrator dynamics", "abstract": "This paper extends some existing results in consensus algorithms for double-integrator dynamics. We propose consensus algorithms for double-integrator dynamics in four cases: (i) with a bounded control input, (ii) without relative velocity measurement, (iii) without relative velocity measurement in the presence of a group reference velocity, and (iv) with a bounded control input and with partial access to a group reference state. We show that consensus is reached asymptotically for the first two cases if the undirected interaction graph is connected. We further show that consensus is reached asymptotically for the third case if the directed interaction graph has a directed spanning tree and the gain for velocity matching with the group reference velocity is above a certain bound. We also show that consensus is reached asymptotically for the fourth case if and only if the group reference state flows directly or indirectly to all of the vehicles in the team.", "corpus_id": 62778473, "score": 1 }, { "doc_id": "16594865", "title": "On the use of correlation as a measure of network connectivity", "abstract": "Numerous studies have demonstrated that brain networks derived from neuroimaging data have nontrivial topological features, such as small-world organization, modular structure and highly connected hubs. In these studies, the extent of connectivity between pairs of brain regions has often been measured using some form of statistical correlation. This article demonstrates that correlation as a measure of connectivity in and of itself gives rise to networks with non-random topological features. In particular, networks in which connectivity is measured using correlation are inherently more clustered than random networks, and as such are more likely to be small-world networks. Partial correlation as a measure of connectivity also gives rise to networks with non-random topological features. Partial correlation networks are inherently less clustered than random networks. Network measures in correlation networks should be benchmarked against null networks that respect the topological structure induced by correlation measurements. Prevalently used random rewiring algorithms do not yield appropriate null networks for some network measures. Null networks are proposed to explicitly normalize for the inherent topological structure found in correlation networks, resulting in more conservative estimates of small-world organization. A number of steps may be needed to normalize each network measure individually and control for distinct features (e.g. degree distribution). The main conclusion of this article is that correlation can and should be used to measure connectivity, however appropriate null networks should be used to benchmark network measures in correlation networks.", "corpus_id": 16594865, "score": 0 }, { "doc_id": "16703143", "title": "Distributed Coordinated Tracking With Reduced Interaction via a Variable Structure Approach", "abstract": "A distributed coordinated tracking problem is solved via a variable structure approach when there exists a dynamic virtual leader who is a neighbor of only a subset of a group of followers, all followers have only local interaction, and only partial measurements of the states of the virtual leader and the followers are available. In the context of coordinated tracking, we focus on both consensus tracking and swarm tracking algorithms. In the case of first-order kinematics, we propose a distributed consensus tracking algorithm without velocity measurements under both fixed and switching network topologies. In particular, we show that distributed consensus tracking can be achieved in finite time. The algorithm is then extended to achieve distributed swarm tracking without velocity measurements. In the case of second-order dynamics, we first propose two distributed consensus tracking algorithms without acceleration measurements when the velocity of the virtual leader is varying under, respectively, a fixed and switching network topology. In particular, we show that the proposed algorithms guarantee at least global exponential tracking. We then propose a distributed consensus tracking algorithm and a distributed swarm tracking algorithm when the velocity of the virtual leader is constant. When the velocity of the virtual leader is varying, distributed swarm tracking is solved by using a distributed estimator. For distributed consensus tracking, a mild connectivity requirement is proposed by adopting an adaptive connectivity maintenance mechanism in which the adjacency matrix is defined in a proper way. Similarly, a mild connectivity requirement is proposed for distributed swarm tracking by adopting a connectivity maintenance mechanism in which the potential function is defined in a proper way. Several simulation examples are presented as a proof of concept.", "corpus_id": 16703143, "score": 0 }, { "doc_id": "992905", "title": "Flocking while preserving network connectivity", "abstract": "Coordinated motion of multiple agents raises fundamental and novel problems in control theory and robotics. In particular, in applications such as consensus seeking or flocking by a group of mobile agents, a great new challenge is the development of robust distributed motion algorithms that can always achieve the desired coordination. In this paper, we address this challenge by embedding the requirement for connectivity of the underlying communication network in the controller specifications. We employ double integrator models for the agents and design nearest neighbor control laws, based on potential fields, that serve a twofold objective. First, they contribute to velocity alignment in the system and second, they regulate switching among different network topologies so that the connectivity requirement is always met. Collision avoidance among neighboring agents is also ensured and under the assumption that the initial network is connected, the overall system is shown to asymptotically flock for all initial conditions. In particular, it is shown that flocking is achieved even in sparse communication networks where connectivity is more prone to failure. We conclude by illustrating a class of interesting problems that can be achieved while preserving connectivity.", "corpus_id": 992905, "score": 1 }, { "doc_id": "40124524", "title": "Rendezvous of multiple mobile agents with preserved network connectivity", "abstract": "Abstract In coordinative control of a network of multi-agent systems, to guarantee the stability of the coordinated motion, a basic assumption typically is that the underlying topology of the network can maintain its connectivity frequently enough during the motion evolution. However, for a given set of initial conditions, this assumption is very difficult to satisfy and verify. In particular, the connectivity of the initial network generally cannot guarantee the connectivity of the network throughout the evolution. In this paper, we propose a rendezvous protocol with double-integrator dynamics, which combines the functions of motion control and connectivity preservation. This protocol can enable the group of mobile agents to converge to the same position and move with the same velocity while preserving the connectivity of the whole network during the evolution if the initial network is connected. We find that there is a trade-off between the maximum overshoot and the settling time of the velocity convergence. Furthermore, we investigate the rendezvous protocol with a virtual leader and show that all agents can asymptotically attain a desired velocity even if only one agent in the team has information about the virtual leader. We finally show some numerical simulations to verify and illustrate the theoretical results.", "corpus_id": 40124524, "score": 1 }, { "doc_id": "15657826", "title": "Distributed Coordination Control of Multiagent Systems While Preserving Connectedness", "abstract": "This paper addresses the connectedness issue in multiagent coordination, i.e., the problem of ensuring that a group of mobile agents stays connected while achieving some performance objective. In particular, we study the rendezvous and the formation control problems over dynamic interaction graphs, and by adding appropriate weights to the edges in the graphs, we guarantee that the graphs stay connected.", "corpus_id": 15657826, "score": 1 }, { "doc_id": "38459292", "title": "Flocking of multiple autonomous agents with preserved network connectivity and heterogeneous nonlinear dynamics", "abstract": "Abstract This paper investigates a flocking problem of multiple agents with heterogeneous nonlinear dynamics. In order to avoid fragmentation, we construct a potential function and a connectivity-preserving flocking algorithm to enable the multiple agents to move with the same velocity while preserving the connectivity of underlying networks with a mild assumption that the initial network is connected and the coupling strength of the initial network of the nonlinear velocity consensus term is larger than a threshold value. Furthermore the proposed flocking algorithm is extended to solve the problem of multi-agent systems with a nonlinear dynamical virtual leader. The result is that all agents' velocities asymptotically approach to the velocity of the virtual leader, and the distance between any two agents is asymptotically stabilized to avoid collisions among agents. Finally, some numerical simulations are presented to illustrate the effectiveness of the theoretical results.", "corpus_id": 38459292, "score": 0 }, { "doc_id": "17743524", "title": "Decentralized Control of Connectivity for Multi-Agent Systems", "abstract": "In this paper we propose a decentralized algorithm to increase the connectivity of a multi-agent system. The connectivity property of the multi-agent system is quantified through the second smallest eigenvalue of the state dependent Laplacian of the proximity graph of agents. An exponential decay model is used to characterize the connection between agents. A supergradient algorithm is then used in conjunction with a recently developed decentralized algorithm for eigenvector computation to maximize the second smallest eigenvalue of the Laplacian of the proximity graph. A potential based control law is utilized to achieve the distances dictated by the supergradient algorithm. The algorithm is completely decentralized, where each agent receives information only from its neighbors, and uses this information to update its control law at each step of the iteration. Simulations demonstrate the effectiveness of the algorithm", "corpus_id": 17743524, "score": 0 }, { "doc_id": "125226216", "title": "Coordination of groups of mobile autonomous agents using nearest neighbor rules", "abstract": "Vicsek et al. proposed (1995) a simple but compelling discrete-time model of n autonomous agents {i.e., points or particles} all moving in the plane with the same speed but with different headings. Each agent's heading is updated using a local rule based on the average of its own heading plus the headings of its \"neighbors\". In their paper, Vicsek et al. provide simulation results which demonstrate that the nearest neighbor rule they are studying can cause all agents to eventually move in the same direction despite the absence of centralized coordination and despite the fact that each agent's set of nearest neighbors change with time as the system evolves. This paper provides a theoretical explanation for this observed behavior. In addition, convergence results are derived for several other similarly inspired models. The Vicsek model proves to be a graphic example of a switched linear system which is stable, but for which there does not exist a common quadratic Lyapunov function.", "corpus_id": 125226216, "score": 0 }, { "doc_id": "8368512", "title": "Consensus problems in networks of agents with switching topology and time-delays", "abstract": "In this paper, we discuss consensus problems for networks of dynamic agents with fixed and switching topologies. We analyze three cases: 1) directed networks with fixed topology; 2) directed networks with switching topology; and 3) undirected networks with communication time-delays and fixed topology. We introduce two consensus protocols for networks with and without time-delays and provide a convergence analysis in all three cases. We establish a direct connection between the algebraic connectivity (or Fiedler eigenvalue) of the network and the performance (or negotiation speed) of a linear consensus protocol. This required the generalization of the notion of algebraic connectivity of undirected graphs to digraphs. It turns out that balanced digraphs play a key role in addressing average-consensus problems. We introduce disagreement functions for convergence analysis of consensus protocols. A disagreement function is a Lyapunov function for the disagreement network dynamics. We proposed a simple disagreement function that is a common Lyapunov function for the disagreement dynamics of a directed network with switching topology. A distinctive feature of this work is to address consensus problems for networks with directed information flow. We provide analytical tools that rely on algebraic graph theory, matrix theory, and control theory. Simulations are provided that demonstrate the effectiveness of our theoretical results.", "corpus_id": 8368512, "score": 0 }, { "doc_id": "22982277", "title": "Flocking of Multi-Agents With a Virtual Leader", "abstract": "All agents being informed and the virtual leader traveling at a constant velocity are the two critical assumptions seen in the recent literature on flocking in multi-agent systems. Under these assumptions, Olfati-Saber in a recent IEEE Transactions on Automatic Control paper proposed a flocking algorithm which by incorporating a navigational feedback enables a group of agents to track a virtual leader. This paper revisits the problem of multi-agent flocking in the absence of the above two assumptions. We first show that, even when only a fraction of agents are informed, the Olfati-Saber flocking algorithm still enables all the informed agents to move with the desired constant velocity, and an uninformed agent to also move with the same desired velocity if it can be influenced by the informed agents from time to time during the evolution. Numerical simulation demonstrates that a very small group of the informed agents can cause most of the agents to move with the desired velocity and the larger the informed group is the bigger portion of agents will move with the desired velocity. In the situation where the virtual leader travels with a varying velocity, we propose modification to the Olfati-Saber algorithm and show that the resulting algorithm enables the asymptotic tracking of the virtual leader. That is, the position and velocity of the center of mass of all agents will converge exponentially to those of the virtual leader. The convergent rate is also given.", "corpus_id": 22982277, "score": 0 }, { "doc_id": "3816352", "title": "Semi-Global Leader-Following Consensus of Linear Multi-Agent Systems With Input Saturation via Low Gain Feedback", "abstract": "This paper investigates the problem of leader-following consensus of a linear multi-agent system on a switching network. The input of each agent is subject to saturation. Low gain feedback based distributed consensus protocols are developed. It is established that, under the assumptions that each agent is asymptotically null controllable with bounded controls and that the network is connected or jointly connected, semi-global leader-following consensus of the multi-agent system can be achieved. Numerical examples are presented to illustrate this result.", "corpus_id": 3816352, "score": 0 }, { "doc_id": "16885197", "title": "Flocking Control of Groups of Mobile Autonomous Agents Via Local Feedback", "abstract": "This paper considers a group of mobile autonomous agents moving in Euclidean space with point mass dynamics. We introduce a set of coordination control laws that enable the group to generate the desired stable flocking motion. The control laws are a combination of attractive/repulsive and alignment forces. By using the control laws, all agent velocities asymptotically approach the desired velocity, collisions can be avoided between agents, and the final tight formation minimizes all agent potentials. Moreover, we prove that the velocity of the center of mass (CoM) either is equal to the desired velocity or exponentially converges to it. Finally, for the case that not all agents know the desired final velocity, we show that the desired flocking motion can still be guaranteed", "corpus_id": 16885197, "score": 0 } ]

{ "doc_id": "129581535", "title": "Upper crustal structure and axial topography at intermediate spreading ridges: Seismic constraints from the southern Juan de Fuca Ridge", "abstract": "[1] We use multichannel seismic reflection data to image the upper crustal structure of 0–620 ka crust along the southern Juan de Fuca Ridge. The study area comprises two segments spreading at intermediate rate with an axial high morphology with narrow (Cleft) and wide (Vance) axial summit grabens (ASG). Along most of the axis of both segments we image the top of an axial magma chamber (AMC). The AMC along Cleft deepens from south to north, from 2.0 km beneath the RIDGE Cleft Observatory and hydrothermal vents near the southern end of the segment to 2.3 km at the northern end near the site of the 1980s eruptive event. Along the Vance segment, the AMC also deepens from south to north, from 2.4 to 2.7 km. Seismic layer 2A, interpreted as the basaltic extrusive layer, is 250–300 m thick at the ridge axis along the Cleft segment and 300–350 m thick along the axis of the Vance segment. However, off-axis layer 2A is similar in both segments (500–600 m), indicating ∼90% and ∼60% off-axis thickening at the Cleft and Vance segments, respectively. Half of the thickening occurs sharply at the walls of the ASG, with the remaining thickening occurring within 3–4 km of the ASG. Along the full length of both segments, layer 2A is thinner within the ASG, compared to the ridge flanks. Previous studies argued that the ASG is a cyclic feature formed by alternating periods of magmatism and tectonic extension. Our observations agree with the evolving nature of the ASG. However, we suggest that its evolution is related to large changes in axial morphology produced by small fluctuations in magma supply. Thus the ASG, rather than being formed by excess volcanism, is a rifted flexural axial high. The changes in axial morphology affect the distribution of lava flows along the ridge flanks, as indicated by the pattern of layer 2A thickness. The fluctuations in magma supply may occur at all spreading rates, but its effects on crustal structure and axial morphology are most pronounced along intermediate spreading rate ridges.", "corpus_id": 129581535 }

[ { "doc_id": "129015652", "title": "Crustal thickness and the average depth and degree of melting in fractional melting models of passive flow beneath mid‐ocean ridges", "abstract": "In simple models of passive flow beneath mid-ocean ridges, fractional melting of the upwelling mantle produces unexpected relationships amongst crustal thickness, degree of partial melting, and the average depth of melting. If the degree of melting is estimated on the basis of basalt composition, then the average degree of melting is one-third the maximum degree of melting, and the average depth of melting is about two-thirds the maximum depth in the simplest models. The crustal thickness is about 1.5 times the product of the average fraction of melting and the height of the melting column. If the average degree of melting represented in mid-ocean ridge basalts were 10% and melt production continued to the base of the crust, then only a 40-km-high residual melting column would be required to produce a 6-km-thick crust. In more realistic models, melting beginning at 60 km below the base of the crust and continuing to the top of the mantle would produce a 6-km-thick crust with average degree of melting of 6.67% or melting beginning at 67 km and ending at 30 km below the base of the crust would produce a 6-km-thick crust with an average degree of melting of only about 5.4%. Models of composition produced by fractional melting must consider the rate of melt production and the degree of melting throughout the melting region at the points where the melt is actually produced.", "corpus_id": 129015652, "score": 0 }, { "doc_id": "129731609", "title": "Structure of the East Pacific Rise crest from multichannel seismic reflection data", "abstract": "Computer-processed multichannel seismic reflection profiles from the crestal zone of the East Pacific Rise near the Siqueiros Fracture Zone have revealed distinct layering in the structure not previously observed in single-channel reflection records. After processing, which included common depth point gathering, normal move-out and stack, time-varying predictive deconvolution, and wave equation migration, three distinct crustal layers emerge as coherent events across the rise crest. The base of the third layer appears to be at a depth of about 2 km below the sea floor and may represent the top of a low-velocity magma chamber, as postulated by Orcutt et al. (1975, 1976) from the results of ocean bottom seismometer refraction data. This layer appears to thicken away from the rise crest toward the edge of the raised axial block that characterizes the East Pacific Rise (Anderson and Noltimier, 1973). Illustrated in this article is the ability of modern processing techniques as applied to multichannel seismic data to enhance weak arrivals, to minimize sound source bubble-pulse reverberations, and to remove the diffraction patterns caused by rough topography.", "corpus_id": 129731609, "score": 0 }, { "doc_id": "15795064", "title": "Geochemistry of gabbro sills in the crust-mantle transition zone of the Oman ophiolite: implications for the origin of the oceanic lower crust", "abstract": "Gabbroic sills intruding dunite in the crust-mantle transition zone (MTZ) of the Oman ophiolite have textures and compositions very similar to those in modally layered gabbros that form the lower part of the gabbro section in the ophiolite, and different from those in non-layered gabbros near the dike-gabbro transition. The presence of gabbroic sills in the MTZ indicates that modally layered gabbros can form far below the level of magmatic neutral buoyancy and far below the dike-gabbro transition. Minerals in the sills and lower, layered gabbros are in FeMg and trace element exchange equilibrium with liquids identical to those that formed the sheeted dikes and lavas in the ophiolite. In contrast, many of the upper, non-layered gabbros resemble crystallized liquid compositions, similar to the dikes and lavas. The lower, layered gabbros probably formed in sills similar to those in the MTZ. Mantle-derived magmas cooled in these sills, where they crystallized from a few percent to 50% of their mass. Residual liquids then rose to form upper gabbros, dikes and lavas. Sills may form beneath permeability barriers created by the crystallization of cooling liquid migrating by porous flow. Once permeability barriers are present, however, porous flow becomes a less important mode of magma ascent, compared to ponding in sills, gradual increase in magma pressure, and periodic ascent in hydrofractures. Thus, gabbroic sills in the MTZ may represent the transition in fast-spreading ridge environments from continuous porous flow in the mantle to periodic diking in the crust.", "corpus_id": 15795064, "score": 0 }, { "doc_id": "128689343", "title": "Three‐dimensional seismic structure and physical properties of the crust and shallow mantle beneath the East Pacific Rise at 9°30'N", "abstract": "The seismic structure of the crust and shallow mantle beneath the East Pacific Rise near 9°3O′N is imaged by inverting P wave travel time data. Our tomographic results constrain for the first time the three-dimensional structure of the lower crust in this region and allow us to compare it to shallow crustal and mantle structure. The seismic structure is characterized by a low-velocity volume (LVV) that extends from 1.2 km depth below the seafloor into the mantle. The cross-axis width of the LVV is narrow in the crust (5–7 km) and broad in the mantle (∼18 km). Although the width of the top of the LVV is similar to previous estimates, its narrow shape at lower crustal depths and its significant widening in the mantle are previously unknown features of the rise velocity structure. In the rise-parallel direction the LVV varies in magnitude such that the lowest velocities are located between two minor rise axis discontinuities near 9°28′N and 9°35′N. From the seismic results we estimate the thermal structure and melt distribution beneath the rise. The thermal structure suggests that heat removal is relatively efficient throughout the crust yet inefficient at Moho and mantle depths. Estimates of the melt distribution indicate that magma accumulates at two levels in the magmatic system. One is at the top of the magmatic system and is capped by the shallow melt lens detected by seismic reflection surveys; the other is within the Moho transition zone and topmost portion of the mantle. The highest melt fractions occur within the upper reservoir, whereas the lower reservoir contains a lower melt fraction distributed over a broader area. By volume, however, there may be up to 40% more melt in the lower reservoir than in the upper reservoir. Along-axis variations in crustal melt content are similar to those in the mantle, supporting the hypothesis that the mantle, midway between the 9°28′N and 9°35′N devais, is presently delivering greater amounts of melt to the lower crust than to regions immediately to the north or south. We see no evidence (from seismic anisotropy) for diapiric mantle flow, suggesting that solid-state flow and melt migration are decoupled in the shallow mantle. Our results are not compatible with models that require a large, segment-scale redistribution of melt within the crust. Instead, our results imply that crustal magma chambers are replenished at closely spaced intervals along the rise.", "corpus_id": 128689343, "score": 0 }, { "doc_id": "13572471", "title": "Evidence for a smaller magma chamber beneath the East Pacific Rise at 9°30′ N", "abstract": "THE size and shape of magma chambers beneath mid-ocean ridges are fundamental features that control the availability of melt, composition of magmas and formation of oceanic crust. Models derived from the study of ophiolites1, and from thermal considerations2, include a very large magma chamber, which can exceed 10–20 km in width. Cross-axis seismic reflection profiles from the East Pacific Rise, however, constrain the width of the axial magma chamber to be < 3–4 km (ref. 3). Even this may be an over-estimate, arising from the under-migration of diffracted energy generated at the edges of a smaller magma chamber. Here we show that forward modelling of these diffraction hyperbolae yields a distance between the best-fitting point diffractors, and by inference a magma chamber width, of only 800–1,200 m. Reflectivity modelling also suggests that the available data are consistent with a magma chamber comprising only a thin layer of melt. A narrow and thin axial magma chamber would inhibit along-axis mixing4, and might thereby account for variations in magma composition along the East Pacific Rise5.", "corpus_id": 13572471, "score": 0 }, { "doc_id": "129835860", "title": "Upper crustal structure as a function of plate age", "abstract": "Each Lamont-Doherty sonobuoy located on well-dated crust has been carefully analyzed to determine crustal structure down to oceanic layer 3. Results from the Atlantic and the Pacific are compiled separately in order to study crustal structure as a function of plate age in both oceans, since they have very different spreading rates. \n \nLayer 2A (refraction velocity about 3.6 km/s) in the North Atlantic is 1.5 km thick at the ridge crest and thins consistently to about 100 m as the crust ages to about 60 m.y. Layer 2A in the east Pacific is 0.7 km thick at the ridge and thins to about 100 m at about 30 m.y. This difference in thickness is probably attributable to the much faster spreading rate in the Pacific. A poorly refractive acoustic basement layer about 200 m thick with similarities to layer 2A but not necessarily composed of the same materials is measured sporadically in the Pacific M-Series plates and even less consistently in the Atlantic. This layer is not recorded in the Cretaceous or the Jurassic quiet zones. \n \nRegressions of refraction velocities in layer 2A as a function of age show that its velocity increases from about 3.3 km/s at the ridge crests to that of layer 2B on crust about 40 m.y. old. There is no corresponding increase of velocity with age in any of the deeper layers. \n \nThe high resolution of the air gun/sonobuoy records shows that the layer 2B refraction line breaks directly to layer 3 velocities (46 times in the present work) or to a line with a velocity of 6.1 km/s (114 times in the present work), which we call layer 2C. The variance of the velocities in 2C is one fourth that of 2A and 2B, which indicates relative lithological uniformity in 2C. \n \nIt does not seem likely that layer 2A really thins; what appears to be a thinning of the layer may actually be the result of an increase of its refraction velocity with age. However, the 2A/2B interface is well-defined by large amplitude refractions from 2B on crust that is younger than about 30 m.y., which seems to rule out a transitional zone at the base of layer 2A where it ‘converts’ to 2B. The seismic observations seem to require a diagenetic process or repeated basaltic intrusions; both processes raise serious objections.", "corpus_id": 129835860, "score": 0 }, { "doc_id": "46367263", "title": "In situ evidence for the nature of the seismic layer 2/3 boundary in oceanic crust", "abstract": "THE igneous oceanic crust is typically thought of as comprising two layers: an upper crust ('seismic layer 2') characterized by a rapid increase in seismic velocity with depth, and a thicker lower crust ('seismic layer 3') which is distinguished from layer 2 by both a higher P-wave velocity (6.69 ± 0.26 km s -l) and a much smaller vertical velocity gradient (<1 km s-1 km-1)1–3. A direct correlation has never been established between this seismic layering and the in situ lithological and physical properties of oceanic crust. The transition between seismic layers 2 and 3 has been variously interpreted as a change in igneous rock texture from doleritic sheeted dykes to gabbro4,5, an increase in metamorphic grade from greenschist- to amphibolite-facies rocks2,6–9, or a change in bulk crustal porosity with depth2,10. We have re-examined available seismic refraction data from around Hole504B, the deepest (>1.8 km) continuous hole drilled into the oceanic crust11–13, and find that at this location the seismic layer 2/3 boundary lies within the sheeted-dyke complex, where it is associated with gradual downhole changes in crustal porosity and alteration, not a litho-logical transition from sheeted dykes to gabbro.", "corpus_id": 46367263, "score": 0 }, { "doc_id": "129794326", "title": "Lava flow layer‐East Pacific Rise", "abstract": "A multichannel seismic reflection profile across the East Pacific Rise near 9°N reveals an approximately 400 m thick layer at the top of the oceanic crust with seismic velocity of about 2.8 km/s at the Rise crest. This velocity increases to about 3.8 km/s, 210 km east of the Rise crest. These low velocities suggest that this layer is probably a porous lava flow layer (layer 2A of seismic refraction studies) generated by volcanic activity at the spreading center. Reflections from the base of the layer imply a relatively sharp transition between the lava flows and the underlying layer (presumably a sheeted dike complex). The underlying layer is a zone about 1.4 km thick (with velocity about 5.7 km/s) whose base may coincide with the top of a low velocity magma chamber from which the crust develops.", "corpus_id": 129794326, "score": 0 }, { "doc_id": "129624589", "title": "A multichannel seismic investigation of upper crustal structure at 9°N on the East Pacific Rise: Implications for crustal accretion", "abstract": "Reprocessed multichannel seismic profiles from the 9°N segment of the East Pacific Rise reveal prominent shallow subbasement events. These events are identified as wide-angle reflections from the base of seismic layer 2A, based upon modeling of expanding spread profile data and velocity functions. The layer 2A reflections typically increase from 0.15 s after the seafloor reflection at the rise axis to 0.3–0.45 s within 1–2 km of the axis, corresponding to an increase in layer thickness of 200–600 m. No further systematic increase in layer thickness is observed, although lateral variability of the order of a few hundred meters in thickness is observed at greater offsets from the rise axis. However, the intermittent character of the imaged layer 2A reflection is attributed to focusing and defocusing of energy by the seafloor bathymetry rather than necessarily to intrinsic lateral variability at the base of the layer. The base of layer 2A is interpreted as corresponding to the transition between the extrusive section, pillow basalts and sheet flows, and a sheeted dike complex. The rapid thickening of the layer near the rise axis is attributed to successive lava flows burying the initially shallow top of the sheeted dike complex as the layer passes through the neovolcanic zone. Lateral variability of layer 2A can significantly affect the imaging of the underlying axial magma chambers as average velocities within layer 2A are approximately half that of layer 2B. For an along-axis profile, apparent along-axis variability in the depth of the axial magma chamber is traced to variability in the thickness of layer 2A caused by wandering of the profile relative to axis. Within the resolution of the data, the time delay of the magma chamber reflection relative to the base of layer 2A is constant.", "corpus_id": 129624589, "score": 1 }, { "doc_id": "129657188", "title": "A global analysis of mid-ocean ridge axial topography", "abstract": "SUMMARY \n \nCurrent views of mid-ocean ridges are strongly influenced by extensive mapping of the Mid-Atlantic Ridge and East Pacific Rise. The global picture of the mid-ocean ridge system, particularly in the sparsely surveyed Southern Oceans, is still based primarily on underway bathymetry profiles collected over the past 40 years. This study presents a quantitative analysis of global mid-ocean ridge morphology based on 156 of these underway bathymetric profiles, thereby allowing commonly recognized features such as axial valleys and axial ridges to be compared on a global basis. An Empirical Orthogonal Function (EOF) analysis is used to separate deterministic and stochastic components of axial morphology and to quantify the dependence of each on parameters such as spreading rate and axial depth. It is found that approximately 50 per cent of the variance in axial morphology may be described as a linear combination of five independent symmetric and anti-symmetric modes; the remainder is considered stochastic. Maximum axial valley relief decreases with spreading rate for rates less than 80 mm yr-1 while axial ridge relief remains relatively constant for all rates greater than 50 mm yr-1. The stochastic component of the axial morphology, referred to as bathymetric roughness, also decreases with spreading rate for rates less than 80 mm yr-1 and remains relatively constant at higher rates. Although both axial valley relief and bathymetric roughness near the ridge axis show a similar spreading rate dependence, they are weakly correlated at slow spreading centres. The distinct differences in morphologic variability of fast and slow spreading ridges may result from the episodicity of magmatic heat input which controls the lithospheric rheology at slow spreading ridges. These observations support the notion of a critical threshold separating two dynamically distinct modes of lithospheric accretion on mid-ocean ridges.", "corpus_id": 129657188, "score": 0 }, { "doc_id": "127630537", "title": "Bathymetric roughness of the Southeast Indian Ridge: Implications for crustal accretion at intermediate spreading rate mid-ocean ridges (Paper 97JB01280)", "abstract": "The nature of the transition from axial highs to axial valleys at mid-ocean ridges and the physical processes involved in the transition are important for understanding how axial morphology changes with spreading rate, mantle temperature, and lithospheric strength at mid-ocean ridges. In order to provide observational constraints on the nature of the changes in axial morphology, we examined the regional- and segment-scale variations in axial and flank morphology at the intermediate spreading Southeast Indian Ridge (SEIR) using newly collected geophysical data. An empirical orthogonal function analysis was used to separate regional and local components of the topography field and to estimate bathymetric roughness. Three distinct types of axial morphology were identified from the regional component of ridge topography in our area: axial highs, shallow axial valleys, and “Mid-Atlantic Ridge-type” deep axial valleys. Axial depth increases by ∼2100 m from 88°E and 118°E, while off-axis depth only increases by ∼500 m. In addition, except for one segment with a deep axial valley, there is little change in off-axis depth within segments, in contrast to the large intrasegment variations in axial depth. These observations indicate that the overall and intrasegment variations in crustal thickness are much smaller than would be predicted from the variations in axial depth and that the major portion of the variations in ridge axis depth are dynamically supported. There are step-like increases in bathymetric roughness as axial morphology changes from an axial high to a shallow axial valley and from a shallow axial valley to a deep axial valley. The step changes in roughness imply that the change from one mode of axial morphology to another is accompanied by an abrupt change in the strength of the lithosphere. The abrupt changes in lithospheric strength may be due to the existence of a “threshold” mantle temperature or crustal thickness about which the lithospheric strength is very sensitive to small fluctuations. Systematic intrasegment variations in roughness are also observed. Roughness shows V-shaped patterns within segments with axial highs but no clear pattern within segments with axial valleys. The different patterns in roughness at axial highs and axial valleys on the SEIR may result from the presence or absence of a magma chamber. The presence of a magma chamber at a ridge segment with an axial high implies weaker axial lithosphere and hence lower roughness near the center of segments relative to the segment ends.", "corpus_id": 127630537, "score": 0 }, { "doc_id": "4692003", "title": "Causes for axial high topography at mid-ocean ridges and the role of crustal thermal structure", "abstract": "Mid-ocean ridge topography is modeled as the flexural response to loads using a thin plate approximation and setting thermal structure of the lithosphere to allow, but not require, a region of rapid cooling near the axis. Loads on the lithosphere arise from the presence of low-density melt, densification due to cooling with distance from the ridge axis, and thermal contraction stresses. We find two end-member classes of temperature and melt structure that can produce axial high topography and gravity observed at the East Pacific Rise (EPR). One class is very similar to previous models, requiring a narrow column of melt extending to at least 30 km depth within the mantle and lithosphere which cools and thickens very gradually with distance from the ridge axis. The other is a new class, predicting lithosphere which cools rapidly within a few kilometers of the axis and then slowly farther from the axis, with melt which is contained primarily within the crust. The latter solution is consistent with tomography and compliance studies at the EPR which predict rapid crustal cooling within a few kilometers of the axis that is attributed to hydrothermal circulation. This solution also allows the melt region to be coupled to crustal thermal structure and requires no melt anomaly within the mantle. Model fits predict 0–30% melt in the lower crust, depending on how temperatures are distributed within the lithosphere and the degree to which thermal contraction stresses are assumed to contribute to topography. The model generally predicts a wider axial high for lithosphere which is thin over a wider region near the axis. This is consistent with previous correlations between large cross-sectional area of the high and indicators of higher melt presence or a warmer crustal thermal regime. For a slightly slower rate of lithospheric cooling at distances more than ∼5 km from the axis the model predicts a trough at the base of the axial high. Such troughs have been previously observed at the base of the high on the western flank of the southern EPR, where subsidence rates are anomalously low. Finally, thick axial lithosphere reduces the amplitude of the high, making it sometimes difficult to distinguish from long-wavelength subsidence. This morphology is comparable to that of some intermediate spreading ridges, where topography is relatively flat, suggesting a transition from fast to intermediate style morphology.", "corpus_id": 4692003, "score": 0 }, { "doc_id": "128829658", "title": "Relationship between axial morphology, crustal thickness, and mantle temperature along the Juan de Fuca and Gorda Ridges", "abstract": "We analyze gravity data over the Juan de Fuca and northern Gorda Ridges to understand the lithospheric structure of two ridges with contrasting axial morphologies spreading at the same intermediate rate (28 mm/yr half rate). The Cleft Segment, at the south end of the Juan de Fuca Ridge, has an axial high morphology while the northern segment of the Gorda Ridge has a rift valley. Residual mantle Bouguer anomalies (RMBA) on the northern Gorda Ridge are elevated relative to the Cleft Segment by 10–20 mGal, indicating thinner crust and/or a colder mantle. The minimum value (−50 mGal) of the RMBA along the Juan de Fuca Ridge is over Axial Seamount and gradually increases south toward the Blanco Transform. The observed RMBA are interpreted to result from along axis variations in crustal thickness and mantle density, both of which are controlled by temperatures in the upper mantle where decompression melting occurs. We estimate that mantle temperatures are elevated by 30°–40°C beneath Axial Seamount, resulting in an excess crustal thickness of ∼1.7 km. The Cleft Segment is associated with crust that is estimated to be only 300–700 m thicker, and mantle temperatures are only 10°–15°C higher than beneath the northern Gorda Ridge. However, even these small differences in crustal thickness and mantle temperature appear to be sufficient to produce a major change in lithospheric strength and axial morphology. These results are consistent with the predicted sensitivity of recent thermo-mechanical models for rift valley formation to small changes in crustal thickness and mantle temperature at intermediate spreading rates. We attribute the systematic differences in axial morphology, crustal thickness, mantle temperature, and lithospheric strength along the Juan de Fuca/Gorda ridge system to the presence of the Cobb thermal anomaly at Axial Seamount. The hotter mantle beneath the Juan de Fuca Ridge results in greater amounts of decompression melting and the formation of a thicker crust and a thinner, weaker lithosphere than along the Gorda Ridge.", "corpus_id": 128829658, "score": 0 }, { "doc_id": "128535335", "title": "Transitions in axial morphology along the Southeast Indian Ridge", "abstract": "Shipboard bathymetric and magnetic profiles across the Southeast Indian Ridge (SEIR) were analyzed in order to examine the nature of along-axis variations in axial morphology at this intermediate spreading rate ridge. Three types of axial morphology are observed along the SEIR: an axial high, a shallow (200–700 m deep) axial valley and a deep (>1000 m deep) axial valley. An axial high is found to the east of the Australian-Antarctic Discordance (AAD) (east of 128°E) and between 82°E and 104°E. A shallow rift valley is found from 104°E to 114°E and from 82°E westward past the Amerstdam/St. Paul hotspot (ASP) to about 30°S, 75°E. Deep rift valleys are found from 114°E to 128°E in the vicinity of the AAD and from the Indian Ocean Triple Junction (IOTJ) at 25°S, 70°E to about 30°S, 75°E. The transition near 30°S occurs in an area of constant zero-age depth and does not appear to result from an increase in mantle temperature. It could be the result of the rapid increase in spreading rate along that portion of the SEIR. The most likely cause of the other transitions in axial morphology is variations in mantle temperature. The transitions between the different types of axial morphology are well defined and occur over a limited distance. Transitions in axial morphology are accompanied by significant changes in ridge flank topographic roughness. The transitions from axial valleys to axial highs are also accompanied by changes in the amplitude of the seafloor magnetic anomalies. Our observations suggest that there are distinct modes rather than a continuum of axial morphology on the SEIR and that there appears to be a “threshold” mechanism for a rapid change between different states of axial morphology. The ASP has only a limited influence on the SEIR. The ridge axis is marked by an axial valley for the entire distance from the IOTJ up to and past the ASP. The ridge axis becomes shallower as the ASP is approached from the northwest but only by about 300 m over a distance of 800 km. In addition, the ridge continues to become shallower away from Amsterdam Island toward the transition to an axial high at 82°E, 350 km to the east of the ASP. The Kerguelen hotspot appears to exert a major influence on the morphology of the SEIR by feeding asthenospheric material to the ridge axis. A long, narrow finger-like gravity high extends ENE away from the Kerguelen Plateau for a distance of 500 km. Shipboard data show that the gravity high results from a large volcanic ridge. The ridge appears analogous to the Rodriguez Ridge extending from the Reunion hotspot toward the Central Indian Ridge. A series of lower and broader lineated gravity highs extend from the volcanic ridge toward the SEIR in the ridge segment between the 81°E and 85°E transforms, which is the westernmost segment with an axial high. The only region of significant off-ridge seismicity on the Antarctic flank of the SEIR is a diffuse band of epicenters extending from Kerguelen to the SEIR within the segment between the 81°E and 85°E fracture zones. The along-axis gradient in depth from 86°E to the AAD and the transitions in axial morphology at 104°E and 114°E most likely reflect along-axis variations in mantle temperature and melt production rate due to distance from the Kerguelen hotspot and the influence of the AAD.", "corpus_id": 128535335, "score": 0 }, { "doc_id": "128612353", "title": "Variations in axial morphology along the Galápagos spreading center and the influence of the Galápagos hotspot", "abstract": "The Galapagos Spreading Center (GSC) is marked by systematic changes in axial morphology between the Inca Fracture Zone (FZ) at 85.5°W and the 95.5°W propagator. We analyze these changes using new swath bathymetry and magnetic data acquired aboard the B/O Hesperides during the Galapagos'96 experiment. Within ∼350 km of the Galapagos hotspot the ridge axis is associated with an East Pacific Rise (EPR)-like axial high. At increasing distance from the hotspot the axial high broadens and deepens forming a distinctive transitional axial morphology (TAM). The axis in this transitional region is typically a broad zone (∼20 km wide) consisting of very rough volcanic and fault-generated topography. West of 95°W, this TAM evolves into a 20–40 km wide, 400–1500 m deep axial valley typical of the slow spreading Mid-Atlantic Ridge (MAR). There is not an abrupt change from axial high to rift valley along the GSC, but a distinct TAM occurs over a distance of ∼200–300 km along-axis and is accompanied by a gravity-estimated crustal thickening of >1–2 km. The boundary between an axial high and this TAM is quite abrupt and occurs along a segment that is less than 9 km long. These changes in axial morphology are primarily caused by variations in magma supply along the GSC due to the entrainment and dispersal of plume mantle from the Galapagos hotspot. However, the changes in morphology are not symmetric about the Galapagos FZ at 91°W. The axial high topography extends farther east of the 91°W FZ than to the west, and the rift valley which develops west of 94°W is not found at comparable distances along the GSC east of the hotspot. Axial depth variations are also asymmetric across the 91°W FZ. This asymmetry in both morphology and axial depth variation is attributed to a full spreading rate increase along the GSC from 46 mm/yr at 97°W to 64 mm/yr at 85°W. Off-axis depth changes are symmetric about the 91°W FZ and suggest that 15–40% of on-axis depth variation is dynamically supported.", "corpus_id": 128612353, "score": 0 }, { "doc_id": "128441609", "title": "Seismic constraints on shallow crustal emplacement processes at the fast spreading East Pacific Rise", "abstract": "We present the results of nine on-bottom seismic refraction experiments carried out over young East Pacific Rise crust. The experiments are unusual in that both the source and receiver are located within a few meters of the seafloor, allowing high-resolution determinations of shallow crustal structure. Three experiments were located within the axial summit caldera (ASC) over “zero-age” crust. The seismic structure at these three locations is fundamentally the same, with a thin (<60 m) surficial low-velocity (<2.5 km/s) layer, a 100 to 150-m-thick transition zone with velocities increasing by ∼2.5 km/s, and a layer with velocities of ∼5 km/s at a depth beneath the seafloor of ∼130–190 m. The surficial low-velocity layer and transition zone are defined as seismic layer 2A, and the ∼5 km/s layer is defined as the top of layer 2B. Both the surficial low-velocity layer and the transition zone double in thickness within ∼1 km of the rise axis. We model layer 2A as the extrusive sequence and transition zone and the 2A/2B boundary as the top of the sheeted dikes. The primary implication of this interpretation is that the depth to the top of the sheeted dikes deepens from ∼150 m to ∼300 m within 1 km of the ASC. The thickening of the extrusive layer is interpreted to be due to lava that either overflows the ASC walls, is emplaced through eruptions outside of the ASC, or travels laterally from the ASC through conduits. The most probable cause for the thickening of the transition zone is sill emplacement outside of the ASC, either from magma that does not reach the surface in an off-axis eruption or magma that is transported laterally during the drainage process creating the ASC. We suggest that the mechanism controlling the magnitude and rate of the dike subsidence is the mechanism that determines the thickness of the extrusive section and the total thickness of layer 2A.", "corpus_id": 128441609, "score": 0 }, { "doc_id": "53625537", "title": "Constraining crustal emplacement processes from the variation in seismic layer 2A thickness at the East Pacific Rise", "abstract": "Abstract A stochastic model for the emplacement of dikes and lava flows at a fast spreading ridge can generate an upper oceanic crustal structure similar to that observed in seismic data from the East Pacific Rise (EPR), in ocean drill holes, and in ophiolites. In this model the location of successive dike intrusion events relative to the ridge axis is determined by a Gaussian probability function and the cumulative flow lengths of the erupted lavas are chosen to build a Gaussian-shaped lava pile. We interpret wide-angle seismic reflections from the steep velocity gradient at the base of seismic layer 2A to be the extrusive/sheeted dike contact. Seismic data from the northern and southern EPR place constraints on the on-axis extrusive layer thickness (230 ± 50 m), the distance over which the thickening of the extrusive layer occurs (width of the accretion zone = 1–3 km) and its off-axis thickness (300–800 m). Ophiolites and ocean drill holes (DSDP Hole 504B) provide additional estimates of the thickness of the extrusive layer and constrain the thickness of the transition region from extrusives to sheeted dikes (∼ 100–200 m). A simple stochastic emplacement model, where the lavas are described by one mean flow length, fits the thickening of the extrusive layer off-axis inferred from the deepening of seismic layer 2A, but the predicted transition from sheeted dikes to extrusives is too thick. In order to match the dimensions and flat-topped shape of the seismic layer 2A boundary as well as the thickness of the extrusive-sheeted dike transition, a bimodal distribution of lava flows is used. Short flows, confined within the axial summit caldera (ASC), build up approximately half the extrusive volume. Occasional voluminous flows spill out of the ASC, or erupt outside of the ASC, and pond at a considerable distance off-axis to build up the remainder of the extrusive section. The upper part of the final extrusive section will be dominated by the off-axis flows, while the lower portions will be primarily composed of short flows erupted within the ASC. Magnetic transition widths predicted from the overlap of lavas (∼ 2 km) in this model are similar to those measured in deep-tow studies. Assuming a smoothing function which acts over one seismic wavelength, the upper crustal velocity structure predicted by the bimodal lava emplacement model is consistent with the shallow seismic velocity structure measured on the EPR. The ages of seafloor lavas in this model are younger than the tectonic spreading model ages by ∼ 30–70 kyr, in agreement with anomalously young lava ages obtained from radioisotope dating of seafloor basalts near the EPR.", "corpus_id": 53625537, "score": 1 }, { "doc_id": "55144654", "title": "Channelized lava flows at the East Pacific Rise crest 9°–10°N: The importance of off‐axis lava transport in developing the architecture of young oceanic crust", "abstract": "[1] Submarine lava flows are the building blocks of young oceanic crust. Lava erupted at the ridge axis is transported across the ridge crest in a manner dictated by the rheology of the lava, the characteristics of the eruption, and the topography it encounters. The resulting lava flows can vary dramatically in form and consequently in their impact on the physical characteristics of the seafloor and the architecture of the upper 50–500 m of the oceanic crust. We have mapped and measured numerous submarine channelized lava flows at the East Pacific Rise (EPR) crest 9°–10°N that reflect the high-effusion-rate and high-flow-velocity end-member of lava eruption and transport at mid-ocean ridges. Channel systems composed of identifiable segments 50–1000 m in length extend up to 3 km from the axial summit trough (AST) and have widths of 10–50 m and depths of 2–3 m. Samples collected within the channels are N-MORB with Mg# indicating eruption from the AST. We produce detailed maps of lava surface morphology across the channel surface from mosaics of digital images that show lineated or flat sheets at the channel center bounded by brecciated lava at the channel margins. Modeled velocity profiles across the channel surface allow us to determine flux through the channels from 0.4 to 4.7 × 103 m3/s, and modeled shear rates help explain the surface morphology variation. We suggest that channelized lava flows are a primary mechanism by which lava accumulates in the off-axis region (1–3 km) and produces the layer 2A thickening that is observed at fast and superfast spreading ridges. In addition, the rapid, high-volume-flux eruptions necessary to produce channelized flows may act as an indicator of the local magma budget along the EPR. We find that high concentrations of channelized lava flows correlate with local, across-axis ridge morphology indicative of an elevated magma budget. Additionally, in locations where channelized flows are located dominantly to the east or west of the AST, the ridge crest is asymmetric, and layer 2A appears to thicken over a greater distance from the AST toward the side of the ridge crest where the channels are located.", "corpus_id": 55144654, "score": 0 }, { "doc_id": "59577995", "title": "Correlated geophysical, geochemical, and volcanological manifestations of plume-ridge interaction along the Galápagos Spreading Center", "abstract": "[1] As the Galapagos hot spot is approached from the west along the Galapagos Spreading Center there are systematic increases in crustal thickness and in the K/Ti, Nb/Zr, 3He/4He, H2O, and Na2O content of lavas recovered from the spreading axis. These increases correlate with progressive transitions from rift valley to axial high morphology along with decreases in average swell depth, residual mantle Bouguer gravity anomaly, magma chamber depth, average lava Mg #, Ca/Al ratio, and the frequency of point-fed versus fissure-fed volcanism. Magma chamber depth and axial morphology display a “threshold” effect in which small changes in magma supply result in large changes in these variables. These correlated variations in geophysical, geochemical, and volcanological manifestations of plume-ridge interaction along the western Galapagos Spreading Center reflect the combined effects of changes in mantle temperature and source composition on melt generation processes, and the consequences of these variations on magma supply, axial thermal structure, basalt chemistry, and styles of volcanism.", "corpus_id": 59577995, "score": 0 }, { "doc_id": "128756469", "title": "The structure of 0‐ to 0.2‐m.y.‐old oceanic crust at 9°N on the East Pacific Rise from expanded spread profiles", "abstract": "We analyze four expanded spread profiles acquired at distances of 0, 2.1, 3.1, and 10 km (0–0.2 m.y.) from the axis of the East Pacific Rise between 9° and 10°N. Velocity-depth models for these profiles have been obtained by travel time inversion in the τ-p domain, and by x-t forward modeling using the WKBJ and the reflectivity methods. We observe refracted arrivals that allow us to determine directly the uppermost crustal velocity structure (layer 2A). At the seafloor we find very low Vp and VS/Vp values around 2.2 km/s and ≤ 0.43. In the topmost 100–200 m of the crust, Vp remains low (≤ 2.5 km/s) then rapidly increases to 5 km/s at ∼500 m below the seafloor. High attenuation values (Qp < 100) are suggested in the topmost ∼500 m of the crust. The layer 2–3 transition probably occurs within the dike unit, a few hundred meters above the dike-gabbro transition. This transition may mark the maximum depth of penetration by a cracking front and associated hydrothermal circulation in the axial region above the axial magma chamber (AMC). The on-axis profile shows arrivals that correspond to the bright AMC event seen in reflection lines within 2 km of the rise axis. The top of the AMC lies 1.6 km below the seafloor and consists of molten material where Vp ≈ 3 km/s and VS = 0. Immediately above the AMC, there is a zone of large negative velocity gradients where, on the average, Vp decreases from ∼6.3 to 3 km/s over a depth of approximately 250 m. Associated with the AMC there is a low velocity zone (LVZ) that extends to a distance no greater than 10 km away from the rise axis. At the top of the LVZ, sharp velocity contrasts are confined to within 2 km of the rise axis and are associated with molten material or material with a high percentage of melt which would be concentrated only in a thin zone at the apex of the LVZ, in the axial region where the AMC event is seen in reflection lines. Away from the axis, the transition to the LVZ is smoother, the top of the LVZ is deeper, and the LVZ is less pronounced. The bottom of the LVZ is probably located near the bottom of the crust and above the Moho. Moho arrivals are observed in the profiles at zero and at 10 km from the rise axis. Rather than a single discontinuity, these arrivals indicate an approximately 1-km-thick Moho transition zone.", "corpus_id": 128756469, "score": 0 }, { "doc_id": "128936652", "title": "Variations in upper crustal structure due to variable mantle temperature along the Southeast Indian Ridge", "abstract": "[1] There is a systematic variation in axial morphology and axial depth along the Southeast Indian Ridge (SEIR) with distance away from the Australian Antarctic Discordance, an area of cold uppermost mantle. Since spreading rate (72–76 mm/yr) and mantle geochemistry appear constant along this portion of the SEIR, the observed variations in axial morphology and axial depth are attributed to a gradient in mantle temperature. In this study, we report results from a multichannel seismic investigation of on-axis crustal structure along this portion of the SEIR. Three distinct forms of ridge crest morphology are found within our study area: axial highs, rifted axial highs, and shallow axial valleys. Axial highs have a shallow (∼1500 m below seafloor (bsf)) magma lens and a thin (∼300 m) layer 2A along the ridge crest. Rifted axial highs have a deeper (∼2100 m bsf) magma lens and thicker (∼450 m) layer 2A on-axis. Beneath shallow axial valleys, no magma lens is imaged, and layer 2A is thick (∼450 + m). There are step-like transitions in magma lens depth and layer 2A thickness with changes in morphology along the SEIR. The transitions between the different modes of axial morphology and shallow structure are abrupt, suggesting a threshold-type mechanism. Variations in crustal structure along the SEIR appear to be steady state, persisting for at least 1 m.y. Portions of segments in which a magma lens is found are characterized by lower relief abyssal hills on the ridge flank, shallower ridge flank depths, and at the location of along-axis Mantle Bouguer Anomaly (MBA) lows. The long-wavelength variation in ridge morphology along the SEIR from axial high segments to the west to axial valley segments to the east is linked to the regional gradient in mantle temperature. Superimposed on the long-wavelength trend are segment to segment variations that are related to the absolute motion of the SEIR to the northeast which influence mantle melt production and delivery to the ridge.", "corpus_id": 128936652, "score": 0 }, { "doc_id": "129913652", "title": "Volcanic and hydrothermal processes associated with a recent phase of seafloor spreading at the northern Cleft segment: Juan de Fuca Ridge", "abstract": "The northern portion of the Cleft segment, which is the southernmost segment of the Juan de Fuca Ridge, is the site of a seafloor spreading episode during the mid-1980s that was originally discovered by the occurrence of anomalous hydrothermal bursts (megaplumes) and later documented by seafloor mapping of new pillow mounds (NPM) that were erupted. Several field seasons of investigations using sidescan sonar, a deep-tow camera system, and the submersible Alvin reveal that about 30 km of the ridge crest is hydrothermally active and/or has experienced recent volcanic and tectonic activity associated with this episode. The most intense hydrothermal activity within this area and all the known high-temperature vents lie along a fissure from which a young sheet flow (YSF) erupted. Extinct chimneys located within 100–200 m on either side of the fissure system represent an older (>100 years) and probably less intense, hydrothermal regime. The bathymetry and the morphology of the YSF suggest that this eruption occurred over a 1–2 km section of the fissure system that forms its eastern boundary and that it flowed to the south. Fields of lava pillars concentrated at the margins of the YSF where lava probably formed when the lava stagnated near the edges of the flow. A comparison of sidescan data sets collected in 1982 and 1987 implies that the YSF was erupted at least 7 months prior to the NPM, consistent with analysis of bottom photographs that suggests that the eruptions of the YSF and NPM were only separated by a few years. The low hydrothermal flux over the NPM relative to the YSF suggests a rapidly cooled underlying heat source beneath the former. We propose that the NPM were erupted from a dike or dikes injected laterally to the north from a magma body lying beneath the YSF. Recent evidence of a decrease in the intensity of the overlying hydrothermal plumes suggests that the system is continuing to cool down.", "corpus_id": 129913652, "score": 0 }, { "doc_id": "129752513", "title": "Active hydrothermal vents and sulfide deposits on the southern Juan de Fuca Ridge", "abstract": "Massive-sulfide deposits rich in zinc and silver were recovered from the Juan de Fuca Ridge 500 km west of Oregon in September 1981. The samples recovered are composed largely of zinc sulfide, with lesser amounts of iron, lead, and copper sulfide. Most of the deposits occur at a series of hydrothermal vents within a relatively continuous depression in the center of a smooth 1-km-wide valley along the ridge axis. The depression appears to be formed by collapse of a lava lake possibly modified by extensional faulting. The axial valley floor outside the depression is underlain by fresh, glassy, ferrobasalt sheet and lobate flows. Two types of sulfide-mineral deposits were dredged from one of the hydrothermal vents: (1) angular slabs of dark-gray zinc sulfide; and (2) subrounded fragments of porous light-gray zinc sulfide. The samples contain fresh sphalerite, zoned wurtzite, pyrite, and minor amounts of marcasite, galena, and chalcopyrite-cubanite. The spreading rate of the Juan de Fuca Ridge and the composition of the sulfide samples are generally similar to the East Pacific Rise lat 21° N site; however, the texture and geologic setting of the sulfide deposits are significantly different.", "corpus_id": 129752513, "score": 1 }, { "doc_id": "140677610", "title": "Bathymetry of the mid-atlantic ridge, 24°-31°N: A map series", "abstract": "This paper presents a series of eleven maps of the bathymetry of a 900 km long section of the crestal region of the Mid-Atlantic Ridge. Along with a twelfth key map, this series defines the morphology of fifteen discrete spreading segments and shows convincingly that no transform faults exist between the Kane and Atlantis fracture zones. The publication of these multi beam bathymetry data with a contour interval of 50 m and at a scale of 30 inches per degree of longitude is intended to allow easy access by a broad community of marine earth scientists to this unique and powerful data set.", "corpus_id": 140677610, "score": 0 }, { "doc_id": "129516041", "title": "High-resolution bathymetric surveys using scanning sonars: Lava flow morphology, hydrothermal vents, and geologic structure at recent eruption sites on the Juan de Fuca Ridge", "abstract": "The CoAxial and Cleft segments of the Juan de Fuca Ridge have isolated, chronic, high-temperature, and focused hydrothermal vent sites. Both segments also have experienced recent volcanic eruptions which produced extensive, ephemeral, low-temperature, and diffuse hydrothermal venting. To study the geologic setting of these sites, high-resolution bathymetric surveys at eight locations on the CoAxial and Cleft segments were collected between 1993 and 1999. Two 675-kHz scanning sonar systems were used, Mesotech on the submersible Alvin and Imagenex on the remotely operated vehicle Jason. The bathymetry from these surveys can be gridded at a scale of 2–4 m and contoured at 1 m and thus can resolve many fine-scale features on the seafloor that are indistinguishable in multibeam bathymetry collected at the sea surface. Bathymetric data at this resolution are particularly useful for identifying geologic features related to diking, faulting, and lava flow emplacement. For example, the high-resolution bathymetric maps show that submarine fissure eruptions that form pillow lavas last long enough to become localized and to produce point source constructs along their length, and their extrusion rate is low enough that no significant drainback occurs. In contrast, lobate sheet flows are formed by short-lived, high-effusion rate eruptions in which no localization of output occurs along the eruptive fissure, and inflation is quickly followed by drainback, resulting in extensive collapse features. However, if the process of submarine lava flow inflation occurs at a slower rate and over a longer period of time, it can create lava rises up to 25 m high with distinctive structure and morphology. The scanning sonar data also show that fissures and grabens have formed or reactivated where dikes approach the surface adjacent to recent eruptive sites. The fine-scale bathymetry establishes that all the hydrothermal vent sites studied at the CoAxial and Cleft segments are located along prominent volcanic or tectonic extensional structures which provide the physical pathway for fluids from the subsurface to the seafloor. Furthermore, the fine-scale morphology of recent lava flows can be used as a qualitative indication of eruption duration.", "corpus_id": 129516041, "score": 0 }, { "doc_id": "129128554", "title": "The axial summit graben and cross-sectional shape of the East Pacific Rise as indicators of axial magma chambers and recent volcanic eruptions", "abstract": "Abstract The axis of the East Pacific Rise (EPR) undulates up and down hundreds of meters over distances of 30–200 km along strike, the deep areas occurring at transform faults and other ridge axis discontinuities such as overlapping spreading centers (OSCs). We have suggested that systematic variations in depth and cross-sectional shape of the rise are indicators of the changes in the local axial magmatic budget along a given ridge segment [1]. A comparison of recently collected multichannel seismic (MCS) data [2] with our Sea Beam and SeaMARC II data have allowed us to test and advance this hypothesis. Along the EPR from 9° to 13°N there is an excellent correlation between three parameters that are all directly related to the phase of a magmatic cycle along a given ridge segment: the cross-sectional shape of the rise, the presence or absence of an axial summit graben, and the presence or absence of a shallow axial magma chamber (as interpreted from MCS data). Where the axial magma chamber is present, the cross-sectional shape of the ridge is broad and an axial summit graben is recognized along the axis. In contrast, where the cross-sectional shape of the rise is narrow and triangular, an axial magma chamber is not detected and an axial summit graben is absent. These ridge axis characteristics tend to occur along deeper portions of a given ridge segment, often near ridge axis discontinuities. We suggest that these systematic variations in ridge axis morphology (cross-sectional shape) and structure (presence or absence of an axial graben) reflect spatial and temporal variations in the magmatic budget of the ridge axis. Where the magmatic budget is waxing, shallow-level magma reservoirs in the crust and underlying upper mantle swell, creating a broad axial bulge with a summit graben. Where the magmatic budget is diminished, the crustal magma chamber is small ( This proposed correlation of shape, structure and magmatic parameters fails along only two short portions of the ridge. In these areas there is evidence for an axial magma chamber and the rise has a broad cross-sectional shape, but there is no summit graben. Bottom photographs and submersible results, however, show that in these areas the rise crest is covered with very fresh lavas undisrupted by faulting, suggesting that the summit graben has been recently filled in by lava flows, and the development of a summit graben (or a linear caldera) by volcano-tectonic collapse has not yet occurred.", "corpus_id": 129128554, "score": 0 }, { "doc_id": "128588478", "title": "Axial summit trough of the East Pacific Rice 9°–10°N: Geological characteristics and evolution of the axial zone on fast spreading mid‐ocean ridge", "abstract": "The nature and morphological characteristics of axial summit troughs on fast (∼90–130 mm/yr−1 full spreading rate) and superfast spreading (>130 mm/yr−1) mid-ocean ridge crests reflect the time-integrated effects of long-term magmatic cycles, short-term volcanic episodicity, and the tensional stress regime imposed on young ocean crust. Two principal types of axial trough morphology have been identified and associated with distinct volcanic and tectonic processes occurring at fast and superfast spreading mid-ocean ridge crests. (1) Narrow axial troughs, ∼300–2000 m wide and ∼30–100 m deep) on the East Pacific Rise crest are classified as axial summit graben. The dimensions of axial summit graben, as well as the morphological and structural character of their walls and floors, suggest a primary tectonic origin. An axial summit graben may contain a nested axial summit collapse trough, implying that processes responsible for these endemic features may be linked. Near-bottom, side-looking sonar and observational data collected using the towed vehicle Argo I and submersible Alvin have been used to characterize the axial summit trough of the fast spreading East Pacific Rise between 9° and 10°N. A four-stage model is presented for the evolution of this axial summit collapse trough, as well as for other well-studied portions of the East Pacific Rise crest from 21°N to ∼20°S. We propose that the transition from a narrow, surface collapse-dominated axial trough to a broader, fault-bounded graben is controlled by the relative importance of diking, volcanism, hydrothermal cooling, and tectonism along a ridge segment over time periods <104 years.", "corpus_id": 128588478, "score": 0 }, { "doc_id": "129927532", "title": "Volcanic and structural morphology of the south flank of Axial Volcano, Juan de Fuca Ridge: Results from a Sea MARC I side scan sonar survey", "abstract": "A 1500 km2 Sea MARC I side scan sonar survey south of Axial volcano investigated the geological structure and constitution of the South Axial Rift Zone (SARZ) and the northern 30 km of the Vance spreading segment. Relative age assignments based on structural relationships indicate that recent volcanism on the southern flank of Axial volcano has been restricted to the SARZ. The surficial volcanic morphology of the SARZ changes downrift, from linear volcanic ridges (north) to small (1-km diameter) cratered cones (south), perhaps indicating a variation in eruptive vent geometry from fissures to point sources downrift. Recent lavas on the northern and central SARZ erupted along preexisting faults in the underlying crust. By acting as pathways for SARZ magmas, these faults may have controlled the orientation of SARZ volcanic ridges and perhaps the orientation of the entire SARZ edifice. The Vance spreading segment terminates at 45°40′N and is not linked with a transform fault. The axis of spreading between 45°40′N and 46°00′N is offset west of the Vance segment and is constrained to lie between 129°54′W and 130°06′W. A discrete, structurally defined spreading axis, however, is not evident over the southern flank of Axial volcano. The divergent plate boundary may now underlie the SARZ massif, although South Helium Basin (an embayment in the southeast flank of Axial volcano) has undergone, and may continue to accommodate, crustal extension. A 48 km2 lava field discovered east of the SARZ is composed of lavas that are inferred to have erupted from the SARZ. These lavas can be traced eastward from the SARZ into the axial valley of the northern Vance segment and partially fill the valley with lavas up to 60 m thick. The eruption of these lavas, which occupy an estimated volume of 1.8 km3, may have contributed to the formation of Axial volcano's summit caldera.", "corpus_id": 129927532, "score": 0 }, { "doc_id": "129721739", "title": "Volcanic Episodicity and a Non‐Steady State Rift Valley Along Northeast Pacific Spreading Centers: Evidence From Sea MARC I", "abstract": "Sea MARC I side-looking sonar images and Sea Beam bathymetry along a 400-km stretch of the Juan de Fuca Ridge crest provide evidence that excessive extrusive volcanism periodically builds a crestal ridge along the axis of seafloor spreading. An elongate summit depression (ESD), or rift valley, is commonly observed in the spine of this crestal ridge. The crestal ridge volcanic landform has a distinctive shape that is recognized in bathymetric contours both along the spreading axis and at least up to 30 km away from the axis. The landform has a plan-form shape that resembles a side view of an archer's bow with the long dimension of the bow form parallel to the strike of the ridge. In cross section, the bow form is flat on top and has steep flanks. These bow-form shapes can be explained by magma that rises into the crust at a discrete center and flows laterally into belts of ridge-parallel dikes, similar to Icelandic fissure eruptions. Both the variable dimensions of the ESD along axis of the Juan de Fuca Ridge and the relationship among volcanic flow morphologies within and beyond the ESD suggest the four different segments of the Juan de Fuca Ridge presented in detail here display different stages in a cycle of oceanic crust accretion. This cycle includes episodes in which there is (1) extrusive volcanic construction which widen the crestal ridge prior to the collapse of the summit depression, (2) collapse within the summit region of the crestal ridge to form an ESD during a phase of volcanic inactivity, and (3) renewed magmatism in the ESD as its floor widens by extension and brittle fracture of the upper crust. This episodic model implies that the width of the young seafloor affected by volcanic extrusion or dominated by tectonic stretching varies through time.", "corpus_id": 129721739, "score": 1 }, { "doc_id": "128701731", "title": "Lava flows from a mid‐1980s submarine eruption on the Cleft segment, Juan de Fuca Ridge", "abstract": "A series of lava flows with a total volume of 0.05 km3 were erupted in the mid-1980s along 17 km of the northern Cleft segment of the Juan de Fuca Ridge. Observations from camera tows and submersible dives show that the new flows are all similar in appearance and consist entirely of pillow lava with a mixture of smooth and striated surface textures, suggesting a relatively uniform eruption rate approaching 1 m3/s at point source vents. The flows vary in size from small patches to large steep-sided ridges and were probably erupted from a dike intruded along the ridge axis because they are aligned along a linear fissure/graben system. Observations at north Cleft show that the physical appearance of new flows changes more rapidly than previously realized and that earlier qualitative dating of young lavas based on sediment cover and glassy surface texture were probably overestimates by an order of magnitude. Sediment accumulation on the lavas is quite variable and locally surprisingly substantial, mainly due to hydrothermal deposits that formed while the lava flows were cooling. Biological vent communities photographed on the new flows in 1989 show that vent animals can colonize new vent sites rapidly but that warm water was still venting only in a few places. Nonvent animals are much slower to colonize the new flows and rates of colonization observed at north Cleft may be useful for making improved age estimates of young (<10 years) lava flows elsewhere. The north Cleft eruption represents about 2% of the estimated average annual volcanic output along the global mid-ocean ridge, implying that many other submarine eruptions are occurring undetected.", "corpus_id": 128701731, "score": 0 }, { "doc_id": "129141909", "title": "No spreading across the Southern Juan de Fuca Ridge axial cleft during 1994–1996", "abstract": "Direct-path acoustic measurements between seafloor transponders observed no significant extension (-10 ± 14 mm/yr) from August 1994 to September 1996 at the southern Juan de Fuca Ridge (44°40' N and 130°20' W). The acoustic path for the measurement is a 691-m baseline straddling the axial cleft, which bounds the Pacific and Juan de Fuca plates. Given an expected full-spreading rate of 56 mm/yr, these data suggest that extension across this plate boundary occurs episodically within the narrow (∼ 1 km) region of the axial valley floor, and that active deformation is occurring between the axial cleft and the plate interior. A cleft-parallel 714-m baseline located 300 m to the west of the cleft on the Pacific plate monitored system performance and, as expected, observed no motion (+5 ± 7 mm/yr) between the 1994 and 1996 surveys.", "corpus_id": 129141909, "score": 0 }, { "doc_id": "131517661", "title": "Structure of the southern Juan de Fuca Ridge from seismic reflection records", "abstract": "Twenty-four-channel seismic reflection records were obtained from the axial region of the southern Juan de Fuca Ridge. Two profiles are normal to the strike of the spreading center and intersect the ridge at latitude 44°40′N and 45°05′N; a third profile extends south along the ridge axis from latitude 45°20′N and crosses the Blanco Fracture Zone. Processing of the axial portions of the cross-strike lines resolved a weak reflection centered beneath the axis. The reflector is at a depth similar to seismically detected magma chambers on the East Pacific Rise and a Lau Basin spreading center; we suggest that the reflector represents the top of an axial magma chamber. In the migrated sections the top of the probable magma chamber is relatively flat and 1–2 km wide, and the subbottom depth of the chamber is greater where the depth to the ridge axis is greater.", "corpus_id": 131517661, "score": 0 }, { "doc_id": "129111054", "title": "Seismic structure and anisotropy of the Juan de Fuca Ridge at 45°N", "abstract": "A seismic refraction experiment was conducted with air guns and ocean bottom seismometers on the Juan de Fuca Ridge at 45°N, at the northern Cleft segment and at the overlapping rift zone between the Cleft and Vance segments. These data determine the average velocity structure of the upper crust and map the thickness variability of the shallow low-velocity layer, which we interpret as the extrusive volcanic layer. The experiment is unique because a large number of travel times were measured along ray paths oriented at all azimuths within a small (20 km by 35 km) area. These travel times provide evidence for compressional velocity anisotropy in the upper several hundred meters of oceanic crust, presumed to be caused by ridge-parallel fracturing. Compressional velocities are 3.35 km/s in the ridge strike direction and 2.25 km/s across strike. Travel time residuals are simultaneously inverted for anisotropy as well as lateral thickness variations in the low-velocity layer. Extrusive layer thickness ranges from approximately 200 m to 550 m with an average of 350 m. The zone of the thinnest low-velocity layer is within the northern Cleft segment axial valley, in a region of significant hydrothermal activity. Layer thickness variability is greatest near the Cleft-Vance overlapping rift zone, where changes of 300 m occur over as little as several kilometers laterally. These low-velocity layer thickness changes may correspond to fault block rotations in an episodic spreading system, where the low side of each fault block accumulates more extrusive volcanics.", "corpus_id": 129111054, "score": 1 }, { "doc_id": "130982876", "title": "Petrology and geochemistry of basalts from the southern Juan de Fuca Ridge: Controls on the spatial and temporal evolution of mid‐ocean ridge basalt", "abstract": "Three morphologically distinct regions within the neovolcanic zone of the Cleft segment of the southern Juan de Fuca Ridge were investigated and sampled in detail using the DSRV Alvin. Additional along-strike and off-axis samples were recovered by dredge. The southernmost region, the Southern Cleft site, is characterized by a 3-km-wide axial valley floored by ponded sheet flows and bisected by a 30- to 50-m-wide cleft. Farther north at the “Young Sheet Flow” site, the ridge axis is characterized by a distinct 500-m-wide inner graben that is largely covered by distinctly younger looking sheet flows. The northernmost of the three regions is defined by a linear series of discontinuous constructional pillow mounds that extend the trend of the Cleft segment well into the zone of overlap with the neighboring Vance segment. The pillowed lavas at the “Young Pillow Mound” site represent the most recent episode of volcanism along the Cleft segment. Strong correlations exist between degrees of fractionation, relative ages of lavas, and latitude; lavas are progressively younger looking and more mafic to the north. The compositional range of mid-ocean ridge basalts from the neovolcanic zone can generally be accounted for by 35–40% low-pressure fractional crystallization of relatively primitive, but not primary, depleted (N-type) melts. Scatter of the geochemical data about calculated liquid lines of descent is probably the result of mixing of magmas with slightly different parental compositions, generated from small-scale mantle heterogeneities. Furthermore, the chemical variability may be the result of mixing of very depleted and more enriched sources or melts that are present beneath the southern Juan de Fuca Ridge. The more primitive nature of the young pillow mound basalts and their slightly different chemical characteristics indicates they cannot be simply related to the older southernmost lavas by along-axis flow in a continuous axial magma chamber or conduit. Rather, the data suggest lavas were derived from discrete magma chambers or lenses, each in a different stage of evolution. The youngest events may be associated with a new influx of magma into the northern part of the segment and subsequent northward diking and propagation to form the new pillow mounds. The oldest stage (∼40% additional crystallization of the most mafic composition) is associated with focused hydrothermal activity and tectonic extension, whereas the youngest events are characterized by ridge inflation, diking, and dispersed hydrothermal activity. Geochemical and tectonomagmatic features observed along the Cleft segment are similar to those recently documented along the East Pacific Rise from 9°30′N–10°N suggesting the scales, processes, and stages of magmagenesis are similar along medium to fast spreading ridge segments.", "corpus_id": 130982876, "score": 0 }, { "doc_id": "140723606", "title": "Hydrothermal circulation at the Cleft-Vance overlapping spreading center : results of a magnetometric resistivity survey", "abstract": "We report on a magnetometric resistivity sounding carried out in the overlapping spreading center between the Cleft and Vance segments of the Juan de Fuca Ridge. The data collected reveal a strong three dimensionality in the crustal electrical resistivity structure on wavelengths of a few kilometers. Areas of reduced crustal electrical resistivities, with values approaching that of seawater, are seen beneath the neovolcanic zones of both active spreading centers. We interpret these reduced resistivities as evidence of active hydrothermal circulation within the uppermost 1 km of hot, young oceanic crust.", "corpus_id": 140723606, "score": 0 }, { "doc_id": "128828511", "title": "Fine‐scale magnetic anomaly field over the southern Juan de Fuca Ridge: Axial magnetization low and implications for crustal structure", "abstract": "Sea surface, deep tow, and submersible magnetic surveys show that the spreading axis of the Cleft segment of the southern Juan de Fuca Ridge (SJDF) is overlain by a distinctive magnetic anomaly low in contrast to the more typical magnetic anomaly high found over the adjacent Vance segment and most mid-ocean ridge spreading centers. Forward iterative thickness modeling, based on the near-bottom magnetic data, shows that this axial magnetic low can be produced by a thin magnetic source layer beneath the Cleft axial valley. Thick crust is required to produce the magnetic anomaly high over the Vance axial valley. This magnetic modeling demonstrates that variations in the base of the magnetic source layer, which is assumed to be equivalent to the base of the extrusive lavas, can produce a significant proportion of the observed short-wavelength magnetic anomaly signal. These magnetic layer thickness models also correlate quite well with nearby seismic results which show that seismic layer 2A thins beneath the axial valley of the Cleft and is thicker beneath the Vance axial valley. Recent seismic results over other fast and medium spreading rifts also show rapid changes in the thickness of the uppermost crust near the axis of spreading, which could produce significant magnetic contrasts. The results of this study and the correlation with independent seismic measurements suggest that while magnetization may vary due to geomagnetic behavior or because of petrology or alteration, first-order change in upper crustal thickness is one of the most important variables to consider in the production of fine-scale magnetic anomalies in young ocean crust.", "corpus_id": 128828511, "score": 0 }, { "doc_id": "140727943", "title": "The Wave Equation Applied to Migration", "abstract": "Claerbout's method has been implemented for the migration of stacked seismic data. A simplified description of the method is given together with an account of some of the practical programming problems and the types of inaccuracy encountered. Routine production results are considered to be comparable or superior to the results derived from alternative migration techniques. Particular advantages are 1) the possibility of using a detailed velocity model for the migration and 2) the preservation of the amplitude and character of the seismic events on the migrated time section.", "corpus_id": 140727943, "score": 0 }, { "doc_id": "128773016", "title": "Suppression of sea-floor-scattered energy using a dip-moveout approach; application to the mid-ocean ridge environment", "abstract": "Multichannel seismic (MCS) images are often contaminated with in- and out-of-plane scattering from the sea floor. This problem is especially acute in the mid-ocean ridge environment where sea-floor roughness is pronounced. Energy shed from the unsedimented basaltic sea floor can obscure primary reflections such as Moho, and scattering off of elongated sea-floor features like abyssal hills and fault scarps can produce linear events in the seismic data that could be misinterpreted as subsurface reflections. Moreover, stacking at normal subsurface velocities may enhance these water-borne events, whose stacking velocity depends on azimuth and generally increases with time, making them indistinguishable from subsurface arrivals. To suppress scattered energy in deep water settings, we propose a processing scheme that invokes the application of dip moveout (DMO) to deliberately increase the differential moveout between sea-floor-scattered and subsurface events, thereby facilitating the removal of unwanted energy in the stacked section. After application of DMO, all sea-floor scatterers stack at the water velocity, while subsurface reflections like Moho still stack at their original velocity. The application of DMO in this manner is contrary to the intended use that reduces the differential moveout between dipping events and allows a single stacking velocity to be used. Unlike previous approaches to suppress scattered energy, dip filtering is applied in the common-midpoint (CMP) domain after DMO. Moveover, our DMO-based approach suppresses out-of-plane scattering, and therefore is not limited to removal of in-plane scattering as is the case with shot and receiver dip filtering techniques. The success of our DMO-based suppression scheme is limited to deep water (a few kilometers of water depth for conventional offsets), where the traveltime moveout of energy scattered from the sea floor has a hyperbolic moveout with a stacking velocity that depends on the cosine of the scatterer steering angle in a manner analogous to how the moveout of a dipping reflector depends on the dip angle. The application of DMO-based suppression to synthetics and MCS data collected along the southern East Pacific Rise demonstrates the effectiveness of our approach. Cleaner images of primary reflectors such as Moho are produced, even though present shot coverage along the East Pacific Rise is unduly sparse, resulting in a limited effective spatial bandwidth.", "corpus_id": 128773016, "score": 0 }, { "doc_id": "128995175", "title": "SEISMIC VELOCITIES OF THE UPPERMOST IGNEOUS CRUST VERSUS AGE", "abstract": "SUMMARY \n \nSeismic refraction velocity data from the acoustic basement (called layer 2A) have been compiled for different mid-ocean ridges. The data from post-1970 studies show a strong correlation between velocity and basement age. Importantly, velocities double in less than 10 Myr for all ridges, but for older crust, up to 160 Myr in age, velocities do not increase significantly.", "corpus_id": 128995175, "score": 0 }, { "doc_id": "131320082", "title": "Seismic traveltime inversion for 2-D crustal velocity structure", "abstract": "SUMMARY A method of seismic traveltime inversion for simultaneous determination of 2-D velocity and interface structure is presented that is applicable to any type of body-wave seismic data. The advantage of inversion, as opposed to trial-and-error forward modelling, is that it provides estimates of model parameter resolution, uncertainty and non-uniqueness, and an assurance that the data have been fit according to a specified norm. In addition, the time required to interpret data is significantly reduced. The inversion scheme is iterative and is based on a model parametrization and a method of ray tracing suited to the forward step of an inverse approach. The number and position of velocity and boundary nodes can be adapted to the shot-receiver geometry and subsurface ray coverage, and to the complexity of the near-surface. The model parametrization also allows ancillary amplitude information to be used to constrain model features not adequately resolved by the traveltime data alone. The method of ray tracing uses an efficient numerical solution of the ray tracing equations, an automatic determination of take-off angles, and a simulation of smooth layer boundaries that yields more stable inversion results. The partial derivatives of traveltime with respect to velocity and the depth of boundary nodes are calculated analytically during ray tracing and a damped least-squares technique is used to determine the updated parameter values, both velocities and boundary depths simultaneously. The stopping criteria and optimum number of velocity and boundary nodes are based on the trade-off between RMS traveltime residual and parameter resolution, as well as the ability to trace rays to all observations. Methods for estimating spatial resolution and absolute parameter uncertainty are presented. An example using synthetic data demonstrates the algorithm's accuracy, rapid convergence and sensitivity to realistic noise levels. An inversion of refraction and wide-angle reflection traveltimes from the 1986 IRISPASSCAL Nevada, USA (Basin and Range province) seismic experiment illustrates the methodology and practical considerations necessary for handling real data. A comparison of our final 2-D velocity model with results from studies using other 1-D and 2-D forward and inverse methods serves as a check on the validity of the inversion scheme and provides estimates of parameter uncertainties that account for the bias introduced by the modelling approach and the interpreter.", "corpus_id": 131320082, "score": 0 }, { "doc_id": "129155455", "title": "CRUSTAL STRUCTURE OF ENDEAVOUR RIDGE SEGMENT, JUAN DE FUCA RIDGE, FROM A DETAILED SEISMIC REFRACTION SURVEY", "abstract": "A detailed seismic refraction survey was carried out over the Endeavour Segment of the Juan de Fuca Ridge, a medium-rate spreading center which lies off western North America, to investigate the creation and evolution of oceanic crust. A bathymetric high and the presence of hydrothermal vents suggested that the study area was the most recent locus of spreading. Travel time and amplitude data from 15 in-line air gun/ocean bottom seismometer profiles were forward modeled using asymptotic ray theory to obtain two-dimensional velocity models consisting of four primary layers which correlate well with classic models of oceanic crust. Significant lateral variations in thicknesses and velocities on the scale of a few to 10 km are superimposed on this basic velocity structure, but they appear to be random rather than distributed symmetrically about the ridge. We attribute them to fracturing which causes porosity changes, hydrothermal circulation which fills voids and fractures with alteration products, and variations in magmatic and/or deformational processes at the spreading center. Layer 2A is found to have low (2.6–2.8 km/s) velocities, to average 0.4 km in thickness with variations up to 0.2 km, and to be bounded at its base by a sharp velocity increase to 4.8 km/s. Along the axial ridge, velocities 0.4–0.6 km/s higher than average are interpreted for layers 2B and 2C, but these values are confined to a 2-km-wide zone centered below the ridge. Velocities along ridge-parallel lines offset 10 km are normal, indicating that maturation to off-ridge structure has occurred within at most 0.3 Ma. Layer 3 velocities decrease by 0.1–0.2 km/s for arrivals traveling along and under the axial ridge, perhaps caused by higher temperatures. However, we find no anomalously low velocities beneath the ridge, indicating that no large crustal magma chamber exists. On the basis of this study, we conclude that magmatic accretion is a fully three-dimensional process within ridge segments such as Endeavour Ridge.", "corpus_id": 129155455, "score": 0 }, { "doc_id": "54054420", "title": "Fine‐scale seismic structure of the shallow volcanic crust on the East Pacific Rise at 9°50′N", "abstract": "upper crust in a � 3 � 3 km field area centered on the East Pacific Rise at 9� 50 0 N. We detonated 18 explosive shots (18 sources) in a circular pattern (1.5 km radius) on the rise axis and recorded seismic arrivals with eight ocean bottom seismometers (eight receivers). We observed 30–40 Hz compressional body waves from all shots (144 P waves) and 1–3 Hz Stoneley (interface) waves on a subset of source-receiver pairs (58 interface waves). Using a station correction inversion, we find that roughly half of the variance in the P wave first-arrival times results from lateral variations in the thickness of the surface low-velocity layer (SLVL), a layer of extremely porous lava and basalt breccia with an average P wave velocity of 2.2 km s � 1 . The SLVL thickness increases from <20 m along the axial summit trough (AST) to � 120 m at near-axis lava depocenters, which are not symmetric about the rise axis. Depocenters are located � 0.5 km to the west and � 1.5 km to the east of the rise axis. Tomographic inversion of the Stoneley wave first arrivals reveals that shear velocities in the SLVL covary with the layer thickness, exhibiting a similar asymmetric pattern, with shear velocities increasing from � 320 m s � 1 near the AST to � 520 m s � 1 at the near-axis depocenters. Our analysis demonstrates that the seismic characteristics of the extrusive layer near the rise axis are related primarily to volcanic features and processes. The thickness and velocity of the SLVL are low on the axis and within channel networks that deliver lava flows away from the axis and then increase rapidly at the distal ends of the channels where the lavas are deposited. We find that azimuthal anisotropy exerts only a weak influence on our P wave first-arrival times, which we model as weak (4%) seismic azimuthal anisotropy in the upper dikes with a fast axis oriented N23� –32� W. We find no evidence for seismic azimuthal anisotropy in the extrusive layer. INDEX TERMS: 3025 Marine Geology and Geophysics: Marine seismics (0935); 3035 Marine Geology and Geophysics: Midocean ridge processes; 7220 Seismology: Oceanic crust;", "corpus_id": 54054420, "score": 0 }, { "doc_id": "4416648", "title": "Melt to mush variations in crustal magma properties along the ridge crest at the southern East Pacific Rise", "abstract": "The determination of along-axis variations in melt properties within the crustal axial magma chamber beneath fast spreading axes is important for understanding melt delivery from the mantle, eruption history along the ridge crest, and the process of crustal accretion. Seismic reflection images have shown the molten sill to be continuous along the ridge crest for many tens of kilometres with varying widths (250–4,500 m), but variations in its seismic properties and thickness have remained elusive, despite several attempts to constrain these properties. Here we report that the melt sill along the southern East Pacific Rise, which is about 50 m thick, undergoes abrupt changes in its internal properties, ranging from pure melt to mush. The 60-km-long ridge-crest segment near 14° 00′ S is characterized by three 2–4-km sections containing pure melt embedded within a magma chamber rich in mush. These small pure melt pockets may represent a fresh supply of magma from the mantle, capable of erupting and forming the upper crust. Conversely, the 80–90% of the magma chamber which is mushy is unlikely to erupt and may influence the lower-crustal accretion.", "corpus_id": 4416648, "score": 0 }, { "doc_id": "18343787", "title": "Influence of magma supply and spreading rate on crustal magma bodies and emplacement of the extrusive layer: Insights from the East Pacific Rise at lat 16°N", "abstract": "Seismic reflection data from the East Pacific Rise at lat 16°N, which is spreading at the high end of intermediate rates, suggest that the depths at which axial magma chambers reside do not vary smoothly as a function of spreading rate. Rather, magma-chamber depths form two distinct populations, each associated with a distinct axial morphology and with an abrupt transition occurring within the intermediate-spreading-rate range. Our data (1) show that the melt lens at high-intermediate-spreading ridges lies at a shallow level similar to lens depths at faster-spreading ridges, and (2) provide further support for the spreading-rate invariance of ridges with axial highs noted in other ridge properties. The axial morphology of the two ridge segments within the study area differs markedly, and a large contrast in magma supply is inferred. The ridge segment with greater magma supply is associated with a broader and more continuous melt lens, a wider region over which the extrusive crust accumulates, and a thicker extrusive layer off-axis where supply to the ridge segment appears to be centered. However, on-axis, the extrusive layer is thinnest where magma supply is robust and a shallower melt lens is observed, consistent with a model in which magma pressure controls the thickness of the extrusive layer accumulated above the magma lens.", "corpus_id": 18343787, "score": 0 }, { "doc_id": "129717002", "title": "Small-scale spatial and temporal variations in mid-ocean ridge crest magmatic processes", "abstract": "Data from a suite of closely spaced lava flows recovered within the axial summit caldera and on the crestal plateau of the East Pacific Rise around lat 9°31′N indicate that eruptions on this fast-spreading part of the mid-ocean ridge occur throughout the crestal region and are not restricted to the axis. These eruptions contribute to a complex distribution of basalts of various ages and a significant thickening of seismic layer 2A away from the axis in our study area. Small-scale (<600 m) diversity and nonsystematic distribution of lava types may reflect rapid changes in magma chemistry that occur during crystallization and replenishment in small magma lenses, coupled with the effects of frequent low-volume eruptions both within and outside of the axial summit caldera.", "corpus_id": 129717002, "score": 0 }, { "doc_id": "128772193", "title": "Aberrant youth: Chemical and isotopic constraints on the origin of off‐axis lavas from the East Pacific Rise, 9°–10°N", "abstract": "[1] We report measurements of U-series disequilibria, Sr, Nd, Hf, and Pb isotopic compositions and major and trace element abundances in a suite of well-located, off-axis MORBs that span the East Pacific Rise (EPR) ridge crest from 9°48′–52′N and across it for ∼4 km on either side. The geological context of the samples are well constrained as they were collected by submersible in an area that has been extensively imaged by remote sensing techniques. Sr, Nd, Hf and 208Pb/206Pb isotopic compositions of the off-axis N-MORB are identical to the axial lavas from this same region, suggesting that their sources are similar and that melting processes are the dominant influence in establishing the U-Th-Ra disequilibria and trace element fractionations. A majority of off-axis samples have U-Th and Th-Ra disequilibria that are larger, and model ages that are younger, than would be predicted from their off-axis distance and the time-integrated spreading rate. There are, however, a few off-axis samples with U-Th ages that are consistent with their spreading rate ages. It is likely that these samples erupted within or close to the axial summit trough (AST) and aged at a rate proportional to the spreading rate. The anomalously young ages determined for most of the off-axis lavas suggest that volcanic construction along this region is occurring over a zone that is wider (at least 4 km) than the AST (10s to 100s of meters). The combined observational, chemical and isotopic data support a model for the 9°0′N area that includes a significant component of crustal accumulation resulting from lavas that breach the AST and flow down the flanks of the EPR ridge crest. However, these data also require a minor component of off-axis eruptions that occur on distinct pillow mounds and ridges. This suggests that MOR construction involves several volcanic and tectonic processes acting in concert to form a complex patchwork of lava ages and compositions along, and across, this fast spreading ridge crest.", "corpus_id": 128772193, "score": 0 }, { "doc_id": "16836066", "title": "Gridding with continuous curvature splines in tension", "abstract": "A gridding method commonly called minimum curvature is widely used in the earth sciences. The method interpolates the data to be gridded with a surface having continuous second derivatives and minimal total squared curvature. The minimum-curvature surface has an analogy in elastic plate flexure and approximates the shape adopted by a thin plate flexed to pass through the data points. Minimum-curvature surfaces may have large oscillations and extraneous inflection points which make them unsuitable for gridding in many of the applications where they are commonly used. These extraneous inflection points can be eliminated by adding tension to the elastic-plate flexure equation. It is straightforward to generalize minimum-curvature gridding algorithms to include a tension parameter; the same system of equations must be solved in either case and only the relative weights of the coefficients change. Therefore, solutions under tension require no more computational effort than minimum-curvature solutions, and any algorithm which can solve the minimum-curvature equations can solve the more general system. We give common geologic examples where minimum-curvature gridding produces erroneous results but gridding with tension yields a good solution. We also outline how to improve the convergence of an iterative method of solution for the gridding equations.", "corpus_id": 16836066, "score": 0 }, { "doc_id": "24565969", "title": "Seismic Structure of the Southern East Pacific Rise", "abstract": "Seismic data from the ultrafast-spreading (150 to 162 millimeters per year) southern East Pacific Rise show that the rise axis is underlain by a thin (less than 200 meters thick) extrusive volcanic layer (seismic layer 2A) that thickens rapidly off axis. Also beneath the rise axis is a narrow (less than 1 kilometer wide) melt sill that is in some places less than 1000 meters below the sea floor. The small dimensions of this molten body indicate that magma chamber size does not depend strongly on spreading rate as predicted by many ridge-crest thermal models. However, the shallow depth of this body is consistent with an inverse correlation between magma chamber depth and spreading rate. These observations indicate that the paradigm of ridge crest magma chambers as small, sill-like, midcrustal bodies is applicable to a wide range of intermediate- and fast-spreading ridges.", "corpus_id": 24565969, "score": 0 }, { "doc_id": "129706962", "title": "High sensitivity of ocean ridge thermal structure to changes in magma supply: the Galápagos Spreading Center", "abstract": "Abstract We explore the physical mechanisms for the observed apparent sensitivity of ridge axis topography and crustal magma systems to small changes in magma supply at intermediate spreading rates. Numerical experiments were carried out to simulate crustal temperature structure of the Galapagos Spreading Center, which spreads at intermediate spreading rates with its various sections appear to have been influenced to different degrees by the nearby Galapagos hotspot. Model results show a strong ‘threshold’ effect: as the crustal thickness decreases from 7.4 km at the 92°W area with an axial high westward to 6.0 km at the 94°W area with a transitional topography, the depth to the top of a magma lens is calculated to increase from 1.7 to 2.5 km. In contrast, at the 97°W area, where crustal thickness is only 5.6 km and a rift valley is present, the model results predict no steady-state magma lens in the crust. These model calculations provide a simple physical explanation for the recent observations along the Galapagos Spreading Center, where abrupt changes in both magma lens and axial morphology occur within a short distance but crustal thickness changes only modestly. Results of this investigation illustrate the critical importance of hotspots in influencing mid-ocean ridge crustal thickness and the associated changes in thermal structure, especially for ridges that spread at the sensitive range of intermediate spreading rates.", "corpus_id": 129706962, "score": 1 }, { "doc_id": "21718107", "title": "Crustal thickness along the western Galápagos Spreading Center and the compensation of the Galápagos hotspot swell", "abstract": "Wide-angle refraction and multichannel reflection seismic data show that oceanic crust along the Galapagos Spreading Center (GSC) between 97‡W and 91‡25PW thickens by 2.3 km as the Galapagos plume is approached from the west. This crustal thickening can account for V52% of the 700 m amplitude of the Galapagos swell. After correcting for changes in crustal thickness, the residual mantle Bouguer gravity anomaly associated with the Galapagos swell shows a minimum of 325 mGal near 92‡15PW, the area where the GSC is intersected by the Wolf^ Darwin volcanic lineament (WDL). The remaining depth and gravity anomalies indicate an eastward reduction of mantle density, estimated to be most prominent above a compensation depth of 50^100 km. Melting calculations assuming adiabatic, passive mantle upwelling predict the observed crustal thickening to arise from a small increase in mantle potential temperature of V30‡C. The associated thermal expansion and increase in melt depletion reduce mantle densities, but to a degree that is insufficient to explain the geophysical observations. The largest density anomalies appear at the intersection of the GSC and the WDL. Our results therefore require the existence of compositionally buoyant mantle beneath the GSC near the Galapagos plume. Possible origins of this excess buoyancy include melt retained in the mantle as well as mantle depleted by melting in the upwelling plume beneath the Galapagos Islands that is later transported to the GSC. Our estimate for the buoyancy flux of the Galapagos plume (700 kg s 31 ) is lower than previous estimates, while the total crustal production rate of the Galapagos plume (5.5 m 3 s 31 ) is comparable to that of the Icelandic and Hawaiian plumes.", "corpus_id": 21718107, "score": 0 }, { "doc_id": "129289673", "title": "Controls on extrusion at mid-ocean ridges", "abstract": "A magma lens can erupt to form extrusives only if it is under greater pressure than the static pressure in a column of magma reaching from the lens to the surface. The excess pressure results partly from overburden pressure caused by the presence of high- and low-density rocks (dikes and extrusives, respectively) above the lens. The thicker the pile of low-density extrusives, the lower the average overburden density. Thus, extrusion above a lens should be self-regulating, in that thickening the extrusive layer reduces the driving pressure for subsequent eruptions. Flexural stresses may affect extrusion by altering the pressure on a magma chamber. For ridges lacking an axial valley, we predict that deeper magma lenses should correlate with thicker extrusive layers, consistent with recent observations.", "corpus_id": 129289673, "score": 1 }, { "doc_id": "36743776", "title": "Crustal Thickness on the Mid-Atlantic Ridge: Bull's-Eye Gravity Anomalies and Focused Accretion", "abstract": "Spreading segments of the Mid-Atlantic Ridge show negative bull's-eye anomalies in the mantle Bouguer gravity field. Seismic refraction results from 33�S indicate that these anomalies can be accounted for by variations in crustal thickness along a segment. The crust is thicker in the center and thinner at the end of the spreading segment, and these changes are attributable to variations in the thickness of layer 3. The results show that accretion is focused at a slow-spreading ridge, that axial valley depth reflects the thickness of the underlying crust, and that along-axis density variations should be considered in the interpretation of gravity data.", "corpus_id": 36743776, "score": 0 }, { "doc_id": "128871092", "title": "Glass compositions, plume‐ridge interaction, and hydrous melting along the Galápagos Spreading Center, 90.5°W to 98°W", "abstract": "[1] The Galapagos Spreading Center (GSC) between 90.5°W and 98°W manifests its interaction with the nearby Galapagos plume by way of variations in lava geochemistry, crustal thickness, and morphology along the ridge axis. Natural glasses from stations with ∼9 km average spacing were analyzed for major and minor elements, H2O, and CO2. Samples can be classified as enriched mid-ocean ridge basalts (E-MORB), transitional MORB (T-MORB), or normal MORB (N-MORB) on the basis of K/Ti ratios. E-MORB dominate the GSC east of 92.6°W. T-MORB are mainly found between 92.6°W and 95.5°W. West of the propagating rift tip at 95.5°W, N-MORB dominate. High K/Ti E-MORB also have higher H2O, Al2O3, and Na2O and lower FeO*, SiO2, and CaO/Al2O3 relative to N-MORB at similar values of MgO, characteristics consistent with lower mean extents of partial melting relative to N-MORB. We examine the melting process along this section of the GSC with a set of equations that simulate a deep zone of hydrous melting related to the depression of the mantle solidus by H2O. This model constrains the range of mantle source compositions, the depth of the additional hydrous melting zone, the melt productivity in the hydrous region, and the ratio of mantle flow rate through the hydrous zone relative to the anhydrous zone (Uw/U0) that can explain the measured crustal thickness as well as the fractionation-corrected concentrations of K, Na2O, H2O, and Ti along the GSC. Far from the hot spot, the measured crustal thickness and N-MORB compositions are explained by passive mantle upwelling (Uw/U0 = 1), mean melt fraction () ∼ 0.06, and a source with ∼35 ppm K, 130 ppm H2O, 2300 ppm Na2O, and 1050 ppm Ti. The transitional zone has a source enriched in K and could have a slight excess plume-driven flow through the hydrous melting zone (Uw/U0 ≤ 1.5). The crustal thickness and glass compositions in the “enriched” region of the GSC nearest the hot spot are best explained by only a slight increase in the temperature of the mantle (<∼20°C), coupled with a mantle source moderately enriched (relative to N-MORB source) and plume-driven flow through the hydrous zone of Uw/U0 = 1.5–3.5.", "corpus_id": 128871092, "score": 0 }, { "doc_id": "129523051", "title": "The East Pacific Rise in cross section: A seismic model", "abstract": "In 1982 we undertook a seismic refraction experiment, known as the MAGMA expedition, to examine the detailed structure of the East Pacific Rise near 12°50′N. This segment of the rise, where the full spreading rate is about 110 mm/yr, is near the projected trace of the O'Gorman fracture zone and is the site of an overlapping spreading center as well as “black smoker” hydrothermal activity. In this paper we describe the analysis of a subset of the travel time data collected during the MAGMA expedition, namely the data from profiles which were oriented normal to the rise axis. These profiles provide a data set roughly equivalent to those collected on other experiments and sample the cross-sectional structure of the rise. We have modeled these data using a two-dimensional ray-tracing program. We have found that the seismic velocities in the young oceanic crust are rather high, with velocity gradients of 4.0–5.5 s−1 in the uppermost crust. The highest velocities at the seafloor occur beneath the rise axis itself and seem to decrease as the crust ages to 0.1 Ma. This decrease in velocity must result from an increase in porosity in the upper crust and may coincide with the development of abundant surface fissures as the crust spreads. The decrease in velocity does not appear to penetrate deeper than about 0.5 km and may reverse itself as hydrothermal alteration fills the pores and cracks. The fact that the highest velocities occur under the rise axis suggests that the hydrothermal circulation responsible for the black smokers is confined to seismically unresolved conduits, a result consistent with the high temperatures and discrete nature of the vents. Our best model includes a magma chamber some 4 km wide and extending from the Moho to within about 1.1 km of the seafloor. This magma chamber is far smaller than many models for the rise axis have predicted but larger than those inferred from seismic refraction experiments at other sites on the East Pacific Rise. These discrepancies probably arise because the magma chamber under the East Pacific Rise is not a steady state feature but changes with time because of hydrothermal cooling and perhaps because of an episodic supply of magma from the mantle or along the rise axis.", "corpus_id": 129523051, "score": 0 }, { "doc_id": "130059732", "title": "Bending as a mechanism for triggering off-axis volcanism on the East Pacific Rise", "abstract": "We propose that bending stresses play a key role in triggering volcanism on the flanks of the East Pacific Rise by simultaneously opening tensile cracks near the surface and increasing the pore pressure of melt bodies trapped in the lower crust. In addition, crack-tip stress intensities remain high during tensile opening, such that bending cracks propagate downward efficiently and thus have the potential to tap overpressured melt bodies trapped in the lower crust. We find that bending increases the vulnerability of the lithosphere to magmatic penetration out to distances of ∼20 km from the rise axis, corresponding to the region of abyssal hill formation and isolated seamount generation.", "corpus_id": 130059732, "score": 0 }, { "doc_id": "4357788", "title": "Volcanic growth faults and the origin of Pacific abyssal hills", "abstract": "The topographic features known as abyssal hills characterize >30% of the ocean floor, and yet their origin has been the subject of vigorous debate for over 40 years. Submersible-based investigations show that Pacific abyssal hills are created on the flanks of the East Pacific Rise as horsts and grabens which lengthen with time. Hills are bounded on one side by ridge-facing scarps produced by normal faulting, and on the other by more gentle slopes produced by volcanic growth faulting.", "corpus_id": 4357788, "score": 0 }, { "doc_id": "129211290", "title": "Nd- and Pb-isotopic variations through the upper oceanic crust in DSDP/ODP Hole 504B, Costa Rica Rift", "abstract": "Abstract The DSDP/ODP Hole 504B, drilled in the 5.9 Ma southern flank of the Costa Rica Rift, represents the deepest section through modern ocean floor basaltic basement. The hole penetrates a 570 m thick volcanic zone, a 210 m thick transition zone of volcanic rocks and dykes, and 1056 m of dykes. A representative selection of these basalt types has been investigated with respect to Nd and Pb isotopes. The ϵ Nd of the basalts varies from 7.62 to 11.16. This range in the Nd-isotope composition represents about 67% of the total range reported for Pacific MORB. The Pb-isotope composition also shows significant variation, with 206 Pb/ 204 Pb varying from 17.90 to 18.82. The isotopic data show that a small volume of enriched mantle existed in the source. The large ranges in isotopic composition in a single drill hole demonstrate the importance of small-scale mantle heterogeneities in the petrogenesis of MORB. Fractional melting and extraction of small magma batches by channelled flow, and small, short-lived crustal magma reservoirs, with limited potential for mixing of the mantle derived magmas, are favored by these isotopic data.", "corpus_id": 129211290, "score": 0 }, { "doc_id": "128428505", "title": "Upper crustal seismic velocity structure and microearthquake depths at the Endeavour Segment, Juan de Fuca Ridge", "abstract": "[1] We present the results of a study to invert microearthquake and explosive shot data from the Endeavour segment of the intermediate-spreading Juan de Fuca Ridge. The average isotropic P wave velocity structure, derived from the shot data, in the uppermost 1.5 km of the oceanic crust is characterized by an increase with age of ∼8% from the axis to at least 0.5 Ma, that is attributed to the sealing of layer 2A porosity by hydrothermal processes. Superimposed on this variation are axis-parallel, 2-km-wide, alternating bands of high and low velocity with a peak-to-peak variation of 5–12%. High and low velocities away from the axis correspond to bathymetric trenches and ridges, respectively and are likely due to variations in layer 2A thickness. P wave azimuthal anisotropy is present in the data that is best fit with a model of 9% anisotropy at 750 m depth, decreasing to 1% at 3 km depth and is likely due to the preferential alignment of vertical cracks and fissures in the along-axis direction. Anisotropy and velocity heterogeneity are coupled; anisotropy alone may explain the form but not the magnitude of the axis-parallel bands. There are strong trade-offs between the hypocentral depths of microearthquakes and the P and S wave velocity structures. Changing the mean hypocentral depth by up to 0.5 km leads to only modest increases in the travel time RMS but the resulting velocity models appear more feasible when the earthquakes are forced deeper than when they are forced shallower.", "corpus_id": 128428505, "score": 0 }, { "doc_id": "129011688", "title": "Accretional curvature of lithosphere at magmatic spreading centers and the flexural support of axial highs", "abstract": "Fluid magma should tend to rise up to the level of local isostatic equilibrium at an axis of plate spreading. The magma and underlying partial melt accretes to the side of the separating plates and gets denser as it cools and freezes. This load bends down the lithosphere and additional accretion forms a plate with concave upward curvature. The topography resulting from a curved plate passively moving off axis can be described analytically for accretion on the vertical side of uniform lithosphere when its flexural response is that of a thin elastic plate. Model predictions are consistent with the shape of the axial highs at fast spreading centers (typically ∼400m high and ∼20 km wide) as well as related gravity anomalies. This model requires at least several kilometers of lithospheric thickening within a few kilometers of the ridge axis. Seismic data appear consistent with this lithospheric structure. The magnitude and lateral distribution of faulting on the flanks of axial highs is crudely consistent with formation during plate unbending as lithosphere moves away from the axis. According to this model abandoned fast spreading centers should retain an elastically supported axial high, while for previous models abandoned highs should collapse.", "corpus_id": 129011688, "score": 0 }, { "doc_id": "128892850", "title": "Dike-induced faulting in rift zones of Iceland and Afar", "abstract": "Geodetic data and field observations demonstrate that the emplacement of dikes in volcanic rift zones frequently generates normal faulting and graben subsidence at the Earth9s surface. Elastic modeling of the vertical ground-surface displacements above dikes and faults indicates that the extent of graben subsidence can be achieved only if fault slip extends virtually to or beyond the dike plane at depth. A mechanical model that includes dikes and frictional faults shows that dike opening tends to compress and lock faults located to either side of the dike. Therefore, slip extending into or beyond the dike cavity must occur either (1) on faults that intersect the dike near its top, above the zone of dike-induced compression, or (2) on faults that slip ahead of the dike as it propagates laterally. Data from Iceland indicate that slip occurred on deep faults that presumably slipped in advance of the laterally propagating dike.", "corpus_id": 128892850, "score": 0 }, { "doc_id": "128901754", "title": "Dike‐induced faulting and graben subsidence in volcanic rift zones", "abstract": "Field observations and geodetic data indicate that dike intrusion in volcanic rift zones typically generates normal faulting and graben subsidence at the Earth's surface. Elastic models indicate that two-dimensional (infinite strike length) dikes do not lower the ground surface above the dike and that normal faults do not lower the surface significantly, more than one down-dip fault length from the fault trace. Dikes of finite length produce subsidence above the dike, but not by an appreciable amount, for appropriate dike lengths. Therefore the observed graben subsidence can be achieved only if fault slip extends virtually to the dike plane at depth. Dike intrusion increases the horizontal compression adjacent to the dike and decreases the compression beyond the dike perimeter. Therefore fault slip extending to the dike plane is most likely to occur above or in front of the laterally propagating dike. Two data sets documenting the change in surface elevation accompanying dike intrusion in the Krafla rift zone, Iceland, were inverted to determine the dike and fault geometry at depth. Ten kilometers south of the Krafla caldera, subsidence of a graben 1.5 km wide was produced by fault slip to 1.5–2 km depth, essentially to the dike top. Forty kilometers north of the caldera, subsidence of a graben 6 km wide was produced by fault slip to 4–5 km depth, well within the zone of compression adjacent to the dike. In order to determine if fault slip in front of the dike could have produced the observed subsidence north of the caldera, a three-dimensional boundary element model that computes fault slip during lateral dike propagation was developed. Results indicate that fault slip in front of the dike is capable of producing most of the subsidence observed. Additional subsidence could result from reasonable mechanical anisotropy of the rift zone. The lack of deep fault slip south of the caldera is attributed to a less favorable initial stress state. This is consistent with differences in the tectonic history of the two regions over the past several centuries.", "corpus_id": 128901754, "score": 0 }, { "doc_id": "19870103", "title": "Direct measurement of magnetic reversal polarity boundaries in a cross-section of oceanic crust", "abstract": "Magnetic field measurements made by submersible define the cross-sectional geometry of a magnetic polarity rever- sal boundary and the vertical variation of crustal magnetization in upper oceanic crust. Measured polarity boundaries show a systematic pattern of shallow dip towards the spreading axis within the upper extrusive lavas, and steeper dip in the lower extrusive lavas. This geometry is a consequence of the em- placement of extrusive lava at a midocean ridge. Reversal boundary geometry and magnetization estimates are used to calculate the magnetic contribution of the extrusive lava se- quence to the overlying marine magnetic anomaly signal. From the forward modeling, the highly magnetized extrusive lavas contribute the majority (50-75%) of the observed sea surface magnetic anomaly, consistent with the extrusive crust forming the primary source layer for young marine magnetic anomalies.", "corpus_id": 19870103, "score": 0 } ]

{ "doc_id": "129942513", "title": "Does the 5-Aminosalicylate Concentration Correlate with the Efficacy of Oral 5-Aminosalicylate and Predict Response in Patients with Inflammatory Bowel Disease? A Systematic Review", "abstract": "Background: Oral 5-aminosalicylic acid (5-ASA, mesalazine) is the first choice therapeutic agent for treating mild-to-moderate ulcerative colitis (UC). Unfortunately a significant group of patients fail to respond. Therapeutic drug monitoring might help to maintain or induce remission by providing a tool for optimization of 5-ASA therapy. However, plasma and urine concentrations of 5-ASA reflect systemic uptake and are not useful to evaluate therapeutic effect. Objectives: To explore if mucosal and faecal 5-ASA values correlate with disease activity and/or therapeutic effects in patients with inflammatory bowel disease, especially UC. Method: We identified studies that analysed 5-ASA in faeces or mucosa of humans using an oral 5-ASA formulation, using PubMed and Embase. Results: In total, 39 studies (n = 939) were included, 27 on faecal 5-ASA, 9 on mucosal concentrations, and 3 on both faecal and mucosal values. We included 33 cross-sectional studies, 3 randomised clinical trials, 2 longitudinal cohorts and 1 randomized cross-over study. Mucosal 5-ASA concentrations in healthy subjects and patients on equivalent doses of 5-ASA were not found to differ remarkably. In the sub-analysis of mucosal 5-ASA concentrations in patients with active or quiescent UC, a higher concentration was seen during remission. Faecal concentrations were associated with 5-ASA doses but not with disease activity. Differences in faecal or mucosal 5-ASA values could not be ascribed to different 5-ASA formulations. Conclusions: An increase of the mucosal 5-ASA concentrations was observed during remission in patients with UC. No clear relationship between the faecal 5-ASA excretion and the therapeutic efficacy was identified.", "corpus_id": 129942513 }

[ { "doc_id": "32940", "title": "Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies", "abstract": "BACKGROUND\nInflammatory bowel disease is a global disease in the 21st century. We aimed to assess the changing incidence and prevalence of inflammatory bowel disease around the world.\n\n\nMETHODS\nWe searched MEDLINE and Embase up to and including Dec 31, 2016, to identify observational, population-based studies reporting the incidence or prevalence of Crohn's disease or ulcerative colitis from 1990 or later. A study was regarded as population-based if it involved all residents within a specific area and the patients were representative of that area. To be included in the systematic review, ulcerative colitis and Crohn's disease needed to be reported separately. Studies that did not report original data and studies that reported only the incidence or prevalence of paediatric-onset inflammatory bowel disease (diagnosis at age <16 years) were excluded. We created choropleth maps for the incidence (119 studies) and prevalence (69 studies) of Crohn's disease and ulcerative colitis. We used temporal trend analyses to report changes as an annual percentage change (APC) with 95% CI.\n\n\nFINDINGS\nWe identified 147 studies that were eligible for final inclusion in the systematic review, including 119 studies of incidence and 69 studies of prevalence. The highest reported prevalence values were in Europe (ulcerative colitis 505 per 100 000 in Norway; Crohn's disease 322 per 100 000 in Germany) and North America (ulcerative colitis 286 per 100 000 in the USA; Crohn's disease 319 per 100 000 in Canada). The prevalence of inflammatory bowel disease exceeded 0·3% in North America, Oceania, and many countries in Europe. Overall, 16 (72·7%) of 22 studies on Crohn's disease and 15 (83·3%) of 18 studies on ulcerative colitis reported stable or decreasing incidence of inflammatory bowel disease in North America and Europe. Since 1990, incidence has been rising in newly industrialised countries in Africa, Asia, and South America, including Brazil (APC for Crohn's disease +11·1% [95% CI 4·8-17·8] and APC for ulcerative colitis +14·9% [10·4-19·6]) and Taiwan (APC for Crohn's disease +4·0% [1·0-7·1] and APC for ulcerative colitis +4·8% [1·8-8·0]).\n\n\nINTERPRETATION\nAt the turn of the 21st century, inflammatory bowel disease has become a global disease with accelerating incidence in newly industrialised countries whose societies have become more westernised. Although incidence is stabilising in western countries, burden remains high as prevalence surpasses 0·3%. These data highlight the need for research into prevention of inflammatory bowel disease and innovations in health-care systems to manage this complex and costly disease.\n\n\nFUNDING\nNone.", "corpus_id": 32940, "score": 0 }, { "doc_id": "35027193", "title": "Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.", "abstract": "BACKGROUND\nThe newer 5-ASA preparations were intended to avoid the adverse effects of SASP while maintaining its therapeutic benefits. The efficacy and safety of 5-ASA preparations have been evaluated in numerous clinical trials that have often lacked sufficient statistical power to arrive at definitive conclusions. Previously, it was found that newer 5-ASA drugs in doses of at least 2g/day, were more effective than placebo but no more effective than SASP in inducing remission in ulcerative colitis. This updated review includes more recent studies and evaluates the effectiveness, dose-responsiveness, and safety of 5-ASA preparations in terms of more precise outcome measures.\n\n\nOBJECTIVES\nTo assess the efficacy, dose-responsiveness and safety of the newer release formulations of 5-aminosalicylic acid (5-ASA) compared to placebo or sulfasalazine (SASP) for the induction of remission in active ulcerative colitis.\n\n\nSEARCH STRATEGY\nA computer-assisted literature search for relevant studies (1981-2003) was performed using MEDLINE, BIOS, the Cochrane Controlled Trials Register, the Cochrane IBD group specialized trials register and the Science Citation Index, followed by a manual search of reference lists from previously retrieved articles, review articles, symposia proceedings, and abstracts from major gastrointestinal conferences.\n\n\nSELECTION CRITERIA\nStudies were accepted for analysis if they were randomized, double-blinded, and controlled clinical trials of parallel design, with treatment durations of a minimum of four weeks.\n\n\nDATA COLLECTION AND ANALYSIS\nBased on an intention to treat principle, the outcomes of interest in the treatment of active disease were the failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, or endoscopic improvement.\n\n\nMAIN RESULTS\n5-ASA was superior to placebo with regard to all measured outcome variables. For the failure to induce global/clinical improvement or remission, the pooled Peto odds ratio was 0.51 (95% CI, 0.35 to 0.76). A dose-response trend for 5-ASA was also observed. When 5-ASA was compared to SASP, the pooled Peto odds ratio was 0.87 (CI, 0.63 to 1.21) for the failure to induce global/clinical improvement or remission, and 0.66 (CI, 0.42 to 1.04) for the failure to induce endoscopic improvement. SASP was not as well tolerated as 5-ASA.\n\n\nREVIEWER'S CONCLUSIONS\nThe newer 5-ASA preparations were superior to placebo and tended towards therapeutic benefit over SASP. However, considering their relative costs, a clinical advantage to using the newer 5-ASA preparations in place of SASP appears unlikely. This review updates the existing review of oral 5-aminosalicylic acid for induction of remission in ulcerative colitis which was published in the Cochrane Library (Issue 2, 2003).", "corpus_id": 35027193, "score": 0 }, { "doc_id": "17105585", "title": "Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study", "abstract": "Objective The introduction of anti tumour necrosis factor-α (anti-TNFα) therapy might impact healthcare expenditures, but there are limited data regarding the costs of inflammatory bowel diseases (IBD) following the introduction of these drugs. We aimed to assess the healthcare costs and productivity losses in a large cohort of IBD patients. Design Crohn's disease (CD) and ulcerative colitis (UC) patients from seven university hospitals and seven general hospitals were invited to fill-out a web-based questionnaire. Cost items were derived from a 3 month follow-up questionnaire and categorised in outpatient clinic, diagnostics, medication, surgery and hospitalisation. Productivity losses included sick leave of paid and unpaid work. Costs were expressed as mean 3-month costs per patients with a 95% CI obtained using non-parametric bootstrapping. Results A total of 1315 CD patients and 937 UC patients were included. Healthcare costs were almost three times higher in CD as compared with UC, €1625 (95% CI €1476 to €1775) versus €595 (95% CI €505 to €685), respectively (p<0.01). Anti-TNFα use was the main costs driver, accounting for 64% and 31% of the total cost in CD and UC. Hospitalisation and surgery together accounted for 19% and <1% of the healthcare costs in CD and 23% and 1% in UC, respectively. Productivity losses accounted for 16% and 39% of the total costs in CD and UC. Conclusions We showed that healthcare costs are mainly driven by medication costs, most importantly by anti-TNFα therapy. Hospitalisation and surgery accounted only for a minor part of the healthcare costs.", "corpus_id": 17105585, "score": 0 }, { "doc_id": "393874", "title": "Cyclooxygenase-2-dependent and -independent inhibition of proliferation of colon cancer cells by 5-aminosalicylic acid.", "abstract": "The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway may have a pathogenic role in colorectal cancer (CRC). Recent studies suggest that 5-aminosalicylic acid (5-ASA) reduces the risk of inflammatory bowel disease-related CRC, but the mechanism by which 5-ASA interferes with CRC cell growth remains unknown. In this study, we have examined whether the negative effect of 5-ASA on CRC cells is dependent on COX-2/PGE2 axis inhibition. We show that 5-ASA down-regulates both constitutive and TNF-alpha or IL-1beta-induced COX-2 in HT-115 and HT-29 cells. Inhibition of COX-2 by 5-ASA occurs at the RNA and protein level, and is associated with a significant decrease in PGE2 synthesis, arrest of growth and enhanced death of CRC cells. However, exogenous PGE2 does not revert the 5-ASA-mediated CRC cell proliferation block. 5-ASA also inhibits the growth of DLD-1, a COX-deficient CRC cell line, thus suggesting that the anti-proliferative effect of 5-ASA on CRC cells is not strictly dependent on the inhibition of COX-2/PGE2. Taken together our data indicate that 5-ASA causes both a COX-2-dependent and -independent inhibition of CRC cell growth.", "corpus_id": 393874, "score": 0 }, { "doc_id": "40775632", "title": "Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor kappaB activation in mouse colonocytes.", "abstract": "BACKGROUND & AIMS\nDerivatives of 5-aminosalicylic acid (mesalamine) represent a mainstay in inflammatory bowel disease therapy, yet the precise mechanism of their therapeutic action is unknown. Because tumor necrosis factor (TNF)-alpha is important in the pathogenesis of inflammatory bowel disease, we investigated the effect of mesalamine on TNF-alpha-regulated signal transduction and proliferation in intestinal epithelial cells.\n\n\nMETHODS\nYoung adult mouse colon cells were studied with TNF-alpha, epidermal growth factor, or ceramide in the presence or absence of mesalamine. Proliferation was studied by hemocytometry. Mitogen-activated protein (MAP) kinase activation and IkappaBalpha expression were determined by Western blot analysis. Nuclear transcription factor kappaB (NF-kappaB) nuclear translocation was determined by confocal laser immunofluorescent microscopy.\n\n\nRESULTS\nThe antiproliferative effects of TNF-alpha were blocked by mesalamine. TNF-alpha and ceramide activation of MAP kinase were inhibited by mesalamine, whereas epidermal growth factor activation of MAP kinase was unaffected. TNF-alpha-stimulated NF-kappaB activation and nuclear translocation and the degradation of Ikappa-Balpha were blocked by mesalamine.\n\n\nCONCLUSIONS\nMesalamine inhibits TNF-alpha-mediated effects on intestinal epithelial cell proliferation and activation of MAP kinase and NF-kappaB. Therefore, it may function as a therapeutic agent based on its ability to disrupt critical signal transduction events in the intestinal cell necessary for perpetuation of the chronic inflammatory state.", "corpus_id": 40775632, "score": 0 }, { "doc_id": "12824494", "title": "Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1", "abstract": "Graphical abstract (a) PAK1 orchestrates mesalamine activity, (b) mesalamine inhibits PAK1; increases membranous E-cadherin and β-catenin; modulates cell adhesion", "corpus_id": 12824494, "score": 0 }, { "doc_id": "45921584", "title": "5-Aminosalicylic acid is a potent inhibitor of interleukin 1 beta production in organ culture of colonic biopsy specimens from patients with inflammatory bowel disease.", "abstract": "Interleukin 1 beta in biopsy specimens from inflamed colonic mucosa of patients with active inflammatory bowel disease was studied. Compared with normal colonic mucosal biopsy specimens, a significantly greater amount of interleukin 1 beta was present in rectal mucosa before (median (range) 4.3 (2.0-11.8) v 119.2 (30.1-286.8) pg/mg; p less than 0.01) and produced during organ culture (39.1 (9.4-106.8) v 97.6 (28.2-991.6) pg/mg; p less than 0.01). Values of interleukin 1 beta after culture correlated with concentrations of thromboxane B2. Organ culture of inflamed biopsy specimens in the presence of 5 aminosalicylic acid and dexamethasone reduced the amount of interleukin 1 beta detected. At the doses studied, 5 aminosalicylic acid also reduced the amount of leukotriene B4 detected after culture.", "corpus_id": 45921584, "score": 0 }, { "doc_id": "13421283", "title": "5-Aminosalicylic acid prevents oxidant mediated damage of glyceraldehyde-3-phosphate dehydrogenase in colon epithelial cells", "abstract": "Background Reactive oxygen and nitrogen derived species produced by activated neutrophils have been implicated in the damage of mucosal proteins including the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the active inflammatory lesion in patients with inflammatory bowel disease (IBD). This study investigated the efficacy of currently used IBD therapeutics to prevent injury mediated by reactive oxygen and nitrogen derived species. Methods GAPDH activity of human colon epithelial cells was used as a sensitive indicator of injury produced by reactive oxygen and nitrogen derived species. HCT116 cells (106/ml phosphate buffered saline; 37°C) were incubated in the presence of 5-aminosalicylic acid (5-ASA), 6-mercaptopurine, methylprednisolone, or metronidazole before exposure to H2O2, HOCl, or NO in vitro. HCT116 cell GAPDH enzyme activity was determined by standard procedures. Cell free reactions between 5-ASA and HOCl were analysed by spectrophotometry and fluorimetry to characterise the mechanism of oxidant scavenging. Results GAPDH activity of HCT116 cells was inhibited by the oxidants tested: the concentration that produced 50% inhibition (IC50) was 44.5 (2.1) μM for HOCl, 379.8 (21.3) μM for H2O2, and 685.8 (103.8) μM for NO (means (SEM)). 5-ASA was the only therapeutic compound tested to show efficacy (p<0.05) against HOCl mediated inhibition of enzyme activity; however, it was ineffective against H2O2 and NO mediated inhibition of GAPDH. Methylprednisolone, metronidazole, and the thiol-containing 6-mercaptopurine were ineffective against all oxidants. Studies at ratios of HOCl:5-ASA achievable in the mucosa showed direct scavenging to be the mechanism of protection of GAPDH activity. Mixing 5-ASA and HOCl before addition to the cells resulted in significantly greater protection of GAPDH activity than when HOCl was added to cells preincubated with 5-ASA. The addition of 5-ASA after HOCl exposure did not restore GAPDH activity. Conclusions Therapies based on 5-ASA may play a direct role in scavenging the potent neutrophil oxidant HOCl, thereby protecting mucosal GAPDH from oxidative inhibition. These findings suggest that strategies for the further development of new HOCl scavenging compounds may be useful in the treatment of IBD.", "corpus_id": 13421283, "score": 0 }, { "doc_id": "8352428", "title": "Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator–activated receptor-γ", "abstract": "5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator–activated receptor-γ (PPAR-γ) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-γ+/− mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-γ expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element–driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-γ as a target of 5-ASA underlying antiinflammatory effects in the colon.", "corpus_id": 8352428, "score": 0 }, { "doc_id": "25226847", "title": "Pharmacokinetics of 5-aminosalicylic acid in man following administration of intravenous bolus andper os slow-release formulation", "abstract": "The fate of 5-aminosalicylic acid (5-ASA), which is used in the treatment of chronic inflammatory bowel diseases, was studied in six healthy volunteers receiving doses of 100 mg and 250 mg intravenous bolus as well as 250 mgper os (slow release). Following intravenous administration, the drug was rapidly eliminated with a plasma half-life of about 40 min, mainly due to rapid metabolism. No parent drug was recovered in feces, and the total recovery following oral administration (30%) was significantly lower than following the intravenous doses (77% and 72%). Nonlinear pharmacokinetics were suggested as the 2.5-fold increase in intravenous dose was followed by a significant relative increase (>2.5) in the renal elimination of 5-ASA, as well as a significant decrease (<2.5) in the elimination of the metaboliteN-acetyl-5-ASA. There was also a trend towards a decreasing total body clearance and metabolic ratio. The present study confirms earlier findings on the pharmacokinetics of 5-ASA and suggests a possible saturation of theN-acetylating system in the dose range studied. This may be of interest in the design of controlled-release formulations and dosage regimes for the treatment of diseases of the small-bowel, where 5-ASA is easily absorbed. Further, for the first time, a marked difference in the intestinal fate compared to the systemic fate of the drug is demonstrated, suggesting alternative presystemic metabolism of 5-ASA, which may bear relevance to its mode of action. Further studies on the pharmacokinetics of 5-ASA, preferably in patients, are warranted.", "corpus_id": 25226847, "score": 0 }, { "doc_id": "23150636", "title": "Dose loading with delayed-release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters.", "abstract": "AIMS\nTissue concentrations of 5-aminosalicylic acid (5ASA) and its metabolites may influence the clinical course of inflammatory bowel disease. Since the factors that determine tissue drug concentrations are unknown we have studied the relationships between the oral dose of delayed-release mesalazine, rectal tissue drug concentrations and standard pharmacokinetic parameters.\n\n\nMETHODS\nTwelve healthy volunteers were studied following 7 days treatment with 1.2, 2.4 and 4.8 g of delayed-release mesalazine daily. 5-aminosalicylic acid and N-acetyl 5-aminosalicylic acid concentrations were measured in serum, urine, stool and rectal tissue biopsies.\n\n\nRESULTS\nSerum concentrations and 24 h urinary excretion of 5ASA and N-acetyl 5ASA increased as the oral dose of mesalazine was increased from 1.2 g through 2.4 g to 4.8 g daily (serum area under curve (AUC):5ASA = 3. 9, 15.4 and 46.8 microg ml-1 h, P < 0.0001; N-acetyl 5ASA = 17.2, 30. 9 and 57.8 microg ml-1 h, P < 0.0001: urinary excretion: 5ASA = 1.8, 85.5 and 445 mg, P < 0.0001; N-acetyl 5ASA = 250, 524 and 1468 mg, P < 0.0001, respectively). Faecal 5ASA excretion increased as the oral dose increased from 1.2 g to 2.4 g but did not increase further with 4.8 g daily dosing whereas faecal N-acetyl 5ASA excretion was similar at all three doses. Rectal tissue concentrations of 5ASA increased markedly, and N-acetyl 5ASA increased modestly, as the dose of oral mesalazine increased from 1.2 g to 2.4 g daily but neither increased further with 4.8 g daily dosing.\n\n\nCONCLUSIONS\nThe relationship between the ingested dose of delayed-release mesalazine and rectal tissue drug concentrations is complex. Factors other than dose are likely to be important determinants of rectal tissue drug concentrations.", "corpus_id": 23150636, "score": 1 }, { "doc_id": "6942456", "title": "Intestinal metabolism and transport of 5-aminosalicylate.", "abstract": "The purpose of this study was to determine the characteristics of intestinal absorption and metabolism of 5-aminosalicylic acid (5ASA). Regional perfusions of 5ASA in the anesthetized rat resulted in the appearance of N-acetyl-5-aminosalicylic acid in the intestinal lumen. Lumenal metabolite appearance was proportional to 5ASA permeability, which was 5-fold higher in the jejunum than in the ileum. Intestinal elimination significantly decreases 5ASA absorption at low lumenal drug concentrations and this process is saturated at high drug concentrations. Metabolite levels in intestinal tissue were higher than plasma levels at low perfusion drug concentrations, whereas the reverse was observed at high concentrations. Transport and metabolism of 5ASA was studied in Caco-2 monolayers. At low drug concentrations, 5ASA was preferentially transported in the basolateral (BL) to apical (AP) direction. With 5ASA incubation in either the AP or BL chamber, the N-acetyl metabolite appeared only in the AP compartment. Transport of N-acetyl-5-aminosalicylic acid was also exclusively observed in the BL to AP direction. Clinical data indicate that anti-inflammatory response to oral 5ASA correlates with the amount of 5ASA delivered to the intestinal tissue. This study shows that at lumenal levels below 200 microg/ml (concentrations that are typically achieved by controlled release dosage forms), intestinal secretion of 5ASA accounts for more than 50% of the total elimination and can significantly affect tissue levels and, therefore, may be an important factor in determining the response to 5ASA therapy.", "corpus_id": 6942456, "score": 0 }, { "doc_id": "12887341", "title": "Mesalazine preparations for the treatment of ulcerative colitis: Are all created equal?", "abstract": "Oral mesalazine (also known as mesalamine) is a 5-aminosalicylic acid compound used in the treatment of mild to moderate ulcerative colitis, with high rates of efficacy in induction and maintenance of remission. The therapeutic effect of mesalazine occurs topically at the site of diseased colonic mucosa. A myriad of oral mesalazine preparations have been formulated with various drug delivery methods to minimize systemic absorption and maximise drug availability at the inflamed colonic epithelium. It remains unclear whether different oral mesalazine formulations are bioequivalent. This review aims to evaluate the differences between mesalazine formulations based on the currently available literature and explore factors which may influence the selection of one agent above another.", "corpus_id": 12887341, "score": 0 }, { "doc_id": "7228224", "title": "Ulcerative Colitis Remission Status After Induction With Mesalazine Predicts Maintenance Outcomes: the MOMENTUM Trial", "abstract": "Background and Aims: This study assessed the efficacy of maintenance treatment with multimatrix mesalazine following achievement of complete or partial remission after induction treatment with high-dose multimatrix mesalazine. Methods: In this phase 3b/4, open-label, multicentre, prospective, single-arm study, patients with mild-to-moderate ulcerative colitis were treated with multimatrix mesalazine 4.8g/day once daily for 8 weeks [induction phase]. At Week 8, those who achieved complete or partial remission, based on predefined clinical and endoscopic criteria, were eligible to receive 12 months of multimatrix mesalazine 2.4g/day once daily maintenance therapy. The primary endpoint was the proportion of patients in complete remission at Month 12. Results: A total of 717 patients received induction treatment; 25.9% and 39.3% of patients achieved complete and partial remission, respectively, at Week 8. A total of 461 patients entered the maintenance phase. The likelihood of remaining in/achieving complete remission at Month 12 was higher for patients who entered the maintenance phase in complete remission compared with those who began maintenance in partial remission [47.8% vs 26.0%; p < 0.001]. At Month 12, mucosal healing [endoscopy score ≤ 1] was demonstrated in 76.4% [139/182] and 63.5% [176/277] of those who were in complete and partial remission, respectively, at the end of induction. Conclusion: Patients achieving complete remission before dose reduction were more likely to remain in remission at Month 12.", "corpus_id": 7228224, "score": 0 }, { "doc_id": "26478950", "title": "Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis.", "abstract": "BACKGROUND AND AIMS\nIt is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC.\n\n\nMETHODS\nA multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physician's Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment.\n\n\nRESULTS\nThe primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, -11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events.\n\n\nCONCLUSIONS\nDelayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC.", "corpus_id": 26478950, "score": 0 }, { "doc_id": "1250315", "title": "Five-Aminosalicylic Acid: An Update for the Reappraisal of an Old Drug", "abstract": "Inflammatory bowel disease (IBD) comprises several conditions with chronic or recurring immune response and inflammation of the gastrointestinal apparatus, of which ulcerative colitis and Crohn's disease are the commonest forms. This disease has a significant prevalence and it is of an unknown aethiology. Five-aminosalicylic acid (5-ASA) and its derivatives are among the oldest drugs approved for the treatment of the IBD. In this review we reapprise aspects of 5-ASA mechanism of action, safety, and efficacy that in our opinion make it a valuable drug that can be fruitfully tailored in personalised treatments as a therapeutic option alongside other immune-modifying agents.", "corpus_id": 1250315, "score": 0 }, { "doc_id": "5299459", "title": "Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches.", "abstract": "Intestinal microbiota are involved in the pathogenesis of Crohn's disease, ulcerative colitis, and pouchitis. We review the mechanisms by which these gut bacteria, fungi, and viruses mediate mucosal homeostasis via their composite genes (metagenome) and metabolic products (metabolome). We explain how alterations to their profiles and functions under conditions of dysbiosis contribute to inflammation and effector immune responses that mediate inflammatory bowel diseases (IBD) in humans and enterocolitis in mice. It could be possible to engineer the intestinal environment by modifying the microbiota community structure or function to treat patients with IBD-either with individual agents, via dietary management, or as adjuncts to immunosuppressive drugs. We summarize the latest information on therapeutic use of fecal microbial transplantation and propose improved strategies to selectively normalize the dysbiotic microbiome in personalized approaches to treatment.", "corpus_id": 5299459, "score": 0 }, { "doc_id": "18347678", "title": "Therapeutic drug monitoring for tomorrow", "abstract": "Therapeutic drug monitoring (TDM) represents an early approach to personalised medicine. It helps the clinician to individualise drug treatment and guide dosage to reach systemic drug concentrations associated with therapeutic efficacy and/or to reduce the risk of concentration-dependent adverse effects. Well into the fifth decade of TDM as a service to healthcare, this concept is still expanding, and new areas for clinical implementation continue to emerge. The aim of this overview is to discuss promising new therapeutic areas in future TDM services, how to improve the clinical interpretation of single drug measurements and how recent technology development opens the doors to research and new applications.", "corpus_id": 18347678, "score": 0 }, { "doc_id": "37921089", "title": "Clinical Pharmacokinetics in the 21st Century", "abstract": "Clinical pharmacokinetics emerged as a clinical discipline in the late 1960s and early 1970s. Clinical pharmacokinetic monitoring (CPM) helped many pharmacists to enter the clinical arena, but the focus was more on the pharmacists and tools. With the widespread acceptance of pharmaceutical care and patientfocused pharmacy, we now must take a sobering look at how clinical pharmacokinetics fits into the pharmaceutical care process.The existing literature is laden with articles that evaluate the effect of CPM on surrogate end-points. Many pharmacists have also had personal experiences that attest to the usefulness of CPM. Decreased mortality, decreased length of treatment, decreased length of hospital stay, decreased morbidity, and decreased adverse effects from drug therapy have been examined in an effort to measure and evaluate the impact of CPM on patient outcomes. While many of these studies demonstrated significant positive outcomes, several showed that CPM did not have a significant impact on specific patient outcomes. A few studies even found a negative impact on specific patient outcomes. Ultimately, there is good evidence in only a few specific patient groups to support the benefit of CPM.Despite the limitations of data supporting the routine use of CPM in managing drug therapy in diverse populations, many pharmacists continue to expend considerable time and effort in this activity. We need to define those patients who are most likely to benefit from CPM and incorporate this into our provision of pharmaceutical care, while minimising the time and money spent on CPM that provides no value.In redefining the patients who will benefit from CPM, we need to critically re-evaluate clinical studies on the relationship between drug concentration and response. Similarly, we need to pay special attention to recent studies evaluating the impact of CPM on outcomes in specific subpopulations. In the absence of specific studies demonstrating the value of CPM in particular patients, we propose that a more comprehensive decision-making process be undertaken that culminates in the quintessential question: ‘Will the results of the drug assay make a significant difference in the clinical decision-making process and provide more information than sound clinical judgement alone?’ We also need to consider opportunities to expand the use of CPM for new drugs and where new evidence suggests benefit.Even when there is strong evidence that CPM is useful in managing therapy in particular patient groups, clinicians need to remember that the therapeutic range is no more than a confidence interval and, therefore, we need to ‘treat the patient and not the level’. We need to incorporate the patient-specific and outcome-oriented principles of pharmaceutical care into our CPM, even as we utilise CPM as an essential tool in pharmaceutical care.", "corpus_id": 37921089, "score": 0 }, { "doc_id": "45925389", "title": "Review article: delivery and efficacy of topical 5‐aminosalicylic acid (mesalazine) therapy in the treatment of ulcerative colitis", "abstract": "Aliment Pharmacol Ther 2011; 33: 996–1009", "corpus_id": 45925389, "score": 0 }, { "doc_id": "30534976", "title": "Systemic absorption of 5-aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine", "abstract": "Objective: To compare the systemic load of 5-aminosalicylic acid (5-ASA) as a basis for potential long-term toxicity during treatment in usual dosage with olsalazine (Dipentum) and one controlled-release mesalazine preparation (Salofalk) in patients with inactive ulcerative colitis. Design: Open, randomized, crossover study. Treatment schedule: Olsalazine 500 mg twice daily for 7 days and mesalazine 500 mg thrice daily for 7 days consecutively. Patients: Fifteen patients (12 males/3 females) aged between 18–70 years with ulcerative colitis in endoscopically confirmed remission for at least one month. Methods: A morning predose plasma sample and a 24-h urine collection on days 6 and 7 of each course were obtained from all patients for quantitative determination of 5-ASA and acetyl-5-ASA (Ac-5-ASA) concentrations. High performance liquid chromatography was used and all analyses were performed blindly on coded samples. Results: Treatment with mesalazine compared with olsalazine gave significantly higher levels of 5-ASA and Ac-5-ASA in plasma and urine. Maximum values and ranges of all variables were higher in the mesalazine group than in the olsalazine group. It is noteworthy that there was clear discriminance in the range of urine 5-ASA and Ac-5-ASA concentrations after mesalazine and olsalazine treatment. Conclusion: 1. The mesalazine preparation used, in comparison with olsalazine given in usual dosages, causes significantly higher levels of 5-ASA and Ac-5-ASA in plasma and urine in patients with inactive ulcerative colitis. 2. The lower systemic load of 5-ASA may reduce the potential risk of adverse events and in particular of nephrotoxicity. European Journal of Gastroenterology & Hepatology 1996, 8:1083–1088", "corpus_id": 30534976, "score": 0 }, { "doc_id": "23783228", "title": "Review article: 5‐aminosalicylate formulations for the treatment of ulcerative colitis – methods of comparing release rates and delivery of 5‐aminosalicylate to the colonic mucosa", "abstract": "Background  Many oral 5‐aminosalicylic acid (5‐ASA) formulations are designed to maximize 5‐ASA release in the colon where it acts topically on the colonic mucosa. Delayed‐release formulations and azo‐prodrugs minimize 5‐ASA absorption in the upper gastrointestinal (GI) tract.", "corpus_id": 23783228, "score": 0 }, { "doc_id": "20141094", "title": "The pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro‐drugs used in the management of ulcerative colitis", "abstract": "Aim : To quantify through systematic review the pharmacokinetic profiles of the oral delayed release and sustained release mesalazine (5‐aminosalicylate, 5ASA) formulations (Asacol, Salofalk, Mesasal, Claversal, Pentasa) and pro‐drugs (sulfasalazine, olsalazine, balsalazide) used in the management of ulcerative colitis.", "corpus_id": 20141094, "score": 0 }, { "doc_id": "34365192", "title": "Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement", "abstract": "David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses", "corpus_id": 34365192, "score": 0 }, { "doc_id": "30489942", "title": "Distribution studies of salicylazosulfapyridine and its metabolites.", "abstract": "Abstract Previous studies in the rat have indicated that the initial reaction of salicylazosulfapyridine (SAS) metabolism, reduction of the azo bond, can be attributed exclusively to the action of the intestinal bacteria. This finding raises questions concerning the amount of intact SAS that reaches its possible site of action within the lumen in inflammatory disease of the lower intestine. Accordingly, a study of the distribution of SAS and its metabolites in the rat and in man has been undertaken. In both species only small amounts of SAS were recovered in the urine. The drug was not recovered in the feces of rats but small amounts were found in the feces of 4 of 11 human subjects. In both species a consistent finding was high levels of sulfapyridine in the urine and high levels of 5-aminosalicylate in the feces. Indeed the level of 5aminosalicylate in rat feces greatly exceeded that found when an equimolar amount of 5-aminosalicylate itself was fed orally to the rats. These studies indicate that SAS is almost completely metabolized in both human subjects and rats and that there is a tendency for its metabolite 5-aminosalicylate to reach relatively high levels in the feces.", "corpus_id": 30489942, "score": 0 }, { "doc_id": "17632923", "title": "Distribution and metabolism in healthy volunteers of disodium azodisalicylate, a potential therapeutic agent for ulcerative colitis.", "abstract": "A series of experiments has been performed in healthy male volunteers to investigate the disposition of orally administered disodium azodisalicylate, a potentially useful drug for the treatment of ulcerative colitis. The drug was given by mouth in doses of up to 2 g a day for six weeks and there were no adverse effects. Serum concentrations of the intact compound were low and the serum half-time was 4-12.8 days, probably because of a combination of a low clearance rate and a high apparent volume of distribution. Less than 5% of the ingested dose was excreted unchanged in the urine. Circulating concentrations of 5-ASA and N-acetyl-5-ASA were low and 30% of the equivalent daily dose was excreted in the urine, predominantly as N-acetyl-5-ASA. In most subjects more than 30% of the equivalent daily dose of 5-ASA was recovered from the faeces, either as 5-ASA itself or as the acetylated derivative. As 5-ASA has been shown to be the active therapeutic moiety of sulphasalazine, disodium azodisalicylate appears to be suitable for therapeutic trial in ulcerative colitis.", "corpus_id": 17632923, "score": 1 }, { "doc_id": "9356722", "title": "Colonic azodisalicylate metabolism determined by in vivo dialysis in healthy volunteers and patients with ulcerative colitis.", "abstract": "Azodisalicylate, a second generation drug of sulfasalazine, delivers twice the amount of 5-aminosalicylic acid to the colonic lumen on a molar basis when split by bacterial azoreductases. In 6 patients with inactive ulcerative colitis, the colonic metabolism of sulfasalazine and azodisalicylate was studied by equilibrium in vivo dialysis of feces to measure the therapeutically relevant concentrations of their metabolites (5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid) in free fecal water. After oral intake of sulfasalazine (2 g/day) the total luminal concentrations of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid determined by high-performance liquid chromatography were higher (median 14 mmol/L) than previously reported and almost doubled (median 25 mmol/L, p less than 0.05) when sulfasalazine was replaced by the same dose of azodisalicylate. In contrast, the corresponding serum concentrations were negligible. After administration of azodisalicylate to 12 healthy volunteers, a similar distribution of the metabolites was found. In nearly all cases, the concentrations of azodisalicylate in fecal dialysates were below the detection limit (6 mumol/L). We conclude, therefore, that oral azodisalicylate is a highly effective means of delivery of 5-aminosalicylic acid to the colonic mucosa. In addition, determination of the active metabolites in free fecal water seems important for the interpretation of results obtained in vitro concerning the mode of drug action.", "corpus_id": 9356722, "score": 1 }, { "doc_id": "19838417", "title": "Simple method for the determination of 5-aminosalicylic and N-acetyl-5-aminosalicylic acid in rectal tissue biopsies.", "abstract": "We describe a sensitive high-performance liquid chromatographic method for the determination of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid in rectal tissue biopsies. Samples were derivatised using propionic anhydride and proteins were precipitated with methanol. A Supelcosil ABZ column (150x4.6 mm I.D., 5 microm silica particles) was used with a mobile phase comprising 0.1 M acetic acid, acetonitrile and triethylamine (1600:114:6, v/v/v). Fluorescence detection was employed and detection limits were 0.2 ng/mg tissue at a signal-to-noise ratio of three (measured concentration: 5-aminosalicylic acid, 0.254 (0.228-0.286) ng/mg, C.V. 10.7%; N-acetyl-5-aminosalicylic acid, 0.18 (0.154-0.198) ng/mg, C.V 9.8%). This assay was validated for use with serum, urine and faecal samples for which it proved to be both precise and accurate (C.V.<10%, measured concentration within 10%).", "corpus_id": 19838417, "score": 1 }, { "doc_id": "31849972", "title": "Mesalazine release from coated tablets: effect of dietary fibre.", "abstract": "Delayed-release mesalazine formulations relay on pH-dependent coat dissolution to ensure delivery of 5-aminosalicylic acid (5-ASA) to the colon. As dietary fibre acidifies the colonic lumen we have studied the effect of fibre supplementation in 10 patients with quiescent colitis. Greater intake of dietary fibre was associated with a decrease in stool pH and an increase in stool frequency and faecal mass. However, the 24 h faecal and urinary excretion of 5-ASA and N-acetyl-5-ASA was unchanged. The percentage of total faecal ASA excreted as N-acetyl-5-ASA correlated with whole-gut transit time, suggesting that prolonged transit may be disadvantageous to patients with colitis as N-acetyl-5-ASA appears to be inactive.", "corpus_id": 31849972, "score": 0 }, { "doc_id": "2588286", "title": "Influence of intestinal transit time on azo-reduction of salicylazosulphapyridine (Salazopyrin).", "abstract": "During a normal and an accelerated intestinal transit, in seven healthy volunteers, the recoveries of salicylazosulphapyridine (SASP) and its split products sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA) were determined in urine and faeces. The azo-reduction of SASP and consequently the recovery of 5-ASA in the faeces was found to be substantially decreased during an accelerated intestinal transit. In addition, in 18 patients with inflammatory disease of the colon during maintenance therapy of SASP it could be demonstrated that the serum SP levels were related to the diarrhoeal state and did not correlate with disease activity. As recent studies have reported that 5-ASA is possibly the active therapeutic moiety of SASP, the ineffectiveness of SASP therapy in patients with active colitis may be ascribed to the reduced azo reduction of SASP as the result of profuse diarrhoea.", "corpus_id": 2588286, "score": 0 }, { "doc_id": "14089877", "title": "Longterm olsalazine treatment: pharmacokinetics, tolerance and effects on local eicosanoid formation in ulcerative colitis and Crohn's colitis.", "abstract": "To examine pharmacokinetics and tolerance of long term administration of olsalazine (azodisalicylate), increasing doses of the drug were given for one year to 31 patients with ulcerative colitis (UC) and nine patients with Crohn's colitis (CC), refractory to, or intolerant of sulphasalazine, until sustained remission was obtained or a maximum of 4 g/day was reached. Colonic drug metabolism was studied by equilibrium in vivo dialysis of faeces. Complete azoreduction occurred in most cases. Concentrations of 5-aminosalicylic acid, but not N-acetyl-5-aminosalicylic acid, in faecal dialysates increased dose dependently. Serum concentrations disclosed no cumulation in the long term and olsalazine was well tolerated, although loose stools occurred transiently in some patients with extensive disease: this was associated with a larger proportion of unsplit olsalazine in the faecal dialysates. Patients with ulcerative colitis having a high prostaglandin E2 concentration (greater than ng/ml) determined by equilibrium dialysis of rectum, were less likely to benefit from treatment. Olsalazine is a very effective means of delivery of 5-aminosalicylic acid to the colonic mucosa in active disease. Use of the drug in controlled trials may be considered safe even in prolonged high dosage.", "corpus_id": 14089877, "score": 1 }, { "doc_id": "1199240", "title": "Pharmacokinetics of 5-aminosalicylic acid from controlled-release capsules in man", "abstract": "One gram single dose of Pentasa controlled-release capsules was administered to 24 healthy volunteers under fasting condition. Mean plasma 5-aminosalicylic acid (5-ASA) and acetyl 5-ASA concentrations peaked at 0.53 μg · ml−1 and 1.33 μg · ml−1 from 3 to 4 hours following dosing, respectively. The half-lives of both compounds could not be determined as absorption of 5-ASA was continuous throughout the gastrointestinal tract. An average of 29.4% (CV: 27%) of the dose was excreted in the urine primarily as acetyl 5-ASA. Up to 91.1% of the dose was released from the capsules. Forty percent of the dose (CV: 40%) was eliminated in the feces, with 8.9% of the dose remained as formulation bounded 5-ASA, indicating that controlled-release capsules continue to release drug throughout the GI tract. 5-ASA contributed 46.7% of the salicylates eliminated in the feces and acetyl 5-ASA accounted for the balance. Controlled-release capsules produced three times more total salicylates and 10 times more total and free 5-ASA in the feces than did 5-ASA suspension. Thus, while lower systemic levels of salicylates were absorbed, greater therapeutic quantities of 5-ASA were available in the bowel.", "corpus_id": 1199240, "score": 0 }, { "doc_id": "73250278", "title": "Olsalazine in the Treatment of Active Ulcerative Colitis: A Placebo Controlled Clinical Trial and Assessment of Drug Disposition", "abstract": "The efficacy, safety and disposition of olsalazine was assessed in patients with left-sided ulcerative colitis or proctitis in a double-blind placebo controlled trial. Thirty patients with a mild-to-moderate attack of ulcerative colitis were randomly allocated to olsalazine capsules, 1 g b.d., or placebo for 6 weeks. Good clinical response was found in six patients receiving olsalazine and in two receiving placebo. Improvement in sigmoidoscopic findings and histological appearance of rectal biopsies was also seen more often in olsalazine-treated patients. Plasma concentrations of olsalazine were significantly higher in patients who improved. Olsalazine showed an advantage over placebo which needs to be confirmed by further studies; it was safe in sulphasalazine-sensitive patients but appeared to cause watery diarrhoea in two patients.", "corpus_id": 73250278, "score": 0 }, { "doc_id": "59078691", "title": "Is 5-Aminosalicylic Acid Delivered Directly to the Colon by Olsalazine?", "abstract": "The aims of this investigation were to determine the amount of olsalazine which is delivered to the colon and the amount biotransformed to 5-ASA and N-acetyl-5-ASA, and to study the effect of concomitant food intake on the availability of 5-ASA and acetyl-5-ASA after olsalazine, 1 g. Studies in 10 subjects who received a single 1 g oral dose showed that olsalazine is transported intact to the colon and that less than 3% is absorbed. Olsalazine is, therefore, biologically transformed to 5-ASA and acetyl-5-ASA in the large intestine. The small amount of olsalazine absorbed has a short β half-life of 56 minutes. The simultaneous intake of food in a study involving eight healthy volunteers slightly diminished the low absorption of olsalazine, though the effect was not significant, and no effect was seen on the absorption of 5-ASA.", "corpus_id": 59078691, "score": 0 }, { "doc_id": "72568310", "title": "Su1081 A Novel Method to Investigate Local Concentrations of Mesalamine in the Gastrointestinal Tract of Healthy Volunteers", "abstract": "Background: Recent observatory studies suggest that non-adherence to 5-ASA therapy during remission is a main factor for relapse in ulcerative colitis (UC) (1). Patient education may improve adherence. We investigated demographic and clinical parameters associated with non-adherence and influence of patient education on 5-ASA adherence in a randomized, prospective clinical trial. Methods: 247 patients with inactive or mildly active UC (CAI 60 yrs: 30.2%; 13/43). High levels of non-adherence were associated with short duration of disease (2-5 yrs: 55.9%; 57/102 vs. 5-10 yrs: 52.2%; 35/67, 10-15 yrs: 51.2%; 21/41 and >15 yrs: 44.7%; 17/38). A trend for a relationship between non-adherence and low education levels was seen (low education (only basic school): 63.8%, 30/47 vs. higher education levels (trade school): 41.8 %, 28/67 and \"Abitur\"/university: 58%, 65/ 112). Conclusion: Although >25% of the population were not in remission throughout the study no relationship between disease activity and adherence was seen. Non adherence was associated with younger age, short duration of disease and lower education levels. While a structured intervention using a patient education program failed to improve adherence in this particular group, efforts should be maximized to motivate this high-risk population for adherence. Lit :(1) Khan et al., Aliment Pharmacol Therap 2012", "corpus_id": 72568310, "score": 0 }, { "doc_id": "2094056", "title": "5-ASA colonic mucosal concentrations resulting from different pharmaceutical formulations in ulcerative colitis.", "abstract": "AIM\nTo compare the mucosal concentrations of 5-aminosalicylic acid (5-ASA) resulting from different pharmaceutical formulations and analyse the influence of inflammation on the mucosal concentrations.\n\n\nMETHODS\nThe study included 130 inflammatory bowel disease (IBD) patients receiving 5-ASA as pH-dependent-release formulations (73 patients), time-dependent-release formulations (11 patients), or pro-drugs (18 patients). In addition, 28 patients were receiving topical treatment (2-4 g/d) with pH-dependent-release formulations. Endoscopic biopsies were obtained from the sigmoid region during the colonoscopy. The 5-ASA concentrations (ng/mg) were measured in tissue homogenates using high-pressure liquid chromatography with electrochemical detection. The t test and Mann-Whitney test, when appropriate, were used for statistical analysis.\n\n\nRESULTS\nPatients receiving pH-dependent-release formulations showed significantly higher mucosal concentrations of 5-ASA (51.75 ± 5.72 ng/mg) compared with patients receiving pro-drugs (33.35 ± 5.78 ng/mg, P = 0.01) or time-dependent-release formulations (38.24 ± 5.53 ng/mg, P = 0.04). Patients with endoscopic remission had significantly higher mucosal concentrations of 5-ASA than patients with active disease (60.14 ± 7.95 ng/mg vs 35.66 ± 5.68 ng/mg, P = 0.02). Similar results were obtained when we compared patients with the histological appearance of remission and patients with active histological inflammation (67.53 ± 9.22 ng/mg vs 35.53 ± 5.63 ng/mg, P < 0.001). Significantly higher mucosal concentrations of 5-ASA were detected in patients treated with both oral and topical treatments in combination compared with patients who received oral treatment with pH-dependent-release formulations alone (72.33 ± 11.23 ng/mg vs 51.75 ± 5.72 ng/mg, P = 0.03).\n\n\nCONCLUSION\nIBD patients showed significant variability in mucosal 5-ASA concentrations depending on the type of formulation, and the highest mean concentration was achieved using pH-dependent-release formulations.", "corpus_id": 2094056, "score": 1 }, { "doc_id": "25453938", "title": "Measurement of Colonic Mucosal Concentrations of 5-Aminosalicylic Acid Is Useful for Estimating Its Therapeutic Efficacy in Distal Ulcerative Colitis: Comparison of Orally Administered Mesalamine and Sulfasalazine", "abstract": "ObjectivesOral 5-aminosalicylic acid (5-ASA) preparations have been used frequently in the treatment of ulcerative colitis. However, there have been few reports investigating the relationship between colonic mucosal concentrations of 5-ASA and its clinical efficacy when oral sulfasalazine or 5-ASA compounds were administered. The aim of this study is to compare the mucosal concentrations of 5-ASA ensured by sulfasalazine or mesalamine, and to define the clinical significance of the measurement of 5-ASA concentrations in the treatment of distal ulcerative colitis. Materials and MethodsBiopsies were taken from the rectum and sigmoid colon of the oral sulfasalazine group (n = 13) and the slow-release 5-ASA (mesalamine) group with (n = 5) or without (n = 11) rectal administration of 5-ASA. High-pressure liquid chromatography was used to measure the tissue concentrations of 5-ASA and its metabolites. We compared the 5-ASA concentrations of the sulfasalazine group with the mesalamine group. Furthermore, we analyzed the relationship between tissue 5-ASA concentrations and the Disease Activity Index (DAI). ResultsThe concentrations of 5-ASA and acetyl-5-ASA in the sulfasalazine group were higher than those in the group taking oral mesalamine alone (p < 0.01). The concentration of 5-ASA was much higher in the patients who received oral and rectal mesalamine in an enema than in the patients who had oral mesalamine alone. There was a significant inverse correlation between the DAI and concentrations of 5-ASA in the rectum (r = 0.712, p < 0.001). ConclusionsWe demonstrated that the colonic mucosal concentration of 5-ASA was significantly higher in the sulfasalazine group than in the mesalamine group. Furthermore, the concentrations of mucosal 5-ASA may be a good marker for the estimation of its efficacy in the treatment of ulcerative colitis.", "corpus_id": 25453938, "score": 1 }, { "doc_id": "6066345", "title": "Mucosal 5-aminosalicylic acid concentration inversely correlates with severity of colonic inflammation in patients with ulcerative colitis", "abstract": "BACKGROUND AND AIM The treatment of ulcerative colitis (UC) with 5-aminosalicylic acid (5-ASA) does not have the same therapeutic effect in all patients. We tested the hypothesis that the effectiveness of the drug is related to its mucosal concentration. PATIENTS Twenty one UC patients receiving oral 5-ASA (2.4–3.2 g/day) were enrolled in the study. Four were also receiving topical treatment (2 g/day). METHODS Six endoscopic biopsies were taken from the rectum for measurement of 5-ASA concentrations (ng/mg) by HPLC; soluble interleukin 2 receptor (sIL-2R) concentrations (U/ml) were measured by ELISA and histology. Endoscopic and histological appearance was graded on a four point scale (0–3). The Wilcoxon's rank test and Pearson's correlation coefficient were used for statistical analysis. RESULTS Mucosal concentrations of 5-ASA were significantly higher (p=0.03) in patients with endoscopic scores of 0–1 compared with those with scores of 2–3 (16.1 (range 10.2–45) v 5.5 (3.5–17.4), respectively) and in patients with lower histological inflammation compared with those with more severe scores (17.4 (10.5–45)v 8.9 (3.5–17.2), respectively) (p<0.01). In contrast, mucosal sIL2-R concentrations were significantly lower in patients with slight endoscopic and histological lesions than in those with more severe disease. A significative inverse correlation (r=−0.85) was found between 5-ASA and sIL-2R mucosal concentrations (p=0.00008). CONCLUSIONS In patients with UC, in the same area of the intestinal tract, we found that the higher the 5-ASA mucosal concentrations, the lower the IL-2R levels and endoscopic and histological scores. We hypothesise that maintenance of high mucosal 5-ASA concentrations in all colonic segments could contribute to improve clinical outcome in UC patients.", "corpus_id": 6066345, "score": 0 }, { "doc_id": "26683748", "title": "Once versus divided daily dosing with delayed‐release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters", "abstract": "Delayed‐release mesalazine is traditionally taken as three divided doses. However, it is well‐recognized that dosing frequency has a significant impact on compliance and that once daily dosing is preferable.", "corpus_id": 26683748, "score": 0 }, { "doc_id": "42407720", "title": "High-performance liquid chromatographic assay for the determination of 5-aminosalicylic acid and acetyl-5-aminosalicylic acid concentrations in endoscopic intestinal biopsy in humans.", "abstract": "A high-performance liquid chromatographic method for the simultaneous determination of 5-amino-salicylic acid (5-ASA) and N-acetyl-5-ASA (Ac-5-ASA) concentrations in endoscopic mucosal biopsy homogenates is presented. The mean recoveries of 5-ASA and Ac-5-ASA from spiked blank biopsy homogenates ranged from 95.9 to 120% and from 92.5 to 100%, respectively. The coefficients of variation for 5-ASA and Ac-5-ASA were 0.7-8.6% and 1.4-12.9%, respectively. This method is useful for direct determination of topical availability of 5-ASA and Ac-5-ASA and probably an accurate parameter of drug bioavailability.", "corpus_id": 42407720, "score": 0 }, { "doc_id": "9375863", "title": "Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion.", "abstract": "To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.", "corpus_id": 9375863, "score": 0 }, { "doc_id": "8007209", "title": "Disposition of 5-aminosalicylic acid from 5-aminosalicylic acid-delivering drugs during accelerated intestinal transit in healthy volunteers.", "abstract": "In eight healthy volunteers accelerated intestinal transit time was induced with bisacodyl, and urinary and faecal excretion of sulphasalazine, olsalazine, 5-aminosalicylic acid (5-ASA), and acetyl-5-ASA was studied after a single oral dose of 3.3 mmol sulphasalazine, olsalazine, Pentasa, and Salofalk and 2.6 mmol of Asacol. The faecal and urinary excretion of acetyl-5-ASA was lowest after intake of sulphasalazine and olsalazine and highest after intake of Pentasa and Salofalk. The figures for Asacol were intermediate. This indicates insufficient release of 5-ASA from sulphasalazine and olsalazine. When the results of this study are compared with those of a previous study without accelerated transit time, the disposition of 5-ASA from all the 5-ASA-delivering drugs is influenced unfavourably by an accelerated gut transit but most pronounced in the case of sulphasalazine, olsalazine, and Asacol. The impaired release from the azo compounds sulphasalazine and olsalazine is a result of far less complete splitting of the diazo bond.", "corpus_id": 8007209, "score": 0 }, { "doc_id": "5602714", "title": "Pharmacokinetics and safety of single and multiple doses of Asacol tablets in Japanese healthy volunteers", "abstract": "IntroductionThe pharmacokinetics and safety of Asacol® (Tillotts Pharma AG, Ziefen, Switzerland), which has been used worldwide to treat ulcerative colitis and Crohn’s disease, were studied in Japanese healthy male volunteers.MethodsDrug plasma concentrations and urinary and fecal excretions after a single dose (400–4800 mg) and multiple doses (3600 mg/day for 7 days) were investigated.ResultsAll adverse events were “not serious.” The peak plasma concentration (Cmax) was reached at 12.3–18.0 hours after a single dose, and the Cmax and area under the plasma concentration-time curve (AUC) of mesalazine and its N-acetyl metabolite were proportional to the doses. The Cmax and AUC in non-Japanese subjects reported in the literature were closely correlated to findings in Japanese subjects, and external excretions were also similar in the Japanese and non-Japanese subjects.ConclusionsAsacol was safe and well tolerated in this Japanese population, and the non-Japanese clinical data could be extrapolated to the Japanese population.", "corpus_id": 5602714, "score": 0 }, { "doc_id": "23111829", "title": "Disposition of disodium azodisalicylate in healthy subjects. A possible new drug for inflammatory bowel disease.", "abstract": "The disposition of disodium azodisalicylate and salicylazosulfapyridine was studied in 6 healthy volunteers. After a single oral dose (1.0 g disodium azodisalicylate; 2.3 g salicylazosulfapyridine) maximum serum concentrations of the intact compound ranged between 1.4 and 6.8 mumol/L and 32 and 114 mumol/L, respectively. Mean residence time and serum half-life of disodium azodisalicylate were considerably longer than those of salicylazosulfapyridine, probably because of a higher apparent volume of distribution. Both compounds were largely split by colonic bacteria and comparable amounts of the active moiety, (acetyl-)5-aminosalicylic acid, were recovered in feces. During long-term ingestion of disodium azodisalicylate (1.0 g/day) it took 6-19 days to reach a steady state. Serum concentrations of disodium azodisalicylate at steady state were low: 2.2-8.4 mumol/L. The serum half-life was 6-10 days. It is concluded that the disposition of disodium azodisalicylate is similar, in important respects, to that of salicylazosulfapyridine. Disodium azodisalicylate, therefore, deserves therapeutic trial.", "corpus_id": 23111829, "score": 0 }, { "doc_id": "38488967", "title": "Disposition of mesalazine from mesalazine-delivering drugs in patients with inflammatory bowel disease, with and without diarrhoea.", "abstract": "The disposition of mesalazine from the azo compounds sulphasalazine and olsalazine (Dipentum) and from the slow-release mesalazine drugs Pentasa, Asacol, and Salofalk was studied in 20 patients with inflammatory bowel disease. Ten of them had diarrhoea, and 10 had normal stools. On the last 2 days of a 7-day maintenance treatment with each of the study drugs urine and faeces were collected for determination of mesalazine, acetyl-mesalazine, and unsplit azo compound. In patients with and without diarrhoea the urinary and the faecal excretion of acetyl-mesalazine was lowest during treatment with olsalazine. The proportion of acetyl-mesalazine in faeces was highest during treatment with Pentasa in both groups. The presence of diarrhoea was associated with a decrease in the proportion of acetyl-mesalazine in faeces during treatment with all drugs, not significant only for Pentasa. The proportion of unsplit azo compound in faeces increased in the case of diarrhoea to almost 50%. It is concluded that in patients with inflammatory bowel disease diarrhoea substantially influences the disposition from all these drugs except Pentasa.", "corpus_id": 38488967, "score": 1 }, { "doc_id": "257693", "title": "Bioavailability of 5-aminosalicylic acid from slow release 5-aminosalicylic acid drug and sulfasalazine in normal children", "abstract": "The bioavailability of a controlled release 5-aminosalicylic acid preparation (Pentasa) was investigated in nine healthy children after a medication period of six days (1000 mg/day) and compared with sulfasalazine (Salazopyrin) (2000 mg/day). The local bioavailability in the distal gut lumen, reflected by the 5-aminosalicylic acid concentration in the fecal water, showed comparable values after Pentasa (4.44 mmol/liter) and Salazopyrin (6.25 mmol/liter). The concentration ofN-acetyl-5-ASA was significantly higher after Pentasa, reflecting the more proximal release of 5-aminosalicylic acid compared with Salazopyrin. No relation was found between the 5-aminosalicylic acid fecal water concentration and the 5-aminosalicylic acid dose per kilogram of body weight. The urinary excretion of 5-aminosalicylic acid andN-acetyl-5-aminosalicylic acid was higher after Pentasa than after Salazopyrin (32% vs 25%). Dose interval plasma concentration curves showed low values after both preparations. Based on the concept that the fecal water concentration is decisive for the efficacy of 5-aminosalicylic acid in distal inflammatory bowel disease, Pentasa treatment offers a relevant alternative in cases of Salazopyrin intolerance or allergy in children. The higher systemic bioavailability from Pentasa warrants monitoring of the renal function.", "corpus_id": 257693, "score": 0 }, { "doc_id": "42828305", "title": "Pharmacokinetics of a 5‐aminosalicylic acid enteric‐coated tablet and suppository dosage form", "abstract": "An Eudragit‐L coated oral 5‐aminosalicylic acid (5‐ASA; mesalazine) product (Mesasal), has been formulated to deliver 5‐ASA to the distal small intestine and colon for the treatment of inflammatory bowel disease. The purpose of this study was to compare the pharmacokinetic profile of this product to sulphasalazine (SASP; Salazopyrin) and to assess the pharmacokinetics of a suppository 5‐ASA dosage form.", "corpus_id": 42828305, "score": 0 }, { "doc_id": "14335599", "title": "Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study", "abstract": "Background and aims: Oral aminosalicylates are well established in the treatment of active mild/moderate ulcerative colitis (UC) when the disease is extensive (that is, beyond the splenic flexure). The majority of clinical symptoms relate to disease activity in the distal part of the colon and therefore this study was designed to investigate if adding a mesalazine enema to oral mesalazine has additional benefit for patients with extensive mild/moderate active UC. Methods: A randomised double blind study was performed in 127 ambulatory patients. All received 4 g/day (twice daily dosing) oral mesalazine for eight weeks. During the initial four weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index, with clinical and endoscopic signs at four and eight weeks. Results: Remission was obtained in 44% (95% confidence interval (CI) 31%, 58%) of the mesalazine enema group (Me) and in 34% (95% CI 21%, 49%) of the placebo enema group (Pl) at four weeks (p = 0.31) and in 64% (95% CI 50%, 76%) of the Me group versus 43% (95% CI 28%, 58%) of the Pl group at eight weeks (p = 0.03). Improvement was obtained in 89% (95% CI 78%, 96%) of the Me group versus 62% (95% CI 46%, 75%) of the Pl group at four weeks (p = 0.0008) and in 86% (95% CI 75%, 94%) of the Me group versus 68% (95% CI 53%, 81%) of the Pl group at eight weeks (p = 0.026). Conclusion: In patients with extensive mild/moderate active UC, the combination therapy is superior to oral therapy. It is safe, well accepted, and may be regarded as firstline treatment.", "corpus_id": 14335599, "score": 0 }, { "doc_id": "14557625", "title": "Mesalazine vanishing time from rectal mucosa following its topical administration.", "abstract": "To investigate how long and how much Mesalazine (M) is available inside the rectal mucosa following its topical instillation, in patients (pts) with Ulcerative Colitis (UC). Two rectal biopsies for M concentration were obtained from 45 UC pts in clinical remission and on oral M treatment (OT), before a 4g enema randomly given to consentient pts every day (Group A, 15 pts), every 2 days (Group B, 15 pts) and every 3 days (Group C, 15 pts). Two additional biopsies were taken 1, 2 and 3 days after the last enema in group A, B and C respectively, at least 10 days later. All biopsies were immediately frozen at -80°C for later assay by means of high-performance light chromatography (HPLC). Data were analyzed using Student's t-test. Mean values±standard deviation of M mucosal concentration (ng/mg of tissue) were 1.32±1.41, 56.1±39.2, 9.65±6.60, and 6.39±5.03 in pts receiving OT alone, groups A, B and C, respectively. Values in Group A were statistically higher (p<0.001) than those in Groups B and C while no differences were found between Groups B and C. Values of OT were lower than groups A, B and C. M mucosal concentration rapidly decreases 2 days after a 4g enema, but after three days is still higher than OT alone. These results may provide data which would be useful to plan topical therapy and improve adherence to treatment.", "corpus_id": 14557625, "score": 0 }, { "doc_id": "4389664", "title": "Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract.", "abstract": "As an orally administered, locally acting gastrointestinal drug, mesalamine products are designed to achieve high local drug concentration in the gastrointestinal (GI) tract for the treatment of ulcerative colitis. The aim of this study was to directly measure and compare drug dissolution of three mesalamine formulations in human GI tract and to correlate their GI concentration with drug concentration in plasma. Healthy human subjects were orally administered Pentasa, Apriso, or Lialda. GI fluids were aspirated from stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum regions. Mesalamine (5-ASA) and its primary metabolite acetyl-5-mesalamine (Ac-5-ASA) were measured using LC-MS/MS. GI tract pH was measured from each GI fluid sample, which averaged 1.82, 4.97, 5.67, 6.17, and 6.62 in the stomach, duodenum, proximal jejunum, middle jejunum, and distal jejunum, respectively. For Pentasa, high levels of 5-ASA in solution were observed in the stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum from 1 to 7 h. Apriso had minimal 5-ASA levels in stomach, low to medium levels of 5-ASA in duodenum and proximal jejunum from 4 to 7 h, and high levels of 5-ASA in distal jejunum from 3 to 7 h. In contrast, Lialda had minimal 5-ASA levels from stomach and early small intestine. A composite appearance rate (CAR) was calculated from the deconvolution of individual plasma concentration to reflect drug release, dissolution, transit, and absorption in the GI tract. Individuals dosed with Pentasa had high levels of CAR from 1 to 10 h; individuals dosed with Apriso had low levels of CAR from 1 to 4 h and high levels of CAR from 5 to 10 h; Lialda showed minimal levels of CAR from 0 to 5 h, then increased to medium levels from 5 to 12 h, and then decreased to further lower levels after 12 h. In the colon region, Pentasa and Apriso showed similar levels of accumulated 5-ASA excreted in the feces, while Lialda showed slightly higher 5-ASA accumulation in feces. However, all three formulations showed similar levels of metabolite Ac-5-ASA in the feces. These results provide direct measurement of drug dissolution in the GI tract, which can serve as a basis for investigation of bioequivalence for locally acting drug products.", "corpus_id": 4389664, "score": 0 }, { "doc_id": "7516326", "title": "Concentrations of 5-ASA and Ac-5-ASA in human ileocolonic biopsy homogenates after oral 5-ASA preparations.", "abstract": "Intramucosal 5-aminosalicylic acid (5-ASA) and acetylated 5-ASA (Ac-5-ASA) concentrations were determined in ileocolonic biopsy specimens from 61 patients with irritable bowel syndrome treated for one week with near equimolar doses of different slow release preparations of 5-ASA (Claversal, Asacol, or Pentasa) or azo-bound drugs (Salazopyrin, Dipentum). The transit time in these patients was accelerated by a laxative, metoclopramide, and colonic lavage. The presence of 5-ASA in the mucosa was confirmed by autofluorescence. The highest concentrations of 5-ASA were obtained after Asacol (mean (SEM), 298.5 (37.3) ng/mg wet wt), followed by Claversal 500 mg (108.8 (11.7) ng/mg wet wt) and Pentasa (25.7 (2.2) ng/mg wet wt). Very low concentrations only were observed after Claversal 250 mg (0.3 (0.03) ng/mg wet wt), Salazopyrine (1.2 (0.1) ng/mg wet wt), and Dipentum (11.0 (3.2) ng/mg wet wt). The results for Ac-5-ASA were similar but the concentrations were generally lower. Serum concentration-time curves over eight hours were obtained from 34 healthy volunteers after a single oral dose of 400 to 500 mg of the different drugs. For the slow release forms, an apparently inverse relationship was found between the area under the curve of the serum concentrations and the intramucosal concentrations, supporting the importance of the local availability of the drug. This inverse relationship was absent for the azo-bound drugs. Colonic washout induced mechanical removal of intraluminal 5-ASA with a secondary disturbance in absorption resulting in a rapid decline in the serum concentrations. However, only for Dipentum did this result in significantly lower 5-ASA mucosal concentrations. This is the first reported attempt to evaluate the mucosal availability of 5-ASA after different oral preparations. It shows that where transit time is accelerated higher mucosal concentrations occur after slow release preparations (except for Claversal 250 mg) than after azo-bound drugs. Additional studies are necessary to correlate these concentrations with clinical effects.", "corpus_id": 7516326, "score": 0 }, { "doc_id": "30660588", "title": "Anastomotic configuration and mucosal 5-aminosalicyclic acid (5-ASA) concentrations in patients with Crohn's disease: a GISC study. Gruppo Italiano per lo Studio del Colon e del Retto.", "abstract": "OBJECTIVE\nRecurrence of Crohn's disease quite inevitably occurs after resection of distal small bowel and proximal colon, involving the neoterminal ileum close to the anastomosis. Oral 5-aminosalicylic acid (5-ASA) administered soon after surgery delays recurrence and reduces its severity. We recently observed that in operated patients submitted to prophylactic treatment with oral 5-ASA the rate of recurrence was significantly higher in those with end-to-end anastomosis than in those with other types of anastomosis (end-to-side, side-to-side). The hypothesis investigated in the present study was that patients with end-to-side or side-to-side anastomosis would benefit from a higher mucosal concentration of 5-ASA with respect to patients with end-to-end anastomosis. Therefore, the mucosal 5-ASA concentration was measured in the perianastomotic area of both groups.\n\n\nMETHODS\nThe study was carried out in 19 patients submitted to radical surgery for Crohn's ileitis or ileocolitis, under oral prophylactic treatment with 5-ASA (Asacol). All patients were on regular endoscopic follow-up and were free of recurrence. Two biopsies were collected 3 cm from the anastomosis, in the neoterminal ileum, and two biopsies were collected at the colonic site 3 cm below the anastomosis. 5-ASA concentrations (ng/mg) were measured in tissue homogenates by high-performance liquid chromatography (HPLC) with electrochemical detection.\n\n\nRESULTS\nThe mucosal concentration of 5-ASA in the neoterminal ileum was significantly lower in patients with end-to-end anastomosis than in those with other types of anastomosis (median values: 29.4 ng/mg vs 92.9 ng/mg respectively; p < 0.001). Six of 10 patients (60%) with end-to-end anastomosis, but none of the nine patients with other types of anastomosis, showed 5-ASA mucosal concentrations <40 ng/mg at the neoterminal ileum. On the contrary, no patients with end-to-end anastomosis showed mucosal concentrations of 5-ASA >90 ng/mg, compared with the 57% of patients in the group with other types of anastomosis. No differences were observed for colonic biopsies.\n\n\nCONCLUSIONS\nThe different mucosal concentrations in these two groups may be explained by the difference in segmental transit time induced by the different anastomotic configurations. A slower preanastomotic transit time, demonstrated in patients with end-to-side or side-to-side anastomosis, could offer a prolonged contact time between the intestinal content and the mucosa, resulting in an increase in drug absorption.", "corpus_id": 30660588, "score": 0 }, { "doc_id": "2434534", "title": "Steady-state kinetics of 5-aminosalicylic acid and sulfapyridine during sulfasalazine prophylaxis in ulcerative colitis.", "abstract": "Fifteen adult and 19 pediatric outpatients with ulcerative colitis were studied to determine the steady-state kinetics of 5-aminosalicylic acid (5-ASA) released from salazosulfapyridine (SASP). Results of excretion in adults (mean 24-h recovery of 5-ASA, 21% in urine and 57% in feces) were compatible with those of healthy volunteers. Since mean SASP dose/kg body weight (about 50 mg/kg) and compliance (reflected in sulfapyridine recovery) were equal in adults and pediatric patients, the results of the patient groups could be compared. Near-complete azo reduction of SASP occurs in children. Absorption and excretion of 5-ASA and metabolism to acetyl-5-ASA did not differ statistically between pediatric and adult patients. However, the fecal excretion of the drug and its metabolites was significantly lower in young patients, although fecal concentrations were the same. The present results demonstrate that SASP is an excellent sustained-release drug for the delivery of 5-ASA to the lower part of the bowel system and provide a reference for comparison of 5-ASA kinetics after treatment with newer 5-ASA preparations.", "corpus_id": 2434534, "score": 0 }, { "doc_id": "27526532", "title": "Stability of disodium azodisalicylate (olsalazine) and metabolites in urine and faeces stored at different temperatures.", "abstract": "METHODS\nThe stability of disodium azodisalicylate, 5-aminosalicylic acid and acetyl-5-aminosalicylic acid dissolved in distilled water and in urine or mixed with faeces to which HgCl2 was added, was studied at -20 degrees C, 4 degrees C and room temperature.\n\n\nRESULTS\nIn water, no marked differences were found between the three storage regimens. In urine, disodium azodisalicylate and acetyl-5-aminosalicylic acid were stable, while the 5-ASA concentration decreased when stored at 4 degrees C and room temperature. In faeces stored during seven days, a marked decrease in 5-aminosalicylic acid concentration to about zero was found when it was kept at 4 degrees C and room temperature. No marked change in the concentration of disodium azodisalicylate and 5-aminosalicylic acid added to the faeces-HgCl2-mixtures appeared.", "corpus_id": 27526532, "score": 0 }, { "doc_id": "37329999", "title": "Release of 5-aminosalicylic acid from Pentasa during normal and accelerated intestinal transit time.", "abstract": "The influence of intestinal transit time on the release of 5-aminosalicylic acid (5-ASA) from a peroral, slow-release preparation (Pentasa) was studied at steady state in seven healthy volunteers. Daily dose was 1500 mg Pentasa, normal transit time (NTT) was 24 h (16-26 h) and accelerated transit time (ATT), caused by a laxative, was 5 h (4-9 h). Median total recovery (24 h, 5-ASA + acetyl-5-ASA) was 87% (61-129%) (NTT) and 81% (56-100%) (ATT), respectively, (P greater than 0.10). The total faecal excretion of 5-ASA (per cent of dose) increased from 16%, (9-21%) (NTT) to 29%, (16-38%) (ATT) (P less than 0.02). Free 5-ASA rose from 12% (4-19%) to 17% (10-25%), the retained part (in granules) from 4% (2-5%) to 12% (4-24%). Urinary excretion decreased correspondingly from 32% (19-59%) to 21% (11-38%), predominantly as Ac-5-ASA (P less than 0.05). Mean plasma Ac-5-ASA concentration decreased from 1.42 micrograms ml-1 to 0.86 microgram ml-1 (P less than 0.05). An almost complete release of 5-ASA from Pentasa takes place during NTT. At ATT conditions about 88% is released, indicating Pentasa to be an acceptable source of 5-ASA in diarrhoeal states.", "corpus_id": 37329999, "score": 0 }, { "doc_id": "10758663", "title": "Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs", "abstract": "Measurements of luminal pH in the normal gastrointestinal tract have shown a progressive increase in pH from the duodenum to the terminal ileum, a decrease in the caecum, and then a slow rise along the colon to the rectum. Some data in patients with ulcerative colitis suggest a substantial reduction below normal values in the right colon, while limited results in Crohn's disease have been contradictory. Determinants of luminal pH in the colon include mucosal bicarbonate and lactate production, bacterial fermentation of carbohydrates and mucosal absorption of short chain fatty acids, and possibly intestinal transit. Alterations in these factors, as a result of mucosal disease and changes in diet, are likely to explain abnormal pH measurements in inflammatory bowel disease (IBD). It is conceivable that reduced intracolonic pH in active ulcerative colitis impairs bioavailability of 5-aminosalicylic acid from pH dependent release formulations (Asacol, Salofalk) and those requiring cleavage by bacterial azo reductase (sulphasalazine, olsalazine, balsalazide), but further pharmacokinetic studies are needed to confirm this possibility. Reports that balsalazide and olsalazine may be more efficacious in active and quiescent ulcerative colitis, respectively, than Asacol suggest that low pH may be a more critical factor in patients taking directly pH dependent release than azo bonded preparations. Reduced intracolonic pH also needs to be considered in the development of pH dependent colonic release formulations of budesonide and azathioprine for use in ulcerative and Crohn's colitis. This paper reviews methods for measuring gut pH, its changes in IBD, and how these may influence current and future therapies.", "corpus_id": 10758663, "score": 0 }, { "doc_id": "23964364", "title": "Epithelial barrier defects in ulcerative colitis: characterization and quantification by electrophysiological imaging.", "abstract": "BACKGROUND & AIMS\nIn ulcerative colitis (UC), the epithelial barrier is impaired by erosion/ulcer-type lesions and epithelial apoptosis causing local leaks, and generalized tight junction alterations increasing the basal permeability. We quantified the contribution of these mechanisms to the increased colonic ion permeability.\n\n\nMETHODS\nSigmoid colon was stripped, and the spatial distribution of current clamped across the viable epithelium was recorded by a microelectrode probe, using the conductance scanning method. Local leaks (circumscribed conductive peaks) were marked, and structural changes were studied in H&E-stained series sections.\n\n\nRESULTS\nOverall conductivity increased from 8.4 +/- 0.7 mS/cm(2) (mean +/- SEM) in controls to 11.7 +/- 0.6 in specimens with mild inflammation (i.e., with intact epithelium) and 34.4 +/- 6.2 mS/cm(2) in moderate-to-severe inflammation (i.e., with visible epithelial lesions). Only in part this was caused by a generalized increase in basal conductivity (12.2 +/- 1.5 mS/cm(2) in moderate-to-severe UC vs. 8.3 +/- 0.7 in controls). More importantly, the spatial distribution of conductivity, which was even in controls, showed dramatic leaks in UC. Leaks found in mild inflammation without epithelial lesion turned out to be foci of epithelial apoptosis. In moderate-to-severe inflammation, leaks correlated with epithelial erosion/ulcer-type lesions or crypt abscesses.\n\n\nCONCLUSIONS\nIn early UC, but not in controls, seemingly intact epithelium comprises leaks at apoptotic foci. With more intensive inflammation, erosion/ulcer-type lesions are highly conductive, even if covered with fibrin. Local leaks contribute 19% to the overall epithelial conductivity in mild and 65% in moderate-to-severe inflammation.", "corpus_id": 23964364, "score": 0 }, { "doc_id": "1280653", "title": "The association between the gut microbiota and the inflammatory bowel disease activity: a systematic review and meta-analysis", "abstract": "Abstract Background: The pathogenesis of inflammatory bowel diseases (IBD) involves complex interactions between the microbiome and the immune system. We evaluated the association between the gut microbiota and disease activity in IBD patients. Methods: Systematic review of clinical studies based on a published protocol. Included patients had ulcerative colitis (UC) or Crohn’s disease (CD) classified as active or in remission. We selected bacteria assessed in at least three studies identified through electronic and manual searches (November 2015). Bias control was evaluated with the Newcastle Ottawa scale (NOS). Results of random-effects meta-analyses were presented as mean differences (MD). Results: Three prospective and seven cross-sectional studies (NOS score 6–8) were included. Five studies included patients with CD (231 patients) and eight included patients with UC (392 patients). Compared to patients in remission, patients with active IBD had lower abundance of Clostridium coccoides (MD = −0.49, 95% CI: −0.79 to −0.19), Clostridium leptum (MD = −0.44, 95% CI: −0.74 to −0.14), Faecalibacterium prausnitzii (MD = −0.81, 95% CI: −1.23 to −0.39) and Bifidobacterium (MD = −0.37, 95% CI: −0.56 to −0.17). Subgroup analyses showed a difference in all four bacteria between patients with UC classified as active or in remission. Patients with active CD had fewer C. leptum, F. prausnitzii and Bifidobacterium, but not C. coccoides. Conclusion: This systematic review suggests that dysbiosis may be involved in the activity of IBD and that there may be differences between patients with CD and UC.", "corpus_id": 1280653, "score": 0 } ]

{ "doc_id": "16525332", "title": "Negative online word-of-mouth: Behavioral indicator or emotional release?", "abstract": "The influence of negative online word-of-mouth on the behavior of those receiving it has been addressed extensively in the academic literature. Remarkably, the question whether negative online word-of-mouth should also be seen as a behavioral indicator of its sender remains unaddressed. Answering this question is relevant as it provides companies with insight into the need to engage in interaction with those who negatively express themselves online or whether these expressions should be seen as temporary emotional releases without any intended conduct. To fill the existing research gap, this research paper proposes and empirically tests a sender-oriented model, investigating the influence of emotions, negative online word-of-mouth on repatronage and switching intentions. As disclosing negative feedback online may also reflect the sender's motivation to inform the consumer community or to provide constructive feedback to the company responsible for the dissatisfying consumption, community usefulness and company usefulness are included as behavioral moderators. The results of an empirical survey conducted amongst real senders of negative information confirm that negative online word-of-mouth is directly driven by positive and negative emotions and is strongly predictive for the sender's intended conduct. The motivation to help other consumers was demonstrated to function as behavioral moderator. The paper concludes with theoretical and managerial implications, and suggests avenues for further research.", "corpus_id": 16525332 }

[ { "doc_id": "16358599", "title": "Electronic word-of-mouth via consumer-opinion platforms: What motivates consumers to articulate themselves on the Internet?", "abstract": "Through Web-based consumer opinion platforms (e.g., epinions.com), the Internet enables customers to share their opinions on, and experiences with, goods and services with a multitude of other consumers; that is, to engage in electronic wordof-mouth (eWOM) communication. Drawing on findings from research on virtual communities and traditional word-of-mouth literature, a typology for motives of consumer online articulation is", "corpus_id": 16358599, "score": 1 }, { "doc_id": "59144015", "title": "Angry customers don't come back, they get back: The experience and behavioral implications of anger and dissatisfaction in services", "abstract": "This article investigates the specific experience of anger and dissatisfaction and their effects on customers' behavioral responses to failed service encounters across industries. Study 1 demonstrates that anger and dissatisfaction are qualitatively different emotions with respect to their idiosyncratic experiential content. Study 2 builds on these findings and shows how anger and service encounter dissatisfaction differentially affect customer behavior. It provides empirical support for the contention that anger mediates the relationship between service encounter dissatisfaction and customers' behavioral responses. The findings of Study 2 diverge from previous findings in marketing on the interrelationships between customer satisfaction/dissatisfaction, related consumption emotions, and customers' behavioral responses to service failure. The implications of these findings for services marketing theory and practice are delineated.", "corpus_id": 59144015, "score": 0 }, { "doc_id": "29962296", "title": "An empirical investigation of electronic word-of-mouth: Informational motive and corporate response strategy", "abstract": "The proliferation of the Internet has given birth to a number of complaint web sites where dissatisfied and frustrated consumers can easily articulate their opinions and comments on products, services, or companies. Little attention, however, has been paid to the influence of online complaints on potential consumers' behaviors. This study attempts to provide the understanding of causal attribution process in the online complaining behaviors. The results showed that informational factors, such as vividness and consensus, facilitated consumers' attribution to companies' responsibility for the negative events, and subsequently led to changing their evaluation of the companies. In addition, we found that corporate response strategies to online complaints should be different from the conventional response strategies.", "corpus_id": 29962296, "score": 0 }, { "doc_id": "8531351", "title": "Self‐disclosure in computer‐mediated communication: The role of self‐awareness and visual anonymity", "abstract": "Three studies examined the notion that computer-mediated communication (CMC) can be characterised by high levels of self-disclosure. In Study One, significantly higher levels of spontaneous self-disclosure were found in computer-mediated compared to face-to-face discussions. Study Two examined the role of visual anonymity in encouraging self-disclosure during CMC. Visually anonymous participants disclosed significantly more information about themselves than non-visually anonymous participants. In Study Three, private and public self-awareness were independently manipulated, using video-conferencing cameras and accountability cues, to create a 2 × 2 design public self-awareness (high and low)×private self-awareness (high and low). It was found that heightened private self-awareness, when combined with reduced public self-awareness, was associated with significantly higher levels of spontaneous self-disclosure during computer-mediated communication. Copyright © 2001 John Wiley & Sons, Ltd.", "corpus_id": 8531351, "score": 0 }, { "doc_id": "11595949", "title": "Selective Posting: Willingness to post a message online", "abstract": "The communication environment in CMC is particularly relevant to the discourses of the traditional communication theory, spiral of silence. This paper embarked on the task of developing an experimental research method to test willingness to speak out in the spiral of silence theory on an online forum and to test subsequent attitudinal and behavioral changes as measured in issue position, climate of opinion perception, and message posting. A 2x2 factorial design (congruent messages vs. incongruent messages and anonymity vs. nonanonymity) tested the willingness to speak out on an online discussion forum. The result of the paper suggested a new theoretical framework, selective posting, and called for the modification of the psychological explanation of spiral of silence.", "corpus_id": 11595949, "score": 0 }, { "doc_id": "167701655", "title": "Word-of-Mouth for Movies: Its Dynamics and Impact on Box Office Revenue", "abstract": "Abstract This article uses actual word-of-mouth (WOM) information to examine the dynamic patterns of WOM and how it helps explain box office revenue. The WOM data were collected from the Yahoo Movies Web site. The results show that WOM activities are the most active during a movie's prerelease and opening week and that movie audiences tend to hold relatively high expectations before release but become more critical in the opening week. More important, WOM information offers significant explanatory power for both aggregate and weekly box office revenue, especially in the early weeks after a movie opens. However, most of this explanatory power comes from the volume of WOM and not from its valence, as measured by the percentages of positive and negative messages.", "corpus_id": 167701655, "score": 0 }, { "doc_id": "17502373", "title": "Do online reviews matter? - An empirical investigation of panel data", "abstract": "This study examines the persuasive effect and awareness effect of online user reviews on movies' daily box office performance. In contrast to earlier studies that take online user reviews as an exogenous factor, we consider reviews both influencing and influenced by movie sales. The consideration of the endogenous nature of online user reviews significantly changes the analysis. Our result shows that the rating of online user reviews has no significant impact on movies' box office revenues after accounting for the endogeneity, indicating that online user reviews have little persuasive effect on consumer purchase decisions. Nevertheless, we find that box office sales are significantly influenced by the volume of online posting, suggesting the importance of awareness effect. The finding of awareness effect for online user reviews is surprising as online reviews under the analysis are posted to the same website and are not expected to increase product awareness. We attribute the effect to online user reviews as an indicator of the intensity of underlying word-of-mouth that plays a dominant role in driving box office revenues.", "corpus_id": 17502373, "score": 0 }, { "doc_id": "168094772", "title": "Born Unequal: A Study of the Helpfulness of User-Generated Product Reviews", "abstract": "Online user-generated product reviews have become an indispensible tool for consumers and thus for retailers who want to attract and retain consumers. Yet, relatively little is known about what causes consumers to find an online peer review helpful to their shopping tasks. Prior research examines mostly the effects of product reviews on consumer product attitude, product choice, and product sales. This paper, however, provides an analysis of the determinants of review helpfulness. In two studies, we examine the effects of review characteristics, product type, and reviewer characteristics on perceived review helpfulness. With data collected from a real online retailer, we provide empirical evidence to support our conceptual predictions. Specifically, both review valence and length have positive effects on review helpfulness, but the product type (i.e., experiential vs. utilitarian product) moderates these effects. Using content analysis of reviews, we develop a measure of expressed reviewer innovativeness (i.e., the predisposition toward new products as revealed in review content). A curvilinear relationship exists between expressed reviewer innovativeness and review helpfulness. These findings lead to pertinent managerial implications.", "corpus_id": 168094772, "score": 0 }, { "doc_id": "47819523", "title": "Why are you telling me this? An examination into negative consumer reviews on the Web", "abstract": "Although word-of-mouth (WOM) is recognized as a powerful force in persuasion,we know little about the new communication phenomenon known as e-WOM. One of the main forms of e-WOM is the product reviews consumers post on different Web sites, and how this form of e-WOM stands up to this claim is yet unknown. For example, do consumers trust the accuracy of these reviews posted by anonymous reviewers, and, do readers trust negative and positive reviews equally? Past research has shown that people tend to weight negative information more than positive information during evaluation. Through an observation study and two laboratory experiments, we investigate the existence of this negativity effect in e-WOM consumer reviews for utilitarian versus hedonic products, and investigate the influence of the reader's attributions regarding the reviewer's motivations on this. Both types of studies show that product type moderates the effect of review valence, and readers exhibit a negativity bias for utilitarian product reviews only. Furthermore, the lab studies show that the reader's attributions about the motivations of the reviewer mediate the effect of this moderation on their attitude about the review. We find that compared with the utilitarian case, readers of negative hedonic product reviews are more likely to attribute the negative opinions expressed, to the reviewer's internal (or non-product related) reasons; and therefore are less likely to find the negative reviews useful. However, in the utilitarian case, readers’ are more likely to attribute the reviewer's negative opinions to external (or product related) motivations, and therefore find negative reviews more useful than positive reviews on average.", "corpus_id": 47819523, "score": 0 }, { "doc_id": "145356375", "title": "Emotion Elicits the Social Sharing of Emotion: Theory and Empirical Review", "abstract": "This review demonstrates that an individualist view of emotion and regulation is untenable. First, I question the plausibility of a developmental shift away from social interdependency in emotion regulation. Second, I show that there are multiple reasons for emotional experiences in adults to elicit a process of social sharing of emotion, and I review the supporting evidence. Third, I look at effects that emotion sharing entails at the interpersonal and at the collective levels. Fourth, I examine the contribution of emotional sharing to emotion regulation together with the relevant empirical evidence. Finally, the various functions that the social sharing of emotion fulfills are reviewed and the relevance of the social sharing of emotion for emotion scientists is discussed.", "corpus_id": 145356375, "score": 0 }, { "doc_id": "14426590", "title": "Self-perception: An alternative interpretation of cognitive dissonance phenomena.", "abstract": "A theory of self-percepti on is proposed to provide an alternative interpretation for several of the major phenomena embraced by Festinger's theory of cognitive dissonance and to explicate some of the secondary patterns of data that have appeared in dissonance experiments. It is suggested that the attitude statements which comprise the major dependent variables in dissonance experiments may be regarded as interpersonal judgments in which the observer and the observed happen to be the same individual and that it is unnecessary to postulate an aversive motivational drive toward consistency to account for the attitude change phenomena observed. Supporting experiments are presented, and metatheoretical contrasts between the \"radical\" behavioral approach utilized and the phenomenological approach typified by dissonance theory are discussed.", "corpus_id": 14426590, "score": 0 }, { "doc_id": "206611786", "title": "The interactional effects of atmospherics and perceptual curiosity on emotions and online shopping intention", "abstract": "With increasing importance of online stores, a great number of studies have focused on extending our knowledge related to successful functional aspects increasing ease of use and usefulness. More recent studies have focused on identifying the effects produced by hedonic aspects of online store environment such as web atmospherics on emotional responses of customers. However, previous studies have been somewhat deficient in their investigation of studying diverse aspects of online consumer characteristics, which may have an impact on customer evaluation of atmospheric cues. Building on this research tradition, the present study addresses two critical issues. The present study adopting a well validated S-O-R framework tests the effect of atmospheric cues of online stores on the intervening affective emotional states of consumers, which have a subsequent impact on behavioral intention. Additionally, the model hypothesizes that perceptual curiosity (PC) moderates the relationships between atmospheric cues and shoppers' emotional reactions. Structure equation model confirmed that online atmospherics such as graphics, colors, and links have an impact on customer emotions such as pleasure and arousal, both of which have subsequent effects on intention. The moderating effect of perceptual curiosity has also been supported. Theoretical and practical implications, limitations, and directions for future research are discussed in conclusion.", "corpus_id": 206611786, "score": 0 }, { "doc_id": "37707729", "title": "Interface design and emotions experienced on B2C Web sites: Empirical testing of a research model", "abstract": "This paper examines the impact of four Web site interface features on the cognitive process that trigger online shoppers' emotions, operationalized as mental states of readiness that arise from appraisal of events and considered as direct antecedents to approach or avoidance behaviors. A research model was tested with data collected from 215 Web shopping episodes for low-touch merchandise. Results show that shoppers experienced all six emotions posited in the model. The emotions of liking and joy were experienced intensively by a substantial number of shoppers. The results also demonstrate that interface features - key components of the usability of a Web site - influenced the three cognitive appraisals illustrated in the research model. Moreover, the cognitive appraisals of situational state and control potential impacted the six emotions examined. This paper also highlights several theoretical contributions and managerial implications that should help managers and Web site managers improve the interface design of their Web sites in order to facilitate information gathering and better support online shopping processes.", "corpus_id": 37707729, "score": 0 }, { "doc_id": "144708846", "title": "Seeking something different? A model of schema typicality, consumer affect, purchase intentions and perceived shopping value", "abstract": "Abstract A study is presented that examines the effect of specific retail elements on deviations from the expected schema, or prototypicality, of a retail store. The results suggest that subtle differences in the store name, the location, and the appearance of its salespeople can evoke contrast in the form of variable typicality scores. A structural model is presented that shows the outcomes of this variance in a retail context involving women's apparel stores. Low typicality is associated with increased excitement and discomfort, and these emotions affect patronage intentions and perceived shopping value. This finding is counterbalanced by a direct, positive link between typicality and patronage intentions.", "corpus_id": 144708846, "score": 0 }, { "doc_id": "168131166", "title": "The relative incidence of positive and negative word of mouth: A multi-category study", "abstract": "Abstract In 15 studies, positive word of mouth (PWOM) is more common than negative word of mouth (NWOM) in every case. The incidence ratio averages 3 to 1. Categories with high levels of NWOM tend to have high levels of PWOM, and individuals who produce NWOM also tend to produce PWOM. In follow-up studies, using two alternative measures of WOM, we confirm that PWOM occurs approximately three times as often as NWOM. Further exploratory studies indicate that most PWOM is about a consumer's main brand; as a consequence, the incidence of PWOM in a category is distributed according to brand market share. We discuss possible explanations for these results and develop six propositions to guide further research on word of mouth.", "corpus_id": 168131166, "score": 0 }, { "doc_id": "1071693", "title": "Describing and Measuring Emotional Response to Shopping Experience", "abstract": "Abstract Research has shown that shopping environments can evoke emotional responses in consumers and that such emotions, in turn, influence shopping behaviors and outcomes. This article broadens our understanding of emotions within the shopping context in two ways. First, it provides a descriptive account of emotions consumers feel across a variety of shopping environments. Second, it empirically compares the three emotion measures most frequently used in marketing to determine which best captures the various emotions shoppers experience. The results indicate that the broad range of emotions felt in the shopping context vary considerably across different retail environments. They also show that the Izard (Izard, C. E.: Human Emotions, Plenum, New York. 1977) and Plutchik (Plutchik, R.: Emotion: A Psychoevolutionary Synthesis, Harper and Row, New York. 1980) measures outperform the Mehrabian and Russell (Mehrabian, A., and Russell, J. A.: An Approach to Environmental Psychology, MIT Press, Cambridge, MA. 1974) measure by offering a richer assessment of emotional responses to the shopping experience.", "corpus_id": 1071693, "score": 0 }, { "doc_id": "143578415", "title": "Effects of complaining versus negative word of mouth on subsequent changes in satisfaction: The role of public commitment", "abstract": "This research reviews the motivation for voice behavior by dissatisfied consumers and demonstrates that facilitating complaining behavior results in reduced levels of negative word-of-mouth activity. Support is found for the hypotheses that dissatisfied consumers who complain to the marketer will experience venting-induced reduction in dissatisfaction, and that they will engage in reduced levels of negative word of mouth. On the other hand, dissatisfied consumers who engage in the relatively public act of negative word of mouth become committed to their level of dissatisfaction and hence do not exhibit any subsequent venting-induced reduction in dissatisfaction. The role of public commitment in binding individuals to their prior evaluations is discussed, along with the managerial implications. © 2005 Wiley Periodicals, Inc.", "corpus_id": 143578415, "score": 0 }, { "doc_id": "146325052", "title": "A study of the relationships between cognitive appraisals and consumption emotions", "abstract": "While emotions have been shown to be significant determinants of various consumer behaviors, the antecedents of these emotions have not received much attention in the marketing literature. The current research examines a cognitive model of emotion and uses an experiment to show that the appraisals of goal relevance, goal congruence, and coping potential are determinants of consumption emotions such as anger, sadness, and joy/satisfaction. These emotions are also shown to be determinants of postconsumption behaviors such as word-of-mouth intentions.", "corpus_id": 146325052, "score": 1 }, { "doc_id": "147246544", "title": "Product/Consumption-Based Affective Responses and Postpurchase Processes", "abstract": "The author examines consumer affective responses to product/consumption experiences and their relationship to selected aspects of postpurchase processes. In separate field studies of automobile owners and CATV subscribers, subjects reported the nature and frequency of emotional experiences in connection with product ownership and usage. Analysis confirms hypotheses about the existence of independent dimensions of positive and negative affect. Both dimensions of affective response are found directly related to the favorability of consumer satisfaction judgments, extent of seller-directed complaint behavior, and extent of word-of-mouth transmission.", "corpus_id": 147246544, "score": 0 }, { "doc_id": "8000534", "title": "What drives consumers to spread electronic word of mouth in online consumer-opinion platforms", "abstract": "The advance of the Internet facilitates consumers to share and exchange consumption-related advice through online consumer reviews. This relatively new form of word-of-mouth communication, electronic word-of-mouth (eWOM) communication, has only recently received significant managerial and academic attention. Many academic studies have looked at the effectiveness of positive eWOM communication, examining the process by which eWOM influences consumer purchasing decisions. eWOM behavior is primarily explained from the individual rational perspective that emphasizes a cost and benefit analysis. However, we felt there was a need for an extensive study that examines consumers' motives for eWOM. In this paper, we focus on the factors that drive consumers to spread positive eWOM in online consumer-opinion platforms. Building on the social psychology literature, we identified a number of key motives of consumers' eWOM intention and developed an associated model. We empirically tested the research model with a sample of 203 members of a consumer review community, OpenRice.com. The model explains 69% of the variance, with reputation, sense of belonging and enjoyment of helping other consumers significantly related to consumers' eWOM intention. The results of this study provide important implications for research and practice. Highlights? In this study, we developed a model examining motives of consumers' eWOM intention. ? We tested the model with a sample of 203 members of a consumer review community. ? The model explains 69 percent of the variance. ? Reputation, sense of belonging, and enjoyment of helping are significant factors.", "corpus_id": 8000534, "score": 0 }, { "doc_id": "168095136", "title": "Online damage control: the effects of proactive versus reactive webcare interventions in consumer-generated and brand-generated platforms", "abstract": "Web 2.0 has empowered consumers to voice complaints with reduced costs (physical and psychological), and to share these with a multitude of other consumers on the Internet. As a public phenomenon, online complaints have a negative impact on consumers' evaluations of brands that are under attack in online complaints. By means of an experiment, we study the most effective means for companies to counter complaints as expressed in negative electronic word of mouth (NWOM). The results show that negative brand evaluations engendered by NWOM can be attenuated by webcare interventions dependent on type of strategy (proactive vs. reactive) and platform used (consumer-generated vs. brand-generated blog). This effect appeared to be mediated by conversational human voice. The findings are discussed in the light of practical implications for online complaint management.", "corpus_id": 168095136, "score": 0 }, { "doc_id": "167327463", "title": "Customer Satisfaction and Word of Mouth", "abstract": "Do dissatisfied customers engage in more or less word of mouth than satisfied customers? There is theoretical and empirical support for both possibilities. To better understand this issue, the authors developed a utility-based model of the relationship between customer satisfaction and word of mouth. The hypothesized functional form-an asymmetric U-shape-cannot be rejected based on data from the United States and Sweden. In addition, the estimation results based on the two samples are similar, suggesting that the proposed relationship is generalizable. The findings also indicate that although dissatisfied customers do engage in greater word of mouth than satisfied ones, common suppositions concerning the size of this difference appear to be exaggerated.", "corpus_id": 167327463, "score": 0 }, { "doc_id": "36213375", "title": "Complaining: a function of attitude, personality, and situation", "abstract": "The random nature of situations where an acquired product or service contains a defect or deficiency means that consumers usually have no experience of seeking redress (i.e., complaining), or their experience may be from totally different situations. Because of this, most people have not formed a clear attitude about how to behave in the specific situation and they may also be uncertain about social norms for proper behavior. Hence, their behavior is guided by more general traits and dispositions as well as by situation-specific factors, which are bound to exert a relatively strong influence on behavior. This study confirms that the likelihood that consumers will complain over defects and deficiencies depends a lot on the situation and specifically on the size of the loss due to the defect and deficiency. However, some individuals refrain from complaining even in serious cases. This study shows that the propensity to complain depends on the person’s attitude toward complaining and on personality traits (inclination to become dissatisfied). The two latter variables reinforce one another.", "corpus_id": 36213375, "score": 0 }, { "doc_id": "205424377", "title": "Electronic word-of-mouth in hospitality and tourism management", "abstract": "Abstract Interpersonal influence and word-of-mouth (WOM) are ranked the most important information source when a consumer is making a purchase decision. These influences are especially important in the hospitality and tourism industry, whose intangible products are difficult to evaluate prior to their consumption. When WOM becomes digital, the large-scale, anonymous, ephemeral nature of the Internet induces new ways of capturing, analyzing, interpreting, and managing the influence that one consumer may have on another. This paper describes online interpersonal influence, or eWOM, as a potentially cost-effective means for marketing hospitality and tourism, and discusses some of the nascent technological and ethical issues facing marketers as they seek to harness emerging eWOM technologies.", "corpus_id": 205424377, "score": 0 }, { "doc_id": "28189919", "title": "Intentions to use social media in organizing and taking vacation trips", "abstract": "This work proposes a theoretical model to explain the factors determining the intentions to use social media when organizing and taking vacation trips. Understanding the antecedents of the tourists' use of these technologies is considered to be crucial for organization managers and destination policy makers. This use of social media technologies determines which elements of the trip might be used by the tourist thus having a great impact on the market. The model and its hypotheses have been tested by means of an approach based on structural equations with the PLS technique. The study was conducted on a sample of 404 individuals who normally use the Internet and had traveled on vacation in the previous 12months. The conclusions of the study reveal that the intentions to use social media are directly influenced by the perceived benefits of that use (functional, psychological and hedonic and social); however, the costs do not significantly affect the predisposition to use such technologies. It is also shown that there is a series of incentives such as altruism, availability, individual predisposition or trust in the contributions of others which facilitate and promote the use of this type of technology when organizing and taking tourist trips.", "corpus_id": 28189919, "score": 0 }, { "doc_id": "15075129", "title": "Word of mouth communication within online communities: Conceptualizing the online social network", "abstract": "Word of mouth (WOM) communication is a major part of online consumerinteractions, particularly within the environment of online communities.-Nevertheless, existing (offline) theory may be inappropriate to describe online WOM and its influence on evaluation and purchase. The authors report the results of a two-stage study aimed at investigating online WOM: a set of in-depth qualitative interviews followed by a social network analysis of a single online community. Combined, the results provide strong evidence that individuals behave as if Web sites themselves are primary “actors” in online social networks and that online communities can act as a social proxy for individual identification. The authors offer a conceptualization of online social networks which takes the Web site into account as an actor, an initial exploration of the concept of a consumer–Web site relationship, and a conceptual model of the online interaction and information evaluation process.", "corpus_id": 15075129, "score": 1 }, { "doc_id": "146749378", "title": "The Impact of Relationship Satisfaction on Attributions, Emotions, and Behaviors Following Service Failure", "abstract": "This article investigates the processes through which relationship quality influences attributional, emotional, and behavioral responses to service failures. Results indicate that relationship quality reduces the likelihood of adverse behaviors by making blame and anger less intense. Results confirm the importance of relationship building behaviors and suggest strategies for reducing vulnerability to customer defection and adverse communications. To reduce negative word-of-mouth, managers should use relationship-building efforts to augment service recovery programs. To make customer exit less likely, service managers should invest in relationship building efforts that help to differentiate their service offers and increase barriers to exit.", "corpus_id": 146749378, "score": 0 }, { "doc_id": "167770071", "title": "E‐complaining: a content analysis of an Internet complaint forum", "abstract": "The emergence of the Internet and its communication capabilities has given rise to a number of complaint sites that function as central forums for consumers to share their bad experiences with other consumers. Companies are reacting by adopting anti‐domain sites in an attempt to prevent the creation of such complaint forums. Data from one complaint forum are analyzed to identify the nature of the complaints, whether the complaints were initially voiced to contact personnel, what other attempts were made to resolve the problem, whether the Internet consumer complaint forum was the initial method used for complaining, the responsiveness of the company to non‐Internet complaints as well as Internet complaints, and the demographics of complainers using the Internet complaint forum. The suggestion is made that companies should embrace consumer complaints, and compete with the independent complaint forums (rather than try to block them) on the basis of ease of the complaint process and the likelihood of response. Recommendations are offered that are specific to Internet use and benefits to the company are described.", "corpus_id": 167770071, "score": 0 }, { "doc_id": "46652676", "title": "The profitable art of service recovery.", "abstract": "In services, mistakes are a fact of life. No matter how hard companies try, they can't prevent the occasional late flight or missed delivery. But they can learn to recover from them. Consider how Club Med-Cancun turned a service nightmare into a memorable experience. When a flight to Cancun left New York six hours late, made two unexpected stops, ran out of food, and had a rough landing, the vacationers on board were certain their holiday was ruined. But the Club Med manager greeted the travelers with food and music and chauffeured them back to the resort. In the end, the vacationers had a better time than if the flight had gone like clockwork. Service recovery starts with identifying the problem. The Bank of Maine in Portland pays customers $1 for writing a letter about the service they received. American Express uses an \"800\" number to solicit customer complaints. Once they've identified a problem, service companies must act fast. When Smith & Hawken realized that it was taking months to resolve customers' problems by mail, the company decided to use the phone instead. Most important, service companies should encourage frontline employees to deviate from the rules when necessary. Some companies use role playing to help employees develop the creative thinking needed to deal with unusual situations. Sonesta Hotels uses a game in which teams win points for coming up with good solutions to realistic problems. Also, employees must have the authority and responsibility to act on their beliefs-to make phone calls, credit accounts, or send flowers.(ABSTRACT TRUNCATED AT 250 WORDS)", "corpus_id": 46652676, "score": 0 }, { "doc_id": "167562126", "title": "Service recovery: Impact on satisfaction and intentions", "abstract": "Examines the relative importance of service recovery in determining overall satisfaction and behavioral intentions. Recommendations include suggestions for implementing a service recovery program and for encouraging dissatisfied customers to complain.", "corpus_id": 167562126, "score": 0 }, { "doc_id": "5382483", "title": "Online Word-of-Mouth (or Mouse): An Exploration of Its Antecedents and Consequences", "abstract": "This study developed an integrated model to explore the antecedents and consequences of online word-of-mouth in the context of music-related communication. Based on survey data from college students, online word-of-mouth was measured with two components: online opinion leadership and online opinion seeking. The results identified innovativeness, Internet usage, and Internet social connection as significant predictors of online word-of-mouth, and online forwarding and online chatting as behavioral consequences of online word-of-mouth. Contrary to the original hypothesis, music involvement was found not to be significantly related to online word-of-mouth. Theoretical implications of the findings and future research directions are discussed.", "corpus_id": 5382483, "score": 0 }, { "doc_id": "145193373", "title": "What Drives Immediate and Ongoing Word of Mouth?", "abstract": "Word of mouth (WOM) affects diffusion and sales, but why are certain products talked about more than others, both right after consumers first experience them and in the months that follow? This article examines psychological drivers of immediate and ongoing WOM. The authors analyze a unique data set of everyday conversations for more than 300 products and conduct both a large field experiment across various cities and a controlled laboratory experiment with real conversations. The results indicate that more interesting products get more immediate WOM but, contrary to intuition, do not receive more ongoing WOM over multiple months or overall. In contrast, products that are cued more by the environment or are more publicly visible receive more WOM both right away and over time. Additional analyses demonstrate which promotional giveaways in WOM marketing campaigns are associated with increased WOM. overall, the findings shed light on psychological drivers of WOM and provide insight into designing more effective WOM campaigns.", "corpus_id": 145193373, "score": 0 }, { "doc_id": "54013178", "title": "The Role of Marketing in Social Media: How Online Consumer Reviews Evolve", "abstract": "Social media provide an unparalleled platform for consumers to publicize their personal evaluations of purchased products and thus facilitate word-of-mouth communication. This paper examines relationships between consumer posting behavior and marketing variables - such as product price and quality - and explores how these relationships evolve as the Internet and consumer review websites attract more universal acceptance. Based on automobile-model data from several leading online consumer review sources that were collected in 2001 and 2008, this study demonstrates that the relationships between marketing variables and consumer online-posting behavior are different at the early and mature stages of Internet usage. For instance, in the early stage of consumer Internet usage, price is negatively correlated with the propensity to post a review. As consumer Internet usage becomes prevalent, however, the relationship between price and the number of online consumer reviews shifts to a U-shape. In contrast, in the early years, price has a U-shaped relationship with overall consumer rating, but this correlation between price and overall rating becomes less significant in the later period. Such differences at the two different stages of Internet usage can be driven by different groups of consumers with different motivations for online review posting.", "corpus_id": 54013178, "score": 0 }, { "doc_id": "7093661", "title": "The Different Roles of Product Originality and Usefulness in Generating Word of Mouth", "abstract": "This paper explores how the dimensions of new products, specifically, the originality and usefulness of the products, influence word-of-mouth (WOM). In four studies, using lab and field setups, we find that originality and usefulness have different effects on WOM. We show that consumers spread more WOM about original products, but the valence of what they say depends on the usefulness of the product. Therefore, originality enhances the effect of usefulness such that consumers spread relatively more and more positively valenced WOM about original and useful products compared to less original but equally useful products. Conversely, consumers spread more and more negatively valenced WOM about original products that are not useful compared to less original products with the same level of low usefulness. The results indicate that product originality should be managed carefully when developing and positioning new products. Although originality increases buzz, it might lead to negatively valenced WOM when the usefulness of the product is perceived to be low.", "corpus_id": 7093661, "score": 0 }, { "doc_id": "9804869", "title": "Do Online Reviews Reflect a Product's True Perceived Quality? - An Investigation of Online Movie Reviews Across Cultures", "abstract": "When does the reported average of online ratings match perceived average assessment? We apply behavioral theory to capture intentions in rating online movie reviews in two dissimilar countries - China and the United States. We argue that consumers' rating behaviors are affected by cultural influences. Based on data collected from imdb.com and douban.com, we found significant differences across raters from these two different cultures. Additionally, we examined how cultural elements influence rating behavior for a hybrid culture - Singapore. Under-reporting bias occurs when consumers with extreme opinions are more likely to report their opinions than consumers with moderate reviews, resulting in reviews that may be biased estimators of quality and certainly have higher variance. An experimental study shows that under-reporting is more prevalent among U.S. online social network, and thus that online reviews are more reflective of a movie's true perceived quality in Chinese and Singapore than in the U.S.", "corpus_id": 9804869, "score": 0 }, { "doc_id": "144959534", "title": "Long-lasting Cognitive and Social Consequences of Emotion: Social Sharing and Rumination", "abstract": "It is proposed that emotion has long-lasting cognitive and social consequences as it is observed for traumatic events. Indeed, emotion, like trauma, is characterized by a sudden disruption of the normal course of events, challenging people's belief systems about themselves and the world and calling for extensive cognitive and social processing. We propose that mental rumination and social sharing constitute fundamental aspects of this processing. In this chapter, we present the results of an integrated programme of research investigating the nature and functions of mental ruminations and social sharing that follow emotional events. A number of questions are addressed, such as whether people do share their emotions, to what extent, with whom, and for which types of emotion. Culture, sex and age differences are also considered. A functional model of rumination and social sharing in emotion is proposed and tested. Finally, five theoretical arguments relate the empirical findings of our research programme to ...", "corpus_id": 144959534, "score": 0 }, { "doc_id": "154594721", "title": "Information direction, website reputation and eWOM effect: A moderating role of product type", "abstract": "This article examines how the electronic word of mouth (eWOM) information direction (positive vs. negative) and a website's reputation (established vs. unestablished) contribute to the eWOM effect. The article describes a study focusing on the moderating role of the product type (search vs. experience). The results of the experiment show that the eWOM effect is greater for negative eWOM than for positive eWOM, greater for established websites than for unestablished websites, and greater for experience goods than for search goods. The results support the moderating effects of product type on the eWOM information direction-website reputation-eWOM effect relationship. The impact of negative eWOM on the eWOM effect is greater for experience goods than for search goods. Similarly, the impact of website reputation on the eWOM effect is greater for experience goods than for search goods. The findings provide managerial implications for an Internet marketing strategy.", "corpus_id": 154594721, "score": 0 }, { "doc_id": "144099600", "title": "Experiential goods with network externalities effects: An empirical study of online rating system", "abstract": "This paper uses online users' reviews and sales information from May 2003 to March 2007 to study a new experiential product: online video game (or virtual world). The results suggest that, first of all, for a hedonic product such as an online video game, the availability of online review system could not fully transform experience attributes into search attributes. The empirical study confirms that negative word-of-mouth has more significant impact than positive reviews. The study empirically verifies that the existence of direct network externalities (i.e. a product's value increases when more consumers join the network) is crucial for a hedonic product. The size of the user base signals the quality of the game, and works like a search attribute for potential users. A large user base will reduce the negative impact from unfavorable reviews.", "corpus_id": 144099600, "score": 0 }, { "doc_id": "46452667", "title": "'Arrivederci CIAO.com, Buongiorno Bing.com' - Electronic word-of-mouth (eWOM), antecedences and consequences", "abstract": "The Internet facilitates access to online product reviews and comments written by consumers. This paper offers new insights on the motives and antecedents of the reading behaviour of consumer reviews in online opinion platforms. This research was carried out from 2005 to 2008 using a case study approach. The case involved working with a prominent and successful online opinion platform (CIAO.com). The company was so successful it was purchased by Microsoft for $486 million in 2008 and is now incorporated into their main search engine which is still a market leader today. The research highlights four different types of motives that drive customers to read online reviews: decision-involvement, product-involvement, social-involvement and economic-involvement motives. The outcomes also demonstrated four different new types of motives: self-involvement motives, consumer-empowerment motives, new social-involvement motives and site-administration motives. Several related themes were also investigated, such as the preference for reading or writing online reviews and the reasons for choosing one over the other. The research tested the relevance of the online reading motives and their influence on consumer buying and communication behaviour. In summary, some theoretical and practical implications are highlighted and discussed.", "corpus_id": 46452667, "score": 0 }, { "doc_id": "167854567", "title": "The Assimilative and Contrastive Effects of Word-of-Mouth Volume: An Experimental Examination of Online Consumer Ratings", "abstract": "The popularity of online rate-and-review websites has increased the importance of word-of-mouth (WOM) volume (number of ratings) yet the retail literature has not paid adequate attention to understanding its impact. This paper highlights WOM volume as a high-scope, decision-making cue upon which the influence of other WOM-relevant characteristics on a WOM message's persuability depends. We begin, via a pretest, by demonstrating the intuitive expectation that high volume, relative to low volume, accentuates or assimilates perceptions of positivity or negativity of WOM targets. Then, through two experimental studies, we show that depending upon how high volume interacts with WOM consensus and consumer decision precommitment, it can contrast preference away from the valence of a target also. In our third and final experimental study, we demonstrate that consumers differ in their susceptibility to the influence of high volume. Those with a higher desire to be different from others, compared to those with a higher desire to be similar, are resistant to high volume's assimilative sway and do not show the valence-accentuating effects demonstrated in the pretest. Retail managers and researchers should find these insights about the different roles of WOM volume beneficial.", "corpus_id": 167854567, "score": 0 }, { "doc_id": "143725084", "title": "Emotional expressions in online user reviews: How they influence consumers' product evaluations", "abstract": "This article investigates an understudied aspect of online word-of-mouth (eWOM) — the effects of emotional expressions in eWOM. Two experiments investigate how consumers interpret emotional expressions in online user reviews and the subsequent impact on their product evaluations. The findings reveal that negative emotional expressions in a single negative review tend to decrease the reviews' informative value and make consumers' product evaluations less negative because consumers attribute the negative emotions to the reviewer's irrational dispositions. However, positive emotional expressions in a single positive review do not influence consumers' product evaluations significantly even though consumers attribute the positive emotions to the product. Next, when multiple convergent emotional expressions are present in multiple user reviews, both positive and negative emotional expressions increase informative value of the reviews and polarize consumers' product evaluations in the respective direction.", "corpus_id": 143725084, "score": 0 }, { "doc_id": "145011125", "title": "How Much Can You Trust Online Information? Cues for Perceived Trustworthiness of Consumer-generated Online Information", "abstract": "Consumers increasingly rely on the Internet to obtain product information and advice from other consumers. However, since the information available on the Internet is easily manipulated, they have to seek cues for the trustworthiness of the online information. The present study proposes and tests the effects on perceived trust of online information and subsequent attitude of (1) perceived strong vs. weak social relationships among net pals and (2) positive vs. negative messages. The moderating effects of credence vs. experience goods are also examined in the research. Results show that, for experience goods, either positive or negative online messages will be perceived as credible as long as the messages are posted by those perceived to have close social relationships. On the other hand, for credence goods, negative online messages are perceived to be more credible than positive online messages when the messages are posted by those perceived to have close social relationships. Results also show the main effect of positive/negative messages on credibility of information, as well as that the effect of credibility of information on product attitude is weaker in the credence goods group than in the experience goods group.", "corpus_id": 145011125, "score": 0 }, { "doc_id": "143907863", "title": "A comparison of leading theories for the prediction of goal‐directed behaviours", "abstract": "A number of attitude theories have been proposed recently to explain behaviours subject to thwarting by internal and external impediments. The present research compares the theory of reasoned action, the theory of planned behaviour, a portion of the theory of self-regulation, and the theory of trying and performs tests of their ability to predict two actions relatively low in perceived behavioural control: exercising and dieting. Respondents were 142 students who participated in a two-wave survey over a two-week period. The results indicate that, while attitudes significantly predicted intentions in all theories, subjective norms lead to intentions only under the theory of trying. Further, the effects of past behaviour were not channelled entirely through attitudes, subjective norms, or perceived behavioural control but rather had direct effects on intentions and subsequent behaviour. When past behaviour was taken into account, it was found that the performance of the target acts were not functions of intentions, and perceived behavioural control failed to predict either intentions or behaviour. Desires had strong direct effects on intentions and mediated most of the impact of attitudes. A number of theoretical implications of the findings are discussed.", "corpus_id": 143907863, "score": 0 }, { "doc_id": "39958897", "title": "The role of desires and anticipated emotions in goal-directed behaviours: broadening and deepening the theory of planned behaviour.", "abstract": "Building on the theory of planned behaviour (TPB), we develop a new model of purposive behaviour which suggests that desires are the proximal causes of intentions, and the traditional antecedents in the TPB work through desires. In addition, perceived consequences of goal achievement and goal failure are modelled as anticipated emotions, which also function as determinants of desires. The new model is tested in two studies: an investigation of bodyweight regulation by 108 Italians at the University of Rome and an investigation of effort expended in studying by 122 students at the University of Rome. Frequency and recency of past behaviour are controlled for in tests of hypotheses. The findings show that desires fully mediated the effects of attitudes, subjective norms, perceived behavioural control and anticipated emotions on intentions. Significantly greater amounts of variance are explained in intentions and behaviour by the new model in comparison to the TPB and variants of the TPB that include either anticipated emotions and/or past behaviour.", "corpus_id": 39958897, "score": 0 }, { "doc_id": "143333487", "title": "An approach to environmental psychology", "abstract": "Environmental psychology, though a fast-growing field, is one of the most difficult to fit into the confines of scientific inquiry. Measuring such subjective data as reactions to color, heat, light, and sound would seem to be an almost impossible task; indeed, until now there has been no theory around which the research in this field could be organized. This volume represents a preliminary effort to identify the relevant variables involved and fit them into a systematic framework. Furthermore, it presents extensive sets of measures for investigating the theory and implementing it in a variety of everyday environments.Basically, the framework outlined here proposes that environmental stimuli are linked to behavioral responses by the primary emotional responses of arousal, pleasure, and dominance. By considering the impact of the environment on these basic emotional responses, the effects of diverse stimulus components within or across sense modalities can be readily compared. An additional concept, information rate, is used to compare the effects of different environments, each with stimulation in many sense modalities. In the final chapters the authors present a series of hypotheses which relate the emotional response variables to a diversity of behaviors such as physical approach, performance, affiliation, and verbally or nonverbally expressed preference.", "corpus_id": 143333487, "score": 0 }, { "doc_id": "10997707", "title": "Impulsive action and motivation", "abstract": "This paper explores the way in which emotions are causal determinants of action. It argues that emotional events, as appraised by the individual, elicit changes in motive states (called states of action readiness), which in turn may (or may not) cause action. Actions can be elicited automatically, without prior intention (called impulsive actions), or intentionally. Impulsive actions reflect the simplest and biologically most general form in which emotions can cause action, since they require no reflection, no foresight, and no planning. Impulsive actions are determined conjointly by the nature of action readiness, the affordances perceived in the eliciting event as appraised, and the individual's action repertoire. Those actions from one's repertoire are performed that both match the perceived affordances and the aim of the state of action readiness.", "corpus_id": 10997707, "score": 0 }, { "doc_id": "144859102", "title": "Relations among emotion, appraisal, and emotional action readiness", "abstract": "Deux etudes examinent les relations entre differents types d'appreciation et de disposition a l'action et des categories emotionnelles variees dans des epreuves de memorisation d'experiences d'etats emotionnels", "corpus_id": 144859102, "score": 0 }, { "doc_id": "143729012", "title": "Emotion and Adaptation", "abstract": "Part I: BACKGROUND: About emotion Issues of research, classification and measurements Part II: THE COGNITIVE-MOTIVATIONAL-RELATIONAL THEORY: The person-environment relationship: motivation and coping Cognition and emotion Issues of causality Part III: INDIVIDUAL EMOTIONS: Goal incongruent (negative) emotions Goal congruent (positive) and problematic emotions Part IV: EMOTIONAL DEVELOPMENT: Individual development Social influence Part V: PRACTICAL APPLICATIONS: Emotions and health Implications for research, assessment, treatment and disease prevention References Index.", "corpus_id": 143729012, "score": 0 }, { "doc_id": "7679194", "title": "Development and validation of brief measures of positive and negative affect: the PANAS scales.", "abstract": "In recent studies of the structure of affect, positive and negative affect have consistently emerged as two dominant and relatively independent dimensions. A number of mood scales have been created to measure these factors; however, many existing measures are inadequate, showing low reliability or poor convergent or discriminant validity. To fill the need for reliable and valid Positive Affect and Negative Affect scales that are also brief and easy to administer, we developed two 10-item mood scales that comprise the Positive and Negative Affect Schedule (PANAS). The scales are shown to be highly internally consistent, largely uncorrelated, and stable at appropriate levels over a 2-month time period. Normative data and factorial and external evidence of convergent and discriminant validity for the scales are also presented.", "corpus_id": 7679194, "score": 0 }, { "doc_id": "154415234", "title": "Exit, voice, and loyalty : responses to decline in firms, organizations, and states", "abstract": "1. Introduction and Doctrinal Background Enter \"exit\" and \"voice\" Latitude for deterioration, and slack in economic thought Exit and voice as impersonations of economics and politics 2. Exit How the exit option works Competition as collusive behavior 3. Voice Voice as a residual of exit Voice as an alternative to exit 4. A Special Difficulty in Combining Exit and Voice 5. How Monopoly Can be Comforted by Competition 6. On Spatial Duopoly and the Dynamics of Two-Party Systems 7. A Theory of Loyalty The activation of voice as a function of loyalty Loyalist behavior as modified by severe initiation and high penalties for exit Loyalty and the difficult exit from public goods (and evils) 8. Exit and Voice in American Ideology and Practice 9. The Elusive Optimal Mix of Exit and Voice Appendixes A. A simple diagrammatic representation of voice and exit B. The choice between voice and exit C. The reversal phenomenon D. Consumer reactions to price rise and quality decline in the case of several connoisseur goods F. The effects of severity of initiation on activism: design for an experiment (in collaboration with Philip G. Zimbardo and Mark Snyder) Index", "corpus_id": 154415234, "score": 0 }, { "doc_id": "144168190", "title": "Voice, exit, and negative word-of-mouth behaviors: An investigation across three service categories", "abstract": "Drawing upon Hirschman’s (1970) framework for Exit, Voice and Loyalty, a model is proposed which predicts and explains variation in voice, exit, and negative work-of-mouth behaviors. The findings from extant consumer complaining behavior (CCB) literature are also incorporated into the hypothesized model. Using data from customer dissatisfaction with three different service categories, the proposed model is subjected to empirical investigation. Despite the parsimony of Hirschman’s framework, results show that the hypothesized model provides good model-fit indices in each of the three data sets. In addition, the explanatory power of the model is encouraging, ranging from 36 percent to 50 percent variance explained. However, the support for the hypothesized pattern of CCB rates across the service categories is mixed. Specifically, while voice responses conform to the hypothesized pattern, exit responses do not. Implications stemming from a comparative analysis of the results are discussed, and directions for future research outlined.", "corpus_id": 144168190, "score": 0 }, { "doc_id": "143610515", "title": "Why don’t some people complain? A cognitive-emotive process model of consumer complaint behavior", "abstract": "This article reports the development of a theoretical model of consumer complaint behavior by using cognitive appraisal theory as its foundation. Because of its importance to management and lack of attention in the marketing literature, specific emphasis is placed on the phenomenon of noncomplaining and the role of consumer emotion in dissatisfying marketplace experiences. The model presents cognitive appraisal as the key element in the evaluation of consumer threat and harm, which subsequently may result in psychological stress. Stressful appraisal outcomes are suggested to elicit emotive reactions that, in conjunction with cognitive appraisal, influence the type of coping strategy used by the consumer. Three coping strategies (problem focused, emotion focused, and avoidance) are identified and discussed. Key propositions are illustrated by using in-depth interview data from a sample of older female consumers.", "corpus_id": 143610515, "score": 1 }, { "doc_id": "54634258", "title": "Inducing word-of-mouth by eliciting surprise ? a pilot investigation", "abstract": "This research - using the critical incident technique - brings to the fore the emotion of surprise and its (direct and indirect) influence on word-of-mouth (WOM). The results show - as expected - that the frequency and amount of WOM are larger for negatively and positively surprising consumption/purchase experiences than for non surprising experiences of the same kind and that the intensity of surprise is significantly correlated with positive and negative WOM.", "corpus_id": 54634258, "score": 0 }, { "doc_id": "143754076", "title": "Receiving word-of-mouth from the service customer: An emotion-based effectiveness assessment", "abstract": "Abstract This study examines how receiving negative and positive word-of-mouth from satisfied and dissatisfied customers influences the potential customer. By explicitly including responses in terms of emotions—which hitherto have been neglected in research on word-of-mouth—it was found that emotional contagion and affect infusion were involved in the response process. The net effect was that receiving positive word-of-mouth as opposed to receiving negative word-of-mouth produced more positive evaluations of the service firm in the word-of-mouth conversation and higher levels of purchase intent vis-a-vis this firm. The results are thereby consonant with implicit assumptions in existing literature that word-of-mouth from the existing customer may have a significant impact on the potential customer, and this study indicates that emotional variables play an important role in the influence process.", "corpus_id": 143754076, "score": 0 }, { "doc_id": "144155735", "title": "The effect of consumption emotions on satisfaction and word‐of‐mouth communications", "abstract": "This paper examines the impact of consumption emotions on consumers' satisfaction and how it affects what they tell other consumers. The conceptual model is based on the premise that pleasure and arousal influence satisfaction, word-of-mouth (WOM) communications, and the likelihood of generating WOM. A study of 470 moviegoers in a French Canadian city supports most of these relationships. The results indicate that even when the effects of satisfaction are accounted for, pleasure and arousal have significant effects on WOM. © 2007 Wiley Periodicals, Inc.", "corpus_id": 144155735, "score": 0 }, { "doc_id": "55951464", "title": "Emotions in consumer behavior: A hierarchical approach", "abstract": "Abstract A growing body of consumer research studies emotions evoked by marketing stimuli, products and brands. Yet, there has been a wide divergence in the content and structure of emotions used in these studies. In this paper, we will show that the seemingly diverging research streams can be integrated in a hierarchical consumer emotions model. The superordinate level consists of the frequently encountered general dimensions positive and negative affect. The subordinate level consists of specific emotions, based on Richins' (Richins, Marsha L. Measuring Emotions in the Consumption Experience. J. Consum. Res. 24 (2) (1997) 127–146) Consumption Emotion Set (CES), and as an intermediate level, we propose four negative and four positive basic emotions. We successfully conducted a preliminary test of this second-order model, and compare the superordinate and basic level emotion means for different types of food. The results suggest that basic emotions provide more information about the feelings of the consumer over and above positive and negative affect.", "corpus_id": 55951464, "score": 0 }, { "doc_id": "55679501", "title": "Beyond valence in customer dissatisfaction: A review and new findings on behavioral responses to regret and disappointment in failed services", "abstract": "Abstract Dissatisfied customers may express their dissatisfaction behaviorally. These behavioral responses may impact the firms' profitability. How do we model the impact of emotions on satisfaction and subsequent customer behaviors? There are essentially two approaches: the valence-based approach and the specific emotions approach. The authors indicate theoretically and show empirically that it matters to distinguish these approaches in services research. Dissatisfaction and the specific emotions disappointment and regret were assessed and their influence on customers' behavioral responses (complaining, switching, word-of-mouth, and customer inertia) was examined, using a sample of over 900 customers. It was found that emotions have a direct impact on behavior, over and above the effects of dissatisfaction. Hence, the authors argue against incorporating emotions such as regret and disappointment into a general (dis)satisfaction measure (i.e., the valence-based approach), and in favor of a specific emotions approach to customer dissatisfaction. Implications for services marketing practice and theory are discussed.", "corpus_id": 55679501, "score": 1 }, { "doc_id": "167525289", "title": "Customer satisfaction: A meta-analysis of the empirical evidence", "abstract": "The growing number of academic studies on customer satisfaction and the mixed findings they report complicate efforts among managers and academics to identify the antecedents to, and outcomes of, businesses having more-versus less-satisfied customers. These mixed findings and the growing emphasis by managers on having satisfied customers point to the value of empirically synthesizing the evidence on customer satisfaction to assess current knowledge. To this end, the authors conduct a meta-analysis of the reported findings on customer satisfaction. They document that equity and disconfirmation are most strongly related to customer satisfaction on average. They also find that measurement and method factors that characterize the research often moderate relationship strength between satisfaction and its antecedents and outcomes. The authors discuss the implications surrounding these effects and offer several directions for future research.", "corpus_id": 167525289, "score": 0 }, { "doc_id": "56371906", "title": "The theory of cognitive dissonance: A marketing and management perspective", "abstract": "The theory of cognitive dissonance [1] concentrates on creating knowledge about important psychological processes of individuals. Specifically, it focuses on the relationships among cognitions that are elements of knowledge that people have about their behaviors, attitudes, perceptions, beliefs, feelings, or environments. Since human nature is the main subject of all social sciences, the theory has awakened interest and led to significant research in different academic domains. This study makes a thorough analysis of the theory’s application in psychology, management, and marketing fields with an aim to assess the contribution of the theory to the development of knowledge in these areas. It is observed that the theory is commonly used by marketers to explain consumer behavior while its adoption in the management field to examine human related issues is considerably underdeveloped. Accordingly, the aim of this paper is to extend the literature on cognitive dissonance by discovering the under-investigated areas and pave the way for further theoretical and empirical research. Identification of existing gaps and suggestions for further scholarly inquiries are also believed to contribute to the recent efforts to regenerate interest to topic and to boost its generalizability through its greater utilization in the development of knowledge.", "corpus_id": 56371906, "score": 0 }, { "doc_id": "15793209", "title": "Postswitching Negative Word of Mouth", "abstract": "Previous research has extensively studied the determinants of customer loyalty and switching behavior but has given little attention to what happens after a customer has switched away from a service provider. In this article, the perhaps most important manifestation of such postswitching behavior—namely, postswitching negative word of mouth (PNWOM)—is investigated. Drawing from dissonance theory, hypotheses are developed and tested in an empirical study. Results from the telecommunications industry indicate that PNWOM is given frequently and that product involvement, market mavenism, perceived risk, satisfaction with the new provider, and the reason for switching the provider explain PNWOM. Implications for customer management are discussed.", "corpus_id": 15793209, "score": 0 }, { "doc_id": "10950746", "title": "Customer repurchase intention: A general structural equation model", "abstract": "This paper develops a general service sector model of repurchase intention from the consumer theory literature. A key contribution of the structural equation model is the incorporation of customer perceptions of equity and value and customer brand preference into an integrated repurchase intention analysis. The model describes the extent to which customer repurchase intention is influenced by seven important factors – service quality, equity and value, customer satisfaction, past loyalty, expected switching cost and brand preference. The general model is applied to customers of comprehensive car insurance and personal superannuation services. The analysis finds that although perceived quality does not directly affect customer satisfaction, it does so indirectly via customer equity and value perceptions. The study also finds that past purchase loyalty is not directly related to customer satisfaction or current brand preference and that brand preference is an intervening factor between customer satisfaction and repurchase intention. The main factor influencing brand preference was perceived value with customer satisfaction and expected switching cost having less influence.", "corpus_id": 10950746, "score": 0 }, { "doc_id": "167453982", "title": "Service failure and recovery: The impact of relationship factors on customer satisfaction", "abstract": "This research investigated how customers' relationships with a service organization affect their reactions to service failure and recovery. Our conceptual model proposed that customer-organizational relationships help to shape customers' attributions and expectations when service failures occur. The empirical results showed that customers with higher expectations of relationship continuity had lower service recovery expectations after a service failure and also attributed that failure to a less stable cause. Both the lower recovery expectations and the lower stability attributions were associated with greater satisfaction with the service performance after the recovery. These effects appeared to be key processes by which relationships buffer service organizations when service failures occur.", "corpus_id": 167453982, "score": 0 }, { "doc_id": "168153134", "title": "Employee Satisfaction, Customer Loyalty, and Financial Performance", "abstract": "The service profit chain is a simple conceptual framework linking employee satisfaction and loyalty, customer satisfaction and loyalty, and financial performance. Although widely used by practitioners, the service profit chain's series of hypothesized relationships between employee, customer, and financial outcomes has not been rigorously tested using data that span all components of the model. Panel data from the branches of a large regional bank are used to test individually each of the service profit chain's constituent hypotheses. The results generally support the model, but there are some exceptions. Further work is needed to refine and simplify several critical measures and to enhance the analysis to test the service profit chain as a complete system of related hypotheses.", "corpus_id": 168153134, "score": 0 }, { "doc_id": "167443029", "title": "Customer satisfaction, customer retention, and market share", "abstract": "Abstract We provide a mathematical framework for assessing the value of customer satisfaction. The framework enables managers to determine which customer satisfaction elements have the greatest impact, and how much money should be spent to improve particular customer satisfaction elements. This makes it possible to hold customer satisfaction programs accountable, in the way that other business programs are held accountable, by forcing them to demonstrate their benefits with respect to bottom-line profitability. We use an individual-level model of loyalty and retention, and then build up to market share by aggregation. We demonstrate the application of our approach in a pilot study of a city's retail banking market.", "corpus_id": 167443029, "score": 0 }, { "doc_id": "54817852", "title": "'My' Brand or 'Our' Brand: The Effects of Brand Relationship Dimensions and Self-Construal on Brand Evaluations", "abstract": "Consumer-brand relationships can be formed based on individual- or group-level connections. For example, a consumer's relationship with a Mercedes may be based on the desire to express individual-level unique identity (e.g., self-concept connection), whereas a relationship with a local brand (e.g., Ford) may be based on a group-level patriotic national identity (e.g., country-of-origin connection). We suggest that the effects of self-concept connection and brand country-of-origin connection vary based on self-construal. Results across two studies reveal that, under independent self-construal, self-concept connection is more important. Under interdependent self-construal, brand country-of-origin connection is more important. (c) 2007 by JOURNAL OF CONSUMER RESEARCH, Inc..", "corpus_id": 54817852, "score": 0 }, { "doc_id": "167366538", "title": "A dynamic model of customer complaining behaviour from the perspective of service‐dominant logic", "abstract": "Purpose - The purpose of this paper is to propose a conceptual model of customer complaining behaviour as a dynamic process in accordance with the service-dominant logic perspective of marketing.De ...", "corpus_id": 167366538, "score": 0 }, { "doc_id": "144104453", "title": "When consumers love their brands: Exploring the concept and its dimensions", "abstract": "Consumers may develop feelings of love toward some brands, but the meaning and underlying dimensions of this construct require further development. Through an exploratory Internet study of 843 respondents in France, this research used both qualitative and quantitative approaches to explore the concept of love. Eleven dimensions emerge through a correspondence analysis and the concomitant use of a multiple correspondence analysis and cluster analysis of the wording that respondents use to describe their feeling of love and the special type of relationships they have with the brands they love. These dimensions identified in France compare to dimensions of love found in previous research conducted in the United States.", "corpus_id": 144104453, "score": 0 }, { "doc_id": "145406408", "title": "Consumer–retailer love and attachment: Antecedents and personality moderators", "abstract": "Abstract Because loyalty to services remains elusive and unpredictable, there is a need to study consumer relationships with firms apart from the established satisfaction–loyalty chain approach. To that end, the present paper investigates feelings of attachment and love through two empirical consumer studies of two different grocery retailer brands. The findings of the current study imply that retail store image , perceived transactional value , and corporate social responsibility (CSR) associations positively influence consumer–retailer love levels. Furthermore, we find that for consumers scoring low on the value of warm relationships with others and for consumers characterized by an avoidant attachment style , the effect of consumer–retailer love on re-patronage intentions is less salient. Interestingly, in the case of highly avoidant individuals, the effect of consumer–retailer love is negative. Managerial implications for building consumer-firm love in the context of grocery retail, as well as future research perspectives, are provided at the end of the paper.", "corpus_id": 145406408, "score": 0 }, { "doc_id": "167933256", "title": "Complaining customers, service recovery and continuous improvement", "abstract": "Notes the fact that dissatisfied customers may not complain to the service provider, but will tell a number of people about the bad service they have received. Looks at factors related to the development of a service recovery system to ensure that dissatisfied customers are dealt with effectively so as to ensure they receive appropriate levels of service and to maximize customer retention. Considers factors such as the reasons for customer complaints, reciprocity and complaint handling and ways to instil a service recovery strategy.", "corpus_id": 167933256, "score": 0 }, { "doc_id": "207598694", "title": "The effect of negative online consumer reviews on product attitude: An information processing view", "abstract": "Online consumer reviews provide product information and recommendations from the customer perspective. This study investigates the effects of negative online consumer reviews on consumer product attitude. In particular, it examines the proportion and quality of negative online consumer reviews from the perspective of information processing. The elaboration likelihood model is used to explain the persuasive effect of the proportion and quality depending on product involvement. A high proportion of negative online consumer reviews elicits a conformity effect. As the proportion of negative online consumer reviews increases, high-involvement consumers tend to conform to the perspective of reviewers, depending on the quality of the negative online consumer reviews; in contrast, low-involvement consumers tend to conform to the perspective of reviewers regardless of the quality of the negative online consumer reviews. The experiment in this study uses 248 college students in Korea. The proposed hypotheses are tested by three-way analysis of covariance.", "corpus_id": 207598694, "score": 0 }, { "doc_id": "143130001", "title": "Trend Effects and Gender Differences in Retrospective Judgments of Consumption Emotions", "abstract": "A field study performed at the end of multiday hospital stays investigated trend effects on retrospective global judgments of emotions. Subjects (43 women and 50 men) reported instances of their positive and negative emotions, retrospective global judgments of these emotions, and satisfaction with hospital services. Retrospective global judgments of positive and negative emotions were a positive function of the increase or decrease of the instances of emotions over time. Consistent with predictions based on the literature on gender differences in information processing, men's retrospective judgments of positive emotions were highly sensitive to trend effects but no trend effect was found for negative emotions. In contrast, women demonstrated trend effects primarily in judgments of negative emotions. Trends in positive and negative emotions, however, did not significantly contribute to satisfaction judgements for men and women. Theoretical and managerial implications of the results are discussed. Copyright 1996 by the University of Chicago.", "corpus_id": 143130001, "score": 0 }, { "doc_id": "144564628", "title": "Measuring Emotions in the Consumption Experience", "abstract": "Although consumption-related emotions have been studied with increasing frequency in consumer behavior, issues concerning the appropriate way to measure these emotions remain unresolved This article reviews the emotion measures currently used in consumer research and the theories on which they are based; it concludes that the existing measures are unsuited for the purpose of measuring consumption-related emotions. The article describes six empirical studies that assess the domain of consumption-related emotions, that identify an appropriate set of consumption emotion descriptors (the CES), and that compare the usefulness of this descriptor set with the usefulness of other measures in assessing consumption-related emotions. Copyright 1997 by the University of Chicago.", "corpus_id": 144564628, "score": 0 }, { "doc_id": "936285", "title": "Loneliness, Self-Disclosure, and ICQ (\"I Seek You\") Use", "abstract": "This study investigated the relationships between self-disclosure in ICQ (\"I seek you\") chat, level of loneliness, and ICQ usage. The Revised UCLA Loneliness Scale and the Revised Self-Disclosure Scale (RSDS) were administered to a multistaged stratified random sample of 576 college students. The results indicate that loneliness is not related to level of ICQ use, but inversely related to valence, accuracy, and the amount dimensions of self-disclosure in ICQ chat, and that ICQ usage is significantly related to control of depth and intent of disclosure. Specifically, it was found that the lonelier the student, the more dishonest, more negative, and the less revealing was the quality of the self-disclosure in their ICQ interaction. Conversely, appropriate, honest, positive, and accurate self-disclosure might lead to decreased loneliness when one feels understood, accepted, and cared about on ICQ. More important, as intimate relationships are based on high degrees of depth and intent of self-disclosure, heavy users of ICQ are usually open, personal, and consciously aware of what they are disclosing.", "corpus_id": 936285, "score": 0 }, { "doc_id": "144336913", "title": "A Follow-up Study of the Relationships among Trust, Disclosure, and Interpersonal Solidarity", "abstract": "This study conceptualized perceived trustworthiness of the individual, self-disclosure to the individual, perceived trustworthiness of people in general, and disclosive tendencies to other people in general to be indicants of a broader construct of trust. Self-disclosure and perceived trustworthiness of the individual were found to be related constructs assessing differential aspects of the trust construct. Likewise, self-disclosure and perceived trustworthiness of the individual were found to be criterial attributes of interpersonal solidarity. These communication-related phenomena indicated the solidarity of interpersonal relationships. In the progress of the research, a 20-item measure of perceived interpersonal solidarity was developed as a criterion for assessing the impact of communication-related variables on interpersonal relationships. Other exploratory research issues were investigated.", "corpus_id": 144336913, "score": 0 }, { "doc_id": "167782856", "title": "Excitement at the mall: Determinants and effects on shopping response", "abstract": "Abstract Competition between malls and newer forms of shopping centers has led mall developers and management to consider alternative methods to build excitement with customers. In this study, we examine the relationship between three factors (tenant variety, mall environment and shopping involvement) on shoppers' excitement and desire to stay at a mall. Results show that the three factors have a differential influence on excitement and desire to stay, which in turn are found to influence repatronage intentions and outshopping.", "corpus_id": 167782856, "score": 0 }, { "doc_id": "146300503", "title": "When Does the Service Process Matter? A Test of Two Competing Theories", "abstract": "This article examines the interactive effect of process quality and outcome quality on service evaluation. Experiment 1 shows that the interaction between the two types of quality follows a pattern predicted by two-factor theory. In contrast, experiment 2 demonstrates that when consumers feel uncertain about the service outcome prior to consumption, they will use process quality as a heuristic substitute in their assessment of the trustworthiness of the service provider. The resulting interaction between the types of quality then follows a pattern predicted by fairness heuristic theory.", "corpus_id": 146300503, "score": 0 }, { "doc_id": "12476939", "title": "Perceived Usefulness, Perceived Ease of Use, and User Acceptance of Information Technology", "abstract": "Valid measurement scales for predicting user acceptance of computers are in short supply. Most subjective measures used in practice are unvalidated, and their relationship to system usage is unknown. The present research develops and validates new scales for two specific variables, perceived usefulness and perceived ease of use, which are hypothesized to be fundamental determinants of user acceptance. Definitions of these two variables were used to develop scale items that were pretested for content validity and then tested for reliability and construct validity in two studies involving a total of 152 users and four application programs. The measures were refined and streamlined, resulting in two six-item scales with reliabilities of .98 for usefulness and .94 for ease of use. The scales exhibited hgih convergent, discriminant, and factorial validity. Perceived usefulness was significnatly correlated with both self-reported current usage r = .63, Study 1) and self-predicted future usage r = .85, Study 2). Perceived ease of use was also significantly correlated with current usage r = .45, Study 1) and future usage r = .59, Study 2). In both studies, usefulness had a signficnatly greater correaltion with usage behavior than did ease of use. Regression analyses suggest that perceived ease of use may actually be a causal antecdent to perceived usefulness, as opposed to a parallel, direct determinant of system usage. Implications are drawn for future research on user acceptance.", "corpus_id": 12476939, "score": 0 }, { "doc_id": "151075248", "title": "Systems Analysis by Partial Least Squares", "abstract": "This Collaborative Paper is one of a series embodying the outcome of a workshop and conference on Economic Structural Change: Analytical Issues, held at IIASA in July and August 1983. The conference and workshop formed part of the continuing IIASA program on Patterns of Economic Structural Change and Industrial Adjustment. \n\nStructural change was interpreted very broadly: the topics covered included the nature and causes of changes in different sectors of the world economy, the relationship between international markets and national economies, and issues of organization and incentives in large economic systems. \n\nThere is a general consensus that important economic structural changes are occurring in the world economy. There are, however, several alternative approaches to measuring these changes, to modeling the process, and to devising appropriate responses in terms of policy measures and institutional redesign. Other interesting questions concern the role of the international economic system in transmitting such changes, and the merits of alternative modes of economic organization in responding to structural change. All of these issues were addressed by participants in the workshop and conference, and will be the focus of the continuation of the research program's work.", "corpus_id": 151075248, "score": 0 }, { "doc_id": "16384423", "title": "The Use of Partial Least Squares Path Modeling in International Marketing", "abstract": "In order to determine the status quo of PLS path modeling in international marketing research, we conducted an exhaustive literature review. An evaluation of double-blind reviewed journals through important academic publishing databases (e.g., ABI/Inform, Elsevier ScienceDirect, Emerald Insight, Google Scholar, PsycINFO, Swetswise) revealed that more than 30 academic articles in the domain of international marketing (in a broad sense) used PLS path modeling as means of statistical analysis. We assessed what the main motivation for the use of PLS was in respect of each article. Moreover, we checked for applications of PLS in combination with one or more additional methods, and whether the main reason for conducting any additional method(s) was mentioned.", "corpus_id": 16384423, "score": 0 }, { "doc_id": "144999845", "title": "Scale Development: Theory and Applications", "abstract": "Chapter 1: Overview General Perspectives on Measurement Historical Origins of Measurement in Social Science Later Developments in Measurement The Role of Measurement in the Social Sciences Summary and Preview Chapter 2: Understanding the \"Latent Variable\" Constructs Versus Measures Latent Variable as the Presumed Cause of Item Values Path Diagrams Further Elaboration of the Measurement Model Parallel \"Tests\" Alternative Models Exercises Chapter 3: Reliability Continuous Versus Dichotomous Items Internal Consistency Relability Based on Correlations Between Scale Scores Generalizability Theory Summary and Exercises Chapter 4: Validity Content Validity Criterion-related Validity Construct Validity What About Face Validity? Exercises Chapter 5: Guidelines in Scale Development Step 1: Determine Clearly What it Is You Want to Measure Step 2: Generate an Item Pool Step 3: Determine the Format for Measurement Step 4: Have Initial Item Pool Reviewed by Experts Step 5: Consider Inclusion of Validation Items Step 6: Administer Items to a Development Sample Step 7: Evaluate the Items Step 8: Optimize Scale Length Exercises Chapter 6: Factor Analysis Overview of Factor Analysis Conceptual Description of Factor Analysis Interpreting Factors Principal Components vs Common Factors Confirmatory Factor Analysis Using Factor Analysis in Scale Development Sample Size Conclusion Chapter 7: An Overview of Item Response Theory Item Difficulty Item Discrimination False Positives Item Characteristic Curves Complexities of IRT When to Use IRT Conclusions Chapter 8: Measurement in the Broader Research Context Before the Scale Development After the Scale Administration Final Thoughts References Index About the Author", "corpus_id": 144999845, "score": 0 }, { "doc_id": "141571270", "title": "Scaling Procedures: Issues and Applications", "abstract": "About the Authors Chapter One: Introduction and Overview Purpose of the Book. Perspectives on Measurement in the Social Sciences. Latent Constructs Overview of dimensionality, reliability, and validity Overview of recommended procedures and steps in scale development. Chapter Two: Dimensionality Introduction. Dimensionality of construct, items, and a set of items. Does uni-dimensionality of a set of items imply uni-dimensionality of items or construct? Relevance of uni-dimensionality. How to assess dimensionality of constructs. Chapter Three: Reliability Introduction The true-score model Coefficient alpha Generalizability Theory Chapter Four: Validity Overview of Construct Validity Translation validity Criterion validity Convergent and discriminant validity Known-group validity Nomological validity Chapter Five: Steps 1 and 2: Construct Definition and Generating and Judging Measurement items Chapter 5: Steps 1 and 2: Construct Definition and Judging Measurement Items Introduction Step 1: Construct definition and content domain Step 2: Generating and judging measurement items Applications of Steps 1 and 2. Chapter Six: Step 3: Designing and Conducting Studies to Develop the Scale Introduction Pilot testing Conducting multiple studies for initial development and validation Initial item analyses: Exploratory factor analysis (EFA) Initial item and reliability analyses A final caveat EFA and item and reliability analyses examples from the literature Chapter 7: Step 4: Finalizing the Scale Introduction EFA and additional item analyses Confirmatory Factor Analyses (CFA) Additional evaluations of validity Establishing norms Applying generalizability theory Chapter Eight: Concluding Remarks Index", "corpus_id": 141571270, "score": 0 }, { "doc_id": "153847374", "title": "On assuring valid measures for theoretical models using survey data", "abstract": "Abstract This research critically reviews the process and procedures used in marketing to assure valid and reliable measures for theoretical model tests involving unobserved variables and survey data, and it selectively suggests improvements. The review and suggestions are based on reviews of articles in the marketing literature, and the recent methods literature. This research also provides several perhaps needed explanations and examples, and is aimed at continuous improvement in theoretical model tests involving unobserved variables and survey data.", "corpus_id": 153847374, "score": 0 }, { "doc_id": "5281538", "title": "Common method biases in behavioral research: a critical review of the literature and recommended remedies.", "abstract": "Interest in the problem of method biases has a long history in the behavioral sciences. Despite this, a comprehensive summary of the potential sources of method biases and how to control for them does not exist. Therefore, the purpose of this article is to examine the extent to which method biases influence behavioral research results, identify potential sources of method biases, discuss the cognitive processes through which method biases influence responses to measures, evaluate the many different procedural and statistical techniques that can be used to control method biases, and provide recommendations for how to select appropriate procedural and statistical remedies for different types of research settings.", "corpus_id": 5281538, "score": 0 }, { "doc_id": "145495928", "title": "Temporal Changes in Mood Repair Through Music Consumption: Effects of Mood, Mood Salience, and Individual Differences", "abstract": "Prior research on mood management through media consumption has encountered mixed results. This study seeks to address these discrepancies by incorporating time of measurement into the examination of regulatory outcomes and by identifying trait-like cognitive moderators that presumably are involved in the regulation of negative moods. Results showed that sad mood initially fostered longer listening to mood-compatible music but such preference decreased over time, suggesting the merits of considering temporal changes in the mood-repair process. In addition, ruminative trait was found to be a significant factor in how people cope with their sad moods, whereas mood salience was not.", "corpus_id": 145495928, "score": 0 }, { "doc_id": "20351259", "title": "Retrieving positive memories to regulate negative mood: consequences for mood-congruent memory.", "abstract": "Several researchers have suggested that mood-incongruency effects are due to a mood-regulatory process in which people retrieve positive memories to repair negative moods. The present studies tested this idea by manipulating mood-repair strategies and examining their impact on positive and negative memory retrieval. Mood-congruent retrieval occurred when participants stayed focused on events associated with their negative mood; mood-incongruent retrieval occurred when participants engaged in positive reappraisal (when they reinterpreted events as having positive outcomes). The effects of these strategies on memory retrieval also interacted with personality traits related to negative mood regulation. Individuals high in such traits showed stronger mood-incongruent memory than did individuals low in negative mood-regulation traits. Discussion focuses on integrating mood-regulatory variables and personality variables into existing mood-congruency theories (e.g., associative network models).", "corpus_id": 20351259, "score": 0 }, { "doc_id": "31064341", "title": "Self-Presentation in Online Personals", "abstract": "This study investigates self-disclosure in the novel context of online dating relationships. Using a national random sample of Match.com members (N = 349), the authors tested a model of relational goals, self-disclosure, and perceived success in online dating. The authors’ findings provide support for social penetration theory and the social information processing and hyperpersonal perspectives as well as highlight the positive effect of anticipated future face-to-face interaction on online self-disclosure. The authors find that perceived online dating success is predicted by four dimensions of self-disclosure (honesty, amount, intent, and valence), although honesty has a negative effect. Furthermore, online dating experience is a strong predictor of perceived success in online dating. Additionally, the authors identify predictors of strategic success versus self-presentation success. This research extends existing theory on computer-mediated communication, self-disclosure, and relational success to the increasingly important arena of mixed-mode relationships, in which participants move from mediated to face-to-face communication.", "corpus_id": 31064341, "score": 0 }, { "doc_id": "154601317", "title": "Consumer Power: A Comparison of the Old Economy and the Internet Economy", "abstract": "From the very beginning of the Internet, a decisive shift from supplier power to consumer power was predicted by several authors and is still maintained in recent literature. Although the Internet has grown rapidly within the last years and electronic markets have evolved, a theoretical framework for consumer power on the Internet still cannot be identified. Few authors have taken efforts to apply common concepts of power theory to the characteristics of the Internet. Based on the concept of French and Raven, this paper analyses consumer power in traditional markets and then compares it to the situation on the Internet. This comparison shows that the Internet enables consumers (a) to overcome most information asymmetries that characterize traditional consumer markets and thus obtain high levels of market transparency, (b) to easily band together against companies and impose sanctions via exit and voice, and (c) to take on a more active role in the value chain and influence products and prices according to individual preferences. A broad literature review reveals that empirical findings confirm these hypotheses to a great extent. The authors conclude by summarizing the results and drawing implications from two different angles, namely from a marketing and a consumer policy perspective.", "corpus_id": 154601317, "score": 0 }, { "doc_id": "12566155", "title": "The impact of electronic word-of-mouth: The adoption of online opinions in online customer communities", "abstract": "Purpose – Web‐based technologies have created numerous opportunities for electronic word‐of‐mouth (eWOM) communication. This phenomenon impacts online retailers as this easily accessible information could greatly affect the online consumption decision. The purpose of this paper is to examine the extent to which opinion seekers are willing to accept and adopt online consumer reviews and which factors encourage adoption.Design/methodology/approach – Using dual‐process theories, an information adoption model was developed to examine the factors affecting information adoption of online opinion seekers in online customer communities. The model was tested empirically using a sample of 154 users who had experience within the online customer community, Openrice.com. Users were required to complete a survey regarding the online consumer reviews received from the virtual sharing platform.Findings – The paper found comprehensiveness and relevance to be the most effective components of the argument quality construct ...", "corpus_id": 12566155, "score": 0 }, { "doc_id": "31337844", "title": "The Effect of On-Line Consumer Reviews on Consumer Purchasing Intention: The Moderating Role of Involvement", "abstract": "On-line consumer reviews, functioning both as informants and as recommenders, are important in making purchase decisions and for product sales. Their persuasive impact depends on both their quality and their quantity. This paper uses the elaboration likelihood model to explain how level of involvement with a product moderates these relationships. The study produces three major findings: (1) the quality of on-line reviews has a positive effect on consumers' purchasing intention, (2) purchasing intention increases as the number of reviews increases, and (3) low-involvement consumers are affected by the quantity rather than the quality of reviews, but high-involvement consumers are affected by review quantity mainly when the review quality is high. These findings have implications for on-line sellers in terms of how to manage on-line consumer reviews.", "corpus_id": 31337844, "score": 0 }, { "doc_id": "145801618", "title": "Gratitude, delight, or guilt: The role of consumers' emotions in predicting postconsumption behaviors", "abstract": "This study investigates the relationships among appraisals (goal congruence/incongruence and agency), consumption emotions (gratitude, happiness, guilt, anger, pride, and sadness), and post-consumption behaviors (positive and negative word of mouth, repurchase intention, and complaint behavior). The findings demonstrate that these emotions predict different specific types of post-consumption behaviors and that they are elicited by appraisals specified in the psychology literature. In particular, gratitude but not happiness, predicts repurchase intention and positive word of mouth. By contrast, guilt inhibits complaint behaviors and negative word of mouth. The implications of these findings for marketing practice are discussed. © 2007 Wiley Periodicals, Inc.", "corpus_id": 145801618, "score": 0 }, { "doc_id": "154755190", "title": "Rules of engagement: Practice what you tweet", "abstract": "Abstract This study explored tweets that mention highly engaged companies and compared them to tweets that mention less engaged competitors. Results showed that a highly engaged company received less negative mentions in tweets, but only if the company also practiced dialogical communication. Additionally, less engaged companies received more mentions in tweets and in one instance tweets that mentioned a less engaged company shared more links with others.", "corpus_id": 154755190, "score": 0 }, { "doc_id": "6248482", "title": "Subjectivity and sentiment analysis: An overview of the current state of the area and envisaged developments", "abstract": "In this introduction, we present an overview of the current state of research in the Natural Language Processing tasks of subjectivity and sentiment analysis, as well as their application domains and closely-related research field of emotion detection. Although many definitions exist for these tasks and the research done within their frame spans over approaches with different objectives, we consider subjectivity analysis to deal with the detection of ''private states'' (opinions, emotions, sentiments, beliefs, speculations) and sentiment analysis as the task of detecting, extracting and classifying opinions and sentiments concerning different topics, as expressed in textual input. After describing the key concepts and research directions in these tasks, we present the main achievements obtained so far and the issues that remain to be tackled. Subsequently, we introduce each of the papers in this volume and present their contribution to the research areas of subjectivity and sentiment analysis. Finally, we conclude on the present state of work in these fields and reflect on the possible future developments.", "corpus_id": 6248482, "score": 0 }, { "doc_id": "167793823", "title": "Telecom's search for the ultimate customer loyalty platform", "abstract": "Purpose – The purpose of this paper is to present an up‐to‐date examination of the telecommunications industry and attempt to discover how some of the major players are engaging their customers while trying to constantly diversify their service offerings.Design/methodology/approach – The paper examines, case by case, three major telecommunications companies and identifies current and future offerings as they pertain to service initiatives and customer loyalty and retention. The paper also offers a broader overview of the telecommunications industry as a whole and identifies some major trends in the current landscape.Findings – The paper finds that companies with sound customer strategies can use this as a differentiator in an increasingly muddled market. In an increasingly competitive market, customer loyalty efforts can play a major part in the attraction of new customers and the retention of current ones. Companies must transition to offer a suite of services as “bundling” strategies proliferate and fur...", "corpus_id": 167793823, "score": 0 } ]

{ "doc_id": "52900224", "title": "Thy-1 Deficiency Augments Bone Loss in Obesity by Affecting Bone Formation and Resorption", "abstract": "Healthy bone remodeling results from a balanced bone formation and bone resorption realized by bone-forming osteoblasts and bone-resorbing osteoclasts, respectively. Recently, Thy-1 (CD90) was identified as positive regulator of osteoblast differentiation and activation, thus, promoting bone formation while concurrently inhibiting adipogenesis and obesity in mice. Additionally, Thy-1 did not affect bone resorption. An obesity-related co-morbidity that is increasing in prevalence is a disturbed bone formation resulting in an increased fracture risk. The underlying mechanisms of obesity-induced bone alterations are not yet fully elucidated and therefore therapy options for efficient bone-anabolic treatments are limited. Therefore, we investigated the impact of Thy-1 on bone metabolism under obese conditions. Indeed, high fat diet (HFD) induced obese mice lacking Thy-1 (Thy-1−/−) showed increased body fat mass compared to wildtype (WT) mice while bone mass (−38%) and formation (−57%) were decreased as shown by micro-computed tomography (μCT) measurement, histological analysis, and fourier-transform infrared spectroscopy (FTIR). Interestingly, under obese conditions, lack of Thy-1 affected both osteoblast and osteoclast function. Number (−30%) and activity of osteoblasts were decreased in obese Thy-1−/− mice while osteoclast number (+39%) and activity were increased. Facilitated bone marrow fat accumulation (+56%) in obese Thy-1−/− mice compared to obese WT mice was associated with upregulated tumor necrosis factor α (Tnfα, +46%) and colony stimulating factor 1 receptor (Csf1r) expression, strong promoters of osteoclast differentiation. Moreover, lack of Thy-1 was accompanied by a reduction of osteoprotegerin (Tnfrsf11b) expression (−36%), an inhibitor of osteoclast differentiation. Altered Tnfα, Csf1r, and Tnfrsf11b expression might be responsible for elevated osteoclast activity in obese Thy-1-deficient mice. In summary, our findings show that lack of Thy-1 promotes obesity under HFD conditions while concurrently decreasing bone mass and formation. Mechanistic studies revealed that under obese conditions lack of Thy-1 impairs both bone formation and bone resorption.", "corpus_id": 52900224 }

[ { "doc_id": "2269601", "title": "Bone remodelling at a glance", "abstract": "The bone remodelling cycle (see Poster panel “The bone remodelling cycle”) maintains the integrity of the skeleton through the balanced activities of its constituent cell types. These are the bone-forming osteoblast, a cell that produces the organic bone matrix and aids its mineralisation ([", "corpus_id": 2269601, "score": 0 }, { "doc_id": "34310269", "title": "Isolation and characterization of a molecular complex containing thy‐1 antigen from the surface of murine thymocytes and t cells", "abstract": "A complex containing the Thy‐1 (θ) antigen has been isolated from the surface of murine thymocytes and T cells by cell surface radioiodination, lysis by freezing and thawing, and immunoprecipitation. The specificity of the immunoprecipitation was firmly established using both congenic and noncongenic anti‐Thy‐1 sera and thymocytes from congenic and noncongenic mice.", "corpus_id": 34310269, "score": 0 }, { "doc_id": "9679911", "title": "Expression of Thy-1 on human hematopoietic progenitor cells", "abstract": "Expression of Thy-1 on hematopoietic cells from human fetal liver (FL), cord blood (CB), and bone marrow (BM) was studied with a novel anti-Thy- 1 antibody, 5E10. Specificity of 5E10 for human Thy-1 was demonstrated by immunoprecipitation of a 25-35-kD molecule, and the sequence of a cDNA that was cloned by immunoselection of COS cells transfected with a cDNA library derived from a 5E10+ cell line. Two- and three-color immunofluorescence staining experiments revealed that the Thy-1 expression is restricted to, an average, 1-4% of FL, CB, and BM cells, and binding to these cell types is essentially restricted to a very small subset of lymphoid cells and approximately 25% of CD34+ cells. Thy-1+ CD34+ cells were further characterized as CD38lo/CD45RO+/CD45RA- /CD71lo/c-kit(lo) and rhodamine 123dull. When CD34+ cells were sorted on the basis of Thy-1 expression, the majority of clonogenic cells were recovered in the CD34+Thy-1- fraction, whereas the majority of cells capable of producing myeloid colonies after 5-8 wk of long-term culture (long-term culture initiating cells) were recovered in the Thy-1+CD34+ fraction. In addition to CD34+ cells, Thy-1 was found to be expressed on a variable, very small number (< 1%) of CD34- mononuclear cells in BM, CB, and peripheral blood that were further characterized as CD3+ CD4+ lymphocytes. The restricted expression of Thy-1 on primitive hematopoietic cells is in agreement with a previous report (Baum et al., 1992. Proc. Natl. Acad. Sci. USA. 89:2804) in which Thy-1 expression was used to enrich for primitive hematopoietic cells from fetal tissue. Compared with those previous studies, we found Thy-1 expression on a larger proportion of CD34+ cells (25% in our study vs. 5% in Baum et al.) and furthermore performed studies on Thy-1 expression on CD34+ cells from CB, FL, and BM in relation to markers that are known to be differentially expressed on hematopoietic cells. Taken together our results indicate that Thy-1-specific antibody 5E10 is an attractive tool for further studies on the biology and purification of human stem cells.", "corpus_id": 9679911, "score": 0 }, { "doc_id": "40029707", "title": "Controlling the Balance of Fibroblast Proliferation and Differentiation: Impact of Thy-1.", "abstract": "Fibroblasts provide matrix and regulatory mediators to the microenvironment and thereby contribute to maintenance of tissue homeostasis, wound healing, and tumor progression. In the present study, we addressed the functional relevance of Thy-1 for fibroblast functions in vitro and in vivo. Using fibroblasts from Thy-1(-/-) and wild-type mice, recombinant expression of Thy-1, and analysis of the interaction of fibroblasts with immobilized Thy-1, we showed that Thy-1 has a crucial role in the control of cell growth by suppressing proliferation and promoting apoptosis and differentiation of dermal fibroblasts. Function-blocking studies revealed that Thy-1 mediates the control of apoptosis and proliferation via modulation of β3 integrin function. Interestingly, Thy-1-mediated growth control appears to be a more general mechanism because it also regulates growth of tumor cells of different origin dependent on their β3 integrin expression. In summary, our findings point to an important role of Thy-1 in controlling the balance between proliferation and differentiation in dermal fibroblasts.", "corpus_id": 40029707, "score": 0 }, { "doc_id": "51943049", "title": "Thy-1 (CD90) promotes bone formation and protects against obesity", "abstract": "Thy-1 on mesenchymal stem cells promotes osteogenesis while inhibiting adipogenesis and obesity. Stem cells’ balancing act Mesenchymal stem cells (MSCs) differentiate into multiple cell types. Picke et al. investigated how MSC differentiation is regulated to maintain homeostasis between the bone and fat lineages. Genetic deletion of Thy-1, a protein expressed on multiple cell types including MSCs, prevented MSC differentiation into osteoblasts but promoted differentiation into adipocytes. Thy-1–deficient mice had increased body fat and decreased bone mass. High-fat diet induced obesity in wild-type mice and concurrent reduction in bone formation, which was associated with decreased Thy-1 expression on MSCs. Obese human subjects and subjects with osteoporosis showed reductions in serum soluble Thy-1. This study suggests that Thy-1 regulates the balance between bone and fat lineages, with possible implications for bone and metabolic disorders. Osteoporosis and obesity result from disturbed osteogenic and adipogenic differentiation and present emerging challenges for our aging society. Because of the regulatory role of Thy-1 in mesenchyme-derived fibroblasts, we investigated the impact of Thy-1 expression on mesenchymal stem cell (MSC) fate between osteogenic and adipogenic differentiation and consequences for bone formation and adipose tissue development in vivo. MSCs from Thy-1–deficient mice have decreased osteoblast differentiation and increased adipogenic differentiation compared to MSCs from wild-type mice. Consistently, Thy-1–deficient mice exhibited decreased bone volume and bone formation rate with elevated cortical porosity, resulting in lower bone strength. In parallel, body weight, subcutaneous/epigonadal fat mass, and bone fat volume were increased. Thy-1 deficiency was accompanied by reduced expression of specific Wnt ligands with simultaneous increase of the Wnt inhibitors sclerostin and dickkopf-1 and an altered responsiveness to Wnt. We demonstrated that disturbed bone remodeling in osteoporosis and dysregulated adipose tissue accumulation in patients with obesity were mirrored by reduced serum Thy-1 concentrations. Our findings provide new insights into the mutual regulation of bone formation and obesity and open new perspectives to monitor and to interfere with the dysregulated balance of adipogenesis and osteogenesis in obesity and osteoporosis.", "corpus_id": 51943049, "score": 1 }, { "doc_id": "8761190", "title": "Thy-1-positive cells in the subodontoblastic layer possess high potential to differentiate into hard tissue-forming cells", "abstract": "The cells of the subodontoblastic cell-rich layer in dental pulp are speculated to contain odontoblast progenitor cells because of their positional relationship with odontoblasts as well as their high alkaline phosphatase (ALP) activity. However, it has yet to be determined whether these cells have the ability to differentiate into odontoblastic cells. In the present study, we firstly found that the majority of cells in the subodontoblastic layer expressed Thy-1, a cell-surface marker of stem and progenitor cells. Then, we evaluated the capacity of Thy-1 high- and low-expressing (Thy-1high and Thy-1low) cells separated from rat dental pulp cells by use of a fluorescence-activated cell sorter to differentiate into hard tissue-forming cells in vitro and in vivo. Following stimulation with bone morphogenetic protein-2, Thy-1high cells in vitro showed accelerated induction of ALP activity and formation of alizarin red-positive mineralized matrix compared with Thy-1low cells. Furthermore, subcutaneous implantation of Thy-1high cells efficiently induced the formation of bone-like matrix. These results collectively suggest that Thy-1-positive dental pulp cells localized in the subodontoblastic layer had the ability to differentiate into hard tissue-forming cells, and thus these cells may serve as a source of odontoblastic cells.", "corpus_id": 8761190, "score": 1 }, { "doc_id": "16906394", "title": "CD90 (Thy-1)-positive selection enhances osteogenic capacity of human adipose-derived stromal cells.", "abstract": "BACKGROUND\nStem cell-based bone tissue engineering with adipose-derived stromal cells (ASCs) has shown great promise for revolutionizing treatment of large bone deficits. However, there is still a lack of consensus on cell surface markers identifying osteoprogenitors. Fluorescence-activated cell sorting has identified a subpopulation of CD105(low) cells with enhanced osteogenic differentiation. The purpose of the present study was to compare the ability of CD90 (Thy-1) to identify osteoprogenitors relative to CD(105).\n\n\nMETHODS\nUnsorted cells, CD90(+), CD90(-), CD105(high), and CD105(low) cells were treated with an osteogenic differentiation medium. For evaluation of in vitro osteogenesis, alkaline phosphatase (ALP) staining and alizarin red staining were performed at 7 days and 14 days, respectively. RNA was harvested after 7 and 14 days of differentiation, and osteogenic gene expression was examined by quantitative real-time polymerase chain reaction. For evaluation of in vivo osteogenesis, critical-sized (4-mm) calvarial defects in nude mice were treated with the hydroxyapatite-poly(lactic-co-glycolic acid) scaffold seeded with the above-mentioned subpopulations. Healing was followed using micro-CT scans for 8 weeks. Calvaria were harvested at 8 weeks postoperatively, and sections were stained with Movat's Pentachrome.\n\n\nRESULTS\nTranscriptional analysis revealed that the CD90(+) subpopulation was enriched for a more osteogenic subtype relative to the CD105(low) subpopulation. Staining at day 7 for ALP was greatest in the CD90(+) cells, followed by the CD105(low) cells. Staining at day 14 for alizarin red demonstrated the greatest amount of mineralized extracellular matrix in the CD90(+) cells, again followed by the CD105(low) cells. Quantification of in vivo healing at 2, 4, 6, and 8weeks postoperatively demonstrated increased bone formation in defects treated with CD90(+) ASCs relative to all other groups. On Movat's Pentachrome-stained sections, defects treated with CD90(+) cells showed the most robust bony regeneration. Defects treated with CD90(-) cells, CD105(high) cells, and CD105(low) cells demonstrated some bone formation, but to a lesser degree when compared with the CD90(+) group.\n\n\nCONCLUSIONS\nWhile CD105(low) cells have previously been shown to possess an enhanced osteogenic potential, we found that CD90(+) cells are more capable of forming bone both in vitro and in vivo. These data therefore suggest that CD90 may be a more effective marker than CD105 to isolate a highly osteogenic subpopulation for bone tissue engineering.", "corpus_id": 16906394, "score": 1 }, { "doc_id": "25454950", "title": "Thy1 (CD90) controls adipogenesis by regulating activity of the Src family kinase, Fyn", "abstract": "Worldwide obesity rates are at epidemic levels, and new insight into the regulation of obesity and adipogenesis are required. Thy1 (CD90), a cell surface protein with an enigmatic function, is expressed on subsets of fibroblasts and stem cells. We used a diet‐induced obesity model to show that Thy1‐null mice gain weight at a faster rate and gain 30% more weight than control C57BL/6 mice. During adipogenesis, Thy1 expression is lost in mouse 3T3‐L1 cells. Overexpression of Thy1 blocked adipocyte formation and reduced mRNA and protein expression of an adipocyte marker, fatty acid‐binding protein 4, by 5‐fold. Although preadipocyte fibroblasts expressed Thy1 mRNA and protein, adipocytes from mouse and human fat tissue had almost undetectable Thy1 levels. Thy1 decreases the activity of the adipogenic transcription factor PPARγ by more than 60% as shown by PPARγ‐dependent reporter assays. Using both genetic and pharmacologic approaches, we show Thy1 expression dampens PPARγ by inhibiting the activity of the Src‐family kinase, Fyn. Thus, these studies reveal Thy1 blocks adipogenesis and PPARγ by inhibiting Fyn and support the idea that Thy1 is a novel therapeutic target in obesity.—Woeller, C. F., O'Loughlin, C. W., Pollock, S. J., Thatcher, T. H., Feldon, S. E., Phipps, R. P., Thy1 (CD90) controls adipogenesis by regulating activity of the Src family kinase, Fyn. FASEB J. 29, 920–931 (2015). www.fasebj.org", "corpus_id": 25454950, "score": 1 }, { "doc_id": "25759295", "title": "Thy1 is a positive regulator of osteoblast differentiation and modulates bone homeostasis in obese mice", "abstract": "Thy1 (CD90), a glycosylated, glycophosphatidylinositol‐anchored membrane protein highly expressed by subsets of mesenchymal stem cells and fibroblasts, inhibits adipogenesis. The role of Thy1 on bone structure and function has been poorly studied and represents a major knowledge gap. Therefore, we analyzed the long bones of wild‐type (WT) and Thy1 knockout (KO) mice with micro‐computed tomography (micro‐CT) and histomorphometry to compare changes in bone architecture and overall bone structure. micro‐CT analysis of long bones revealed Thy1 KO and WT mice fed a high‐fat diet demonstrated bone structural parameters at 4 mo that differed significantly between WT and KO mice. A significant reduction in trabecular bone volume was noted in Thy1 KO mice. The most prominent differences were observed in trabecular bone volume ratio and trabecular bone connectivity density. Consistent with micro‐CT measurements, histomorphometric analysis also showed decreased bone volume in the obese Thy1 KO mice compared to obese WT mice. In vitro assays revealed that osteogenic conditions increased Thy1 expression during OB differentiation and absence of Thy1 attenuated osteoblastogenesis. Together, these findings support the concept that Thy1 serves as a major mechanistic link to regulate bone formation and negatively regulate adipogenesis.—Paine, A., Woeller, C. F., Zhang, H., Garcia‐Hernandez, M. L., Huertas, N., Xing, L., Phipps, R. P., Ritchlin, C. T. Thy1 is a positive regulator of osteoblast differentiation and modulates bone homeostasis in obese mice. FASEB J. 32, 3174–3183 (2018). www.fasebj.org", "corpus_id": 25759295, "score": 1 }, { "doc_id": "206213730", "title": "Osteoporosis prevention, screening, and treatment: a review.", "abstract": "Osteoporosis, defined as low bone mass leading to increased fracture risk, is a major health problem that affects approximately 10 million Americans. The aging U.S. population is predicted to contribute to as much as a 50% increase in prevalence by 2025. Although common, osteoporosis can be clinically silent, and without prevention and screening, the costs of osteoporotic fracture-related morbidity and mortality will burden the U.S. healthcare system. This is a particularly relevant concern in the context of diminishing health care resources. Dual-energy X-ray absorptiometry is the most widely used, validated technique for measuring bone mineral density (BMD) and diagnosing osteoporosis. Cost-effectiveness analyses support early detection and treatment of high-risk patients with antiresorptive medications such as bisphosphonates. Moreover, optimization of bone health throughout life can help prevent osteoporosis. Current guidelines recommend screening women by age 65 years, but because no guidelines for screening intervals exist, decisions are made on the basis of clinical judgment alone. Although the recent literature provides some guidance, this review further explores current recommendations in light of newer evidence to provide more clarity on prevention, screening, and management strategies for patients with osteoporosis in the primary care setting.", "corpus_id": 206213730, "score": 0 }, { "doc_id": "4424156", "title": "Inflammation and metabolic disorders", "abstract": "Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.", "corpus_id": 4424156, "score": 0 }, { "doc_id": "34602152", "title": "Obesity: Friend or foe for osteoporosis", "abstract": "Osteoporosis and obesity are worldwide health problems. Interestingly, both are associated with significant morbidity and mortality. Both the diseases have common linkage as bone marrow mesenchymal stromal cells are the common precursors for both osteoblasts and adipocytes. Aging may shift composition of bone marrow by increasing adipocytes, osteoclast activity, and decreasing osteoblast activity, resulting into osteoporosis. Adipocytes secret leptin, adiponectin, adipsin, as well as proinflammatory cytokines, that contributes in pathogenesis of osteoporosis. This new concept supports the hypothesis, that the positive correlation of weight and body mass index (BMI) with bone mineral density (BMD) is not confirmed by large population-based studies. Thus, the previous concept, that obesity is protective for osteoporosis may not stand same as bone marrow fat deposition (adipogenesis) seen in obesity, is detrimental for bone health.", "corpus_id": 34602152, "score": 0 }, { "doc_id": "14739947", "title": "BMI and BMD: The Potential Interplay between Obesity and Bone Fragility", "abstract": "Recent evidence demonstrating an increased fracture risk among obese individuals suggests that adipose tissue may negatively impact bone health, challenging the traditional paradigm of fat mass playing a protective role towards bone health. White adipose tissue, far from being a mere energy depot, is a dynamic tissue actively implicated in metabolic reactions, and in fact secretes several hormones called adipokines and inflammatory factors that may in turn promote bone resorption. More specifically, Visceral Adipose Tissue (VAT) may potentially prove detrimental. It is widely acknowledged that obesity is positively associated to many chronic disorders such as metabolic syndrome, dyslipidemia and type 2 diabetes, conditions that could themselves affect bone health. Although aging is largely known to decrease bone strength, little is yet known on the mechanisms via which obesity and its comorbidities may contribute to such damage. Given the exponentially growing obesity rate in recent years and the increased life expectancy of western countries it appears of utmost importance to timely focus on this topic.", "corpus_id": 14739947, "score": 0 }, { "doc_id": "4439277", "title": "Relation of body composition, fat mass, and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women.", "abstract": "BACKGROUND\nHigher fat mass may be an independent risk factor for osteoporosis and osteoporotic fractures.\n\n\nOBJECTIVE\nWe aimed to determine the independent contribution of fat mass to osteoporosis and to estimate the risk of osteoporotic fractures in relation to body weight, lean mass, and other confounders.\n\n\nDESIGN\nThis was a community-based, cross-sectional study of 7137 men, 4585 premenopausal women, and 2248 postmenopausal women aged 25-64 y. Total-body and hip bone mineral content (BMC) and bone mineral density (BMD) and body composition were measured by dual-energy X-ray absorptiometry. Serum lipids were measured. Sex- and menopause-specific multiple generalized linear models were applied.\n\n\nRESULTS\nAcross 5-kg strata of body weight, fat mass was significantly inversely associated with BMC in the whole body and total hip. When we compared the highest quartile with the lowest quartile of percentage fat mass in men, premenopausal women, and postmenopausal women, the adjusted odds ratios (95% CIs) of osteoporosis defined by hip BMD were 5.2 (2.1, 13.2), 5.0 (1.7, 15.1), and 6.9 (4.3, 11.2), respectively. Significant linear trends existed for higher risks of osteoporosis, osteopenia, and nonspine fractures with higher percentage fat mass. Significant negative relations were found between whole-body BMC and cholesterol, triacylglycerol, LDL, and the ratio of HDL to LDL in all groups.\n\n\nCONCLUSIONS\nRisks of osteoporosis, osteopenia, and nonspine fractures were significantly higher for subjects with higher percentage body fat independent of body weight, physical activity, and age. Thus, fat mass has a negative effect on bone mass in contrast with the positive effect of weight-bearing itself.", "corpus_id": 4439277, "score": 0 }, { "doc_id": "5072335", "title": "Obesity and fracture in men and women: An epidemiologic perspective", "abstract": "In Western societies, mean body weight has increased dramatically in older people, and a similar trend exists in Asia. Yet insufficient attention has been directed to the problem of osteoporotic fractures in the overweight and obese. Many, if not most, osteoporotic fractures occur in overweight or obese people, and obese men may be particularly susceptible. We discuss the potential implications of these findings, including the challenge of identifying individuals at highest risk, screening and treatment strategies, and future research directions. © 2012 American Society for Bone and Mineral Research", "corpus_id": 5072335, "score": 0 }, { "doc_id": "25559853", "title": "Inhibition of osteoblast differentiation by tumor necrosis factor-alpha.", "abstract": "Tumor necrosis factor-alpha (TNF-alpha) has a key role in skeletal disease in which it promotes reduced bone formation by mature osteoblasts and increased osteoclastic resorption. Here we show that TNF inhibits differentiation of osteoblasts from precursor cells. TNF-alpha treatment of fetal calvaria precursor cells, which spontaneously differentiate to the osteoblast phenotype over 21 days, inhibited differentiation as shown by reduced formation of multilayered, mineralizing nodules and decreased secretion of the skeletal-specific matrix protein osteocalcin. The effect of TNF was dose dependent with an IC50 of 0.6 ng/ml, indicating a high sensitivity of these precursor cells. Addition of TNF-alpha from days 2-21, 2-14, 7-14, and 7-10 inhibited nodule formation but addition of TNF after day 14 had no effect. Partial inhibition of differentiation was observed with addition of TNF on only days 7-8, suggesting that TNF could act during a critical period of phenotype selection. Growth of cells on collagen-coated plates did not prevent TNF inhibition of differentiation, suggesting that inhibition of collagen deposition into matrix by proliferating cells could not, alone, explain the effect of TNF. Northern analysis revealed that TNF inhibited the expression of insulin-like growth factor I (IGF-I). TNF had no effect on expression of the osteogenic bone morphogenic proteins (BMPs-2, -4, and -6), or skeletal LIM protein (LMP-1), as determined by semiquantitative RT-PCR. Addition of IGF-I or BMP-6 to fetal calvaria precursor cell cultures enhanced differentiation but could not overcome TNF inhibition, suggesting that TNF acted downstream of these proteins in the differentiation pathway. The clonal osteoblastic cell line, MC3T3-E1-14, which acquires the osteoblast phenotype spontaneously in postconfluent culture, was also studied. TNF inhibited differentiation of MC3T3-E1-14 cells as shown by failure of mineralized matrix formation in the presence of calcium and phosphate. TNF was not cytotoxic to either cell type as shown by continued attachment and metabolism in culture, trypan blue exclusion, and Alamar Blue cytotoxicity assay. These results demonstrate that TNF-alpha is a potent inhibitor of osteoblast differentiation and suggest that TNF acts distal to IGF-I, BMPs, and LMP-1 in the progression toward the osteoblast phenotype.", "corpus_id": 25559853, "score": 0 }, { "doc_id": "17981205", "title": "Classical and Paradoxical Effects of TNF-α on Bone Homeostasis", "abstract": "Tumor necrosis factor-α (TNF-α) plays an essential role in the regulation of bone homeostasis in several chronic immune and inflammatory joint diseases, where inhibition of TNF has led to significant clinical improvement. However, TNF-activated pathways and mechanisms involved in bone remodeling remain unclear. So far, TNF-α was known as an inhibitor of osteoblast differentiation and an activator of osteoclastogenesis. Recent contradictory findings indicated that TNF-α can also activate osteoblastogenesis. The paradoxical role of TNF-α in bone homeostasis seems to depend on the concentration and the differentiation state of the cell type used as well as on the exposure time. This review aims to summarize the recent contradictory findings on the regulation of bone homeostasis by TNF-α at the isolated cell, whole bone, and whole body levels. In addition, the involvement of TNF-α in the bone remodeling imbalance is observed in inflammatory joint diseases including rheumatoid arthritis and ankylosing spondylitis, which are associated with bone destruction and ectopic calcified matrix formation, respectively. Both diseases are associated with systemic/vertebral osteoporosis.", "corpus_id": 17981205, "score": 0 }, { "doc_id": "25689037", "title": "TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL.", "abstract": "TNFalpha is pivotal to the pathogenesis of inflammatory and possibly postmenopausal osteolysis. Much recent work has clarified mechanisms by which TNFalpha promotes osteoclastogenesis, but the means by which it activates osteoclasts to resorb bone remain uncertain. We found that very low concentrations of TNFalpha promoted actin ring formation, which correlates with functional activation in osteoclasts, both in osteoclasts formed in vitro and extracted from newborn rats. TNFalpha was equipotent with RANKL for this action. Activation by TNFalpha was unaffected by blockade of RANKL by OPG, its soluble decoy receptor, suggesting that this was due to a direct action on osteoclasts. Bone resorption was similarly directly and potently stimulated, in a RANKL-independent manner in osteoclasts, whether these were formed in vitro or in vivo. Interestingly, TNFalpha promoted actin ring formation at concentrations an order of magnitude below those required for osteoclastic differentiation. Moreover, TNFalpha strongly synergized with RANKL, such that miniscule concentrations of TNFalpha were sufficient to substantially augment osteoclast activation. The extreme sensitivity of osteoclasts to activation by TNFalpha suggests that the most sensitive osteolytic response of bone to TNFalpha is through activation of existing osteoclasts; and the strong synergy with RANKL provides a mechanism whereby increased osteolysis can be achieved without disturbance to the underlying pattern of osteoclastic localization.", "corpus_id": 25689037, "score": 0 }, { "doc_id": "12599490", "title": "Tumor Necrosis Factor-α (TNF) Stimulates RANKL-induced Osteoclastogenesis via Coupling of TNF Type 1 Receptor and RANK Signaling Pathways*", "abstract": "Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.", "corpus_id": 12599490, "score": 0 }, { "doc_id": "16471252", "title": "M-CSF mediates TNF-induced inflammatory osteolysis.", "abstract": "TNF-alpha is the dominant cytokine in inflammatory osteolysis. Using mice whose BM stromal cells and osteoclast precursors are chimeric for the presence of TNF receptors, we found that both cell types mediated the cytokine's osteoclastogenic properties. The greater contribution was made, however, by stromal cells that express the osteoclastogenic cytokine M-CSF. TNF-alpha stimulated M-CSF gene expression, in vivo, only in the presence of TNF-responsive stromal cells. M-CSF, in turn, induced the key osteoclastogenic cytokine receptor, receptor activator of NF-kappaB (RANK), in osteoclast precursors. In keeping with the proproliferative and survival properties of M-CSF, TNF-alpha enhanced osteoclast precursor number only in the presence of stromal cells bearing TNF receptors. To determine the clinical relevance of these observations, we induced inflammatory arthritis in wild-type mice and treated them with a mAb directed against the M-CSF receptor, c-Fms. Anti-c-Fms mAb selectively and completely arrested the profound pathological osteoclastogenesis attending this condition, the significance of which is reflected by similar blunting of the in vivo bone resorption marker tartrate-resistant acid phosphatase 5b (TRACP 5b). Confirming that inhibition of the M-CSF signaling pathway targets TNF-alpha, anti-c-Fms also completely arrested osteolysis in TNF-injected mice with nominal effect on macrophage number. M-CSF and its receptor, c-Fms, therefore present as candidate therapeutic targets in states of inflammatory bone erosion.", "corpus_id": 16471252, "score": 0 }, { "doc_id": "1129062", "title": "Functions of RANKL/RANK/OPG in bone modeling and remodeling.", "abstract": "The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-kappaB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.", "corpus_id": 1129062, "score": 0 }, { "doc_id": "16754991", "title": "High-Fat Diet Causes Bone Loss in Young Mice by Promoting Osteoclastogenesis Through Alteration of the Bone Marrow Environment", "abstract": "Obesity is a severe health problem in children, afflicting several organ systems including bone. However, the role of obesity on bone homeostasis and bone cell function in children has not been studied in detail. Here we used young mice fed a high-fat diet (HFD) to model childhood obesity and investigate the effect of HFD on the phenotype of cells within the bone marrow environment. Five-week-old male mice were fed a HFD for 3, 6, and 12 weeks. Decreased bone volume was detected after 3 weeks of HFD treatment. After 6 and 12 weeks, HFD-exposed mice had less bone mass and increased osteoclast numbers. Bone marrow cells, but not spleen cells, from HFD-fed mice had increased osteoclast precursor frequency, elevated osteoclast formation, and bone resorption activity, as well as increased expression of osteoclastogenic regulators including RANKL, TNF, and PPAR-gamma. Bone formation rate and osteoblast and adipocyte numbers were also increased in HFD-fed mice. Isolated bone marrow cells also had a corresponding elevation in the expression of positive regulators of osteoblast and adipocyte differentiation. Our findings indicate that in juvenile mice, HFD-induced bone loss is mainly due to increased osteoclast bone resorption by affecting the bone marrow microenvironment. Thus, targeting osteoclast formation may present a new therapeutic approach for bone complications in obese children.", "corpus_id": 16754991, "score": 0 }, { "doc_id": "3645614", "title": "Osteoporosis: A Review of Treatment Options.", "abstract": "Approximately 10 million men and women in the U.S. have osteoporosis,1 a metabolic bone disease characterized by low bone density and deterioration of bone architecture that increase the risk of fractures.2 Osteoporosis-related fractures can increase pain, disability, nursing home placement, total health care costs, and mortality.3 The diagnosis of osteoporosis is primarily determined by measuring bone mineral density (BMD) using noninvasive dual-energy x-ray absorptiometry. Osteoporosis medications include bisphosphonates, receptor activator of nuclear factor kappa-B ligand inhibitors, estrogen agonists/antagonists, parathyroid hormone analogues, and calcitonin.3-6 Emerging therapies utilizing novel mechanisms include a cathepsin K inhibitor and a monoclonal antibody against sclerostin.7,8 While professional organizations have compiled recommendations for the management of osteoporosis in various populations, a consensus has yet to develop as to which is the gold standard; therefore, economic evaluations have been increasingly important to help guide decision-makers. A review of cost-effectiveness literature on the efficacy of oral bisphosphonates has shown alendronate and risedronate to be most cost-effective in women with low BMD without previous fractures.9 Guidelines are inconsistent as to the place in therapy of denosumab (Prolia, Amgen). In economic analyses evaluating treatment of postmenopausal women, denosumab outperformed risedronate and ibandronate; its efficacy was comparable to generic alendronate, but it cost more.10 With regard to older men with osteoporosis, denosumab was also found to be cost-effective when compared with bisphosphonates and teriparatide (Forteo, Lilly).11.", "corpus_id": 3645614, "score": 0 }, { "doc_id": "8155090", "title": "Bone defect regeneration and cortical bone parameters of type 2 diabetic rats are improved by insulin therapy.", "abstract": "Zucker Diabetic Fatty (ZDF) rats represent an established model of type 2 diabetes mellitus (T2DM) and display several features of human diabetic bone disease, including impaired osteoblast function, decreased bone strength, and delayed bone healing. Here, we determined whether glycemic control by insulin treatment prevents skeletal complications associated with diabetes. Subcritical femur defects were created in diabetic (fa/fa) and non-diabetic (+/+) ZDF rats. Diabetic rats were treated once daily with long-lasting insulin glargin for 12weeks for glycemic control. Insulin treatment successfully maintained serum levels of glycated hemoglobin, while untreated diabetic rats showed a 2-fold increase. Trabecular and cortical bone mass measured by μCT were decreased in diabetic rats. Insulin treatment increased bone mass of the cortical, but not of the trabecular bone compartment. Dynamic histomorphometry revealed a lower bone formation rate at the trabecular and periosteal cortical bone in diabetic animals and decreased serum procollagen type 1 N-terminal propeptide (P1NP, -49%) levels. Insulin treatment partially improved these parameters. In T2DM, serum levels of tartrate-resistant acid phosphatase (TRAP, +32%) and C-terminal telopeptide (CTX, +49%) were increased. Insulin treatment further elevated TRAP levels, but did not affect CTX levels. While diabetes impaired bone defect healing, glycemic control with insulin fully reversed these negative effects. In conclusion, insulin treatment reversed the adverse effects of T2DM on bone defect regeneration in rats mainly by improving osteoblast function and bone formation. This article is part of a Special Issue entitled Bone and diabetes.", "corpus_id": 8155090, "score": 0 }, { "doc_id": "24436664", "title": "Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee", "abstract": "RACTITIONERS OF BONE HISTOMORPHOMETRY communicate P with each other in a variety of arcane languages, which in general are unintelligible to those outside the field. Many in the bone and mineral scientific community would like to keep abreast of the contributions of histology to their subject, but are dismayed by the semantic barriers they must overcome. The need for standardization has been recognized for many years,(') during which there has been much talk but no action. To meet the needs of ASBMR members, Dr. B.L. Riggs (President, 19851986) asked the senior author to convene a committee of the Society to develop a unified system of termnology, suitable for adoption by the Journal of Bone and Mineral Research as part of its Instructions to Authors. The committee includes members from Europe and Canada as well as the U.S., and represents most existing systems of nomenclature. A circular letter seeking suggestions and information on current usage was sent to several hundred persons, with names drawn from the Society membership roster and lists of attendees at various recent conferences, to which approximately 40 replies were obtained. These confirmed the magnitude of the semantic problem (for some measurements as many as nine different terms were in use) and suggested a range of solutions likely to be generally acceptable. In formulating the new system. the committee kept in mind certain agreed general principles. First, the primary reason for change was to help other scientists understand bone histomorphometry, not to help bone histomorphometrists undcntand each other. Second. names should be self-explanatory and dcscriptive, without implicit assumptions. Third. symbols should consist mainly of abbreviations that included the first letter of each word in the same order as in the name. without subscripts or superscripts. Fourth. each symbol component should have one and only one meaning, and so eliminate ambiguity. Fifth, primary measurements should be clearly distinguished from derived indices. Finally, the chosen system should be sufficiently flexible to apply to all surfaces and all types of bone, and to accommodate any new primary measurement or derived index. The recommended system shares common elements with. but also differs substantially from. all those in current usc. was tested in practice for several months before the final forniat was chosen, and is as complex and conceptually difficult ;I\\ the field with which it deals. For those within the field we hope that increased readership of their papers will be adequate conipensation for the inconvcnicncc of learning a new systcm. For those outside the field, mastering the new system will be hard work, but if we are able to secure its acceptance by all journals with an interest in bone and mineral metabolism, the effort will only have to be expended once rather than. as at present. rcpeated many times. To this end we give the reasons for our decisions in the areas of controversy and, as well as definitions, provide methods for calculation of derived indices and", "corpus_id": 24436664, "score": 0 }, { "doc_id": "21964331", "title": "High-fat diet decreases cancellous bone mass but has no effect on cortical bone mass in the tibia in mice.", "abstract": "Body mass has a positive effect on bone health. Whether mass derived from an obesity condition or excessive fat accumulation is beneficial to bone has not been established; neither have the mechanisms by which obesity affects bone metabolism. The aim of this study was to examine the effects of obesity on bone structure and osteoblastic expression of key markers involved in bone formation and resorption in a diet-induced obesity mouse model. Six-wk-old male C57BL/6 mice (n=21) were assigned to two groups and fed either a control (10 kcal% energy as fat) or high-fat diet (HFD, 45 kcal% energy as fat) for 14 weeks. Bone marrow stromal/osteoblastic cells (BMSC) were cultured. Osteoprogenitor activity [alkaline phosphatase (ALP) positive colonies] and mineralization (calcium nodule formation) were determined. Gene expression was measured using quantitative real-time PCR. Bone structure of proximal and midshaft tibia was evaluated by micro-computed tomography. Mice fed the HFD were 31% heavier (P<0.01) than those fed the control diet. There were more ALP positive colony forming units at d 14 and calcium nodules at d 28 of culture by BMSC from HFD mice than from control mice (P<0.01). Receptor activator of NF-kappaB ligand (RANKL) mRNA levels and the ratio of RANKL to osteoprotegerin expression in HFD animals was higher (P<0.01) than in control diet animals. Serum tartrate-resistant acid phosphatase levels were higher in HFD fed mice when compared to control diet fed mice (P<0.05). There were no significant differences in tibial fat-free weight, length, and cortical parameters of midshaft between the two groups. Compared with control mice, tibial trabecular bone volume was reduced, and trabecular separation was increased in HFD mice. Trabecular number was lower (P<0.05) and connectivity density tended to be less (P=0.07) in HFD mice than in control mice. In conclusion, our data indicate that obesity induced by a high-fat diet decreases cancellous bone mass but has no effect on cortical bone mass in the tibia in mice.", "corpus_id": 21964331, "score": 0 }, { "doc_id": "4588720", "title": "Diet‐induced obesity alters bone remodeling leading to decreased femoral trabecular bone mass in mice", "abstract": "Obesity‐derived body mass may be detrimental to bone health through not well‐defined mechanisms. In this study we determined changes in bone structure and serum cytokines related to bone metabolism in diet‐induced obese mice. Mice fed a high‐fat diet (HFD) had higher serum tartrate‐resistant acid phosphatase (TRAP) and leptin but lower osteocalcin concentrations than those fed the normal‐fat diet. The HFD increased multinucleated TRAP‐positive osteoclasts in bone marrow compared to the control diet. Despite being much heavier, mice fed the HFD had lower femoral bone volume, trabecular number, and connectivity density and higher trabecular separation than mice on the control diet. These findings suggest that obesity induced by a HFD increases bone resorption that may blunt any positive effects of increased body weight on bone.", "corpus_id": 4588720, "score": 0 }, { "doc_id": "19859079", "title": "Obesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice", "abstract": "Clinical evidence indicates that fat is inversely proportional to bone mass in elderly obese women. However, it remains unclear whether obesity accelerates bone loss. In this report we present evidence that increased visceral fat leads to inflammation and subsequent bone loss in 12-month-old C57BL/6J mice that were fed 10% corn oil (CO)-based diet and a control lab chow (LC) for 6 months. As expected from our previous work, CO-fed mice demonstrated increased visceral fat and enhanced total body fat mass compared to LC. The adipocyte-specific PPARγ and bone marrow (BM) adiposity were increased in CO-fed mice. In correlation with those modifications, inflammatory cytokines (IL-1β, IL-6, TNF-α) were significantly elevated in CO-fed mice compared to LC-fed mice. This inflammatory BM microenvironment resulted in increased superoxide production in osteoclasts and undifferentiated BM cells. In CO-fed mice, the increased number of osteoclasts per trabecular bone length and the increased osteoclastogenesis assessed ex-vivo suggest that CO diet induces bone resorption. Additionally, the up-regulation of osteoclast-specific cathepsin k and RANKL expression and down-regulation of osteoblast-specific RUNX2/Cbfa1 supports this bone resorption in CO-fed mice. Also, CO-fed mice exhibited lower trabecular bone volume in the distal femoral metaphysis and had reduced OPG expression. Collectively, our results suggest that increased bone resorption in mice fed a CO-enriched diet is possibly due to increased inflammation mediated by the accumulation of adipocytes in the BM microenvironment. This inflammation may consequently increase osteoclastogenesis, while reducing osteoblast development in CO-fed mice.", "corpus_id": 19859079, "score": 0 }, { "doc_id": "25683723", "title": "Increased bone resorption and impaired bone microarchitecture in short-term and extended high-fat diet-induced obesity.", "abstract": "Although obesity traditionally has been considered a condition of low risk for osteoporosis, this classic view has recently been questioned. The aim of this study was to assess bone microarchitecture and turnover in a mouse model of high-fat diet-induced obesity. Seven-week-old male C57BL/6J mice (n = 18) were randomized into 3 diet groups. One third (n = 6) received a low-fat diet for 24 weeks, one third was kept on an extended high-fat diet (eHF), and the remaining was switched from low-fat to high-fat chow 3 weeks before sacrifice (sHF). Serum levels of insulin, leptin, adiponectin, osteocalcin, and cross-linked telopeptides of type I collagen (CTX) were measured. In addition, bone microarchitecture was analyzed by micro-computed tomography; and lumbar spine bone density was assessed by dual-energy x-ray absorptiometry. The CTX, body weight, insulin, and leptin were significantly elevated in obese animals (sHF: +48%, +24%, +265%, and +102%; eHF: +43%, +52%, +761%, and +292%). The CTX, body weight, insulin, and leptin showed a negative correlation with bone density and bone volume. Interestingly, short-term high-fat chow caused similar bone loss as extended high-fat feeding. Bone volume was decreased by 12% in sHF and 19% in eHF. Bone mineral density was 25% (sHF) and 27% (eHF) lower when compared with control mice on low-fat diet. As assessed by the structure model index, bone microarchitecture changed from plate- to rod-like appearance upon high-fat challenge. Trabecular and cortical thickness remained unaffected. Short-term and extended high-fat diet-induced obesity caused significant bone loss in male C57BL/6J mice mainly because of resorptive changes in trabecular architecture.", "corpus_id": 25683723, "score": 0 }, { "doc_id": "51712200", "title": "Differential effects of high-fat diet and exercise training on bone and energy metabolism.", "abstract": "Bone microarchitecture and strength are impaired by obesity and physical inactivity, but the underlying molecular regulation of bone metabolism in response to these factors is not well understood. Therefore, we analyzed bone and energy metabolism in male mice fed a high-fat or standard chow diet for 12 weeks with or without free access to running wheels. High-fat diet (HFD) mimicked the human condition of obesity and insulin resistance, including symptoms such as elevated serum glucose and insulin levels and reduced insulin-stimulated glucose uptake into muscle and adipose tissue. Interestingly, HFD also decreased (-44%) glucose uptake into bone marrow. Bone mass was reduced (-45%) by HFD due to a diminished (-45%) bone remodeling rate. Bone matrix quality aspects, such as biomechanical stability, were additionally decreased. Concurrently, the bone marrow adiposity increased (+63%) in response to a HFD. Further, we detected elevated expression of the Wnt signaling inhibitor dickkopf-1 (Dkk-1, +42%) in mice fed a HFD, but this was not reflected in serum samples obtained from obese humans. In mice, exercise attenuated the adverse effects of HFD by reversing the glucose uptake into bone marrow, improving the bone mass and bone matrix quality while decreasing the bone marrow adiposity. This data shows that exercise prevents some, but not all of the negative effects of HFD on bone health and suggests that insulin signaling in bone marrow and Dkk-1 signaling may be involved in the pathogenesis of bone loss induced by HFD.", "corpus_id": 51712200, "score": 0 }, { "doc_id": "37633528", "title": "Relationship of obesity with osteoporosis.", "abstract": "CONTEXT\nThe relationship between obesity and osteoporosis has been widely studied, and epidemiological evidence shows that obesity is correlated with increased bone mass. Previous analyses, however, did not control for the mechanical loading effects of total body weight on bone mass and may have generated a confounded or even biased relationship between obesity and osteoporosis.\n\n\nOBJECTIVE\nThe objective of this study was to reevaluate the relationship between obesity and osteoporosis by accounting for the mechanical loading effects of total body weight on bone mass.\n\n\nMETHODS\nWe measured whole body fat mass, lean mass, percentage fat mass, body mass index, and bone mass in two large samples of different ethnicity: 1988 unrelated Chinese subjects and 4489 Caucasian subjects from 512 pedigrees. We first evaluated the Pearson correlations among different phenotypes. We then dissected the phenotypic correlations into genetic and environmental components with bone mass unadjusted or adjusted for body weight. This allowed us to compare the results with and without controlling for mechanical loading effects of body weight on bone mass.\n\n\nRESULTS\nIn both Chinese and Caucasian subjects, when the mechanical loading effect of body weight on bone mass was adjusted for, the phenotypic correlation (including its genetic and environmental components) between fat mass (or percentage fat mass) and bone mass was negative. Further multivariate analyses in subjects stratified by body weight confirmed the inverse relationship between bone mass and fat mass, after mechanical loading effects due to total body weight were controlled.\n\n\nCONCLUSIONS\nIncreasing fat mass may not have a beneficial effect on bone mass.", "corpus_id": 37633528, "score": 0 }, { "doc_id": "923952", "title": "Individuals with high bone mass have an increased prevalence of radiographic knee osteoarthritis", "abstract": "We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip. HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren–Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM–OA association, using Stata v12. 609 HBM knees in 311 cases (mean age 60.8 years, 74% female) and 1937 control knees in 991 controls (63.4 years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren–Lawrence grade ≥ 2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p < 0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%. Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation.", "corpus_id": 923952, "score": 0 }, { "doc_id": "9701019", "title": "The role of Dickkopf-1 in bone development, homeostasis, and disease.", "abstract": "Wnt/beta-catenin signaling is central to bone development and homeostasis in adulthood and its deregulation is associated with bone pathologies. Dickkopf-1 (DKK1), a soluble inhibitor of Wnt/beta-catenin signaling required for embryonic head development, regulates Wnt signaling by binding to the Wnt coreceptor lipoprotein-related protein-5 (LRP5)/Arrow. LRP5 mutations causing high bone mass syndromes disrupt DKK1-mediated regulation of LRP5. Forced overexpression of Dkk1 in osteoblasts causes osteopenia, disruption of the hematopoietic stem cell (HSC) niche, and defects in HSC function. Dkk1 also inhibits fracture repair. Studies suggest that DKK1 activation in osteoblasts is the underlying cause of glucocorticoid- and estrogen deficiency-mediated osteoporosis, and at least partially underlies the teratogenic effects of thalidomide on limb development. DKK1 induces proliferation of mesenchymal stem cells (MSC) in vitro and may play a role in the development of high-grade undifferentiated pleomorphic sarcomas derived from MSC and osteosarcomas. DKK1 has been implicated in causing erosive arthritis, the osteolytic phenotypes of multiple myeloma and metastatic breast cancer, and osteoblastic metastases of prostate cancer. Preclinical studies have shown that neutralizing DKK1/Dkk1 and/or enhancing Wnt/beta-catenin signaling may prove effective in treating bone pathologies. Here, we review the rapidly growing body of literature defining a pivotal role for DKK1 in bone health and disease.", "corpus_id": 9701019, "score": 0 }, { "doc_id": "40405012", "title": "Wnt signaling in bone formation and its therapeutic potential for bone diseases", "abstract": "The Wnt signaling pathway plays an important role not only in embryonic development but also in the maintenance and differentiation of the stem cells in adulthood. In particular, Wnt signaling has been shown as an important regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. Induction of the Wnt signaling pathway promotes bone formation while inactivation of the pathway leads to osteopenic states. Our current understanding of Wnt signaling in osteogenesis elucidates the molecular mechanisms of classic osteogenic pathologies. Activating and inactivating aberrations of the canonical Wnt signaling pathway in osteogenesis results in sclerosteosis and osteoporosis respectively. Recent studies have sought to target the Wnt signaling pathway to treat osteogenic disorders. Potential therapeutic approaches attempt to stimulate the Wnt signaling pathway by upregulating the intracellular mediators of the Wnt signaling cascade and inhibiting the endogenous antagonists of the pathway. Antibodies against endogenous antagonists, such as sclerostin and dickkopf-1, have demonstrated promising results in promoting bone formation and fracture healing. Lithium, an inhibitor of glycogen synthase kinase 3β, has also been reported to stimulate osteogenesis by stabilizing β catenin. Although manipulating the Wnt signaling pathway has abundant therapeutic potential, it requires cautious approach due to risks of tumorigenesis. The present review discusses the role of the Wnt signaling pathway in osteogenesis and examines its targeted therapeutic potential.", "corpus_id": 40405012, "score": 0 }, { "doc_id": "44143805", "title": "YAP promotes osteogenesis and suppresses adipogenic differentiation by regulating β-catenin signaling", "abstract": "YAP (yes-associated protein) is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP’s function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis. YAP is selectively expressed in osteoblast (OB)-lineage cells. Conditionally knocking out Yap in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss. Mechanistically, YAP interacts with β-catenin and is necessary for maintenance of nuclear β-catenin level and Wnt/β-catenin signaling. Expression of β-catenin in YAP-deficient BMSCs (bone marrow stromal cells) diminishes the osteogenesis deficit. These results thus identify YAP-β-catenin as an important pathway for osteogenesis during adult bone remodeling and uncover a mechanism underlying YAP regulation of bone homeostasis.Bone homeostasis: Genes play a balancing actA key regulatory gene both promotes bone formation and suppresses production of fat-storing bone marrow cells, thus supporting the key process of bone remodeling. As adults, our bones are in a constant state of flux, constantly being dissolved and rebuilt to maintain a steady state known as homeostasis. An international team led by Wen-Cheng Xiong, of Case Western Reserve University, Cleveland, Ohio, studied the role of the gene ‘yes-associated protein’ (YAP), a transcription factor (gene controlling the activity of other genes). Using mice, they found that YAP is essential for osteogenesis, and prevents adipocyte (fat-storing cell) formation. Without a functional YAP gene, mice experienced a loss of a softer type of bone known as trabecular bone. The molecular pathways controlled by YAP may thus be important for bone remodeling in vertebrates.", "corpus_id": 44143805, "score": 0 }, { "doc_id": "16524757", "title": "A reduction in CD90 (THY-1) expression results in increased differentiation of mesenchymal stromal cells", "abstract": "BackgroundMesenchymal stromal cells (MSCs) are multipotent progenitor cells used in several cell therapies. MSCs are characterized by the expression of CD73, CD90, and CD105 cell markers, and the absence of CD34, CD45, CD11a, CD19, and HLA-DR cell markers. CD90 is a glycoprotein present in the MSC membranes and also in adult cells and cancer stem cells. The role of CD90 in MSCs remains unknown. Here, we sought to analyse the role that CD90 plays in the characteristic properties of in vitro expanded human MSCs.MethodsWe investigated the function of CD90 with regard to morphology, proliferation rate, suppression of T-cell proliferation, and osteogenic/adipogenic differentiation of MSCs by reducing the expression of this marker using CD90-target small hairpin RNA lentiviral vectors.ResultsThe present study shows that a reduction in CD90 expression enhances the osteogenic and adipogenic differentiation of MSCs in vitro and, unexpectedly, causes a decrease in CD44 and CD166 expression.ConclusionOur study suggests that CD90 controls the differentiation of MSCs by acting as an obstacle in the pathway of differentiation commitment. This may be overcome in the presence of the correct differentiation stimuli, supporting the idea that CD90 level manipulation may lead to more efficient differentiation rates in vitro.", "corpus_id": 16524757, "score": 0 }, { "doc_id": "6420642", "title": "Long‐Term Changes in Bone Mineral and Biomechanical Properties of Vertebrae and Femur in Aging, Dietary Calcium Restricted, and/or Estrogen‐Deprived/‐Replaced Rats", "abstract": "To study the long‐term effect of aging, low calcium diet (LCD) and/or ovariectomy (OVX), and estrogen replacement therapy (+E) on rat bone quality of both trabecular and cortical bone, 150 female Wistar rats of 4.5 months were divided into baseline, sham‐operation (sham), sham + LCD, OVX, OVX + E, OVX + LCD, OVX + LCD + E, and were observed for 3, 6, and 9 months postsurgery. The bone mineral density (BMD) of the lumbar spine L1–L4, the femoral neck, the midshaft, and the distal metaphysis were determined using dual‐energy X‐ray absorptiometry (DXA) in vitro. Biomechanical tests of the L1 vertebral body and the left femur were performed. The right femoral midshaft and neck were processed undecalcified for determining cross‐sectional moments of inertia (CSMIs). BMD in all groups increased rapidly with aging in the femoral midshaft composed only of cortical bone at 3 months post‐OVX and stabilized or decreased thereafter, but decreased at all observation periods in the distal femoral metaphysis, consisting mostly of trabecular bone. L1 maximum compressive strength and stiffness increased as a function of aging in sham and sham + LCD but not in OVX and OVX + LCD. The order of loss in BMD at all sites and in L1 strength and stiffness was: OVX + LCD > OVX > LCD. LCD reduced while OVX improved the total femoral area, CSMIs in the femoral midshaft, and the torsional strength. Estrogen treatment preserved BMD and prevented OVX‐induced loss in L1 strength. The BMD and biomechanical properties were greater in OVX + E than in OVX + LCD + E. Loss in BMD and CSMIs was greater in the femoral neck than in the midshaft. The data suggest that rat cortical bone might not be matured until 7.5 months of age. It would be more appropriate to consider rats at peak bone mass as a model of mature rat and to perform OVX at that time. LCD and OVX have a great potential for weakening the bone quality of cortical bone and trabecular bone, respectively, and have an additive effect when combined. Estrogen prevents only OVX‐induced bone loss.", "corpus_id": 6420642, "score": 0 }, { "doc_id": "23782947", "title": "IL-6 is produced by osteoblasts and induces bone resorption.", "abstract": "To examine the possible involvement of IL-6 in bone metabolism, a mouse osteoblastic cell line (MC3T3-E1) and primary osteoblast-like cells from fetal mouse calvaria were cultured with several systemic and local bone-resorbing agents and their expression of IL-6 mRNA was determined. Local bone-resorbing agents such as IL-1 alpha, IL-1 beta, TNF-alpha, and LPS greatly induced IL-6 mRNA expression in both MC3T3-E1 cells and primary osteoblast-like cells. Parathyroid hormone slightly increased expression of IL-6 mRNA in primary osteoblast-like cells but not in MC3T3-E1 cells. Neither IL-6 nor 1 alpha,25-dihydroxyvitamin D3 increased expression of IL-6 mRNA in either of the osteoblast-like cells. In agreement with the expression of IL-6 mRNA, biologically active IL-6 was produced in response to the treatment with IL-1 alpha, TNF-alpha, and LPS in MC3T3-E1 cells. Adding IL-6 dose dependently stimulated the release of 45Ca from prelabeled fetal mouse calvaria. Simultaneously adding suboptimal concentrations of IL-6 and IL-1 alpha induced bone resorption cooperatively. In accord with the increase in the release of 45Ca by IL-6, there were three times as many osteoclasts in the bone sections of calvaria cultured with IL-6 for 5 days as in the controls. IL-6 slightly suppressed alkaline phosphatase activity and collagen synthesis in MC3T3-E1 cells. These results indicate that IL-6 is also produced by osteoblasts, preferentially in response to local bone-resorbing agents, and it induces bone resorption both alone and in concert with other bone-resorbing agents.", "corpus_id": 23782947, "score": 0 }, { "doc_id": "6175283", "title": "The p55 TNF receptor mediates TNF inhibition of osteoblast differentiation independently of apoptosis.", "abstract": "After menopause, increased tumor necrosis factor-alpha (TNF-alpha) stimulates bone resorption while inhibiting differentiation of new bone-forming osteoblasts (OB). TNF receptors, p55 and p75, signal similar intracellular pathways, but only p55 activates apoptosis. To evaluate the relationship between the TNF receptor mediating inhibition of OB differentiation and the role of apoptosis, marrow stromal cells (MSC) were cultured from mice deficient in either or both receptors. Cells grown in ascorbate and beta-glycerophosphate produce alkaline phosphatase and osteocalcin and mineralize matrix. Treatment of wild-type or p55(+/+)/p75(-/-) MSC with murine TNF (binds p55 and p75) or human TNF (binds only p55) inhibited OB differentiation. TNF did not inhibit OB differentiation in p55(-/-) MSC. Expression of p75 modestly attenuated sensitivity to TNF. To determine the role of apoptosis, changes in total DNA, cell viability, caspase 3, and percentage of annexin V-positive cells were measured in MSC and preosteoblastic MC3T3 cells. TNF treatment that reduced differentiation by 50% did not decrease cell viability or increase apoptosis, as determined by alamar blue reduction, trypan blue exclusion, and percentage of annexin V-positive cells. TNF increased caspase 3 activity 1.5-fold in MC3T3 and insignificantly in MSC cells compared with > 4-fold after 4 h actinomycin D. Treatment of MSC or MC3T3 cells with three caspase inhibitors failed to reverse the inhibitory effect of TNF on OB differentiation despite inhibition of caspase activity. These results suggest that the p55 receptor is essential, and p75 dispensable, for TNF inhibition of OB differentiation through a mechanism that does not require apoptosis.", "corpus_id": 6175283, "score": 0 }, { "doc_id": "24754641", "title": "Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1", "abstract": "Patients with chronic inflammatory disorders, such as rheumatoid arthritis, often have osteoporosis due to a combination of Tumor necrosis factor‐induced increased bone resorption and reduced bone formation. To test if TNF inhibits bone formation by affecting the commitment and differentiation of mesenchymal stem cells (MSCs) into osteoblasts, we examined the osteogenic potential of MSCs from TNF transgenic (TNF‐Tg) mice, a model of chronic inflammatory arthritis. MSC‐enriched cells were isolated from bone marrow stromal cells using negative selection with anti‐CD45 antibody coated magnetic beads. The expression profile of MSC surface markers the osteogenic, chondrogenic, and adipogenic properties of CD45− cells were confirmed by FACS and cell differentiation assays. MSC‐enriched CD45− cells from TNF‐Tg mice formed significantly decreased numbers of fibroblast and ALP+ colonies and had a decreased expression of osteoblast marker genes. As TNF may upregulate ubiquitin ligases, which negatively regulate osteoblast differentiation, we examined the expression levels of several ubiquitin ligases and found that Wwp1 expression was significantly increased in MSC‐enriched CD45− cells of TNF‐Tg mice. Wwp1 knockdown rescued impaired osteoblast differentiation of TNF‐Tg CD45− cells. Wwp1 promotes ubiquitination and degradation of JunB, an AP‐1 transcription factor that positively regulates osteoblast differentiation. Injection of TNF into wild‐type mice resulted in decreased osteoblast differentiation of MSCs and increased JunB ubiquitination, which was completely blocked in Wwp1−/− mice. Thus, Wwp1 targets JunB for ubiquitination and degradation in MSCs after chronic exposure to TNF, and inhibition of Wwp1 in MSCs could be a new mechanism to limit inflammation‐mediated osteoporosis by promoting their differentiation into osteoblasts. STEM CELLS 2011;29:1601–1610", "corpus_id": 24754641, "score": 0 }, { "doc_id": "45108583", "title": "Participation of TNF‐α in Inhibitory Effects of Adipocytes on Osteoblast Differentiation", "abstract": "Mesenchymal stem cells from bone marrow (BM‐MSCs) and adipose tissue (AT‐MSCs) are attractive tools for cell‐based therapies to repair bone tissue. In this study, we investigated the osteogenic and adipogenic potential of BM‐MSCs and AT‐MSCs as well as the effect of crosstalk between osteoblasts and adipocytes on cell phenotype expression. Rat BM‐MSCs and AT‐MSCs were cultured either in growth, osteogenic, or adipogenic medium to evaluate osteoblast and adipocyte differentiation. Additionally, osteoblasts and adipocytes were indirectly co‐cultured to investigate the effect of adipocytes on osteoblast differentiation and vice versa. BM‐MSCs and AT‐MSCs exhibit osteogenic and adipogenic potential under non‐differentiation‐inducing conditions. When exposed to osteogenic medium, BM‐MSCs exhibited higher expression of bone markers compared with AT‐MSCs. Conversely, under adipogenic conditions, AT‐MSCs displayed higher expression of adipose tissue markers compared with BM‐MSCs. The presence of adipocytes as indirect co‐culture repressed the expression of the osteoblast phenotype, whereas osteoblasts did not exert remarkable effect on adipocytes. The inhibitory effect of adipocytes on osteoblasts was due to the release of tumor necrosis factor alpha (TNF‐α) in culture medium by adipocytes. Indeed, the addition of exogenous TNF‐α in culture medium repressed the differentiation of BM‐MSCs into osteoblasts mimicking the indirect co‐culture effect. In conclusion, our study showed that BM‐MSCs are more osteogenic while AT‐MSCs are more adipogenic. Additionally, we demonstrated the key role of TNF‐α secreted by adipocytes on the inhibition of osteoblast differentiation. Thus, we postulate that the higher osteogenic potential of BM‐MSCs makes them the first choice for inducing bone repair in cell‐based therapies. J. Cell. Physiol. 230: 204–214, 2016. © 2015 Wiley Periodicals, Inc.", "corpus_id": 45108583, "score": 0 }, { "doc_id": "10812215", "title": "Role of autophagy in tumor necrosis factor-α-induced apoptosis of osteoblast cells", "abstract": "The aim of this study is to investigate the role of tumor necrosis factor-α (TNF-α) in apoptosis and autophagy of mouse osteoblast MC3T3-E1 cells, as well as the crosstalk between autophagy and apoptosis. Mouse osteoblast MC3T3-E1 cells were cultured in vitro and treated with 5-fluorouracil (5-FU), rapamycin, 3-methyl adenine (3-MA) and TNF-α either alone or in combination, respectively. MTT assays were used to monitor the cell viability upon different treatments. Annexin-V-FITC/propidium iodide (PI) staining was used to detect the apoptotic rate of osteoblasts. Autophagic structure and apoptotic bodies were visualized by transmission electron microscopy (TEM). Western blot analysis was performed to detect the autophagic marker LC3-II/I, p62 and apoptotic marker cleaved caspase-3. TNF-α inhibits MC3T3-E1 cell viability in a dose-dependent and time-dependent manner. Annexin-V-FITC/PI staining, coupled with TEM, showed that TNF-α induced cell apoptosis and autophagy in MC3T3-E1 cells. The autophagy inducer rapamycin ameliorated TNF-α-induced apoptosis. In contrast, 3-MA, which is an autophagy inhibitor, caused an exaggerated induction of TNF-α-induced apoptosis. TNF-α upregulated autophagy marker LC3-II/I, but downregulated p62 in osteoblasts. Combined treatment of rapamycin and TNF-α further exaggerated this effect, whereas co-treatment of 3-MA and TNF-α decreased LC3-II/I, but increased p62 compared with TNF-α alone. In addition, TNF-α caused an induction of apoptotic marker cleaved caspase-3. TNF-α-mediated induction of cleaved caspase-3 was downregulated by rapamycin, but upregulated by 3-MA, respectively. TNF-α induced both autophagy and apoptosis in osteoblasts, and upregulated autophagy protects the cell by reducing TNF-α-induced apoptosis.", "corpus_id": 10812215, "score": 0 }, { "doc_id": "28557516", "title": "Cytokines, Osteoprotegerin, and RANKL In Vitro and Histomorphometric Indices of Bone Turnover in Patients With Different Bone Diseases", "abstract": "Cytokines are supposed to play an essential role in the regulation of the bone metabolic unit. However, information on cytokine production of primary human osteoblasts from patients with metabolic bone disease is scarce, and few attempts have been made to correlate such data to histomorphometric parameters of individual patients. We investigated 11 patients with metabolic bone disease referred to our outpatient department for bone biopsy and analyzed interleukin (IL)‐1, IL‐6, and TNF‐α protein release and gene expression in primary osteoblast cultures. Compared with four controls, five patients showed normal cytokine protein release, whereas six patients showed much higher levels of interleukin‐6 (26‐fold) and TNF‐α (84‐fold). All three cytokines were strongly correlated concerning gene expression and/or protein levels (r = 0.72–0.96). Histomorphometric analysis of the bone samples showed that eroded surface (ES/BS) as a parameter of bone resorption was significantly associated with TNF‐α. In addition, RANKL gene expression was positively associated with ES/BS and osteoclast surface (Oc.S/BS). Finally, the formation parameters osteoid volume and osteoid surface were negatively associated with TNF‐α. In conclusion, in an in vitro‐ex vivo model of bone cells obtained from a group of 11 patients with different forms of metabolic bone disease, cytokine release in conditioned medium was significantly associated with bone resorption and bone formation, as quantified by histomorphometry. TNF‐α seemed to be the more important cytokine; its effect on bone resorption could be mediated by RANKL.", "corpus_id": 28557516, "score": 0 }, { "doc_id": "10144209", "title": "Immunological Reaction in TNF-α-Mediated Osteoclast Formation and Bone Resorption In Vitro and In Vivo", "abstract": "Tumor necrosis factor-α (TNF-α) is a cytokine produced by monocytes, macrophages, and T cells and is induced by pathogens, endotoxins, or related substances. TNF-α may play a key role in bone metabolism and is important in inflammatory bone diseases such as rheumatoid arthritis. Cells directly involved in osteoclastogenesis include macrophages, which are osteoclast precursor cells, osteoblasts, or stromal cells. These cells express receptor activator of NF-κB ligand (RANKL) to induce osteoclastogenesis, and T cells, which secrete RANKL, promote osteoclastogenesis during inflammation. Elucidating the detailed effects of TNF-α on bone metabolism may enable the identification of therapeutic targets that can efficiently suppress bone destruction in inflammatory bone diseases. TNF-α is considered to act by directly increasing RANK expression in macrophages and by increasing RANKL in stromal cells. Inflammatory cytokines such as interleukin- (IL-) 12, IL-18, and interferon-γ (IFN-γ) strongly inhibit osteoclast formation. IL-12, IL-18, and IFN-γ induce apoptosis in bone marrow cells treated with TNF-α   in vitro, and osteoclastogenesis is inhibited by the interactions of TNF-α-induced Fas and Fas ligand induced by IL-12, IL-18, and IFN-γ. This review describes and discusses the role of cells concerned with osteoclast formation and immunological reactions in TNF-α-mediated osteoclastogenesis in vitro and in vivo.", "corpus_id": 10144209, "score": 0 }, { "doc_id": "206025659", "title": "Tumor Necrosis Factor Alpha Promotes Osteoclast Formation Via PI3K/Akt Pathway‐Mediated Blimp1 Expression Upregulation", "abstract": "Tumor necrosis factor alpha (TNF‐α)‐induced osteoclastogenesis have profound effects in states of inflammatory osteolysis such as rheumatoid arthritis, periprosthetic implant loosening, and periodontitis. However, the exact mechanisms by which TNF‐α promotes RANKL‐induced osteoclast formation remains poorly understood. B lymphocyte‐induced maturation protein‐1 (Blimp1) is a transcriptional repressor that plays crucial roles in the differentiation and/or function of various kinds of cells including osteoclasts. A novel mechanism was identified where TNF‐α‐mediated Blimp1 expression, which contributed to RANKL‐induced osteoclastogenesis. It is shown that TNF‐α could promote the level of Blimp1 expression during osteoclast differentiation. Silencing of Blimp1 in osteoclast precursor cells obviously attenuated the stimulatory effect of TNF‐α on osteoclastogenesis. Mechanistically, TNF‐α‐induced Blimp1 expression was markedly rescued by blocking the PI3K/Akt signaling pathway, which suggested that PI3K/Akt signaling was involved in the regulation of TNF‐α‐stimulated Blimp1 expression. Taken together, the results established a molecular mechanism of TNF‐α‐induced osteoclasts differentiation, and provided insights into the potential contribution of Blimp1 in the regulation of osteoclastogenesis by TNF‐α. J. Cell. Biochem. 118: 1308–1315, 2017. © 2016 Wiley Periodicals, Inc.", "corpus_id": 206025659, "score": 0 }, { "doc_id": "13336687", "title": "Tumor Necrosis Factor α Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl–Rank Interaction", "abstract": "Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of osteoclast progenitors of the monocyte/macrophage lineage into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase–positive osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor α (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases.", "corpus_id": 13336687, "score": 0 }, { "doc_id": "31229360", "title": "TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand.", "abstract": "While TNF-alpha is pivotal to the pathogenesis of inflammatory osteolysis, the means by which it recruits osteoclasts and promotes bone destruction are unknown. We find that a pure population of murine osteoclast precursors fails to undergo osteoclastogenesis when treated with TNF-alpha alone. In contrast, the cytokine dramatically stimulates differentiation in macrophages primed by less than one percent of the amount of RANKL (ligand for the receptor activator of NF-kappaB) required to induce osteoclast formation. Mirroring their synergistic effects on osteoclast differentiation, TNF-alpha and RANKL markedly potentiate NF-kappaB and stress-activated protein kinase/c-Jun NH(2)-terminal kinase activity, two signaling pathways essential for osteoclastogenesis. In vivo administration of TNF-alpha prompts robust osteoclast formation in chimeric animals in which ss-galactosidase positive, TNF-responsive macrophages develop within a TNF-nonresponsive stromal environment. Thus, while TNF-alpha alone does not induce osteoclastogenesis, it does so both in vitro and in vivo by directly targeting macrophages within a stromal environment that expresses permissive levels of RANKL. Given the minuscule amount of RANKL sufficient to synergize with TNF-alpha to promote osteoclastogenesis, TNF-alpha appears to be a more convenient target in arresting inflammatory osteolysis.", "corpus_id": 31229360, "score": 0 }, { "doc_id": "9027428", "title": "Tumor Necrosis Factor-α Induces Differentiation of and Bone Resorption by Osteoclasts*", "abstract": "Osteoclast progenitors differentiate into mature osteoclasts in the presence of receptor activator of NF-κB (RANK) ligand on stromal or osteoblastic cells and monocyte macrophage colony-stimulating factor (M-CSF). The soluble RANK ligand induces the same differentiation in vitro without stromal cells. Tumor necrosis factor-α (TNF-α), a potent cytokine involved in the regulation of osteoclast activity, promotes bone resorption via a primary effect on osteoblasts; however, it remains unclear whether TNF-α can also directly induce the differentiation of osteoclast progenitors into mature osteoclasts. This study revealed that TNF-α directly induced the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs), which produced resorption pits on bone in vitro in the presence of M-CSF. The bone resorption activity of TNF-α-induced MNCs was lower than that of soluble RANK ligand-induced MNCs; however, interleukin-1β stimulated this activity of TNF-α-induced MNCs without an increase in the number of MNCs. In this case, interleukin-1β did not induce TRAP-positive MNC formation. The osteoclast progenitors expressed TNF receptors, p55 and p75; and the induction of TRAP-positive MNCs by TNF-α was inhibited completely by an anti-p55 antibody and partially by an anti-p75 antibody. Our findings presented here are the first to indicate that TNF-α is a crucial differentiation factor for osteoclasts. Our results suggest that TNF-α and M-CSF play an important role in local osteolysis in chronic inflammatory diseases.", "corpus_id": 9027428, "score": 0 }, { "doc_id": "16339983", "title": "Signaling Pathways in Osteoclast Differentiation", "abstract": "Osteoclasts are multinucleated cells of hematopoietic origin that are responsible for the degradation of old bone matrix. Osteoclast differentiation and activity are controlled by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and the receptor activator of nuclear factor-κB ligand (RANKL). M-CSF and RANKL bind to their respective receptors c-Fms and RANK to stimulate osteoclast differentiation through regulation of delicate signaling systems. Here, we summarize the critical or essential signaling pathways for osteoclast differentiation including M-CSF-c-Fms signaling, RANKL-RANK signaling, and costimulatory signaling for RANK.", "corpus_id": 16339983, "score": 0 }, { "doc_id": "8609051", "title": "Bone Marrow Adipose Tissue: To Be or Not To Be a Typical Adipose Tissue?", "abstract": "Bone marrow adipose tissue (BMAT) emerges as a distinct fat depot whose importance has been proved in the bone–fat interaction. Indeed, it is well recognized that adipokines and free fatty acids released by adipocytes can directly or indirectly interfere with cells of bone remodeling or hematopoiesis. In pathological states, such as osteoporosis, each of adipose tissues – subcutaneous white adipose tissue (WAT), visceral WAT, brown adipose tissue (BAT), and BMAT – is differently associated with bone mineral density (BMD) variations. However, compared with the other fat depots, BMAT displays striking features that makes it a substantial actor in bone alterations. BMAT quantity is well associated with BMD loss in aging, menopause, and other metabolic conditions, such as anorexia nervosa. Consequently, BMAT is sensed as a relevant marker of a compromised bone integrity. However, analyses of BMAT development in metabolic diseases (obesity and diabetes) are scarce and should be, thus, more systematically addressed to better apprehend the bone modifications in that pathophysiological contexts. Moreover, bone marrow (BM) adipogenesis occurs throughout the whole life at different rates. Following an ordered spatiotemporal expansion, BMAT has turned to be a heterogeneous fat depot whose adipocytes diverge in their phenotype and their response to stimuli according to their location in bone and BM. In vitro, in vivo, and clinical studies point to a detrimental role of BM adipocytes (BMAs) throughout the release of paracrine factors that modulate osteoblast and/or osteoclast formation and function. However, the anatomical dissemination and the difficulties to access BMAs still hamper our understanding of the relative contribution of BMAT secretions compared with those of peripheral adipose tissues. A further characterization of the phenotype and the functional regulation of BMAs are ever more required. Based on currently available data and comparison with other fat tissues, this review addresses the originality of the BMAT with regard to its development, anatomy, metabolic properties, and response to physiological cues.", "corpus_id": 8609051, "score": 0 } ]

{ "doc_id": "2018686", "title": "Mini Review: Anticholinergic Activity as a Behavioral Pathology of Lewy Body Disease and Proposal of the Concept of “Anticholinergic Spectrum Disorders”", "abstract": "Given the relationship between anticholinergic activity (AA) and Alzheimer's disease (AD), we rereview our hypothesis of the endogenous appearance of AA in AD. Briefly, because acetylcholine (ACh) regulates not only cognitive function but also the inflammatory system, when ACh downregulation reaches a critical level, inflammation increases, triggering the appearance of cytokines with AA. Moreover, based on a case report of a patient with mild AD and slightly deteriorated ACh, we also speculate that AA can appear endogenously in Lewy body disease due to the dual action of the downregulation of ACh and hyperactivity of the hypothalamic-pituitary-adrenal axis. Based on these hypotheses, we consider AA to be a behavioral pathology of Lewy body disease. We also propose the concept of “anticholinergic spectrum disorders,” which encompass a variety of conditions, including AD, Lewy body disease, and delirium. Finally, we suggest the prescription of cholinesterase inhibitors to patients in this spectrum of disorders to abolish AA by upregulating ACh.", "corpus_id": 2018686 }

[ { "doc_id": "20751708", "title": "Serum levels of anticholinergic drugs in treatment of acute extrapyramidal side effects.", "abstract": "A simple, sensitive, and specific radioreceptor assay has been developed for the measurement of anticholinergic drugs in human serum. The assay is based on the competitive inhibition by free anticholinergic drugs in a 0.2-mL sample of serum with the specific binding of the potent muscarinic antagonists, tritiated quinuclidinyl benzilate, to solubilized brain muscarinic receptors. Anticholinergic activity could be detected regardless of drug structure and was quantified against atropine standards. Although the serum levels of anticholinergic drugs varied considerably in 35 patients receiving both neuroleptic and anticholinergic drugs, there was a highly significant inverse correlation between the presence of acute extrapyramidal side effects due to neuroleptics and the serum levels of anticholinergics.", "corpus_id": 20751708, "score": 0 }, { "doc_id": "25502455", "title": "Anticholinergic sensitivity in patients with dementia of the Alzheimer type and age-matched controls. A dose-response study.", "abstract": "We compared the cognitive and behavioral responses to three intravenous doses of scopolamine (0.1, 0.25, and 0.5 mg) and placebo of ten patients with dementia of the Alzheimer type (DAT) and ten age- and sex-matched elderly control subjects. The patients with DAT showed significant behavioral and cognitive but not physiologic changes at a lower scopolamine dose (0.25 mg) than did the normal elderly controls. Cognitive tests of new learning and semantic knowledge revealed significant impairments at the 0.25-mg scopolamine dose in the patients with DAT, while the responses of the control population were essentially unchanged. Behaviorally, mild euphoria, motor incoordination, and hostility occurred in the patients with DAT but not the controls at the 0.25-mg dose. These differences were unrelated to peripheral physiologic changes produced by the different scopolamine doses. These results indicate that central nervous system functions such as cognition and certain elements of behavior are more sensitive to temporary cholinergic blockade in patients with DAT than in normal age-matched controls. We review implications concerning the status of central cholinergic function in patients with DAT in light of neuropathologically demonstrated cholinergic system lesions in DAT.", "corpus_id": 25502455, "score": 0 }, { "doc_id": "13969044", "title": "Cholinesterase inhibitors: A new class of psychotropic compounds.", "abstract": "OBJECTIVE\nThis article reviews evidence indicating that acetylcholinesterase inhibitors have psychotropic properties.\n\n\nMETHOD\nThe author reviewed the English-language literature pertinent to the response of neuropsychiatric symptoms in Alzheimer's disease and related conditions to cholinergic agents.\n\n\nRESULTS\nThe cholinergic system originates in the basal forebrain and projects diffusely to the cerebral cortex; the limbic and paralimbic regions receive the most abundant cholinergic projections. The basal forebrain nuclei are positioned at the interface of the limbic system and cerebral cortex, where they play a role in mediating emotional responses. The basal forebrain nuclei are atrophic in Alzheimer's disease, leading to a widespread cholinergic deficit. The cholinergic disturbance may contribute to neuropsychiatric manifestations of the disease. The treatment of patients with Alzheimer's disease with acetylcholinesterase inhibitors reduces neuropsychiatric symptoms, particularly apathy and visual hallucinations. In some studies, a variety of other neuropsychiatric symptoms have been reported to respond to treatment with acetylcholinesterase inhibitors. Response profiles vary among acetylcholinesterase inhibitors.\n\n\nCONCLUSIONS\nAcetylcholinesterase inhibitors have psychotropic effects and may play an important role in controlling neuropsychiatric and behavioral disturbances in patients with Alzheimer's disease. These agents also may contribute to the management of other disorders with cholinergic system abnormalities and neuropsychiatric symptoms. The beneficial response is most likely mediated through limbic cholinergic structures.", "corpus_id": 13969044, "score": 0 }, { "doc_id": "29791929", "title": "The Cholinergic Deficiency Syndrome and Its Therapeutic Implications", "abstract": "Cholinesterase inhibitors are licensed for treatment of dementia in Alzheimer’s disease. However, the effects of these drugs on the cognitive symptoms of dementia are very small. We suggest that symptoms like impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome (CDS), that may be a much better target for such treatment. Changes in the quantitative electroencephalogram, muscarinic subtype radioimaging and serum anticholinergic activity may potentially help to diagnose the CDS. CDS is suggested to occur in various neurodegenerative diseases like Alzheimer’s disease, Lewy body dementia and Parkinson’s disease and to respond well to cholinesterase inhibitor therapy.", "corpus_id": 29791929, "score": 0 }, { "doc_id": "43354567", "title": "Serum anticholinergic activity changes with acute illness in elderly medical patients.", "abstract": "BACKGROUND\nElevated serum anticholinergic activity levels have been associated with delirium in cross-sectional studies of ill older persons. This study used serial measures of serum anticholinergic activity levels to determine whether these levels change following illness resolution, and if such changes are specific to those with delirium.\n\n\nMETHODS\nTwenty-two nursing home residents with a febrile illness had serum specimens drawn and were evaluated for the presence of delirium during the acute illness and at 1-month follow-up. Delirium was diagnosed using the Confusion Assessment Method. Serum anticholinergic activity was determined using a previously described radionuclide competitive-binding assay.\n\n\nRESULTS\nDelirium was present during illness in 8 of 22 subjects (36%), and had resolved by 1-month follow-up in all but one resident. Serum anticholinergic activity levels were significantly higher during illness than at 1-month follow-up in both the delirious (0.69 +/- 0.85 nM atropine equivalents/200 microL sample versus 0.10 +/- 0.16; p = .06) and non-delirious (0.65 +/- 0.51 nM atropine equivalents/200 microL sample versus 0.08 +/- 0.12; p < .001) groups. Medication changes did not seem to be related to changes in serum anticholinergic activity.\n\n\nCONCLUSIONS\nIn older nursing home residents with a fever, serum anticholinergic activity appears to be elevated during illness, and declines following recovery from illness. This effect does not seem to be specific to those residents with delirium, nor does it seem related to medication changes.", "corpus_id": 43354567, "score": 0 }, { "doc_id": "143151442", "title": "Increased Cortisol Levels and Anticholinergic Activity in Cognitively Unimpaired Patients", "abstract": "Increased patients' serum anticholinergic activity (SAA) is described as a marker of cognitive dysfunction and can be influenced by different exogenous and endogenous factors. The role of cortisol in relation to SAA and cognition in perioperative conditions has not been investigated so far. In 30 men scheduled for urological surgery, the authors determined SAA and cortisol levels in blood and CSF and conducted neuropsychological testing in two subgroups with comparable pre- and intraoperative characteristics, one group with low SAA (mean=2.4 [SD=0.9], n=23) and the other with high SAA (mean=5.1 [SD=2.4], n=7) values. Increased SAA was associated with two times the number of anticholinergic medications but not with patients' age, medical history or impaired cognition. A significant linear correlation was detected between anticholinergic activities and cortisol levels. Thus, endogenous factors such as patients' stress levels should be taken into account for interpretation of the role of SAA.", "corpus_id": 143151442, "score": 1 }, { "doc_id": "26405823", "title": "[Proposal of endogenous anticholinergic hypothesis in Alzheimer disease].", "abstract": "We previously speculated that anticholinergic activity (AA) endogenously appeared in Alzheimer's disease (AD) and accelerated AD pathology. In this article we introduce manuscripts supporting the endogenous appearance of AA in AD and the acceleration of AD pathology. We speculate that acethylcholine (ACh) not only is related to cognitive functions but also regulates the inflammatory system. Therefore in AD, in which the ACh system is down-regulated, the hyperactivity of the inflammatory system may be caused and among cyctokines, substances having anticholinergic properties may appear. We also refer to a case in which serum anticholinergic activity (SAA) disappeared with the prescription of memantine (an antidementia agent that has the property of the N-methyl-D-aspartate (NMDA) receptor blocker) and speculate that because the hyperactivity of the inflammatory system occurs by way of the hyperactivity of NMDA receptor, memantine could abolish the AA.", "corpus_id": 26405823, "score": 1 }, { "doc_id": "1890200", "title": "Serum Anticholinergic Activity: A Possible Peripheral Marker of the Anticholinergic Burden in the Central Nervous System in Alzheimer's Disease", "abstract": "We review the utility of serum anticholinergic activity (SAA) as a peripheral marker of anticholinergic activity (AA) in the central nervous system (CAA). We hypothesize that the compensatory mechanisms of the cholinergic system do not contribute to SAA if their system is intact and that if central cholinergic system deteriorates alone in conditions such as Alzheimer's disease or Lewy body dementia, CAA and SAA are caused by way of hyperactivity of inflammatory system and SAA is a marker of the anticholinergic burden in CNS. Taking into account the diurnal variations in the plasma levels of corticosteroids, which are thought to affect SAA, it should be measured at noon or just afterward.", "corpus_id": 1890200, "score": 1 }, { "doc_id": "15242676", "title": "A Review of the Role of Anticholinergic Activity in Lewy Body Disease and Delirium", "abstract": "We have previously proposed a hypothesis in which we argue that anticholinergic activity (AA) appears endogenously in Alzheimer's disease (AD). Acetylcholine (ACh) controls both cognitive function and inflammation. Consequently, when the downregulation of ACh reaches critical levels, the inflammatory system is upregulated and proinflammatory cytokines with AA appear. However, factors other than downregulation of ACh can produce AA; even if ACh downregulation does not reach critical levels, AA can still appear if one of these other AA-producing factors is added. These factors can include neurocognitive disorders other than AD, such as delirium and Lewy body disease (LBD). In delirium, ACh downregulation fails to reach critical levels, but AA appears due to the use of medicines, physical illnesses or mental stress (termed ‘AA inserts'). In LBD, we speculate that AA appears endogenously, even in the absence of severe cognitive dysfunction, for 2 reasons. One reason is that patterns of ACh deterioration are different in LBD from those in AD, with synergistic actions between amyloid and α-synuclein thought to cause additional or severe symptoms that accelerate the disease course. The second reason is that AA occurs through disinhibition by reduced cortisol levels that result from severe autonomic parasympathetic dysfunction in LBD.", "corpus_id": 15242676, "score": 1 }, { "doc_id": "31282188", "title": "Influence of Anticholinergic Activity in Serum on Clinical Symptoms of Alzheimer’s Disease", "abstract": "Alzheimer’s disease (AD) is well known as a disease characterized by degeneration of cholinergic neuronal activity in the brain. It follows that patients with AD would be sensitive to an ‘anticholinergic burden’, and also that medicine with anticholinergic properties would promote various clinical symptoms of AD. Despite the relevance of this important phenomenon to the clinical therapeutics of AD patients, few reports have been seen concerning the relationship between anticholinergic burden and clinical AD symptoms. Therefore, we wished to investigate the relationship between serum anticholinergic activity (SAA) and the severity of clinical symptoms of AD patients. Twenty-six out of 76 AD patients referred by practitioners to our hospital were positive for anticholinergic activity in their serum, and the remaining 50 patients were negative. Cognitive and psychiatric symptoms in AD patients were compared between the positive SAA (SAA+) group and the negative SAA (SAA–) group. The SAA+ group showed a significantly (p < 0.05) lower total score on the Mini-Mental State Examination, and significantly (p < 0.05) higher scores on the Functional Assessment Staging and the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD). In particular, certain subscales of the BEHAVE-AD, i.e. the items of paranoid and delusional ideation, hallucinations and diurnal rhythm disturbances, had higher scores in the SAA+ group. Moreover, it was shown that many more psychotropic medicines were prescribed to the SAA+ group. By means of logistic regression analysis, the items of paranoid and delusional ideation and diurnal rhythm disturbances in the BEHAVE-AD were positively correlated with SAA in patients. We hypothesized that SAA in AD patients would be associated with clinical symptoms, especially delusion and diurnal rhythm disturbances.", "corpus_id": 31282188, "score": 1 }, { "doc_id": "23382016", "title": "Prevalence, correlates, and disease patterns of antipsychotic use in Taiwan", "abstract": "Aim:  The population‐based National Health Insurance database was used to investigate the prevalence, correlates, and disease patterns of antipsychotic use in Taiwan.", "corpus_id": 23382016, "score": 0 }, { "doc_id": "25031581", "title": "Factors influencing the prescribing of medications by old age psychiatrists for behavioural and psychological symptoms of dementia: a qualitative study.", "abstract": "BACKGROUND\ndespite evidence of limited efficacy, psychotropic medications are widely used as a first line treatment for those with behavioural and psychological symptoms of dementia (BPSD). Clearly various factors must be influencing their continued use; these are explored here.\n\n\nAIMS\nto examine the process by which consultant old age psychiatrists prescribe for BPSD and explore the factors that influence their decisions.\n\n\nMETHOD\na focus group generated initial questions for interviews with eight consultant old age psychiatrists, using a grounded theory methodology.\n\n\nRESULTS\ndifferences in how assessment information was utilised resulted in inconsistencies in choice of medication between psychiatrists. Psychiatrists felt pressured to prescribe, largely due to resource issues and lack of viable alternative treatments.\n\n\nCONCLUSION\nthe ways in which psychiatrists prescribe for BPSD varies amongst clinicians. Guidelines do exist, but are difficult to implement in practice. Alternative non-pharmacological strategies are required, but as yet they are difficult to access and have a questionable evidence base.", "corpus_id": 25031581, "score": 0 }, { "doc_id": "24050265", "title": "The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases", "abstract": "Cultured brain cells are capable of generating many molecules associated with inflammatory and immune functions. They constitute the endogenous immune response system of brain. They include complement proteins and their regulators, inflammatory cytokines, acute phase reactants and many proteases and protease inhibitors. Most of the proteins are made by microglia and astrocytes, but even neurons are producers. Many appear in association with Alzheimer disease lesions, indicating a state of chronic inflammation in Alzheimer disease brain. Such a state can apparently exist without stimulation by peripheral inflammatory mediators or the peripheral immune system. A strong inflammatory response may be autotoxic to neurons, exacerbating the fundamental pathology in Alzheimer disease and perhaps other neurological disorders. Autotoxic processes may contribute to cellular death in chronic inflammatory diseases affecting other parts of the body, suggesting the general therapeutic value of anti-inflammatory agents. With respect to Alzheimer disease, multiple epidemiological studies indicate that patients taking anti-inflammatory drugs or suffering from conditions in which such drugs are routinely used, have a decreased risk of developing Alzheimer disease. In one very preliminary clinical trial, the anti-inflammatory drug indomethacin arrested progress of the disease. New agents directed against the inflammatory processes revealed in studies of Alzheimer disease lesions may have broad therapeutic applications.", "corpus_id": 24050265, "score": 0 }, { "doc_id": "34940545", "title": "Inhibitor of antagonist binding to the muscarinic receptor is elevated in Alzheimer's brain", "abstract": "The 100,000 x g supernatant fraction of human brain contains endogenous inhibitors of antagonist binding to the muscarinic receptor. Significantly greater inhibition was observed with Alzheimer's than non-demented control supernatant fractions. Low molecular weight inhibitor was separated from larger inhibitor species by membrane dialysis (3,500 dalton cut-off). The activity of low molecular weight inhibitor was greatly increased by sulfhydryl reducing agents. While the low molecular weight inhibitor was stable to heat, acid and base for short time periods (< 20 min), it was inactivated by acid hydrolysis (50% loss after 16 h, 100% loss after 96 h). The low molecular weight inhibitor activity is elevated approximately three-fold in Alzheimer's brain. The low molecular weight inhibitor from Alzheimer's brain was found to be a non-competitive inhibitor. This is the first report of endogenous inhibitors in human brain of ligand binding to the muscarinic receptor and of increased inhibitor activity in Alzheimer's disease.", "corpus_id": 34940545, "score": 0 }, { "doc_id": "488320", "title": "Pharmacological Stimulation of the Cholinergic Antiinflammatory Pathway", "abstract": "Efferent activity in the vagus nerve can prevent endotoxin-induced shock by attenuating tumor necrosis factor (TNF) synthesis. Termed the “cholinergic antiinflammatory pathway,” inhibition of TNF synthesis is dependent on nicotinic α-bungarotoxin-sensitive acetylcholine receptors on macrophages. Vagus nerve firing is also stimulated by CNI-1493, a tetravalent guanylhydrazone molecule that inhibits systemic inflammation. Here, we studied the effects of pharmacological and electrical stimulation of the intact vagus nerve in adult male Lewis rats subjected to endotoxin-induced shock to determine whether intact vagus nerve signaling is required for the antiinflammatory action of CNI-1493. CNI-1493 administered via the intracerebroventricular route was 100,000-fold more effective in suppressing endotoxin-induced TNF release and shock as compared with intravenous dosing. Surgical or chemical vagotomy rendered animals sensitive to TNF release and shock, despite treatment with CNI-1493, indicating that an intact cholinergic antiinflammatory pathway is required for antiinflammatory efficacy in vivo. Electrical stimulation of either the right or left intact vagus nerve conferred significant protection against endotoxin-induced shock, and specifically attenuated serum and myocardial TNF, but not pulmonary TNF synthesis, as compared with sham-operated animals. Together, these results indicate that stimulation of the cholinergic antiinflammatory pathway by either pharmacological or electrical methods can attenuate the systemic inflammatory response to endotoxin-induced shock.", "corpus_id": 488320, "score": 0 }, { "doc_id": "13761940", "title": "Activation of the Cholinergic Antiinflammatory Pathway Reduces Ricin-Induced Mortality and Organ Failure in Mice", "abstract": "Exposure to ricin, either by accident through ingestion of castor oil plant seeds or intentionally through its use as a bioweapon, invariably leads to multiple organ damage and death. Currently there is only a vaccine in advanced development to ricin, but no other antidote. Ricin causes systemic inflammation with increased proinflammatory cytokine release and subsequent multiple organ failure, particularly kidney and liver dysfunction. Activation of the cholinergic antiinflammatory pathway, specifically through the alpha7 nicotinic acetylcholine receptor (either indirectly through vagus nerve stimulation or directly through nicotine treatment) reduces proinflammatory gene expression. This activation also increases release of proinflammatory chemokines and cytokines, and has proven effective in a variety of inflammatory diseases. The aim of this study was to investigate whether nicotine treatment protected against ricin toxicity in mice. Male Balb/c mice exposed to ricin had increased serum levels of the inflammatory cytokine tumor necrosis factor-α and markers of both kidney (blood urea nitrogen, creatine) and liver (alanine tranaminase) dysfunction, with a subsequent increase in mortality Nicotine administration 2 h after ricin injection significantly delayed and reduced ricin-induced mortality, an effect coupled with reduced serum levels of tumor necrosis factor-a and markers of kidney and liver dysfunction. Both the kidney and liver had markedly increased cellular oxidative stress following ricin exposure, an effect attenuated by nicotine administration. In conclusion, these data demonstrate that in cases of ricin poisoning, activation of the cholinergic antiinflammatory pathway may prove beneficial by reducing organ damage, delaying mortality, and allowing for a greater chance of survival.", "corpus_id": 13761940, "score": 0 }, { "doc_id": "27536398", "title": "C-reactive protein: a pentraxin with anti-acetylcholine activity.", "abstract": "Purified C-reactive protein (CRP) diminished effects of acetylcholine (ACh) on the vascular tone and the heart rate of rats in vivo. In vitro CRP inhibited breakdown of ACh by acetylcholinesterase (AChE) while did not interact with AChE itself. CRP appears to bind ACh. CRP did not modify the cardiovascular effects of adenosine, another vasorelaxant. The data suggest that there is a new line of cross-talk between the inflammation and cholinergic regulation with CRP acting on endothelium via the ACh-dependent pathway.", "corpus_id": 27536398, "score": 0 }, { "doc_id": "35132104", "title": "Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists.", "abstract": "The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs.", "corpus_id": 35132104, "score": 0 }, { "doc_id": "3786218", "title": "Novel Selective Allosteric Activator of the M1 Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats", "abstract": "Recent studies suggest that subtype-selective activators of M1/M4 muscarinic acetylcholine receptors (mAChRs) may offer a novel approach for the treatment of psychotic symptoms associated with schizophrenia and Alzheimer's disease. Previously developed muscarinic agonists have provided clinical data in support of this hypothesis, but failed in clinical development because of a lack of true subtype specificity and adverse effects associated with activation of other mAChR subtypes. We now report characterization of a novel highly selective agonist for the M1 receptor with no agonist activity at any of the other mAChR subtypes, termed TBPB [1-(1′-2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one]. Mutagenesis and molecular pharmacology studies revealed that TBPB activates M1 through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M1 by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M2 and M4. TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists. Finally, TBPB had effects on the processing of the amyloid precursor protein toward the non-amyloidogenic pathway and decreased Aβ production in vitro. Together, these data suggest that selective activation of M1 may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease.", "corpus_id": 3786218, "score": 0 }, { "doc_id": "6540671", "title": "Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs", "abstract": "The hypothesis that blockade of muscarinic receptors is associated with increased Alzheimer‐type pathology was investigated in Parkinson's disease. Amyloid plaque densities were more than 2.5‐fold higher in cases treated with antimuscarinic medication in the long term compared with untreated or short‐term treated cases (p = 0.005 and 0.00005, respectively). Neurofibrillary tangle densities were also highest in chronic compared with untreated or acute‐treated groups (p = 0.02 and 0.05, respectively). The findings, if replicated, have potential implications for the use of anticholinergic medication in elderly Parkinson's disease patients. Ann Neurol 2003", "corpus_id": 6540671, "score": 0 }, { "doc_id": "6025247", "title": "Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer disease.", "abstract": "OBJECTIVE\nAuthors examined the effect of chronic exposure to anticholinergics in a cohort of Alzheimer disease (AD) patients.\n\n\nMETHODS\nAll patients were examined annually with standard neuropsychologic tests and received the cholinesterase inhibitor donepezil hydrochloride at a dose of 10 mg/day. The study population (N=69) was divided into two groups: those receiving one or more concomitant medications with significant anticholinergic properties (N=16) and those receiving no concomitant medications with anticholinergic properties (N=53).\n\n\nRESULTS\nAt 2 years, MMSE scores were significantly worse for patients receiving anticholinergic medications than for those not on anticholinergics.\n\n\nCONCLUSION\nAlthough very preliminary, these data suggest that concomitant therapy with anticholinergics may be associated with significant deleterious effects on acetylcholinesterase therapy, or, more speculatively, that chronic exposure to anticholinergics may have adverse effects on the clinical course of AD.", "corpus_id": 6025247, "score": 0 }, { "doc_id": "8835631", "title": "Delirium in older people", "abstract": "Few ill health situations are more degrading to people of any age than loss of reasoning, faculties, and personhood. These are the unpleasant consequences of delirium—a common condition affecting ill older people, particularly those with some degree of dementia. It is characterised by recent onset of fluctuating inattention and confusion, linked to one or more triggering factors. \n\n#### SUMMARY POINTS \n\nDelirium is a major burden to healthcare services and has been largely ignored by health service planners and practitioners.1 Moreover, healthcare systems and services often unintentionally stimulate or substantially aggravate the development of delirium in older people.2 This might be understandable if delirium was unavoidable or untreatable, but the existing evidence base for delirium is sufficiently robust for prevention or attenuation of the condition to be a realistic proposition. There is a pressing need to take this action because the outcomes for delirium are poor: it contributes to substantial morbidity and mortality, causes considerable distress to patients and families, and is expensive—an estimated additional $2500 (£1275; €1875) per patient (a $6.9bn annual expenditure for Medicare in 2004).3\n\nWe searched Medline and the Cochrane Library from 1996 to 2006. We drew additional material from our personal libraries of delirium references, focusing particularly on systematic reviews.\n\nDelirium is an important problem for all clinical services providing care for older people, particularly emergency departments; general medical, elderly care, surgical, and …", "corpus_id": 8835631, "score": 0 }, { "doc_id": "21470372", "title": "Autonomic and Adrenocortical Interactions Predict Mental Health in Late Adolescence: The TRAILS Study", "abstract": "The present study is informed by the theory of allostatic load to examine how multiple stress responsive biomarkers are related to mental health outcomes. Data are from the TRAILS study, a large prospective population study of 715 Dutch adolescents (50.9 % girls), assessed at 16.3 and 19.1 years. Reactivity measures of the hypothalamic pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) biomarkers (heart rate, HR; respiratory sinus arrhythmia, RSA; and pre-ejection period, PEP) to a social stress task were used to predict concurrent and longitudinal changes in internalizing and externalizing symptoms. Hierarchical linear modeling revealed relatively few single effects for each biomarker with the exception that high HR reactivity predicted concurrent internalizing problems in boys. More interestingly, interactions were found between HPA-axis reactivity and sympathetic and parasympathetic reactivity. Boys with high HPA reactivity and low RSA reactivity had the largest increases in internalizing problems from 16 to 19 years. Youth with low HPA reactivity along with increased ANS activation characterized by both decreases in RSA and decreases in PEP had the most concurrent externalizing problems, consistent with broad theories of hypo-arousal. Youth with high HPA reactivity along with increases in RSA but decreases in PEP also had elevated concurrent externalizing problems, which increased over time, especially within boys. This profile illustrates the utility of examining the parasympathetic and sympathetic components of the ANS which can act in opposition to one another to achieve, overall, stress responsivity. The framework of allostasis and allostatic load is supported in that examination of multiple biomarkers working together in concert was of value in understanding mental health problems concurrently and longitudinally. Findings argue against an additive panel of risk and instead illustrate the dynamic interplay of stress physiology systems.", "corpus_id": 21470372, "score": 0 }, { "doc_id": "17541240", "title": "Toll-Like Receptor 4 Promotes Autonomic Dysfunction, Inflammation and Microglia Activation in the Hypothalamic Paraventricular Nucleus: Role of Endoplasmic Reticulum Stress", "abstract": "Background & Purpose Toll-like receptor 4 (TLR4) signaling induces tissue pro-inflammatory cytokine release and endoplasmic reticulum (ER) stress. We examined the role of TLR4 in autonomic dysfunction and the contribution of ER stress. Experimental approach Our study included animals divided in 6 experimental groups: rats treated with saline (i.v., 0.9%), LPS (i.v., 10mg/kg), VIPER (i.v., 0.1 mg/kg), or 4-PBA (i.p., 10 mg/kg). Two other groups were pretreated either with VIPER (TLR4 viral inhibitory peptide) LPS + VIPER (i.v., 0.1 mg/kg) or 4-Phenyl butyric acid (4-PBA) LPS + PBA (i.p., 10 mg/kg). Arterial pressure (AP) and heart rate (HR) were measured in conscious Sprague-Dawley rats. AP, HR variability, as well as baroreflex sensitivity (BrS), was determined after LPS or saline treatment for 2 hours. Immunofluorescence staining for NeuN, Ib1a, TLR4 and GRP78 in the hypothalamic paraventricular nucleus (PVN) was performed. TNF-α, TLR4 and GRP78 protein expression in the PVN were evaluated by western blot. Plasma norepinephrine levels were determined by ELISA. Key Results Acute LPS treatment increased HR and plasma norepinephrine concentration. It also decreased HR variability and high frequency (HF) components of HR variability, as well BrS. Acute LPS treatment increased TLR4 and TNF-α protein expression in the PVN. These hemodynamic and molecular effects were partially abrogated with TLR4 blocker or ER stress inhibitor pretreatment. In addition, immunofluorescence study showed that TLR4 is co-localized with GRP78in the neurons. Further inhibition of TLR4 or ER stress was able to attenuate the LPS-induced microglia activation. Conclusions & Implications TLR4 signaling promotes autonomic dysfunction, inflammation and microglia activation, through neuronal ER stress, in the PVN.", "corpus_id": 17541240, "score": 0 }, { "doc_id": "39222207", "title": "Dorsal Motor Nucleus of Vagus protein aggregates in Lewy Body Disease with autonomic dysfunction", "abstract": "The Dorsal Motor Nucleus of Vagus (DMV) is degenerated in many patients with early stage Lewy Body Diseases (LBD). Many patients with LBD also develop symptomatic autonomic dysfunction prior to motor and cognitive symptoms. The DMV, along with the Nucleus Ambiguous (NA) and Raphe Obscurus (RO) regulates a variety of autonomic reflexes, suggesting that there may be an association between the degree of neurodegenerative protein aggregation in the DMV and symptomatic autonomic dysfunction in patients with LBD. Using digital in vivo pathology, we quantified alphasynuclein, tau, ubiquitin and Heat Shock Protein 27 (HSP27) containing neurons in the DMV, NA, RO, in addition to the hypoglossal nucleus in 12 LBD patients. alphaSynuclein, ubiquitin and tau aggregates most greatly affected the DMV followed by the NA, RO, but never the hypoglossal nucleus. There was a positive correlation between DMV alphasynuclein and tau aggregation (p<0.05) and between DMV alphasynuclein and the patients' UPDRS scores (p<0.05) suggesting incremental DMV degeneration with disease progression. However, there was no correlation between DMV alphasynuclein, tau, ubiquitin or HSP27 density and the patient's autonomic dysfunction scores. The specific incremental nature of degeneration in the DMV, suggests that by characterizing region specific molecular mechanisms underpinning DMV as opposed to NA degeneration in LBD, the pathogenesis of the disorder may be better understood. Whether DMV degeneration is causative of symptomatic autonomic dysfunction in LBD remains to be determined.", "corpus_id": 39222207, "score": 0 }, { "doc_id": "14354793", "title": "Diagnosis and management of dementia with Lewy bodies", "abstract": "The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.", "corpus_id": 14354793, "score": 0 }, { "doc_id": "20028272", "title": "Cumulative Anticholinergic Exposure Is Associated with Poor Memory and Executive Function in Older Men", "abstract": "OBJECTIVES: To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men.", "corpus_id": 20028272, "score": 0 }, { "doc_id": "41242122", "title": "Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine.", "abstract": "This article reviews the literature relevant to improving our understanding of the neural underpinnings of delirium. That the characteristic symptoms of delirium occur as a result of a wide diversity of causes supports the concept of a \"\"final common pathway. \" What constitutes this may involve certain brain regions or circuits and certain neurotransmitters. Neuroanatomical data derived from neuroimaging and lesion reports suggest the importance of pathways in prefrontal cortex, thalamus, fusiform cortex, posterior parietal cortex, and basal ganglia. Neurotransmitters most implicated in delirium that could be candidates to mediate the characteristic symptoms of delirium, as well as the electroencephalogram changes, are acetylcholine and dopamine. Acetylcholine deficiency and dopamine excess---absolute and/or relative to each other---appear to be critical in the final common pathway. These neurotransmitters affect each other, depending on the receptor subtype, and their receptor distribution among layers of cortex in areas such as prefrontal cortex and temporal lobe suggests that cholinergic and dopaminergic neurons could interact with each other during delirium. Electroconvulsive therapy is described as a special situation in which excess dopamine and delirium may have a therapeutic effect on depression recovery, in contrast with the usual association of delirium with negative effects.", "corpus_id": 41242122, "score": 0 }, { "doc_id": "19169447", "title": "Serum Anticholinergic Activity in Hospitalized Older Persons with Delirium: A Preliminary Study", "abstract": "OBJECTIVE: To evaluate the relationship between total serum anticholinergic activity (SAA) and the presence or absence of delirium in older hospitalized persons on general medical wards.", "corpus_id": 19169447, "score": 0 }, { "doc_id": "25059597", "title": "Importance of Serum Anticholinergic Activity in the Assessment of Elderly Patients with Delirium", "abstract": "To evaluate the importance of serum anticholinergic activity (SAA) in elderly patients who developed delirium fol lowing hospital admission, we performed a cross-sectional study with consecutively referred inpatients in a university geriatric medical ward. Sixty-one patients aged 66 to 95 years (mean age: 79.2 ± 11.6; 54% females) were recruited. Delirium was assessed by means of the Confusion Assessment Method, SAA determination, questionnaire for cur rent drug treatment, past medical history and clinical examination, and blood chemistries. Patients were divided into two groups according to the absence (N = 49) or the presence (N = 12) of delirium. Delirious patients showed a significantly higher SAA (23.0 vs 3.9 pmol/mL atropine equivalents, P < .004); they were using antibiotics (P < .05), neuroleptics (P < .002), barbiturates (P < .004), and benzodiazepines (P < .005) more frequently. Subjects with delir ium were more likely to have infections and a lower Body Mass Index; they had higher plasma glucose and creatinine. The multivariate analysis identified SAA and use of neuroleptics, and benzodiazepines as the most important fea tures independently associated with delirium. SAA may be a suitable marker for identifying people at risk of developing delirium. Moreover, neuroleptics and benzodiazepines must be carefully used in the elderly because of their relationship with the onset of delirium. (J Geriatr Psychiatry Neurol 1999; 12:82-86).", "corpus_id": 25059597, "score": 0 }, { "doc_id": "23227732", "title": "Serum anticholinergic activity levels and delirium in the elderly.", "abstract": "This article will briefly review the clinical studies focusing on measurement of serum levels of anticholinergic activity in delirious states. Three experimental approaches have been taken. First, to identify medications currently prescribed that have subtle anticholinergic effects. The current \"list\" includes 48 commonly prescribed medications. Second, to associate serum anticholinergic activity with delirium in various clinical states including postcardiotomy delirium, postelectroconvulsive delirium, delirious elderly medical inpatients, and nursing home patients. Third, to intervene in patients with elevated anticholinergic activity by reducing known anticholinergics and correlating this reduction with clinical measures of cognition and delirium. Our most recent data investigate the impact of anticholinergics on demented patients. Prevalence of delirium was significantly higher in patients receiving larger numbers of anticholinergics.", "corpus_id": 23227732, "score": 0 }, { "doc_id": "73204282", "title": "Reversal of central anticholinergic syndrome by galanthamine.", "abstract": "Ten volunteers were given 2 mg scopolamine intravenously (IV) to produce substantial drowsiness and sleepiness. Galanthamine, 0.5 mg/kg IV, effectively reversed the central anticholinergic syndrome produced by scopolamine. Electroencephalographic monitoring of two subjects matched the observed changes of consciousness: scopolamine replaced the dominant awake alpha rhythm with a disorganized, slow, 4- to 6-Hz activity. Galanthamine promptly returned the EEG pattern to the control, awake state. Galanthamine produces effective, safe, and long-lasting reversal of the central anticholinergic syndrome in man. (JAMA238:2293-2294, 1977)", "corpus_id": 73204282, "score": 0 }, { "doc_id": "19786488", "title": "Donepezil Improves Symptoms of Delirium in Dementia: Implications for Future Research", "abstract": "Delirium is a common complication of dementia and may produce considerable morbidity. In addition to psychotic symptoms such as hallucinations and delusions, delirium may produce considerable agitation, which may be refractory to conventional medications such as antipsychotics and benzodiazepines. The main approach to delirium is to treat any underlying medical problem that could cause the delirium. However, delirium is not always reversible, and there is no specific treatment for persistent delirium. The authors present a case of delirium complicating a preexisting dementia that resolved rapidly following initiation of the cholinesterase inhibitor donepezil, suggesting that cholinergic dysfunction may have played a role in the etiology of this patient's delirium. Future research needs to be directed at the issue of cholinergic activity in delirium through monitoring of serum anticholinergic activity and its response to procholinergic therapy.", "corpus_id": 19786488, "score": 0 }, { "doc_id": "14848717", "title": "Challenges in the management of delirium: a case of augmentation with donepezil following inadequate response and adverse effects with risperidone.", "abstract": "Delirium is a common complication in the course of hospitalization characterized by disturbances of awareness and attention, cognition and psychomotor behavior. Further characteristics include an abrupt onset, fluctuating course, as well as an underlying etiology causing this syndrome (APA 2000). In particular, in the intensive care (ICU) setting delirium is very common and the occurrence reaches up to 80%. The standard management approach includes the elimination and treatment of underlying etiologies, which in many instances cannot be achieved to completeness, supportive interventions such as providing a safe environment, structure, and reorientation, as well as pharmacological interventions such as the administration of antipsychotics in order to manage the symptoms of delirium (Trzepacz et al. 1999). A few years ago, following the paradigm of a final pathway of dopamine-acetylcholine imbalance (Trzepacz 2000) with the contribution of various other neurotransmitters (Maldonado 2008), cholinesterase inhibitors (ChEI) were studied in the management of hypoactive delirium with limited evidence (Moretti et al. 2004, Overshott et al. 2008, Gamberini et al. 2009). This approach has not been followed since then, in part, due to the superior results in management with antipsychotics. However, ChEI merit consideration as an augmentation strategy as illustrated in the following case.", "corpus_id": 14848717, "score": 0 } ]

{ "doc_id": "9522510", "title": "Omnivory and grazer functional composition moderate cascading trophic effects in experimental Fucus vesiculosus habitats", "abstract": "We tested the relative strength of direct versus indirect effects of an aquatic omnivore depending on the functional composition of grazers by manipulating the presence of gastropod and amphipod grazers and omnivorous shrimp in outdoor mesocosms. By selectively preying upon amphipods and reducing their abundance by 70–80%, omnivorous shrimp favoured the dominance of gastropods. While gastropods were the main microalgal grazers, amphipods controlled macroalgal biomass in the experiment. However, strong predation on the amphipod by the shrimp had no significant indirect effects on macroalgal biomass, indicating that when amphipod abundances declined, complementary feeding by the omnivore on macroalgae may have suppressed a trophic cascade. Accordingly, in the absence of amphipods, the shrimp grazed significantly on green algae and thereby suppressed the diversity of the macroalgal community. Our experiment demonstrates direct consumer effects by an omnivore on both the grazer and producer trophic levels in an aquatic food web, regulated by prey availability.", "corpus_id": 9522510 }

[ { "doc_id": "53129649", "title": "META-ANALYSIS OF COD-SHRIMP INTERACTIONS REVEALS TOP-DOWN CONTROL IN OCEANIC FOOD WEBS", "abstract": "Here we present a meta-analytic approach to analyzing population interac- tions across the North Atlantic Ocean. We assembled all available biomass time series for a well-documented predator-prey couple, Atlantic cod (Gadus morhua) and northern shrimp (Pandalus borealis), to test whether the temporal dynamics of these populations are con- sistent with the ''top-down'' or the ''bottom-up'' hypothesis. Eight out of nine regions showed inverse correlations of cod and shrimp biomass supporting the ''top-down'' view. Exceptions occurred only close to the southern range limits of both species. Random-effects meta-analysis showed that shrimp biomass was strongly negatively related to cod biomass, but not to ocean temperature in the North Atlantic Ocean. In contrast, cod biomass was positively related to ocean temperature. The strength of the cod-shrimp relationship, how- ever, declined with increasing mean temperature. These results show that changes in predator populations can have strong effects on prey populations in oceanic food webs, and that the strength of these interactions may be sensitive to changes in mean ocean temperature. This means that the effects of overfishing in the ocean cascade down to lower trophic levels, as has been shown previously for lakes and coastal seas. In order to further investigate these processes, we establish a methodological framework to analyze species interactions from time series data.", "corpus_id": 53129649, "score": 0 }, { "doc_id": "3180571", "title": "Trophic cascades triggered by overfishing reveal possible mechanisms of ecosystem regime shifts", "abstract": "Large-scale transitions between alternative states in ecosystems are known as regime shifts. Once described as healthy and dominated by various marine predators, the Black Sea ecosystem by the late 20th century had experienced anthropogenic impacts such as heavy fishing, cultural eutrophication, and invasions by alien species. We studied changes related to these “natural experiments” to reveal the mechanisms of regime shifts. Two major shifts were detected, the first related to a depletion of marine predators and the second to an outburst of the alien comb jelly Mnemiopsis leidyi; both shifts were triggered by intense fishing resulting in system-wide trophic cascades. The complex nature of ecosystem responses to human activities calls for more elaborate approaches than currently provided by traditional environmental and fisheries management. This implies challenging existing practices and implementing explanatory models of ecosystem interactions that can better reconcile conservation and ecosystem management ideals.", "corpus_id": 3180571, "score": 0 }, { "doc_id": "22332630", "title": "Cascading Effects of the Loss of Apex Predatory Sharks from a Coastal Ocean", "abstract": "Impacts of chronic overfishing are evident in population depletions worldwide, yet indirect ecosystem effects induced by predator removal from oceanic food webs remain unpredictable. As abundances of all 11 great sharks that consume other elasmobranchs (rays, skates, and small sharks) fell over the past 35 years, 12 of 14 of these prey species increased in coastal northwest Atlantic ecosystems. Effects of this community restructuring have cascaded downward from the cownose ray, whose enhanced predation on its bay scallop prey was sufficient to terminate a century-long scallop fishery. Analogous top-down effects may be a predictable consequence of eliminating entire functional groups of predators.", "corpus_id": 22332630, "score": 0 }, { "doc_id": "15046290", "title": "Multi-level trophic cascades in a heavily exploited open marine ecosystem", "abstract": "Anthropogenic disturbances intertwined with climatic changes can have a large impact on the upper trophic levels of marine ecosystems, which may cascade down the food web. So far it has been difficult to demonstrate multi-level trophic cascades in pelagic marine environments. Using field data collected during a 33-year period, we show for the first time a four-level community-wide trophic cascade in the open Baltic Sea. The dramatic reduction of the cod (Gadus morhua) population directly affected its main prey, the zooplanktivorous sprat (Sprattus sprattus), and indirectly the summer biomass of zooplankton and phytoplankton (top-down processes). Bottom-up processes and climate–hydrological forces had a weaker influence on sprat and zooplankton, whereas phytoplankton variation was explained solely by top-down mechanisms. Our results suggest that in order to dampen the occasionally harmful algal blooms of the Baltic, effort should be addressed not only to control anthropogenic nutrient inputs but also to preserve structure and functioning of higher trophic levels.", "corpus_id": 15046290, "score": 0 }, { "doc_id": "26122510", "title": "Declines in predatory fish promote bloom-forming macroalgae.", "abstract": "In the Baltic Sea, increased dominance of ephemeral and bloom-forming algae is presently attributed to increased nutrient loads. Simultaneously, coastal predatory fish are in strong decline. Using field data from nine areas covering a 700-km coastline, we examined whether formation of macroalgal blooms could be linked to the composition of the fish community. We then tested whether predator or nutrient availability could explain the field patterns in two small-scale field experiments, by comparing joint effects on algal net production from nutrient enrichment with agricultural fertilizer and exclusion of larger predatory fish with cages. We also manipulated the presence of invertebrate grazers. The abundance of piscivorous fish had a strong negative correlation with the large-scale distribution of bloom-forming macroalgae. Areas with depleted top-predator communities displayed massive increases in their prey, small-bodied fish, and high covers of ephemeral algae. Combining the results from the two experiments showed that excluding larger piscivorous fish: (1) increased the abundance of small-bodied predatory fish; (2) changed the size distribution of the dominating grazers, decreasing the smaller gastropod scrapers; and (3) increased the net production of ephemeral macroalgae. Effects of removing top predators and nutrient enrichment were similar and additive, together increasing the abundance of ephemeral algae many times. Predator effects depended on invertebrate grazers; in the absence of invertebrates there were no significant effects of predator exclusion on algal production. Our results provide strong support for regional declines of larger predatory fish in the Baltic Sea promoting algal production by decreasing invertebrate grazer control. This highlights the importance of trophic interactions for ecosystem responses to eutrophication. The view emerges that to achieve management goals for water quality we need to consider the interplay between top-down and bottom-up processes in future ecosystem management of marine resources.", "corpus_id": 26122510, "score": 1 }, { "doc_id": "15734342", "title": "Cascading effects of overfishing marine systems", "abstract": "Profound indirect ecosystem effects of overfishing have been shown for coastal systems such as coral reefs and kelp forests. A new study from the ecosystem off the Canadian east coast now reveals that the elimination of large predatory fish can also cause marked cascading effects on the pelagic food web. Overall, the view emerges that, in a range of marine ecosystems, the effects of fisheries extend well beyond the collapse of fish exploited stocks.", "corpus_id": 15734342, "score": 0 }, { "doc_id": "21978740", "title": "Eutrophication and overfishing in temperate nearshore pelagic food webs: a network perspective", "abstract": "We investigated the effects of human activ- ities on the pelagic food web structure of nearshore marine ecosystems. Their generic structure was estab- lished on the basis of literature review and analyzed by qualitative structural network analysis. Two main issues were addressed: (1) the role of species capable of forming harmful algal blooms (HABs) and red tides (Noctiluca spp.), as well as the role of jellyfish, in eutrophicated sys- tems; (2) the contribution of human influences on food webs, focusing on bottom-up (increased nutrient loading) and top-down (overfishing) effects. Results suggest that HAB-forming species and Noctiluca stimulate the micro- bial network, but reduce higher trophic levels such as commercially important fish species. Jellyfish act as a buffer in eutrophicated and overfished systems, as they retain nutrients from the water column, but their blooms lead to a massive accumulation of large phytoplankton organisms. Anthropogenic nutrient enrichment favors undesirable species because of their specific position in the food web, and this crucial position may explain their far-reaching effects. Finally, while it appears that over- fishing of piscivorous fishes inhibited HABs and sup- ported blooms of diatoms and other large algae in the past, the present-day loss of planktivorous fishes acts syn- ergistically with nutrient enrichment in promoting HAB species, Noctiluca and jellyfish. These fundamental con- straints, which are inherent in the generic structure of pelagic food webs, thus largely determine community dynamics in marine coastal ecosystems.", "corpus_id": 21978740, "score": 0 }, { "doc_id": "27801798", "title": "Predicting ecological consequences of marine top predator declines.", "abstract": "Recent studies document unprecedented declines in marine top predators that can initiate trophic cascades. Predicting the wider ecological consequences of these declines requires understanding how predators influence communities by inflicting mortality on prey and inducing behavioral modifications (risk effects). Both mechanisms are important in marine communities, and a sole focus on the effects of predator-inflicted mortality might severely underestimate the importance of predators. We outline direct and indirect consequences of marine predator declines and propose an integrated predictive framework that includes risk effects, which appear to be strongest for long-lived prey species and when resources are abundant. We conclude that marine predators should be managed for the maintenance of both density- and risk-driven ecological processes, and not demographic persistence alone.", "corpus_id": 27801798, "score": 0 }, { "doc_id": "85155900", "title": "Food Web Complexity and Community Dynamics", "abstract": "Food webs in nature have multiple, reticulate connections between a diversity of consumers and resources. Such complexity affects web dynamics: it first spreads the direct effects of consumption and productivity throughout the web rather than focusing them at particular \"trophic levels.\" Second, consumer densities are often donor controlled with food from across the trophic spectrum, the herbivore and detrital channels, other habitats, life-history omnivory, and even trophic mutualism. Although consumers usually do not affect these resources, increased numbers often allow consumers to depress other resources to levels lower than if donor-controlled resources were absent. We propose that such donor-controlled and \"multichannel\" omnivory is a general feature of consumer control and central to food web dynamics. This observation is contrary to the normal practice of inferring dynamics by simplifying webs into a few linear \"trophic levels,\" as per \"green world\" theories. Such theories do not accommodate common and dynamically important features of real webs such as the ubiquity of donor control and the importance and dynamics of detritus, omnivory, resources crossing habitats, life history, nutrients (as opposed to energy), pathogens, resource defenses, and trophic symbioses. We conclude that trophic cascades and top-down community regulation as envisioned by trophic-level theories are relatively uncommon in nature.", "corpus_id": 85155900, "score": 1 }, { "doc_id": "1820646", "title": "Omnivory as a Stabilizing Feature of Natural Communities", "abstract": "Omnivory—defined broadly as feeding on more than one trophic level—occupies a prominent position in discussions of food web architecture and dynamics, due in large part to an enduring conflict regarding omnivory's role in community dynamics. According to classical results from mathematical food web theory, omnivory destabilizes ecological communities, whereas more recent conceptual syntheses suggest that omnivory should be a strongly stabilizing factor in food webs. Working with an arthropod assemblage at Mount Saint Helens, I experimentally addressed this controversy using a two‐way factorial design that crossed a manipulation of the degree of omnivory with another “disturbance” manipulation that targeted a specific component of the assemblage. In this statistical design, significant interaction effects (i.e., how the community impacts of the disturbance varied with the degree of omnivory) identified key stabilizing or destabilizing influences of omnivory. Overall, my experimental results indicated that increasing the degree of omnivory stabilized community dynamics, in keeping with recent conceptual syntheses.", "corpus_id": 1820646, "score": 0 }, { "doc_id": "4420271", "title": "Weak trophic interactions and the balance of nature", "abstract": "Ecological models show that complexity usually destabilizes food webs,, predicting that food webs should not amass the large numbers of interacting species that are in fact found in nature. Here, using nonlinear models, we study the influence of interaction strength (likelihood of consumption of one species by another) on food-web dynamics away from equilibrium. Consistent with previous suggestions,, our results show that weak to intermediate strength links are important in promoting community persistence and stability. Weak links act to dampen oscillations between consumers and resources. This tends to maintain population densities further away from zero, decreasing the statistical chance that a population will become extinct (lower population densities are more prone to such chances). Data on interaction strengths in natural food webs indicate that food-web interaction strengths are indeed characterized by many weak interactions and a few strong interactions.", "corpus_id": 4420271, "score": 0 }, { "doc_id": "17617705", "title": "The functional role of biodiversity in ecosystems: incorporating trophic complexity.", "abstract": "Understanding how biodiversity affects functioning of ecosystems requires integrating diversity within trophic levels (horizontal diversity) and across trophic levels (vertical diversity, including food chain length and omnivory). We review theoretical and experimental progress toward this goal. Generally, experiments show that biomass and resource use increase similarly with horizontal diversity of either producers or consumers. Among prey, higher diversity often increases resistance to predation, due to increased probability of including inedible species and reduced efficiency of specialist predators confronted with diverse prey. Among predators, changing diversity can cascade to affect plant biomass, but the strength and sign of this effect depend on the degree of omnivory and prey behaviour. Horizontal and vertical diversity also interact: adding a trophic level can qualitatively change diversity effects at adjacent levels. Multitrophic interactions produce a richer variety of diversity-functioning relationships than the monotonic changes predicted for single trophic levels. This complexity depends on the degree of consumer dietary generalism, trade-offs between competitive ability and resistance to predation, intraguild predation and openness to migration. Although complementarity and selection effects occur in both animals and plants, few studies have conclusively documented the mechanisms mediating diversity effects. Understanding how biodiversity affects functioning of complex ecosystems will benefit from integrating theory and experiments with simulations and network-based approaches.", "corpus_id": 17617705, "score": 0 }, { "doc_id": "45088691", "title": "Trophic Cascades in a Formerly Cod-Dominated Ecosystem", "abstract": "Removal of top predators from ecosystems can result in cascading effects through the trophic levels below, completely restructuring the food web. Cascades have been observed in small-scale or simple food webs, but not in large, complex, open-ocean ecosystems. Using data spanning many decades from a once cod-dominated northwest Atlantic ecosystem, we demonstrate a trophic cascade in a large marine ecosystem. Several cod stocks in other geographic areas have also collapsed without recovery, suggesting the existence of trophic cascades in these systems.", "corpus_id": 45088691, "score": 0 }, { "doc_id": "19203503", "title": "Consequences of omnivory for trophic interactions on a salt marsh shrub.", "abstract": "Although omnivory is common in nature, its impact on trophic interactions is variable. Predicting the food web consequences of omnivory is complicated because omnivores can simultaneously produce conflicting direct and indirect effects on the same species or trophic level. We conducted field and laboratory experiments testing the top-down impacts of an omnivorous salt marsh crab, Armases cinereum, on the shrub Iva frutescens and its herbivorous and predatory arthropod fauna. Armases is a \"true omnivore,\" consuming both Iva and arthropods living on Iva. We hypothesized that Armases would benefit Iva through a top-down trophic cascade, and that this benefit would be stronger than the direct negative effect of Armases on Iva. A field experiment on Sapelo Island, Georgia (USA), supported this hypothesis. Although Armases suppressed predators (spiders), it also suppressed herbivores (aphids), and benefited Iva, increasing leaf number, and reducing the proportion of dead shoots. A one-month laboratory experiment, focusing on the most common species in the food web, also supported this hypothesis. Armases strongly suppressed aphids and consumed fewer Iva leaves if aphids were available as an alternate diet. Armases gained more body mass if they could feed on aphids as well as on Iva. Although Armases had a negative effect on Iva when aphids were not present, Armases benefited Iva if aphids were present, because Armases controlled aphid populations, releasing Iva from herbivory. Although Armases is an omnivore, it produced strong top-down forces and a trophic cascade because it fed preferentially on herbivores rather than plants when both were available. At the same time, the ability of Armases to subsist on a plant diet allows it to persist in the food web when animal food is not available. Because omnivores feed on multiple trophic levels, their effects on food webs may differ from those predicted by standard trophic models that assume that each species feeds only on a single trophic level. To better understand the complexity of real food webs, the variable feeding habits and feeding preferences of different omnivorous species must be taken into consideration.", "corpus_id": 19203503, "score": 1 }, { "doc_id": "86327847", "title": "Cascading effects of predator diversity and omnivory in a marine food web", "abstract": "Over-harvesting, habitat loss and exotic invasions have altered predator diversity and composition in a variety of communities which is predicted to affect other trophic levels and ecosystem functioning. We tested this hypothesis by manipulating predator identity and diversity in outdoor mesocosms that contained five species of macroalgae and a macroinvertebrate herbivore assemblage dominated by amphipods and isopods. We used five common predators including four carnivores (crabs, shrimp, blennies and killifish) and one omnivore (pinfish). Three carnivorous predators each induced a strong trophic cascade by reducing herbivore abundance and increasing algal biomass and diversity. Surprisingly, increasing predator diversity reversed these effects on macroalgae and altered algal composition, largely due to the inclusion and performance of omnivorous fish in diverse predator assemblages. Changes in predator diversity can cascade to lower trophic levels; the exact effects, however, will be difficult to predict due to the many complex interactions that occur in diverse food webs.", "corpus_id": 86327847, "score": 0 }, { "doc_id": "84991750", "title": "Relative consumer sizes and the strengths of direct and indirect interactions in omnivorous feeding relationships", "abstract": "Omnivory (the consumption of resources from more than one trophic level) is widespread in nature and has the potential to produce a richness of indirect effects. Nevertheless, its effects on popula ...", "corpus_id": 84991750, "score": 0 }, { "doc_id": "32310077", "title": "Effects of grazer richness and composition on algal biomass in a closed and open marine system.", "abstract": "Most natural local systems exchange organisms with a regional pool of species through migration and dispersal. Such metacommunity processes of interconnected multispecies assemblages are likely to affect local dynamics of both species and processes. We present results from an artificial marine outdoor rock pool system in which we investigated the factors of (1) local grazer richness and composition, and (2) connectivity of local patches to a regional species pool, and their effects on algal biomass. Local species richness of six grazers was manipulated in both open and closed pools, which were embedded in a regional species pool containing all six grazers. Grazer richness showed significant net biodiversity effects on grazing in the closed, but not in the open, system. Grazer composition, on the other hand, showed significant effects on grazing in both open and closed systems, depending on which species were initially present. The two most efficient grazers were able to compensate for less efficient grazers in species mixtures, hence ensuring the function of grazing. The efficiency of top-down control of algal biomass in open systems thus depends on which particular species are lost. Further, differences in grazing between the open and closed system changed over time due to temporal dynamics in grazer composition. The results emphasize the importance of including system connectivity in experimental designs to allow an extrapolation of biodiversity ecosystem-functioning relationships to natural systems.", "corpus_id": 32310077, "score": 0 }, { "doc_id": "56069737", "title": "Trophic interactions in Zostera marina beds along the Swedish coast", "abstract": "We compared eelgrass Zostera marina communities in 3 regions in Sweden believed to be affected by eutrophication and overfishing, to determine whether bottom-up or top-down processes control the biomass of epiphytic macroalgae and grazers. Nitrogen and carbon isotope signatures were analyzed to explore the food webs and to identify the grazing species feeding on filamentous algae and/or eelgrass. Mixing model (IsoSource version 1.3.1) analysis of the isotope signatures indicated that the amphipods Gammarus locusta and Microdeutopus gryllotalpa fed primarily on filamentous algae and that only 2 small gastropod species consumed eelgrass. Moreover, the grass shrimp Palaemon elegans and F adspersus were ca. 1 trophic level above amphipods and algae, but according to the mixing model played different trophic roles in the different areas. The highest biomass of filamentous algae was found in the west coast beds housing grazers with the lowest biomass and mean size (predominantly G. locusta and M. gryllotalpa, 0.5 to 3 mm). In contrast, the Baltic Sea beds had low algal biomass, but the grazers (mostly G. locusta and Idotea baltica) had higher biomass and were significantly larger (mean size ca. 10 mm). An overall negative correlation was found between grazer biomass and biomass of filamentous algae. The significantly smaller grazers and absence of isopod grazers on the west coast may be due to substantial consumption by small predatory fish. This supports the suggestions that, in Swedish eelgrass beds, grazers are top-down controlled, and overexploitation. of large predators and eutrophication play an important role in the recent increases in algal biomass.", "corpus_id": 56069737, "score": 1 }, { "doc_id": "54948454", "title": "Trophic role of the omnivorous grass shrimp Palaemon elegans in a Swedish eelgrass system", "abstract": "Algal grazers are thought to play a critical role in preventing overgrowth by ephemeral algae in seagrass beds. We studied the interaction between the omnivorous grass shrimp Palaemon elegans, the algal grazer Gammarus locusta and the filamentous green alga Ulva sp. (syn. Entero- morpha sp.) to assess whether the shrimp has a positive or negative effect on the growth of ephemeral algae in eelgrass beds on the Swedish west coast. Laboratory experiments demonstrated that P. ele- gans were effective predators on gammarids 5 mm TL, but negatively affected when G. locusta was smaller. In a field cage experiment, enclosed P. elegans decreased the abundance of gammarids by on average 68%, causing a trophic cascade that increased the biomass of filamentous Ulva sp. 7-fold. These results suggest that P. elegans on the Swedish northwest coast feed mainly on amphipods, including the algal grazer G. locusta, resulting in a positive net trophic effect on the growth of filamentous Ulva sp. This study indicates that P. ele- gans may be an important link between overexploitation of cod in northwest Sweden and the recent increase of algal mats and loss of eelgrass in the area.", "corpus_id": 54948454, "score": 1 }, { "doc_id": "43530463", "title": "Consumers affect prey biomass and diversity through resource partitioning.", "abstract": "Consumer presence and nutrient availability can have contrasting and interactive effects on plant diversity. In a factorial experiment, we manipulated two levels of nutrient supply and the presence of two moderately specialized grazers in different combinations (no grazers, two species in monoculture, and both in combination). We tested how nutrients and grazers regulated the biomass of marine coastal epiphytes and the diversity of algal assemblages, based on the prediction that the effect of consumers on prey diversity depends on productivity and consumer specialization. Nutrient enrichment increased the epiphytic load, while monocultures of single grazer species partly prevented epiphyte growth. However, only the presence of two species with complementary feeding preferences effectively prevented epiphyte overgrowth. The epiphytes comprised micro- and macroalgal species, and the diversity of these algal assemblages differed, depending on grazer identity. For the microalgae, diversity was reduced by nutrient addition when grazer control was inefficient, but not when specialist microalgal grazers were present. Macroalgal diversity was reduced in ambient water with specialist macroalgal grazers compared to the treatment with inefficient ones. These results indicate that grazer composition and productivity are crucial in determining whether consumer pressure will have a positive or negative effect on algal diversity.", "corpus_id": 43530463, "score": 1 }, { "doc_id": "85848182", "title": "A comparative biodiversity study of the associated fauna of perennial fucoids and filamentous algae", "abstract": "Abstract Anthropogenic activities worldwide have contributed to vegetation changes in many coastal areas, changes that may in turn affect faunal and algal assemblages in the involved ecosystems. In the northernmost part of the Baltic Sea the salinity is extremely low (3–4) and the only structurally complex alga present is Fucus radicans . Since in this area F. radicans is living at its salinity tolerance limit, it is potentially very sensitive to environmental changes. Any change in salinity could thus alter the overall algal community, changing it to one dominated solely by filamentous algae. To determine the importance of F. radicans to the associated faunal community, we examined differences between the 2 main vegetation types present, i.e., F. radicans and filamentous algae, in the Kronoren marine reserve in the northernmost part of the Baltic Sea. A similar study was conducted in the Asko area in the northern Baltic Proper, where the more-investigated Fucus vesiculosus is the only large fucoid present. The biomass of associated fauna was significantly higher in both the F. radicans and F. vesiculosus than in the filamentous algal vegetation at some, but not all, sites. The F. radicans community also displayed a greater diversity of associated fauna in 3 of 5 investigated Kronoren sites, whereas no difference in diversity was detected between F. vesiculosus and the filamentous algal vegetations in the Asko sites. Furthermore, the F. radicans community displayed a different faunal community, being the only investigated algal community with a faunal community dominated by K -strategy species, according to abundance–biomass comparison curves. This pattern may be due to the low epiphytic load on these Fucus plants. In contrast, the F. vesiculosus community, as well as the algal communities with no Fucus in both areas, had high biomasses of filamentous algae and an invertebrate fauna dominated by Chironomidae, occurring in great abundance but only with a low biomass. ANOSIM analyses of faunal composition demonstrated a significant difference between the 2 vegetation types in both areas, largely due to greater abundance of Gammarus spp. and Theodoxus fluviatilis in the fucoid vegetation. Differences observed between the F. radicans and filamentous algal vegetation types were generally more pronounced than those between F. vesiculosus and nearby filamentous algal vegetation. These observations may be due to abiotic factors that differ between the 2 investigated areas, factors such as depth distribution, wave action and eutrophication level. This study has demonstrated that the less-investigated F. radicans may be as important as the larger F. vesiculosus for the associated faunal assemblages. At the same time, the limited extent of F. radicans at shallower depths makes F. radicans vegetation potentially more vulnerable to anthropogenic changes, as declines in fucoid vegetation are usually first manifested in populations at their lower depth limits, whereas shallow populations are less affected.", "corpus_id": 85848182, "score": 0 }, { "doc_id": "13512544", "title": "A cross-system synthesis of consumer and nutrient resource control on producer biomass.", "abstract": "Nutrient availability and herbivory control the biomass of primary producer communities to varying degrees across ecosystems. Ecological theory, individual experiments in many different systems, and system-specific quantitative reviews have suggested that (i) bottom-up control is pervasive but top-down control is more influential in aquatic habitats relative to terrestrial systems and (ii) bottom-up and top-down forces are interdependent, with statistical interactions that synergize or dampen relative influences on producer biomass. We used simple dynamic models to review ecological mechanisms that generate independent vs. interactive responses of community-level biomass. We calibrated these mechanistic predictions with the metrics of factorial meta-analysis and tested their prevalence across freshwater, marine and terrestrial ecosystems with a comprehensive meta-analysis of 191 factorial manipulations of herbivores and nutrients. Our analysis showed that producer community biomass increased with fertilization across all systems, although increases were greatest in freshwater habitats. Herbivore removal generally increased producer biomass in both freshwater and marine systems, but effects were inconsistent on land. With the exception of marine temperate rocky reef systems that showed positive synergism of nutrient enrichment and herbivore removal, experimental studies showed limited support for statistical interactions between nutrient and herbivory treatments on producer biomass. Top-down control of herbivores, compensatory behaviour of multiple herbivore guilds, spatial and temporal heterogeneity of interactions, and herbivore-mediated nutrient recycling may lower the probability of consistent interactive effects on producer biomass. Continuing studies should expand the temporal and spatial scales of experiments, particularly in understudied terrestrial systems; broaden factorial designs to manipulate independently multiple producer resources (e.g. nitrogen, phosphorus, light), multiple herbivore taxa or guilds (e.g. vertebrates and invertebrates) and multiple trophic levels; and - in addition to measuring producer biomass - assess the responses of species diversity, community composition and nutrient status.", "corpus_id": 13512544, "score": 0 }, { "doc_id": "85216965", "title": "Life history, growth and production of Theodoxus fluviatilis in Lake Esrom, Denmark", "abstract": "Abstract A population of Theodoxus fluviatilis L in the littoral zone of Lake Esrom was investigated from November 1977 to February 1979. The population was sampled every month in the winter period and twice during the rest of the year. Biomass was estimated as ash-free dry weight (AFDW) of the organic matter both of the soft parts of the animal and the shell itself. The relation between AFDW ( c ) and shell length ( l ) was log  c =2.9509×log ( l )−1.7120. The population comprised more than 1 year-class, which could be separated by shell length, by a narrow band on the shells and the growth of algae on the shell. The life cycle lasted 2 1 2 - 3 years. The oldest animals had a shell length of 7.0–7.5 mm. A few individuals who were estimated to be 3 1 2 years had a shell length up to 8.6 mm. Population density varied between 575 and 2115 individuals m −2 on the stony substratum. The average was 1160 individuals m −2 . Mortality was low during the summer period. In winter many animals died due to the effect of ice and stormy weather on the stony substratum. Growth of the animals was estimated from the shell length. Maximum growth was observed from May to August with no growth during the winter. Egg capsules were found on the stones all year round. New capsules were found from late May to the middle of November. Most freshly laid capsules were observed in May–June and August–September. Capsules from the late summer hatched in spring and capsules laid in the spring hatched in August–September. The average annual net production for the whole population was estimated by three methods. The Allen curve method gave 1.895 AFDW m −2 , the growth-increment method gave 1.784 mg AFDW m −2 and the Hynes method 2.284 mg AFDW m −2 . Corresponding estimated P/B ratios were 1.29, 1.30 and 1.57. Annual net-production of the four investigated year-classes was 16 mg AFDW m −2  year −1 for 1975, 224 mg AFDW m −2  year −1 for 1976, 1.258 mg AFDW m −2  year −1 for 1977 and 287 mg AFDW m −2  year −1 for 1978. P/B ratios for the three oldest year-classes were, respectively, 0.32, 0.50 and 1.67. A comparison with other investigations on gastropod life cycles, reproduction and P/B ratios is made and differences discussed. Variations are correlated to temperature, and food quality and quantity.", "corpus_id": 85216965, "score": 0 }, { "doc_id": "11727147", "title": "Strong bottom-up and top-down control of early life stages of macroalgae", "abstract": "In contrast to most pelagic primary producers, benthic macrophytes pass through morphologically distinct life stages, which can be subject to different ecological controls. Using factorial field experiments, we investigated how grazing pressure (three levels) and nutrient supply (four levels) interact in controlling the passage of marine macroalgae through an apparent recruitment ‘‘bottleneck’’ at the germling stage. In comparative experiments, we asked whether relative bottom-up and top-down effects on early life stages (,4 week germlings) vary (1) between the eutrophic Baltic Sea and the oligotrophic NW Atlantic, (2) across seasons in the NW Atlantic, and (3) among annual and perennial macroalgae. In both systems nutrient enrichment favored and grazers suppressed recruitment of green and brown annual algae; however, enrichment effects were much more pronounced in the Baltic, whereas grazer effects dominated in the NW Atlantic. Grazers induced a shift from grazer-susceptible green to more resistant brown algae in the Baltic without reducing total germling density. In the NW Atlantic, grazers strongly reduced overall recruitment rate throughout all seasons. Effects on perennials were similar in both systems with moderate losses to grazing and no effects of nutrient enrichment. Recruit densities and species composition shifted with season in the NW Atlantic. We conclude that the relative effects of grazers and nutrient enrichment depended on the nutrient status of the system, algal life history strategy, and season. Strong bottom-up and top-down controls shape benthic community composition before macroalgae reach visible size.", "corpus_id": 11727147, "score": 0 }, { "doc_id": "22329291", "title": "Biotic habitat complexity controls species diversity and nutrient effects on net biomass production.", "abstract": "Canopy-forming plants and algae commonly contribute to spatial variation in habitat complexity for associated organisms and thereby create a biotic patchiness of communities. In this study, we tested for interaction effects between biotic habitat complexity and resource availability on net biomass production and species diversity of understory macroalgae by factorial field manipulations of light, nutrients, and algal canopy cover in a subtidal rocky-shore community. Presence of algal canopy cover and/or artificial shadings limited net biomass production and facilitated species diversity. Artificial shadings reduced light to levels similar to those under canopy cover, and net biomass production was significantly and positively correlated to light availability. Considering the comparable and dependent experimental effects from shadings and canopy cover, the results strongly suggest that canopy cover controlled net biomass production and species diversity by limiting light and thereby limiting resource availability for community production. Canopy cover also controlled experimental nutrient effects by preventing a significant increase in net biomass production from nutrient enrichment recorded in ambient light (no shading). Changes in species diversity were mediated by changes in species dominance patterns and species evenness, where canopy cover and shadings facilitated slow-growing crust-forming species and suppressed spatial dominance by Fucus vesiculosus, which was the main contributor to net production of algal biomass. The demonstrated impacts of biotic habitat complexity on biomass production and local diversity contribute significantly to understanding the importance of functionally important species and biodiversity for ecosystem processes. In particular, this study demonstrates how loss of a dominant species and decreased habitat complexity change the response of the remaining assembly to resource loading. This is of potential significance for marine conservation since resource loading often promotes low habitat complexity and canopy species are among the first groups lost in degraded aquatic systems.", "corpus_id": 22329291, "score": 0 }, { "doc_id": "17249868", "title": "Inducible resistance to herbivory in Fucus vesiculosus—duration, spreading and variation with nutrient availability", "abstract": "Inducible resistance in plants is a defense strategy for avoiding the negative conse- quences of herbivory on plant fitness. Since resistance is costly, the induction of resistance may depend on resource availability. Resource-based plant-herbivore hypotheses predict that the cost of producing carbon-based defensive metabolites will be higher when an excess of nutrients is available for growth. We tested experimentally the effect of nutrient availability on the occurrence, duration and within-alga spread of inducible resistance in the brown alga Fucus vesiculosus L. Based on feed- ing preference bioassays using the herbivore Idotea baltica (Pallas), simulated grazing of F. vesiculo- sus caused a clear, rapid, induced resistance that disappeared after 10 to 38 d. Furthermore, the induction of resistance does not spread to neighboring fronds or to growing tips above the point of simulated grazing. Induced resistance against isopod grazing, however, was not explained by increased production of phlorotannins, despite their putative role in the defense against herbivory. Phlorotannin production responded most strongly to nutrient enhancement, which reduced the phlorotannin concentration of the alga. Nutrient enhancement, however, did not affect the induction of resistance. The occurrence of induced resistance together with the lack of correlation between the phlorotannin concentration and the food preferences of herbivores imply that I. baltica is not deterred by the total quantity of phlorotannins; there may, however, be other, as yet unknown, rapidly induc- ing substances in F. vesiculosus that are capable of functioning as feeding deterrents to isopod graz- ers. Resistance may also arise as a side-effect of substances with a functional role, for instance in wound-healing processes. The localized nature and short duration of such deterrence imply that it may be inefficient as a general defense against herbivory, but may benefit the alga by dispersing future damage within the individual and avoiding the breakage of whole fronds.", "corpus_id": 17249868, "score": 0 }, { "doc_id": "54503424", "title": "Grazer identity is crucial for facilitating growth of the perennial brown alga Fucus vesiculosus", "abstract": "Grazer identity is crucial for facilitating growth of the perennial brown alga Fucus vesiculosus", "corpus_id": 54503424, "score": 0 }, { "doc_id": "84386229", "title": "Opposing effects of grazing and nutrients on diversity", "abstract": "Conceptual models predict counteractive effects of herbivores and nutrient enrichment on plant diversity and reversed effects of grazers under different nutrient regimes. I tested these hypotheses in 11 field experiments with periphyton communities in three different aquatic habitats (a highly eutrophic lake, an meso-eutrophic lake, and an meso-eutrophic part of the Baltic Sea coast) and in different seasons. Grazer access and nutrient supply were manipulated in a factorial design. Species richness and evenness were chosen as response variables. Both manipulated factors had significant and contrasting effects on diversity, with variable effect strength between sites and seasons. From the two aspects of diversity, evenness well reflected the changes in community composition. Fertilization tended to increase the dominance of few species and thus to decrease evenness, whereas grazers counteracted these effects by removing dominant life forms. The response of species richness was not as expected, since grazers decreased richness throughout, whereas nutrients had weaker effects but tended to increase richness. Species richness rather reflected changes in periphyton architecture. Grazers reduced algal richness presumably by co-consumption of rare species in the tightly connected periphyton assemblages, whereas enrichment may increase richness by providing more structure via increased dominance of filamentous species. Although grazer and nutrient effects on richness and evenness were opposing, there was no change in the effect of one factor by manipulation of the other.", "corpus_id": 84386229, "score": 0 }, { "doc_id": "8496385", "title": "Consumer versus resource control of producer diversity depends on ecosystem type and producer community structure", "abstract": "Consumer and resource control of diversity in plant communities have long been treated as alternative hypotheses. However, experimental and theoretical evidence suggests that herbivores and nutrient resources interactively regulate the number and relative abundance of coexisting plant species. Experiments have yielded divergent and often contradictory responses within and among ecosystems, and no effort has to date reconciled this empirical variation within a general framework. Using data from 274 experiments from marine, freshwater, and terrestrial ecosystems, we present a cross-system analysis of producer diversity responses to local manipulations of resource supply and/or herbivory. Effects of herbivory and fertilization on producer richness differed substantially between systems: (i) herbivores reduced species richness in freshwater but tended to increase richness in terrestrial systems; (ii) fertilization increased richness in freshwater systems but reduced richness on land. Fertilization consistently reduced evenness, whereas herbivores increased evenness only in marine and terrestrial ecosystems. Producer community evenness and ecosystem productivity mediated fertilization and herbivore effects on diversity across ecosystems. Herbivores increased producer richness in more productive habitats and in producer assemblages with low evenness. These same assemblages also showed the strongest reduction in richness with fertilization, whereas fertilization increased (and herbivory decreased) richness in producer assemblages with high evenness. Our study indicates that system productivity and producer evenness determine the direction and magnitude of top-down and bottom-up control of diversity and may reconcile divergent empirical results within and among ecosystems.", "corpus_id": 8496385, "score": 0 }, { "doc_id": "14327955", "title": "Consumers Control Diversity and Functioning of a Natural Marine Ecosystem", "abstract": "Background Our understanding of the functional consequences of changes in biodiversity has been hampered by several limitations of previous work, including limited attention to trophic interactions, a focus on species richness rather than evenness, and the use of artificially assembled communities. Methodology and Principal Findings In this study, we manipulated the density of an herbivorous snail in natural tide pools and allowed seaweed communities to assemble in an ecologically relevant and non-random manner. Seaweed species evenness and biomass-specific primary productivity (mg O2 h−1 g−1) were higher in tide pools with snails because snails preferentially consumed an otherwise dominant seaweed species that can reduce biomass-specific productivity rates of algal assemblages. Although snails reduced overall seaweed biomass in tide pools, they did not affect gross primary productivity at the scale of tide pools (mg O2 h−1 pool−1 or mg O2 h−1 m−2) because of the enhanced biomass-specific productivity associated with grazer-mediated increases in algal evenness. Significance Our results suggest that increased attention to trophic interactions, diversity measures other than richness, and particularly the effects of consumers on evenness and primary productivity, will improve our understanding of the relationship between diversity and ecosystem functioning and allow more effective links between experimental results and real-world changes in biodiversity.", "corpus_id": 14327955, "score": 0 }, { "doc_id": "54052643", "title": "Diversity effects beyond species richness: evidence from intertidal macroalgal assemblages", "abstract": "Several recent experimental studies have examined the effects of macroalgal diversity on community functioning using synthetic assemblages. However, their predictive relevance for nat- ural systems remains uncertain. Unlike terrestrial habitats, where observational studies in natural systems are profuse, studies on the relationship between diversity and ecosystem functioning in nat- ural marine ecosystems are scarce. In the present study, we explored how different components of biodiversity influence the performance of macroalgal assemblages in natural communities (intertidal boulders). Specifically, we examined the relationships between biomass, species richness, spatial aggregation and evenness and the productivity of macroalgal assemblages. We found the expected positive relationship for biomass and species richness. Additionally, we found significant statistical relationships between both spatial aggregation and evenness and some of the productivity-related variables analyzed: assemblages with a higher degree of spatial aggregation reduced their light capture and photosynthetic efficiency, while increasing evenness increased maximum net primary productivity. Although these patterns should be further tested using experimental approaches, obser- vational studies may provide valuable insights by revealing patterns usually overlooked by experi- mental approaches.", "corpus_id": 54052643, "score": 0 }, { "doc_id": "54654824", "title": "Effects of Pilayella littoralis on Fucus vesiculosus recruitment: implications for community composition", "abstract": "“Effects of Pilayella littoralis on Fucus vesiculosus recruitment: implications for community composition", "corpus_id": 54654824, "score": 0 }, { "doc_id": "54598097", "title": "STRONG IMPACTS OF GRAZING AMPHIPODS ON THE ORGANIZATION OF A BENTHIC COMMUNITY", "abstract": "Large brown seaweeds dominate coastal hard substrata throughout many of the world's oceans. In coastal North Carolina, USA, this dominance by brown seaweeds is facilitated by omnivorous fishes, which feed both on red and green algae and on herbivorous amphipods that graze brown algae. When fish are removed in the field, brown seaweeds are replaced by red seaweeds, and herbivorous amphipods are more abundant. Using an array of large (;4000 L) outdoor mesocosms, we tested three mechanistic hypotheses for this pattern: fish feeding facilitates brown algal dominance (1) by removing red and green algal competitors, (2) by removing amphipods and reducing their feeding on brown sea- weeds, or (3) through an interaction of these mechanisms. Our experiments revealed strong impacts of both fish and amphipods, and a key role for the interaction, in structuring this community. When both fish and amphipods were removed (the latter with dilute insecticide), space was rapidly dominated and held for 17 weeks by fast-growing, primarily filamentous green algae. In contrast, when either fish, amphipods, or both were present, green algae were cropped to a sparse turf, and space was more rapidly dominated by larger macroalgae. The impacts of amphipods and fish on late-successional macroalgal assemblages were comparable in magnitude, but different in sign: red seaweeds prevailed in the amphipod- dominated treatment, whereas browns dominated in the presence of fish. Laboratory feeding assays and amphipod densities in the tanks suggested that the significant effects of am- phipods were attributable largely, if not exclusively, to the single amphipod species Am- pithoe longimana, which fed heavily on brown macroalgae. Our experimental removal of red and green algae failed to enhance cover of brown algae significantly; however, the latter reached substantially lower cover in the grazer-removal treatment, where green algae were very abundant, than in the fish-only treatment, where green algae were sparse. Thus, our results support the third hypothesis: fish-mediated dominance of brown algae involves both suppression of grazing amphipods and removal of algal competitors. Although collective impacts of fish and amphipods on this benthic community were generally comparable in magnitude, impacts normalized to each grazer's aggregate biomass were consistently higher for amphipods than for fish, sometimes by 1-2 orders of magnitude. Thus, the impacts of grazing amphipods (specifically A. longimana) on the benthic community were both strong and disproportionate to their biomass. These experimental results imply that grazing am- phipods, which are ubiquitous in marine vegetation but poorly understood ecologically, may play important roles in the organization of benthic communities, particularly where predation pressure is low.", "corpus_id": 54598097, "score": 0 }, { "doc_id": "205080265", "title": "Intraguild predation: The dynamics of complex trophic interactions.", "abstract": "There is a long-standing debate in ecology concerning the relative importance of competition and predation in determining community structure. Recently, a novel twist has been added with the growing recognition that potentially competing species are often engaged in predator-prey interactions. This blend of competition and predation is called intraguild predation (IGP). The study of IGP will lead to a reconsideration of many classical topics, such as niche shifts, species exclusion and cascading interactions in food webs. Theoretical models suggest that a variety of alternative stable states are likely in IGP systems, and that intermediate predators should tend to be superior in exploitative competition. Many field studies support these expectations. IGP is also important in applied ecological problems, such as the conservation of endangered species and fisheries management.", "corpus_id": 205080265, "score": 0 }, { "doc_id": "84170092", "title": "Species loss and ecosystem functioning : effects of species identity and community composition", "abstract": "Losing a single species from an ecosystem may have large effects on community and ecosystem properties, but this may depend on characteristics of the species and the ecosystem. We examined the effect of losing a single species on productivity and nitrogen retention in experimental grassland communities, concentrating on how these effects varied with the functional identity of the species lost and the diversity and composition of the community from which it was lost. In one experiment, we constructed random plant assemblages that varied in species richness to measure the effect of diversity alone on productivity and nitrogen retention. In another experiment, we constructed plant assemblages to assess the effects of deleting an individual plant species from assemblages differing in their functional and species richness and composition. On average, as species richness declined, productivity decreased but nitrogen retention was unaffected. However, the magnitude and direction of change in ecosystem functioning with declining diversity depended on the identity of the species deleted and the composition of the community from which it was deleted. The functional identity of a species predicted the type of impact its loss had on productivity, but not on nitrogen retention.", "corpus_id": 84170092, "score": 0 }, { "doc_id": "205018808", "title": "Partitioning selection and complementarity in biodiversity experiments", "abstract": "The impact of biodiversity loss on the functioning of ecosystems and their ability to provide ecological services has become a central issue in ecology. Several experiments have provided evidence that reduced species diversity may impair ecosystem processes such as plant biomass production. The interpretation of these experiments, however, has been controversial because two types of mechanism may operate in combination. In the ‘selection effect’, dominance by species with particular traits affects ecosystem processes. In the ‘complementarity effect’, resource partitioning or positive interactions lead to increased total resource use. Here we present a new approach to separate the two effects on the basis of an additive partitioning analogous to the Price equation in evolutionary genetics. Applying this method to data from the pan-European BIODEPTH experiment reveals that the selection effect is zero on average and varies from negative to positive in different localities, depending on whether species with lower- or higher-than-average biomass dominate communities. In contrast, the complementarity effect is positive overall, supporting the hypothesis that plant diversity influences primary production in European grasslands through niche differentiation or facilitation.", "corpus_id": 205018808, "score": 0 }, { "doc_id": "86547253", "title": "Grazer diversity effects on ecosystem functioning in seagrass beds", "abstract": "High plant species richness can enhance primary production, animal diversity, and invasion resistance. Yet theory predicts that plant and herbivore diversity, which often covary in nature, should have countervailing effects on ecosystem properties. Supporting this, we show in a seagrass system that increasing grazer diversity reduced both algal biomass and total community diversity, and facilitated dominance of a grazer-resistant invertebrate. In parallel with previous plant results, however, grazer diversity enhanced secondary production, a critical determinant of fish yield. Although sampling explained some diversity effects, only the most diverse grazer assemblage maximized multiple ecosystem properties simultaneously, producing a distinct ecosystem state. Importantly, ecosystem responses at high grazer diversity often differed in magnitude and sign from those predicted from summed impacts of individual species. Thus, complex interactions, often opposing plant diversity effects, arose as emergent consequences of changing consumer diversity, advising caution in extrapolating conclusions from plant diversity experiments to food webs.", "corpus_id": 86547253, "score": 0 }, { "doc_id": "86707310", "title": "THE ECOLOGICAL CONSEQUENCES OF VARIATION IN PLANTS AND PREY FOR AN OMNIVOROUS INSECT", "abstract": "We conducted a series of laboratory and field experiments to determine the effects of variation in plant quality and prey species on the survival, dispersal, and population size of a common, omnivorous insect. We also tested the hypothesis that plant feeding allows omnivorous “predators” to survive periods when prey are scarce. In addition, we compared the response of omnivores and strict predators to variation in plants and prey. We found that variation in plant parts (pods and leaves) and prey species (moth eggs and aphids) affected the survival, dispersal, and population size of big-eyed bugs, Geocoris punctipes, in Maryland lima beans. The survival of big-eyed bugs fed moth eggs was high and unaffected by the availability of lima bean pods or leaves as supplemental food. The survival of big-eyed bugs fed aphids, however, was relatively low and dramatically improved by the availability of pods. Big-eyed bugs fed only pods developed normally through the first and second instar, but development was arres...", "corpus_id": 86707310, "score": 0 }, { "doc_id": "18183926", "title": "Trophic cascades in a temperate seagrass community", "abstract": "We assessed the relative importance of bottom-up and top-down processes in structuring an eelgrass community in Sweden, a system impacted both by eutrophication and overfishing. Using artificial seagrass as substrate, we manipulated nutrient levels and predator abundance in a full-factorial cage-experiment. The results revealed a seagrass community dominated by strong top-down processes controlling the aggregate biomass of mesograzers and macroalgae. In the absence of predators the large amphipod Gammarus locusta became very abundant resulting in a leaf community with low biomass of algae and smaller mobile fauna. One enclosed gobid fish predator reduced the abundance of adult G. locusta by > 90%, causing a three to six times increase in the biomass of algae, smaller mesograzers and meiofauna. Numerous small predators in uncaged habitats reduced the biomass of G. locusta and other mesograzers by > 95% in comparison to the fish treatment, further increasing the biomass of epiphytic algae and meiofauna. Although water column nutrient enrichment caused a temporal bloom of the filamentous macroalgae Ulva spp., no significant nutrient-effects were found on the algal community at the end of the experiment. The only lasting nutrient-effect was a significant increase in the biomass of G. locusta, but only in the absence of ambient predators. These results demonstrate that mesograzers can respond to enhanced food supply, increase their biomass and control the algal growth when predation rates are low. However, in the assessed system, high predation rates appear to make mesograzers functionally extinct, causing a community-wide trophic cascade that promotes the growth of ephemeral algae. This top-down effect could penetrate down, despite a complex food-web because the interaction strength in the community was strongly skewed towards two functionally dominant algal and grazer species that were vulnerable to consumption. These results indicate that overexploitation of gadoid fish may be linked to increased macroalgal blooms and loss of eelgrass in the area through a trophic cascade affecting the abundance of mesograzers.", "corpus_id": 18183926, "score": 0 }, { "doc_id": "87627144", "title": "Why Are Parts of the World Green? Multiple Factors Control Productivity and the Distribution of Biomass", "abstract": "This paper evaluates the multiple factors that determine the production of plant biomass and its distribution among producers and various trophic groups of con_ ?^)^ Osumers. In rough order of their importance, water and nutrient availability, factors 0*S that deter herbivores (plant defenses, environmental heterogeneity and disturbance, nutrient stoichiometry), and consumption by herbivores appear to be the most universal determinants of the production and distribution of plant biomass. In some times and places, indirect effects from enemies of herbivores (predators, parasites, parasitoids and pathogens) propagate through the food web to influence plant biomass, in a manner somewhat consistent with green world and exploitation ecosystem mechanisms. I discuss why such food web dynamics appear to be much more important in water than on land. The only demonstrated cases of communitylevel trophic cascades occur in water. Although species-level cascades are moderately frequent on land, community-level cascades rarely or never occur.", "corpus_id": 87627144, "score": 0 }, { "doc_id": "11744558", "title": "Predator interactions, mesopredator release and biodiversity conservation.", "abstract": "There is growing recognition of the important roles played by predators in regulating ecosystems and sustaining biodiversity. Much attention has focused on the consequences of predator-regulation of herbivore populations, and associated trophic cascades. However apex predators may also control smaller 'mesopredators' through intraguild interactions. Removal of apex predators can result in changes to intraguild interactions and outbreaks of mesopredators ('mesopredator release'), leading in turn to increased predation on smaller prey. Here we provide a review and synthesis of studies of predator interactions, mesopredator release and their impacts on biodiversity. Mesopredator suppression by apex predators is widespread geographically and taxonomically. Apex predators suppress mesopredators both by killing them, or instilling fear, which motivates changes in behaviour and habitat use that limit mesopredator distribution and abundance. Changes in the abundance of apex predators may have disproportionate (up to fourfold) effects on mesopredator abundance. Outcomes of interactions between predators may however vary with resource availability, habitat complexity and the complexity of predator communities. There is potential for the restoration of apex predators to have benefits for biodiversity conservation through moderation of the impacts of mesopredators on their prey, but this requires a whole-ecosystem view to avoid unforeseen negative effects. 'Nothing has changed since I began. My eye has permitted no change. I am going to keep things like this.' From 'Hawk Roosting', by Ted Hughes.", "corpus_id": 11744558, "score": 0 }, { "doc_id": "2114852", "title": "Network structure and biodiversity loss in food webs: robustness increases with connectance", "abstract": "Food-web structure mediates dramatic effects of biodiversity loss including secondary and ‘cascading’ extinctions. We studied these effects by simulating primary species loss in 16 food webs from terrestrial and aquatic ecosystems and measuring robustness in terms of the secondary extinctions that followed. As observed in other networks, food webs are more robust to random removal of species than to selective removal of species with the most trophic links to other species. More surprisingly, robustness increases with food-web connectance but appears independent of species richness and omnivory. In particular, food webs experience ‘rivet-like’ thresholds past which they display extreme sensitivity to removal of highly connected species. Higher connectance delays the onset of this threshold. Removing species with few trophic connections generally has little effect though there are several striking exceptions. These findings emphasize how the number of species removed affects ecosystems differently depending on the trophic functions of species removed.", "corpus_id": 2114852, "score": 0 }, { "doc_id": "16159889", "title": "Cascading effects from predator removal depend on resource availability in a benthic food web", "abstract": "We tested joint effects of predator loss and increased resource availability on the grazers’ trophic level and the propagation of trophic interactions in a benthic food web by excluding larger predatory fish from cages and manipulating nutrients in the coastal zone of the Baltic Sea. The combination of nutrient enrichment and excluding larger predators induced an increase in medium-sized predatory fish (three-spined stickleback). The meso-predator fish in turn did not change the total abundance of the invertebrate herbivores, but did cause a substantial shift in their community composition towards the dominance of gastropods by reducing amphipods by 40–60%, while gastropods were left unchanged. The shift in grazer composition generated a 23 times higher producer biomass, but only under nutrient enrichment. Our results show that top-predator declines can substantially shift the species composition at the grazers’ level, but that cascading effects on producers by a trophic cascade strongly depend on resource availability.", "corpus_id": 16159889, "score": 0 } ]

{ "doc_id": "26479400", "title": "Nephrotic syndrome-induced thromboembolism in adults", "abstract": "Nephrotic syndrome (NS) is a well-defined syndrome characterized by the presence of nephrotic range of proteinuria, hypoalbuminemia, and hyperlipidemia. Although venous thromboembolism (VTE) is a well-reported complication associated with NS, the incidence, prevalence, risk factors, treatment options, and preventative strategies are not well-established. Thromboembolic phenomena in nephrotic patients are postulated to be a result of the urinary loss of antithrombotic factors by affected kidneys and increased production of prothrombotic factors by the liver. Most cases of VTE associated with NS reported in the literature have a known diagnosis of NS. We report a case of a young female presenting with dyspnea and a pulmonary embolism. She was found to have NS and right renal vein thrombosis. We review the available literature to highlight the best approach for clinicians treating VTE in patients with NS.", "corpus_id": 26479400 }

[ { "doc_id": "15357397", "title": "Primary Nephrotic Syndrome in Adults as a Risk Factor for Pulmonary Embolism: An Up-to-Date Review of the Literature", "abstract": "Patients with nephrotic syndrome are at an increased risk for thrombotic events; deep venous thrombosis, renal vein thrombosis, and pulmonary embolism are quite common in patients with nephrotic syndrome. It is important to note that nephrotic syndrome secondary to membranous nephropathy may impose a greater thrombotic risk for unclear reasons. Increased platelet activation, enhanced red blood cell aggregation, and an imbalance between procoagulant and anticoagulant factors are thought to underlie the excessive thrombotic risk in patients with nephrotic syndrome. The current scientific literature suggests that patients with low serum albumin levels and membranous nephropathy may benefit from primary prophylactic anticoagulation. A thorough approach which includes accounting for all additional thrombotic risk factors is, therefore, essential. Patient counseling regarding the pros and cons of anticoagulation is of paramount importance. Future prospective randomized studies should address the question regarding the utility of primary thromboprophylaxis in patients with nephrotic syndrome.", "corpus_id": 15357397, "score": 1 }, { "doc_id": "23774614", "title": "Pulmonary embolism and renal vein thrombosis in patients with nephrotic syndrome: prospective evaluation of prevalence and risk factors with CT.", "abstract": "PURPOSE\nTo prospectively determine the prevalence of pulmonary embolism ( PE pulmonary embolism ) and renal vein thrombosis ( RVT renal vein thrombosis ) with computed tomography (CT) and to identify markers predictive of PE pulmonary embolism and/or RVT renal vein thrombosis in a large consecutive cohort of patients with nephrotic syndrome.\n\n\nMATERIALS AND METHODS\nThis study was approved by the local institutional review board, and all patients or their guardians provided written informed consent. Consecutive patients with nephrotic syndrome (24-hour urine protein > 3.5 g) underwent combined CT pulmonary angiography for PE pulmonary embolism and renal CT venography for RVT renal vein thrombosis . Prevalence of PE pulmonary embolism and/or RVT renal vein thrombosis was estimated for different ages, sexes, and histopathologic types of nephrotic syndrome. Multivariate analysis was used to determine independent predictors for PE pulmonary embolism and/or RVT renal vein thrombosis in patients with nephrotic syndrome.\n\n\nRESULTS\nThere were 512 patients in the study cohort (331 male patients, 181 female patients; mean age, 37 years ± 17 [standard deviation]; range, 9-81 years), including 80 children. One hundred eighty (35%) of 512 patients had PE pulmonary embolism and/or RVT renal vein thrombosis , with PE pulmonary embolism the more common condition (85% [153 of 180]). PE pulmonary embolism was associated with RVT renal vein thrombosis in 85 (56%) of 153 patients and was isolated in 68 patients (44%). Most patients with PE pulmonary embolism (84% [128 of 153]) were asymptomatic. One hundred twelve (22%) of 505 patients had RVT renal vein thrombosis . PE pulmonary embolism and/or RVT renal vein thrombosis was found in 15 (19%) of 80 children with nephrotic syndrome, while 165 (38%) of 432 adult patients with nephrotic syndrome had PE pulmonary embolism and/or RVT renal vein thrombosis (P = .001). Membranous nephropathy was the most common histopathologic type associated with PE pulmonary embolism and/or RVT renal vein thrombosis (48% [88 of 183]). Membranous nephropathy, age greater than 60 years, high hemoglobin level, long prothrombin time, and high creatinine level were independent predictors of PE pulmonary embolism and/or RVT renal vein thrombosis (P < .05 for all).\n\n\nCONCLUSION\nPE pulmonary embolism and RVT renal vein thrombosis are common in patients with nephrotic syndrome. PE pulmonary embolism is more common than RVT renal vein thrombosis , is most often asymptomatic, and is most frequently found in patients with membranous nephropathy. A high index of suspicion and a low threshold for diagnostic work-up is warranted in these patients.", "corpus_id": 23774614, "score": 1 }, { "doc_id": "7325508", "title": "Retrospective analysis of a novel regimen for the prevention of venous thromboembolism in nephrotic syndrome.", "abstract": "BACKGROUND AND OBJECTIVES\nVenous thromboembolism (VTE) occurs in 7%-40% of nephrotic patients. The risk of VTE depends on the severity and underlying cause of nephrotic syndrome. This study investigated the use of low-dose prophylactic anticoagulation to prevent VTE in patients with nephrotic syndrome caused by primary glomerulonephritis.\n\n\nDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS\nSince 2006, all patients presenting with nephrotic syndrome to Imperial College Kidney and Transplant Centre have been considered for treatment with a novel anticoagulation prophylaxis regimen. All cases of nephrotic syndrome secondary to primary membranous nephropathy, minimal-change disease, and FSGS over a 5-year period were retrospectively reviewed. Patients with serum albumin<2.0 g/dl received prophylactic-dose low-molecular-weight heparin or low-dose warfarin; patients with albumin levels of 2.0-3.0 g/dl received aspirin, 75 mg once daily. All thrombotic events and bleeding complications were recorded.\n\n\nRESULTS\nA total of 143 patients received the prophylactic anticoagulation regimen. Median follow-up was 154 weeks (range, 30-298 weeks). The cohort had features associated with a high risk of developing VTE; 40% of the cohort had an underlying diagnosis of membranous nephropathy, and the initial median serum albumin was 1.5 g/dl (range, 0.5-2.9 g/dl). No VTE occurred in patients established on prophylaxis for at least 1 week. VTE was diagnosed in 2 of 143 patients (1.39%) within the first week after presentation and starting prophylaxis. In both cases, it is unclear whether the thrombus had developed before or after the start of prophylaxis. One of 143 (0.69%) patients receiving prophylaxis was admitted urgently with gastrointestinal hemorrhage. Two of 143 patients (1.40%) had elective blood transfusions and procedures to manage occult gastrointestinal bleeding. No other bleeding events occurred in patients receiving prophylaxis.\n\n\nCONCLUSIONS\nThis regimen of prophylactic antiplatelet or anticoagulant therapy appears effective in preventing VTE in nephrotic syndrome, with relatively few hemorrhagic complications.", "corpus_id": 7325508, "score": 0 }, { "doc_id": "41976190", "title": "Thromboembolic complications in nephrotic syndrome. Coagulation abnormalities, renal vein thrombosis, and other conditions.", "abstract": "In patients with nephrotic syndrome, the presence of a hypercoagulable state is thought to give rise to a high incidence of thromboembolic phenomena. Renal vein thrombosis is a common complication in nephrotic patients, mainly in those with membranous nephropathy, and many other types of thromboembolic complications also occur. The mortality rate in nephrotic patients with thromboembolic complications may be significantly increased, with pulmonary emboli likely being the most common cause of death.", "corpus_id": 41976190, "score": 0 }, { "doc_id": "23611627", "title": "Venous thromboembolism in patients hospitalized with nephrotic syndrome.", "abstract": "PURPOSE\nWhether pulmonary embolism in patients with the nephrotic syndrome is caused by deep venous thrombosis or renal vein thrombosis is controversial. To determine which is the likely cause of pulmonary embolism in patients with the nephrotic syndrome, we investigated data from the National Hospital Discharge Survey.\n\n\nMETHODS\nThe number of patients discharged from nonfederal short-stay hospitals in the United States with a diagnostic code of nephrotic syndrome, deep venous thrombosis, renal vein thrombosis, and pulmonary embolism was obtained using ICD-9-M (International Classification of Diseases, Ninth Revision, Clinical Modification) codes.\n\n\nRESULTS\nFrom 1979 to 2005, 925,000 patients were discharged from hospitals with the nephrotic syndrome and 898,253,000 patients did not have the nephrotic syndrome. With the nephrotic syndrome, 5000 (0.5%) had pulmonary embolism, 14,000 (1.5%) had deep venous thrombosis, and fewer than 5000 had renal vein thrombosis. The relative risk of pulmonary embolism comparing patients with the nephrotic syndrome to those who did not have it was 1.39, and the relative risk of deep venous thrombosis was 1.72. Among patients aged 18-39 years, the relative risk of deep venous thrombosis was 6.81. From 1991-2005, after venous ultrasound was generally available, the relative risk of deep venous thrombosis (all ages) was 1.77.\n\n\nCONCLUSION\nThe nephrotic syndrome is a risk factor for venous thromboembolism. This is strikingly apparent in young adults. Renal vein thrombosis was uncommon. Therefore, pulmonary embolism, if it occurs, is likely to be due to deep venous thrombosis and not renal vein thrombosis.", "corpus_id": 23611627, "score": 0 }, { "doc_id": "22747300", "title": "Thromboembolic complications in childhood nephrotic syndrome: a clinical profile", "abstract": "BackgroundThromboembolism is a rare life-threatening complication of childhood nephrotic syndrome.MethodsWe present the clinical profile and outcome of 34 children with 35 events of thromboembolic complications with nephrotic syndrome.ResultsCerebral venous thrombosis (CVT) was the commonest complication seen in 11 (31.4 %) children followed by pulmonary thromboembolism and deep venous thrombosis in 9 (25.7 %) and 6 (16.6 %) children, respectively. Arterial thrombosis resulting in central nervous system infarcts was observed in 7 (20 %) children and 2 children had thrombosis of the peripheral arteries. Episodes were equal in steroid-resistant nephrotic syndrome and steroid-dependent nephrotic syndrome groups. Most of the thromboembolic complications occurred with relapse but 11.4 % of children developed intracranial thrombosis during remission. The most sensitive symptom of CVT was persistent headache while unexplained respiratory distress and hypoxemia pointed towards pulmonary thromboembolism. Hypoalbuminemia was seen in 82.8 % of children, while concurrent infection was seen in 31.4 %. Coexistence of genetic prothrombotic condition was identified and merits evaluation. Early heparin therapy followed by oral anticoagulants resulted in complete recovery in 91.1 % of children. Death occurred in 3 (8.5 %) children and autopsy revealed pulmonary thromboembolism in 2 children.ConclusionVenous and arterial thrombotic complications can occur in children with nephrotic syndrome. A high index of suspicion is required as the clinical features may be subtle. Neuroimaging and angiographic techniques help in confirming diagnosis. Early aggressive heparin therapy followed by oral anticoagulants is necessary for a favorable outcome.", "corpus_id": 22747300, "score": 0 }, { "doc_id": "24914645", "title": "Thromboembolic complications in membranous nephropathy patients with nephrotic syndrome-a prospective study.", "abstract": "BACKGROUND\nVenous thromboembolism (VTE) is one of the most serious complications in membranous nephropathy (MN). We investigate the incidence of VTE in MN patients with nephrotic syndrome (NS).\n\n\nMETHODS\nA total of 100 MN patients with NS were enrolled into this prospective study. The diagnosis of VTE was based on contrast-enhanced dual source computed tomography angiography.\n\n\nRESULTS\nVenous thromboembolism was demonstrated in 36 patients (36%). 33 patients (33%) had renal vein thrombosis (RVT), 17 patients (17%) had pulmonary embolism (PE). Flank pain was noted in 5 patients and gross hematuria in 2 patients with RVT. Dyspnea and chest pain were present in 9 patients with PE. The positive predictive value for D-dimer level was 69.4%, negative predictive value for D-dimer level was 96.1% in patients with MN. Of all the risk factors presented, D-dimer level, proteinuria, the ratio of proteinuria to serum albumin were independent risk factors for the development of VTE (P<0.05), but the plasma level of antithrombin Ш was not correlated with VTE in this study. In follow up, venous thrombosis disappeared after anticoagulant treatment with low-molecular-weight heparins in 28 patients.\n\n\nCONCLUSION\nVenous thromboembolism was confirmed in 36% of MN patients with NS. Renal vein thrombosis and pulmonary embolism are common and usually asymptomatic. Computed tomography angiography can be used effectively to examine suspected patients. Measurement of D-dimer is helpful in VTE diagnosis. It is important that clinicians are aware that VTE should be considered as a common complication in MN patients with NS.", "corpus_id": 24914645, "score": 1 }, { "doc_id": "11402617", "title": "High Absolute Risks and Predictors of Venous and Arterial Thromboembolic Events in Patients With Nephrotic Syndrome: Results From a Large Retrospective Cohort Study", "abstract": "Background— No data are available on the absolute risk of either venous thromboembolism (VTE) or arterial thromboembolism (ATE) in patients with nephrotic syndrome. Reported risks are based on multiple case reports and small studies with mostly short-term follow-up. We assessed the absolute risk of VTE and ATE in a large, single-center, retrospective cohort study and attempted to identify predictive factors in these patients. Methods and Results— A total of 298 consecutive patients with nephrotic syndrome (59% men; mean age, 42±18 years) were enrolled. Mean follow-up was 10±9 years. Nephrotic syndrome was defined by proteinuria ≥3.5 g/d, and patients were classified according to underlying histological lesions accounting for nephrotic syndrome. Objectively verified symptomatic thromboembolic events were the primary study outcome. Annual incidences of VTE and ATE were 1.02% (95% confidence interval, 0.68 to 1.46) and 1.48% (95% confidence interval, 1.07 to 1.99), respectively. Over the first 6 months of follow-up, these rates were 9.85% and 5.52%, respectively. Proteinuria and serum albumin levels tended to be related to VTE; however, only the predictive value of the ratio of proteinuria to serum albumin was significant (hazard ratio, 5.6; 95% confidence interval, 1.2 to 26.2; P=0.03). In contrast, neither the degree of proteinuria nor serum albumin levels were related to ATE. Sex, age, hypertension, diabetes, smoking, prior ATE, and estimated glomerular filtration rate predicted ATE (P≤0.02). Conclusions— This study verifies high absolute risks of symptomatic VTE and ATE that were remarkably elevated within the first 6 months. Whereas the ratio of proteinuria to serum albumin predicted VTE, estimated glomerular filtration rate and multiple classic risk factors for atherosclerosis were predictors of ATE.", "corpus_id": 11402617, "score": 0 }, { "doc_id": "30915432", "title": "Histological diagnosis and risk of renal vein thrombosis, and other thrombotic complications in primitive nephrotic syndrome.", "abstract": "BACKGROUND\nThe risk of thromboembolic events is increased in patients with nephrotic syndrome (NS) as compared with other medical conditions and is a severe complication associated with significant morbidity and mortality. We aimed to assess the risk of renal vein thrombosis, and other venous thromboembolic events (VTE) in a large cohort of patients with NS and to identify the disease-specific risk for VTE.\n\n\nPATIENTS AND METHODS\nWe performed a prospective observational study including consecutive adult patients with primitive NS admitted to our department. Clinical and biological data were obtained every six months during follow-up. Occurrence of VTE confirmed by imaging techniques was the primary study outcome.\n\n\nRESULTS\nWe enrolled 191 patients (47±15 years, 53% men) with a median follow-up of 24 [IQR:12,36] months. During follow-up, 23 VTE occurred, of which 65.2% in the first six months. The disease-specific risk of VTE during the follow-up period was different across the histological groups, with the lowest risk in minimal change disease and IgA nephropathy and the highest in membranous nephropathy and membranoproliferative glomerulonephritis patients. In the subgroup of membranous, the severity of the subepithelial electron dense deposits did not correlate with the risk for VTE (p=0.5).\n\n\nCONCLUSIONS\nIn this prospective study, the risk of VTE was higher in the first six months of follow-up in NS patients. The histological pattern seems to influence the risk of VTE in this setting.", "corpus_id": 30915432, "score": 1 }, { "doc_id": "207330587", "title": "Venous thromboembolism in patients with membranous nephropathy.", "abstract": "BACKGROUND AND OBJECTIVES\nThe aims of this study were to determine the frequency of venous thromboembolic events in a large cohort of patients with idiopathic membranous nephropathy and to identify predisposing risk factors.\n\n\nDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS\nWe studied patients with biopsy-proven membranous nephropathy from the Glomerular Disease Collaborative Network (n=412) and the Toronto Glomerulonephritis Registry (n=486) inception cohorts. The cohorts were pooled after establishing similar baseline characteristics (total n=898). Clinically apparent and radiologically confirmed venous thromboembolic events were identified. Potential risk factors were evaluated using multivariable logistic regression models.\n\n\nRESULTS\nSixty-five (7.2%) subjects had at least one venous thromboembolic event, and this rate did not differ significantly between registries. Most venous thromboembolic events occurred within 2 years of first clinical assessment (median time to VTE = 3.8 months). After adjusting for age, sex, proteinuria, and immunosuppressive therapy, hypoalbuminemia at diagnosis was the only independent predictor of a venous thromboembolic event. Each 1.0 g/dl reduction in serum albumin was associated with a 2.13-fold increased risk of VTE. An albumin level <2.8 g/dl was the threshold below which risk for a venous thromboembolic event was greatest.\n\n\nCONCLUSIONS\nWe conclude that clinically apparent venous thromboembolic events occur in about 7% of patients with membranous nephropathy. Hypoalbuminemia, particularly <2.8 g/dl, is the most significant independent predictor of venous thrombotic risk.", "corpus_id": 207330587, "score": 0 }, { "doc_id": "7694032", "title": "Proteinuria and hypoalbuminemia are risk factors for thromboembolic events in patients with idiopathic membranous nephropathy: an observational study", "abstract": "BackgroundPatients with nephrotic syndrome are at an increased risk of thromboembolic events (TEs). However, this association has not been thoroughly investigated in adult patients with idiopathic membranous nephropathy (IMN).MethodsA retrospective analysis of all 101 consecutive adult patients with MN diagnosed at our centre during 1995 to 2008 was performed. Pertinent data including thromboembolic events and the risk factors for TEs were recorded.ResultsThe cohort was followed for 7.2 ± 3 years. Out of 78 patients with IMN, 15 (19.2%) had at least one TE. No TEs occurred six months after diagnosis. The incidence of TEs in the first 6 months of diagnosis was 7.69% (95%CI, 2.5-17.0) and all patients except one had venous TEs. At the time of diagnosis of MN, the patients with TEs had lower serum albumin (1.9 ± 0.5 vs. 2.4 ± 0.4 g/dl, TE vs. no TE; p < 0.01) and greater serum cholesterol (414 ± 124 vs. 317 ± 108 mg/dl, TE vs. no TE; p = 0.01) and 24-h proteinuria (10.7 ± 3 vs. 7.1 ± 4 g, TE vs. no TE; p < 0.01). Multivariate logistic regression adjusted for age, sex, cholesterol and creatinine revealed, an odds ratio of 0.8 (95% CI 0.7 – 0.96; p = 0.01) for every one g/dl increase in baseline serum albumin and, an odds ratio of 1.3 (95% CI 1.05-1.58; p = 0.01) for one gram increase in 24-h proteinuria, for TEs.ConclusionsOur study finding confirms IMN as a prothrombotic state particularly in the first six months of diagnosis. Proteinuria, in addition to hypoalbuminemia, is a risk factor for TEs. These results have important implications for clinical care of patients with IMN, particularly with regards to initiation and duration of prophylactic anticoagulation.", "corpus_id": 7694032, "score": 1 }, { "doc_id": "24346530", "title": "Bilateral renal vein thrombosis and pulmonary embolism secondary to membranous glomerulonephritis treated with percutaneous catheter thrombectomy and localized thrombolytic therapy", "abstract": "Renal vein thrombosis (RVT) is a rare event but is prevalent in patients with nephrotic syndrome. Bilateral RVT is even rarer. The literature is relatively sparse in terms of the management of RVT because of its rarity and consists of a few case reports and case series. We present a case with bilateral RVT complicated by a pulmonary embolism in a patient with membranous glomerulonephritis (MGN). A 19-year-old female presented with acute flank pain and worsening renal function after a couple of weeks in hospital while being treated with diuretics for anasarca secondary to MGN. Venography was used for diagnosis. The patient underwent percutaneous catheter thrombectomy and localized thrombolysis achieving resolution of pain and improvement of renal function. The patient was then anticoagulated for life with warfarin.", "corpus_id": 24346530, "score": 0 }, { "doc_id": "7926732", "title": "Personalized prophylactic anticoagulation decision analysis in patients with membranous nephropathy.", "abstract": "Primary membranous nephropathy is associated with increased risk of venous thromboembolic events, which are inversely correlated with serum albumin levels. To evaluate the potential benefit of prophylactic anticoagulation (venous thromboembolic events prevented) relative to the risk (major bleeds), we constructed a Markov decision model. The venous thromboembolic event risk according to serum albumin was obtained from an inception cohort of 898 patients with primary membranous nephropathy. Risk estimates of hemorrhage were obtained from a systematic literature review. Benefit-to-risk ratios were predicted according to bleeding risk and serum albumin. This ratio increased with worsening hypoalbuminemia from 4.5:1 for an albumin under 3 g/dl to 13.1:1 for an albumin under 2 g/dl in patients at low bleeding risk. Patients at intermediate bleeding risk with an albumin under 2 g/dl have a moderately favorable benefit-to-risk ratio (under 5:1). Patients at high bleeding risk are unlikely to benefit from prophylactic anticoagulation regardless of albuminemia. Probabilistic sensitivity analysis, to account for uncertainty in risk estimates, confirmed these trends. From these data, we constructed a tool to estimate the likelihood of benefit based on an individual's bleeding risk profile, serum albumin level, and acceptable benefit-to-risk ratio (www.gntools.com). This tool provides an approach to the decision of prophylactic anticoagulation personalized to the individual's needs and adaptable to dynamic changes in health status and risk profile.", "corpus_id": 7926732, "score": 0 } ]

{ "doc_id": "51920294", "title": "The influence of semi-volatile and reactive primary emissions on the abundance and properties of global organic aerosol", "abstract": "Abstract. Semi-volatile and reactive primary organic aerosols are modeled on a global scale using the GISS GCM II' \"unified\" climate model. We employ the volatility basis set framework to simulate emissions, chemical reactions and phase partitioning of primary and secondary organic aerosol (POA and SOA). The model also incorporates the emissions and reactions of intermediate volatility organic compounds (IVOCs) as a source of organic aerosol (OA), one that has been missing in most prior work. Model predictions are evaluated against a broad set of observational constraints including mass concentrations, degree of oxygenation, volatility and isotopic composition. A traditional model that treats POA as non-volatile and non-reactive is also compared to the same set of observations to highlight the progress made in this effort. The revised model predicts a global dominance of SOA and brings the POA/SOA split into better agreement with ambient measurements. This change is due to traditionally defined POA evaporating and the evaporated vapors oxidizing to form non-traditional SOA. IVOCs (traditionally not included in chemical transport models) oxidize to form condensable products that account for a third of total OA, suggesting that global models have been missing a large source of OA. Predictions of the revised model for the SOA fraction at 17 different locations compared much better to observations than predictions from the traditional model. Model-predicted volatility is compared with thermodenuder data collected at three different different field campaigns: FAME-2008, MILAGRO-2006 and SOAR-2005. The revised model predicts the OA volatility much more closely than the traditional model. When compared against monthly averaged OA mass concentrations measured by the IMPROVE network, predictions of the revised model lie within a factor of two in summer and mostly within a factor of five during winter. A sensitivity analysis indicates that the winter comparison can be improved either by increasing POA emissions or lowering the volatility of those emissions. Model predictions of the isotopic composition of OA are compared against those computed via a radiocarbon isotope analysis of field samples. The contemporary fraction, on average, is slightly under-predicted (20 %) during the summer months but is a factor of two lower during the winter months. We hypothesize that the large wintertime under-prediction of surface OA mass concentrations and the contemporary fraction is due to an under-representation of biofuel (particularly, residential wood burning) emissions in the emissions inventory. Overall, the model evaluation highlights the importance of treating POA as semi-volatile and reactive in order to predict accurately the sources, composition and properties of ambient OA.", "corpus_id": 51920294 }

[ { "doc_id": "236806", "title": "Health effects of air pollution.", "abstract": "The general public, especially patients with upper or lower respiratory symptoms, is aware from media reports that adverse respiratory effects can occur from air pollution. It is important for the allergist to have a current knowledge of the potential health effects of air pollution and how they might affect their patients to advise them accordingly. Specifically, the allergist-clinical immunologist should be keenly aware that both gaseous and particulate outdoor pollutants might aggravate or enhance the underlying pathophysiology of both the upper and lower airways. Epidemiologic and laboratory exposure research studies investigating the health effects of outdoor air pollution each have advantages and disadvantages. Epidemiologic studies can show statistical associations between levels of individual or combined air pollutants and outcomes, such as rates of asthma, emergency visits for asthma, or hospital admissions, but cannot prove a causative role. Human exposure studies, animal models, and tissue or cellular studies provide further information on mechanisms of response but also have inherent limitations. The aim of this rostrum is to review the relevant publications that provide the appropriate context for assessing the risks of air pollution relative to other more modifiable environmental factors in patients with allergic airways disease.", "corpus_id": 236806, "score": 0 }, { "doc_id": "42885140", "title": "Ubiquity and Dominance of Oxygenated Species in Organic Aerosols in", "abstract": "[1] Organic aerosol (OA) data acquired by the Aerosol Mass Spectrometer (AMS) in 37 field campaigns were deconvolved into hydrocarbon-like OA (HOA) and several types of oxygenated OA (OOA) components. HOA has been linked to primary combustion emissions (mainly from fossil fuel) and other primary sources such as meat cooking. OOA is ubiquitous in various atmospheric environments, on average accounting for 64%, 83% and 95% of the total OA in urban, urban downwind, and rural/remote sites, respectively. A case study analysis of a rural site shows that the OOA concentration is much greater than the advected HOA, indicating that HOA oxidation is not an important source of OOA, and that OOA increases are mainly due to SOA. Most global models lack an explicit representation of SOA which may lead to significant biases in the magnitude, spatial and temporal distributions of OA, and in aerosol hygroscopic properties.", "corpus_id": 42885140, "score": 1 }, { "doc_id": "7276007", "title": "Secondary organic aerosol formation from high-NO(x) photo-oxidation of low volatility precursors: n-alkanes.", "abstract": "Smog chamber experiments were conducted to investigate secondary organic aerosol (SOA) formation from photo-oxidation of low-volatility precursors; n-alkanes were chosen as a model system. The experiments feature atmospherically relevant organic aerosol concentrations (C(OA)). Under high-NO(x) conditions SOA yields increased with increasing carbon number (lower volatility) for n-decane, n-dodecane, n-pentadecane, and n-heptadecane, reaching a yield of 0.51 for heptadecane at a C(OA) of 15.4 microg m(-3). As with other photo-oxidation systems, aerosol yield increased with UV intensity. Due to the log-linear relationship between n-alkane carbon number and vapor pressure as well as a relatively consistent product distribution it was possible to develop an empirical parametrization for SOA yields for n-alkanes between C(12) and C(17). This parametrization was implemented using the volatility basis set framework and is designed for use in chemical transport models. For C(OA) < 2 microg m(-3), the SOA mass spectrum, as measured with an aerosol mass spectrometer, had a large contribution from m/z 44, indicative of highly oxygenated products. At higher C(OA), the mass spectrum was dominated by m/z 30, indicative of organic nitrates. The data support the conclusion that lower volatility organic vapors are important SOA precursors.", "corpus_id": 7276007, "score": 0 }, { "doc_id": "10456851", "title": "Global distribution and climate forcing of carbonaceous aerosols", "abstract": "The global distribution of carbonaceous aerosols is simulated online in the Goddard Institute for Space Studies General Circulation Model II-prime (GISS GCM II-prime). Prognostic tracers include black carbon (BC), primary organic aerosol (POA), five groups of biogenic volatile organic compounds (BVOCs), and 14 semivolatile products of BVOC oxidation by O_3, OH, and NO_3, which condense to form secondary organic aerosols (SOA) based on an equilibrium partitioning model and experimental observations. Estimated global burdens of BC, organic carbon (OC), and SOA are 0.22, 1.2, and 0.19 Tg with lifetimes of 6.4, 5.3, and 6.2 days, respectively. The predicted global production of SOA is 11.2 Tg yr^(−1), with 91% due to O_3 and OH oxidation. Globally averaged, top of the atmosphere (TOA) radiative forcing by anthropogenic BC is predicted as +0.51 to +0.8 W m^(−2), the former being for BC in an external mixture and the latter for BC in an internal mixture of sulfate, OC, and BC. Globally averaged, anthropogenic BC, OC, and sulfate are predicted to exert a TOA radiative forcing of −0.39 to −0.78 W m^(−2), depending on the exact assumptions of aerosol mixing and water uptake by OC. Forcing estimates are compared with those published previously.", "corpus_id": 10456851, "score": 1 }, { "doc_id": "18556507", "title": "Regional Visibility Statistics in the United States: Natural and Transboundary Pollution Influences, and Implications for the Regional Haze Rule", "abstract": "The Regional Haze Rule of the US Environmental Protection Agency mandates reduction in US anthropogenic emissions to achieve linear improvement of visibility in wilderness areas over the 2004–18 period toward an endpoint of natural visibility conditions by 2064. Linear improvement is to apply to the mean visibility degradation on the statistically 20% worst days, measured as a Haze Index in units of deciviews (log of aerosol extinction). We use a global chemical transport model (GEOS-Chem) with 11 � 11 horizontal resolution to simulate present-day visibility statistics in the USA, compare them to observations from the Interagency Monitoring of Protected Visual Environments (IMPROVE) surface network, and provide natural and background visibility statistics for application of the Regional Haze Rule. Background is defined by suppression of US anthropogenic emissions but allowance for present-day foreign emissions and associated import of pollution. Our model is highly successful at reproducing the observed variability of visibility statistics for present-day conditions, including the low tail of the frequency distribution that is most representative of natural or background conditions. We find considerable spatial and temporal variability in natural visibility over the USA, especially due to fires in the west. A major uncertainty in estimating natural visibility is the sensitivity of biogenic organic aerosol formation to the availability of preexisting anthropogenic aerosol. Background visibility is more variable than natural visibility and the 20% worst days show large contributions from Canadian and Mexican pollution. Asian pollution, while degrading mean background visibility, is relatively less important on the worst days. Recognizing the influence of uncontrollable transboundary pollution in the Regional Haze Rule would substantially decrease the schedule of emission reductions required in the 2004–18 implementation phase. Meaningful application of the Rule in the future will require projections of future trends in foreign anthropogenic emissions, wildfire frequency, and climate variables. r 2006 Elsevier Ltd. All rights reserved.", "corpus_id": 18556507, "score": 0 }, { "doc_id": "128426374", "title": "Budget of organic carbon in a polluted atmosphere: Results from the New England Air Quality Study in 2002", "abstract": "[1] An extensive set of volatile organic compounds (VOCs) and particulate organic matter (POM) was measured in polluted air during the New England Air Quality Study in 2002. Using VOC ratios, the photochemical age of the sampled air masses was estimated. This approach was validated (1) by comparing the observed rates at which VOCs were removed from the atmosphere with the rates expected from OH oxidation, (2) by comparing the VOC emission ratios inferred from the data with the average composition of urban air, and (3) by the ability to describe the increase of an alkyl nitrate with time in terms of the chemical kinetics. A large part of the variability observed for oxygenated VOCs (OVOCs) and POM could be explained by a description that includes the removal of the primary anthropogenic emissions, the formation and removal of secondary anthropogenic species, and a biogenic contribution parameterized by the emissions of isoprene. The OVOC sources determined from the data are compared with the available literature, and a satisfactory agreement is obtained. The observed sub-μm POM was highly correlated with secondary anthropogenic gas-phase species, strongly suggesting that the POM was from secondary anthropogenic sources. The results are used to describe the speciation and total mass of gas- and particle-phase organic carbon as a function of the photochemical age of an urban air mass. Shortly after emission the organic carbon mass is dominated by primary VOCs, while after two days the dominant contribution is from OVOCs and sub-μm POM. The total measured organic carbon mass decreased by about 40% over the course of two days. The increase in sub-μm POM could not be explained by the removal of aromatic precursors alone, suggesting that other species must have contributed and/or that the mechanism for POM formation is more efficient than previously assumed.", "corpus_id": 128426374, "score": 0 }, { "doc_id": "18090955", "title": "A Large Organic Aerosol Source in the Free Troposphere Missing from Current Models", "abstract": "average 4 m gs m 3 in the 2–6.5 km column with little vertical gradient. These values are 10–100 times higher than computed with a global chemical transport model (CTM) including a standard 2-product simulation of secondary organic aerosol (SOA) formation based on empirical fits to smog chamber data. The same CTM reproduces the observed vertical profiles of sulfate and elemental carbon aerosols, which indicate sharp decreases from the boundary layer to the FT due to wet scavenging. Our results suggest a large, sustained source of SOA in the FT from oxidation of long-lived volatile organic compounds. We find that this SOA is the dominant component of aerosol mass in the FT, with implications for intercontinental pollution transport and radiative forcing of climate. Citation: Heald, C. L., D. J. Jacob, R. J. Park, L. M. Russell, B. J. Huebert, J. H. Seinfeld, H. Liao, and R. J. Weber (2005), A large organic aerosol source in the free troposphere missing from current models, Geophys. Res. Lett., 32, L18809, doi:10.1029/2005GL023831.", "corpus_id": 18090955, "score": 0 }, { "doc_id": "35016603", "title": "Secondary organic aerosol formation from anthropogenic air pollution: Rapid and higher than expected", "abstract": "[1] The atmospheric chemistry of volatile organic compounds (VOCs) in urban areas results in the formation of ‘photochemical smog’, including secondary organic aerosol (SOA). State-of-the-art SOA models parameterize the results of simulation chamber experiments that bracket the conditions found in the polluted urban atmosphere. Here we show that in the real urban atmosphere reactive anthropogenic VOCs (AVOCs) produce much larger amounts of SOA than these models predict, even shortly after sunrise. Contrary to current belief, a significant fraction of the excess SOA is formed from first-generation AVOC oxidation products. Global models deem AVOCs a very minor contributor to SOA compared to biogenic VOCs (BVOCs). If our results are extrapolated to other urban areas, AVOCs could be responsible for additional 3–25 Tg yr−1 SOA production globally, and cause up to −0.1 W m−2 additional top-of-the-atmosphere radiative cooling.", "corpus_id": 35016603, "score": 0 }, { "doc_id": "9967031", "title": "A Particle-into-Liquid Collector for Rapid Measurement of Aerosol Bulk Chemical Composition", "abstract": "We report on a new instrument developed for rapid automated on-line and continuous measurement of ambient aerosol bulk com- position.The general approach is based on earlier devices (Khlystov et al. 1995; Simon and Dasgupta 1995) in which ambient particles are mixed with saturated water vapor to produce droplets easily collected by inertial techniques. The resulting liquid stream is analyzed with an ion chromatograph to quantitatively measure the bulk aerosol ionic components. In this instrument, a modified ver- sion of a particle size magnifier (Okuyama et al. 1984) is employed to activate and grow particles comprising the fine aerosol mass. A single jet inertial impactor is used to collect the droplets onto a vertical glass plate that is continually washed with a constant water diluent flow of nominally 0.10 ml min-1", "corpus_id": 9967031, "score": 0 }, { "doc_id": "20903347", "title": "Rethinking Organic Aerosols: Semivolatile Emissions and Photochemical Aging", "abstract": "Most primary organic-particulate emissions are semivolatile; thus, they partially evaporate with atmospheric dilution, creating substantial amounts of low-volatility gas-phase material. Laboratory experiments show that photo-oxidation of diesel emissions rapidly generates organic aerosol, greatly exceeding the contribution from known secondary organic-aerosol precursors. We attribute this unexplained secondary organic-aerosol production to the oxidation of low-volatility gas-phase species. Accounting for partitioning and photochemical processing of primary emissions creates a more regionally distributed aerosol and brings model predictions into better agreement with observations. Controlling organic particulate-matter concentrations will require substantial changes in the approaches that are currently used to measure and regulate emissions.", "corpus_id": 20903347, "score": 1 }, { "doc_id": "2061019", "title": "Chemically-resolved aerosol volatility measurements from two megacity field studies", "abstract": "Abstract. The volatilities of different chemical species in ambient aerosols are important but remain poorly characterized. The coupling of a recently developed rapid temperature-stepping thermodenuder (TD, operated in the range 54–230°C) with a High-Resolution Time-of-Flight Aerosol Mass Spectrometer (HR-ToF-AMS) during field studies in two polluted megacities has enabled the first direct characterization of chemically-resolved urban particle volatility. Measurements in Riverside, CA and Mexico City are generally consistent and show ambient nitrate as having the highest volatility of any AMS standard aerosol species while sulfate showed the lowest volatility. Total organic aerosol (OA) showed volatility intermediate between nitrate and sulfate, with an evaporation rate of 0.6%·K−1 near ambient temperature, although OA dominates the residual species at the highest temperatures. Different types of OA were characterized with marker ions, diurnal cycles, and positive matrix factorization (PMF) and show significant differences in volatility. Reduced hydrocarbon-like OA (HOA, a surrogate for primary OA, POA), oxygenated OA (OOA, a surrogate for secondary OA, SOA), and biomass-burning OA (BBOA) separated with PMF were all determined to be semi-volatile. The most aged OOA-1 and its dominant ion, CO2+, consistently exhibited the lowest volatility, with HOA, BBOA, and associated ions for each among the highest. The similar or higher volatility of HOA/POA compared to OOA/SOA contradicts the current representations of OA volatility in most atmospheric models and has important implications for aerosol growth and lifetime. A new technique using the AMS background signal was demonstrated to quantify the fraction of species up to four orders-of-magnitude less volatile than those detectable in the MS mode, which for OA represent ~5% of the non-refractory (NR) OA signal. Our results strongly imply that all OA types should be considered semivolatile in models. The study in Riverside identified organosulfur species (e.g. CH3HSO3+ ion, likely from methanesulfonic acid), while both studies identified ions indicative of amines (e.g. C5H12N+) with very different volatility behaviors than inorganic-dominated ions. The oxygen-to-carbon ratio of OA in each ambient study was shown to increase both with TD temperature and from morning to afternoon, while the hydrogen-to-carbon ratio showed the opposite trend.", "corpus_id": 2061019, "score": 0 }, { "doc_id": "15895913", "title": "Evolving mass spectra of the oxidized component of organic aerosol : results from aerosol mass spectrometer analyses of aged diesel emissions", "abstract": "The species and chemistry responsible for secondary organic aerosol (SOA) formation remain highly uncertain. Laboratory studies of the oxidation of individual, high-flux SOA precursors do not lead to particles with mass spectra (MS) matching those of ambient aged organic material. Additionally, the complexity of real organic particles challenges efforts to identify their chemical origins. We have previously hypothesized that SOA can form from the atmospheric oxidation of a large suite of precursors with varying vapor pressures. Here, we support this hypothesis by using an aerosol mass spectrometer to track the chemical evolution of diesel exhaust as it is photochemically oxidized in an environmental chamber. With explicit knowledge of the condensed-phase MS of the primary emissions from our engine, we are able to decompose each recorded MS into contributing primary and secondary spectra throughout the experiment. We find that the SOA becomes increasingly oxidized as a function of time, quickly approaching a final MS that closely resembles that of ambient aged organic particulate matter. This observation is consistent with our hypothesis of an evolving suite of SOA precursors. Low vapor pressure, semi-volatile organic emissions can form condensable products with even a single generation of oxidation, resulting in an early-arising, relatively less-oxidized SOA. Continued gas-phase oxidation can form highly oxidized SOA in surprisingly young air masses via reaction mechanisms that can add multiple oxygen atoms per generation and result in products with sustained or increased reactivity toward OH. Correspondence to: N. M. Donahue (nmd@cmu.edu)", "corpus_id": 15895913, "score": 0 }, { "doc_id": "17968644", "title": "Laboratory investigation of photochemical oxidation of organic aerosol from wood fires 1: measurement and simulation of organic aerosol evolution", "abstract": "Abstract. Experiments were conducted to investigate the effects of photo-oxidation on organic aerosol (OA) emissions from flaming and smoldering hard- and soft-wood fires under plume-like conditions. This was done by exposing the dilute emissions from a small wood stove to UV light in a smog chamber and measuring the gas- and particle-phase pollutant concentrations with a suite of instruments including a Proton Transfer Reaction Mass Spectrometer (PTR-MS), an Aerosol Mass Spectrometer (AMS) and a thermodenuder. The measurements highlight how atmospheric processing can lead to considerable evolution of the mass and volatility of biomass-burning OA. Photochemical oxidation produced substantial new OA, increasing concentrations by a factor of 1.5 to 2.8 after several hours of exposure to typical summertime hydroxyl radical (OH) concentrations. Less than 20% of this new OA could be explained using a state-of-the-art secondary organic aerosol model and the measured decay of traditional SOA precursors. The thermodenuder data indicate that the primary OA is semivolatile; at 50°C between 50 and 80% of the fresh primary OA evaporated. Aging reduced the volatility of the OA; at 50°C only 20 to 40% of aged OA evaporated. The predictions of a volatility basis-set model that explicitly tracks the partitioning and aging of low-volatility organics was compared to the chamber data. The OA production can be explained by the oxidation of low-volatility organic vapors; the model can also reproduce observed changes in OA volatility and composition. The model was used to investigate the competition between photochemical processing and dilution on OA concentrations in plumes.", "corpus_id": 17968644, "score": 0 }, { "doc_id": "206997654", "title": "Photo-oxidation of low-volatility organics found in motor vehicle emissions: production and chemical evolution of organic aerosol mass.", "abstract": "Recent research has proposed that low-volatility organic vapors are an important class of secondary organic aerosol (SOA) precursors. Mixtures of low-volatility organics were photo-oxidized in a smog chamber under low- and high-NO(x) conditions. Separate experiments addressed emission surrogates (diesel fuel and motor oil) and single components (n-pentacosane). Both diesel fuel and motor oil are major components of exhaust from diesel engines. Diesel fuel is a complex mixture of intermediate volatility organic compounds (IVOCs), whereas motor oil is a complex mixture of semivolatile organic compounds (SVOCs). IVOCs exist exclusively in the vapor phase, while SVOCs exist in both the aerosol and vapor phase. Oxidation of SVOC vapors (motor oil and n-pentacosane) creates substantial SOA, but this SOA is largely offset by evaporation of primary organic aerosol (POA). The net effect is a cycling or pumping of SVOCs between the gas and particle phases, which creates more oxygenated organic aerosol (OA) but little new OA mass. Since gas-phase reactions are much faster than heterogeneous ones, the processing of SVOC vapors likely contributes to the production of highly oxidized OA. The interplay between gas-particle partitioning and chemistry also blurs traditional definitions of POA and SOA. Photo-oxidation of diesel fuel (IVOCs) rapidly creates substantial new OA mass, similar to published aging experiments with dilute diesel exhaust. However, aerosol mass spectrometer (AMS) data indicated that the SOA formed from emission surrogates is less oxidized than either the oxygenated organic aerosol (OOA) measured in the atmosphere or SOA formed from the photo-oxidation of dilute diesel exhaust. Therefore, photo-oxidation of IVOCs helps explain the substantial SOA mass produced from aging diesel exhaust, but some component is missing from these emission surrogate experiments that leads to the rapid production of highly oxygenated SOA.", "corpus_id": 206997654, "score": 0 }, { "doc_id": "32946766", "title": "Simulating the formation of semivolatile primary and secondary organic aerosol in a regional chemical transport model.", "abstract": "Recent developments in our understanding of atmospheric organic particulate matter formation have been used to develop a state-of-the-art organic aerosol module for regional chemical transport models (CTMs). The module has been added to the regional CTM, PMCAMx, and has been evaluated against observations in the eastern U.S. The new module uses the volatility basis set framework to simulate primary organic aerosol (POA) partitioning between the gas and particulate phases and the gas-phase oxidation of the corresponding vapors. The formation and chemical aging of secondary organic aerosol (SOA) are modeled using the same volatility distribution approach. The module uses recent results from smog chamber studies for the formation of SOA from anthropogenic and biogenic hydrocarbons. Hourly organic aerosol predictions are evaluated using data from the Pittsburgh Air Quality Study (PAQS), and daily averaged predictions for July 2001 are compared to ambient measurements from the EPA Speciated Trends Network (STN) and the Interagency Monitoring of Protected Visual Environments (IMPROVE). The model reproduces both the absolute organic aerosol concentrations in urban and rural locations as well as the high degree of oxidation of these compounds. The chemical aging of anthropogenic SOA is consistent with the ambient organic aerosol concentration field and has a significant impact on the absolute ground-level concentrations of these compounds.", "corpus_id": 32946766, "score": 1 }, { "doc_id": "129731787", "title": "Use of on-line tracers as a diagnostic tool in general circulation model development 1. Horizontal and vertical transport in the troposphere", "abstract": "The use of passive on-line tracers in a general circulation model (GCM) developmental process is discussed. CFC-11 and 85Kr are used to evaluate interhemispheric transport. It is shown that new boundary layer and convective parameterizations lead to reductions in the interhemispheric exchange times to values in close agreement with observations of little more than one year. Radon 222 is used to evaluate vertical mixing away from the surface. The new convection scheme produces smaller convective fluxes, which substantially reduce the high-altitude concentrations of 222Rn equatorward of 30° latitude. While this result is in better agreement with other models, scarcity of observations prevent any conclusion as to which formulation is more accurate. The effect of altered numerical schemes for solution of the momentum and energy equations in the GCM is shown to have little influence on the model's interhemispheric transport or vertical mixing. Finer vertical resolution increases convective mixing of 222Rn somewhat and allows for larger pollution concentrations of CFC-11 in the boundary layer. Employing on-line passive tracers in the course of model development should allow for improvements in a GCM's horizontal and vertical fluxes and optimization of the model for atmospheric chemistry purposes.", "corpus_id": 129731787, "score": 1 }, { "doc_id": "102817745", "title": "Use of On-Line Tracers as a Diagnostic Tool in General Circulation Model Development", "abstract": "A key component of climate/chemistry modeling is how to handle the influx into (and egress from) the troposphere. This is especially important when considering tropospheric ozone, and its precursors (e.g., NO(x) from aircraft). A study has been conducted with various GISS models to determine the minimum requirements necessary for producing realistic troposphere-stratosphere exchange. Four on-line tracers are employed: CFC-11 and SF6 for mixing from the troposphere into the stratosphere, Rn222 for vertical mixing within the troposphere, and 14C for mixing from the stratosphere into the troposphere. Four standard models are tested, with varying vertical resolution, gravity wave drag and location of the model top, and additional subsidiary models are employed to examine specific features. The results show that proper vertical transport between the troposphere and stratosphere in the GISS models requires lifting the top of the model considerably out of the stratosphere, and including gravity wave drag in the lower stratosphere. Increased vertical resolution without these aspects does not improve troposphere-stratosphere exchange. The transport appears to be driven largely by the residual circulation within the stratosphere; associated E-P flux convergences require both realistic upward propagating energy from the troposphere, and realistic pass-through possibilities. A 23 layer version with a top at the mesopause and incorporating gravity wave drag appears to have reasonable stratospheric-tropospheric exchange, in terms of both the resulting tracer distributions and atmospheric mass fluxes.", "corpus_id": 102817745, "score": 0 }, { "doc_id": "988840", "title": "Global radiative forcing of coupled tropospheric ozone and aerosols in a unified general circulation model", "abstract": "Space Studies (GISS) GCM II 0 , that simulates coupled tropospheric ozone-NOxhydrocarbon chemistry and sulfate, nitrate, ammonium, black carbon, primary organic carbon, and secondary organic carbon aerosols. The fully coupled gas-aerosol unified GCM allows one to evaluate the extent to which global burdens, radiative forcing, and eventually climate feedbacks of ozone and aerosols are influenced by gas-aerosol chemical interactions. Estimated present-day global burdens of sea salt and mineral dust are 6.93 and 18.1 Tg with lifetimes of 0.4 and 3.9 days, respectively. The GCM is applied to estimate current top of atmosphere (TOA) and surface radiative forcing by tropospheric ozone and all natural and anthropogenic aerosol components. The global annual mean value of the radiative forcing by tropospheric ozone is estimated to be +0.53 W m � 2 at TOA and +0.07 W m � 2 at the Earth’s surface. Global, annual average TOA and surface radiative forcing by all aerosols are estimated as � 0.72 and � 4.04 W m � 2 , respectively. While the predicted highest aerosol cooling and heating at TOA are � 10 and +12 W m � 2 , respectively, surface forcing can reach values as high as � 30 W m � 2 , mainly caused by the absorption by black carbon, mineral dust, and OC. We also estimate the effects of chemistry-aerosol coupling on forcing estimates based on currently available understanding of heterogeneous reactions on aerosols. Through altering the burdens of sulfate, nitrate, and ozone, heterogeneous reactions are predicted to change the global mean TOA forcing of aerosols by 17% and influence global mean TOA forcing of tropospheric ozone by 15%. INDEX TERMS: 0305 Atmospheric Composition and Structure: Aerosols and particles (0345, 4801); 0345 Atmospheric Composition and Structure: Pollution—urban and regional (0305); 0365 Atmospheric Composition and Structure: Troposphere—composition and chemistry;", "corpus_id": 988840, "score": 0 }, { "doc_id": "129317527", "title": "Global concentrations of tropospheric sulfate, nitrate, and ammonium aerosol simulated in a general circulation model", "abstract": "Global sulfate aerosol composition is simulated online in the Goddard Institute for Space Studies general circulation model II′ (GISS GCM II-prime). Four sulfur species, hydrogen peroxide, gas phase ammonia, and particulate ammonium are the prognostic tracer species, the emissions, transport, and deposition of which are explicitly simulated. Nitric acid fields are prescribed based on a global chemical transport model. An online thermodynamic equilibrium calculation determines the partitioning of ammonia and nitrate between gas and aerosol phases, and the quantity of aerosol water based on the temperature, relative humidity, and sulfate concentration in each GCM grid cell. The total global burden of sulfate, nitrate, ammonium, and aerosol water is 7.5 Tg and is most sensitive to changes in sulfur emissions. Tropospheric lifetimes for ammonium and ammonia are 4.2 and 0.9 days, respectively; the tropospheric ammonium burden is 0.30 Tg N, compared with 0.14 Tg N for ammonia. Simulated ammonium concentrations are generally within a factor of 2 of observations. Subgrid variability in measured concentrations hinders comparison of observations to predictions. Ammonium nitrate aerosol plays an important role in determining total aerosol mass in polluted continental areas. In the upper troposphere and near the poles, cold temperatures allow unneutralized nitric acid to condense into the aerosol phase. Acidic aerosol species tend to be neutralized by ammonia to a greater degree over continents than over oceans. The aerosol is most basic and gas phase ammonia concentrations are highest over India. Water uptake per mole of sulfate aerosol varies by two orders of magnitude because of changes in relative humidity and aerosol composition. Spatial variations in aerosol composition and water uptake have implications for direct and indirect aerosol radiative forcing.", "corpus_id": 129317527, "score": 0 }, { "doc_id": "17442370", "title": "Modeling global secondary organic aerosol formation and processing with the volatility basis set: Implications for anthropogenic secondary organic aerosol", "abstract": "[1] The volatility basis set, a computationally efficient framework for the description of organic aerosol partitioning and chemical aging, is implemented in the Goddard Institute for Space Studies General Circulation Model II' for a coupled global circulation and chemical transport model to simulate secondary organic aerosol (SOA) formation. The latest smog chamber information about the yields of anthropogenic and biogenic precursors is incorporated in the model. SOA formation from monoterpenes, sesquiterpenes, isoprene, and anthropogenic precursors is estimated as 17.2, 3.9, 6.5, and 1.6 Tg yr -1 , respectively. Reducing water solubility of secondary organic gas from 10 5 to 10 3 mol L -1 atm -1 (1 atm = 1.01325 x 10 5 N m -2 ) leads to a 90% increase in SOA production and an increase of over 340% in total atmospheric burden, from 0.54 to 2.4 Tg. Increasing the temperature sensitivity of SOA leads to a 30% increase in production, to 38.2 Tg yr -1 . Since the additional SOA is formed at high altitude, where deposition time scales are longer, the average lifetime is doubled from 6.8 to 14.3 days, resulting in a near tripling of atmospheric burden to 1.5 Tg. Chemical aging of anthropogenic SOA by gas-phase reaction of the SOA components with the hydroxyl radical adds an additional 2.7-9.3 Tg yr -1 of anthropogenic SOA to the above production rates and nearly doubles annual average total SOA burdens. The possibility of such high anthropogenic SOA production rates challenges the assumption that anthropogenic volatile organic compounds are not important SOA precursors on a global scale. Model predictions with and without SOA aging are compared with data from two surface observation networks: the Interagency Monitoring of Protected Visual Environments for the United States and the European Monitoring and Evaluation Programme.", "corpus_id": 17442370, "score": 1 }, { "doc_id": "140692488", "title": "Global impacts of gas‐phase chemistry‐aerosol interactions on direct radiative forcing by anthropogenic aerosols and ozone", "abstract": "[1] We present here a first global modeling study on the influence of gas-phase chemistry/aerosol interactions on estimates of anthropogenic forcing by tropospheric O3 and aerosols. Concentrations of gas-phase species and sulfate, nitrate, ammonium, black carbon, primary organic carbon, secondary organic carbon, sea salt, and mineral dust aerosols in the preindustrial, present-day, and year 2100 (IPCC SRES A2) atmospheres are simulated online in the Goddard Institute for Space Studies general circulation model II' (GISS GCM II'). With fully coupled chemistry and aerosols, the preindustrial, present-day, and year 2100 global burdens of tropospheric ozone are predicted to be 190, 319, and 519 Tg, respectively. The burdens of sulfate, nitrate, black carbon, and organic carbon are predicted respectively to be 0.32. 0.18, 0.01, 0.33 Tg in preindustrial time, 1.40, 0.48, 0.23, 1.60 Tg in present-day, and 1.37, 1.97, 0.54, 3.31 Tg in year 2100. Anthropogenic O3 is predicted to have a globally and annually averaged present-day forcing of +0.22 W m−2 and year 2100 forcing of +0.57 W m−2 at the top of the atmosphere (TOA). Net anthropogenic TOA forcing by internally mixed sulfate, nitrate, organic carbon, and black carbon aerosols is estimated to be virtually zero in the present-day and +0.34 W m−2 in year 2100, whereas it is predicted to be −0.39 W m−2 in present-day and −0.61 W m−2 in year 2100 if the aerosols are externally mixed. Heterogeneous reactions are shown to be important in affecting anthropogenic forcing. When reactions of N2O5, NO3, NO2, and HO2 on aerosols are accounted for, TOA anthropogenic O3 forcing is less by 20–45% in present-day and by 20–32% in year 2100 at mid to high latitudes in the Northern Hemisphere, as compared with values predicted in the absence of heterogeneous gas-aerosol reactions. Mineral dust uptake of HNO3 and O3 is shown to have practically no influence on anthropogenic O3 forcing. Heterogeneous reactions of N2O5, NO3, NO2, and HO2 are predicted to have noticeable impacts on anthropogenic aerosol forcing over industrialized areas, leading to 0–2 W m−2 more anthropogenic aerosol cooling in present-day and 2–8 W m−2 more cooling in year 2100 in these areas as compared with forcings calculated in the absence of heterogeneous reactions. Sea salt uptake of SO2 reduces the magnitude of TOA aerosol cooling by 0.5–1 W m−2 over the oceans around 60°N in the present-day and year 2100 scenarios. Near dust sources, mineral dust uptake of SO2 and HNO3 leads to less anthropogenic aerosol cooling by 0.5–1 W m−2 in the present-day and 1–2 W m−2 in year 2100.", "corpus_id": 140692488, "score": 0 }, { "doc_id": "31242575", "title": "Coupled partitioning, dilution, and chemical aging of semivolatile organics.", "abstract": "A unified framework of semi-volatile partitioning permits models to efficiently treat both semi-volatile primary emissions and secondary organic aerosol production (SOA), and then to treat the chemical evolution (aging) of the aggregate distribution of semi-volatile material. This framework also reveals critical deficiencies in current emissions and SOA formation measurements. The key feature of this treatment is a uniform basis set of saturation vapor pressures spanning the range of ambient organic saturation concentrations, from effectively nonvolatile material at 0.01 microg m(-3) to vapor-phase effluents at 100 mg m(-3). Chemical evolution can be treated by a transformation matrix coupling the various basis vectors. Using this framework, we show that semi-volatile partitioning can be described in a self-consistent way, with realistic behavior with respect to temperature and varying organic aerosol loading. The time evolution strongly suggests that neglected oxidation of numerous \"intermediate volatility\" vapors (IVOCs, with saturation concentrations above approximately 1 mg m(-3)) may contribute significantly to ambient SOA formation.", "corpus_id": 31242575, "score": 0 }, { "doc_id": "128677567", "title": "Mixing and phase partitioning of primary and secondary organic aerosols", "abstract": "[1] Predicting primary and secondary organic aerosol (POA and SOA) concentrations requires understanding the phase partitioning of semi-volatile organic species. A well-mixed single phase organic aerosol can absorb greater amounts of semi-volatile species but little experimental evidence exists on the phase distribution of particulate organics. We investigated the phase partitioning and mixing of semi-volatile POA and SOA in a smog chamber. Particle time of flight (PToF) data from an Aerodyne aerosol mass spectrometer (AMS) were used to quantify the extent of mixing. The SOA plus motor oil and diesel fuel combination produced a weakly mixed system, in which two particulate organic phases coexist. However, the POA in diesel exhaust readily mixed with SOA, forming a single phase after one hour. Although both POA types contain semi-volatile components, there is a fundamental difference in their partitioning behavior with SOA. The high resolution AMS data reveal minor differences in composition between the two types of POA. This work provides further evidence that there exists a set of unidentified components that influence particulate mixing that affect OA formation and suggests the extent of absorbent phase mixing (strong versus weak) can be observed and quantified with PToF data.", "corpus_id": 128677567, "score": 0 }, { "doc_id": "54219747", "title": "Effect of hydrophobic primary organic aerosols on secondary organic aerosol formation from ozonolysis of α‐pinene", "abstract": "[1] Semi-empirical secondary organic aerosol (SOA) models typically assume a well-mixed organic aerosol phase even in the presence of hydrophobic primary organic aerosols (POA). This assumption significantly enhances the modeled SOA yields as additional organic mass is made available to absorb greater amounts of oxidized secondary organic gases than otherwise. We investigate the applicability of this critical assumption by measuring SOA yields from ozonolysis of a-pinene (a major biogenic SOA precursor) in a smog chamber in the absence and in the presence of dioctyl phthalate (DOP) and lubricating oil seed aerosol. These particles serve as surrogates for urban hydrophobic POA. The results show that these POA did not enhance the SOA yields. If these results are found to apply to other biogenic SOA precursors, then the semiempirical models used in many global models would predict significantly less biogenic SOA mass and display reduced sensitivity to anthropogenic POA emissions than previously thought. Citation: Song, C., R. A. Zaveri, M. L. Alexander, J. A. Thornton, S. Madronich, J. V. Ortega, A. Zelenyuk, X.-Y. Yu, A. Laskin, and D. A. Maughan (2007), Effect of hydrophobic primary organic aerosols on secondary organic aerosol formation from ozonolysis of a-pinene, Geophys. Res. Lett., 34, L20803,", "corpus_id": 54219747, "score": 0 }, { "doc_id": "22748556", "title": "Updating the Conceptual Model for Fine Particle Mass Emissions from Combustion Systems Allen L. Robinson", "abstract": "Abstract Atmospheric transformations determine the contribution of emissions from combustion systems to fine particulate matter (PM) mass. For example, combustion systems emit vapors that condense onto existing particles or form new particles as the emissions are cooled and diluted. Upon entering the atmosphere, emissions are exposed to atmospheric oxidants and sunlight, which causes them to evolve chemically and physically, generating secondary PM. This review discusses these transformations, focusing on organic PM. Organic PM emissions are semi -volatile at atmospheric conditions and thus their partitioning varies continuously with changing temperature and concentration. Because organics contribute a large portion of the PM mass emitted by most combustion sources, these emissions cannot be represented using a traditional, static emission factor. Instead, knowledge of the volatility distribution of emissions is required to explicitly account for changes in gas-particle partitioning. This requires updating how PM emissions from combustion systems are measured and simulated from combustion systems. Secondary PM production often greatly exceeds the direct or primary PM emissions; therefore, secondary PM must be included in any assessment of the contribution of combustion systems to ambient PM concentrations. Low-volatility organic vapors emitted by combustion systems appear to be very important secondary PM precursors that are poorly accounted for in inventories and models. The review concludes by discussing the implications that the dynamic nature of these PM emissions have on source testing for emission inventory development and regulatory purposes. This discussion highlights important linkages between primary and secondary PM, which could lead to simplified certification test procedures while capturing the emission components that contribute most to atmospheric PM mass.", "corpus_id": 22748556, "score": 0 }, { "doc_id": "21044921", "title": "Measurement of emissions from air pollution sources. 3. C1-C29 organic compounds from fireplace combustion of wood.", "abstract": "Organic compound emission rates for volatile organic compounds (VOC), gas-phase semivolatile organic compounds, and particle-phase organic compounds are measured from residential fireplace combustion of wood. Firewood from a conifer tree (pine) and from two deciduous trees (oak and eucalyptus) is burned to determine organic compound emissions profiles for each wood type including the distribution of the alkanes, alkenes, aromatics, polycyclic aromatic hydrocarbons (PAH), phenol and substituted phenols, guaiacol and substituted guaiacol, syringol and substituted syringols, carbonyls, alkanoic acids, resin acids, and levoglucosan. Levoglucosan is the major constituent in the fine particulate emissions from all three wood types, contributing 18-30% of the fine particulate organic compound emissions. Guaiacol (2-methoxyphenol), and guaiacols with additional substituents at position 4 on the molecule, and resin acids are emitted in significant quantities from pine wood combustion. Syringol (2,6-dimethoxyphenol) and syringols with additional substituents at position 4 on the molecule are emitted in large amounts from oak and eucalyptus firewood combustion, but these compounds are not detected in the emissions from pine wood combustion. Syringol and most of the substituted syringols are found to be semivolatile compounds that are present in both the gas and particle phases, but two substituted syringols that have not been previously quantified in wood smoke emissions, propionylsyringol and butyrylsyringol, are found exclusively in the particle phase and can be used to help trace hardwood smoke particles in the atmosphere. Benzene, ethene, and acetylene are often used as tracers for motor vehicle exhaust in the urban atmosphere. The contribution of wood smoke to the ambient concentrations of benzene, ethene, and acetylene could lead to an overestimate of the contribution of motor vehicle tailpipe exhaust to atmospheric VOC concentrations.", "corpus_id": 21044921, "score": 0 }, { "doc_id": "12570034", "title": "Measurement of emissions from air pollution sources. 5. C1-C32 organic compounds from gasoline-powered motor vehicles.", "abstract": "Gas- and particle-phase organic compounds present in the tailpipe emissions from an in-use fleet of gasoline-powered automobiles and light-duty trucks were quantified using a two-stage dilution source sampling system. The vehicles were driven through the cold-start Federal Test Procedure (FTP) urban driving cycle on a transient dynamometer. Emission rates of 66 volatile hydrocarbons, 96 semi-volatile and particle-phase organic compounds, 27 carbonyls, and fine particle mass and chemical composition were quantified. Six isoprenoids and two tricyclic terpanes, which are quantified using new source sampling techniques for semi-volatile organic compounds, have been identified as potential tracers for gasoline-powered motor vehicle emissions. A composite of the commercially distributed California Phase II Reformulated Gasoline used in these tests was analyzed by several analytical methods to quantify the gasoline composition, including some organic compounds that are found in the atmosphere as semi-volatile and particle-phase organic compounds. These results allow a direct comparison of the semi-volatile and particle-phase organic compound emissions from gasoline-powered motor vehicles to the gasoline burned by these vehicles. The distribution of n-alkanes and isoprenoids emitted from the catalyst-equipped gasoline-powered vehicles is the same as the distribution of these compounds found in the gasoline used, whereas the distribution of these compounds in the emissions from the noncatalyst vehicles is very different from the distribution in the fuel. In contrast, the distribution of the polycyclic aromatic hydrocarbons and their methylated homologues in the gasoline is significantly different from the distribution of the PAH in the tailpipe emissions from both types of vehicles.", "corpus_id": 12570034, "score": 0 }, { "doc_id": "18086207", "title": "A technology‐based global inventory of black and organic carbon emissions from combustion", "abstract": "[1] We present a global tabulation of black carbon (BC) and primary organic carbon (OC) particles emitted from combustion. We include emissions from fossil fuels, biofuels, open biomass burning, and burning of urban waste. Previous ‘‘bottom-up’’ inventories of black and organic carbon have assigned emission factors on the basis of fuel type and economic sector alone. Because emission rates are highly dependent on combustion practice, we consider combinations of fuel, combustion type, and emission controls and their prevalence on a regional basis. Central estimates of global annual emissions are 8.0 Tg for black carbon and 33.9 Tg for organic carbon. These estimates are lower than previously published estimates by 25–35%. The present inventory is based on 1996 fuel-use data, updating previous estimates that have relied on consumption data from 1984. An offset between decreased emission factors and increased energy use since the base year of the previous inventory prevents the difference between this work and previous inventories from being greater. The contributions of fossil fuel, biofuel, and open burning are estimated as 38%, 20%, and 42%, respectively, for BC, and 7%, 19%, and 74%, respectively, for OC. We present a bottom-up estimate of uncertainties in source strength by combining uncertainties in particulate matter emission factors, emission characterization, and fuel use. The total uncertainties are about a factor of 2, with uncertainty ranges of 4.3–22 Tg/yr for BC and 17–77 Tg/yr for OC. Low-technology combustion contributes greatly to both the emissions and the uncertainties. Advances in emission characterization for small residential, industrial, and mobile sources and topdown analysis combining field measurements and transport modeling with iterative inventory development will be required to reduce the uncertainties further. INDEX TERMS: 0305 Atmospheric Composition and Structure: Aerosols and particles (0345, 4801); 0322 Atmospheric Composition and Structure: Constituent sources and sinks; 0345 Atmospheric Composition and Structure: Pollution—urban and regional (0305); 0360 Atmospheric Composition and Structure: Transmission and scattering of radiation; 0365 Atmospheric Composition and Structure: Troposphere—composition and chemistry; KEYWORDS: emission, black carbon, organic carbon, fossil fuel, biofuel, biomass burning", "corpus_id": 18086207, "score": 0 }, { "doc_id": "128563484", "title": "Construction of a 1° × 1° fossil fuel emission data set for carbonaceous aerosol and implementation and radiative impact in the ECHAM4 model", "abstract": "Global-scale emissions of carbonaceous aerosol from fossil fuel usage have been calculated with a resolution of 1° × 1°. Emission factors for black and organic carbon have been gathered from the literature and applied to domestic, transport, and industrial combustion of various fuel types. In addition, allowance has been made for the level of development when calculating emissions from a country. Emissions have been calculated for 185 countries for the domestic, industrial, and transport sectors using a fuel usage database published by the United Nations [1993]. Some inconsistencies were found for a small number of countries with regard to the distribution of fuel usage between the industrial and domestic sectors. Care has been taken to correct for this using data from the fuel use database for the period 1970–1990. Emissions based on total particulate matter (TPM) and submicron emission factors have been calculated. Global emissions for 1984 of black carbon total 6.4 TgC yr−1 and organic carbon emissions of 10.1 TgC yr−1 were found using bulk aerosol emission factors, while global black carbon emissions of 5.1 TgC yr−1 and organic carbon emissions of 7.0 TgC yr−1 were found using submicron emission factors. Use of the database is quite flexible and can be easily updated as emission factor data are updated. There is at least a factor of 2 uncertainty in the derived emissions due to the lack of exactly appropriate emission data. The emission fields have been introduced into the ECHAM4 atmospheric general circulation model and run for 5 model years. Monthly mean model results are compared to measurements in regions influenced by anthropogenic fossil fuel emissions. The resultant aerosol fields have been used to calculate the instantaneous solar radiative forcing at the top of the troposphere due to an external mixture of fossil fuel derived black carbon and organic carbon aerosol. Column burdens of 0.143 mgBC m−2 and 0.170 mgOC m−2 were calculated. Because of secondary production of organic carbon aerosol, it is recommended that the burden of organic carbon aerosol be doubled to 0.341 mgOC m−2. The resultant forcing when clouds are included is +0.173 W m−2 for black carbon and −0.024 W m−2 for organic carbon (×2) as a global annual average. The results are compared to previous works, and the differences are discussed.", "corpus_id": 128563484, "score": 0 }, { "doc_id": "11155510", "title": "Determination of the organic aerosol mass to organic carbon ratio in IMPROVE samples.", "abstract": "The ratio of organic mass (OM) to organic carbon (OC) in PM(2.5) aerosols at US national parks in the IMPROVE network was estimated experimentally from solvent extraction of sample filters and from the difference between PM(2.5) mass and chemical constituents other than OC (mass balance) in IMPROVE samples from 1988 to 2003. Archived IMPROVE filters from five IMPROVE sites were extracted with dichloromethane (DCM), acetone and water. The extract residues were weighed to determine OM and analyzed for OC by thermal optical reflectance (TOR). On average, successive extracts of DCM, acetone, and water contained 64%, 21%, and 15%, respectively, of the extractable OC, respectively. On average, the non-blank-corrected recovery of the OC initially measured in these samples by TOR was 115+/-42%. OM/OC ratios from the combined DCM and acetone extracts averaged 1.92 and ranged from 1.58 at Indian Gardens, AZ in the Grand Canyon to 2.58 at Mount Rainier, WA. The average OM/OC ratio determined by mass balance was 2.07 across the IMPROVE network. The sensitivity of this ratio to assumptions concerning sulfate neutralization, water uptake by hygroscopic species, soil mass, and nitrate volatilization were evaluated. These results suggest that the value of 1.4 for the OM/OC ratio commonly used for mass and light extinction reconstruction in IMPROVE is too low.", "corpus_id": 11155510, "score": 0 }, { "doc_id": "24331961", "title": "Constraining the volatility distribution and gas-particle partitioning of combustion aerosols using isothermal dilution and thermodenuder measurements.", "abstract": "The gas-particle partitioning of primary organic aerosol (POA) emissions from a diesel engine and the combustion of hard- and soft-woods in a stove was investigated by isothermally diluting them in a smog chamber or by passing them through a thermodenuder and measuring the extent of evaporation. The experiments were conducted at atmospherically relevant conditions: low concentrations and small temperature perturbations. The partitioning of the POA emissions from both sources varied continuously with changing concentration and temperature. Although the POA emissions are semivolatile, they do not completely evaporate at typical atmospheric conditions. The overall partitioning characteristics of diesel and wood smoke POA are similar, with wood smoke being somewhat less volatile than the diesel exhaust. The gas-particle partitioning of aerosols formed from flash-vaporized engine lubricating oil was also studied; diesel POA is somewhat more volatile than the oil aerosol. The experimental data from the dilution- and thermodenuder-based techniques were fit using absorptive partitioning theory to derive a volatility distribution of the POA emissions from each source. These distributions are suitable for use in chemical transport models that simulate POA concentrations.", "corpus_id": 24331961, "score": 0 }, { "doc_id": "1063623", "title": "Carbon oxidation state as a metric for describing the chemistry of atmospheric organic aerosol.", "abstract": "A detailed understanding of the sources, transformations and fates of organic species in the environment is crucial because of the central roles that they play in human health, biogeochemical cycles and the Earth's climate. However, such an understanding is hindered by the immense chemical complexity of environmental mixtures of organics; for example, atmospheric organic aerosol consists of at least thousands of individual compounds, all of which likely evolve chemically over their atmospheric lifetimes. Here, we demonstrate the utility of describing organic aerosol (and other complex organic mixtures) in terms of average carbon oxidation state, a quantity that always increases with oxidation, and is readily measured using state-of-the-art analytical techniques. Field and laboratory measurements of the average carbon oxidation state, using several such techniques, constrain the chemical properties of the organics and demonstrate that the formation and evolution of organic aerosol involves simultaneous changes to both carbon oxidation state and carbon number.", "corpus_id": 1063623, "score": 0 }, { "doc_id": "54069444", "title": "Tropospheric sulfur simulation and sulfate direct radiative forcing in the Goddard Institute for Space Studies general circulation model", "abstract": "Global simulations of tropospheric sulfur are performed in the Goddard Institute for Space Studies (GISS) general circulation model (GCM) and used to calculate anthropogenic sulfate direct radiative forcing. Prognostic species are in-cloud oxidant H2O2, dimethylsulfide (DMS), methanesulfonic acid (MSA), SO2 and sulfate. Compared with most previous models (except others with prognostic H2O2), this model has relatively high anthropogenic SO2 and sulfate burden. We show that this is due partly to the depletion of the prognostic H2O2 and that moist convection delivers significant levels of SO2 to the free troposphere in polluted regions. Model agreement with surface observations is not remarkably different from previous studies. Following some previous studies, we propose that an additional in-cloud or heterogeneous oxidant is likely to improve the simulation near the surface. Our DMS source is lower than sources in previous studies, and sulfur values in remote regions are generally lower than those observed. Because of the high flux of SO2 to the free troposphere and the relatively low natural source, our model indicates a larger global anthropogenic contribution to the sulfate burden (77%) than was estimated by previous global models. Additional high-altitude observations of the sulfur species are needed for model validation and resolution of this issue. Direct radiative forcing calculations give an annual average anthropogenic sulfate forcing of −0.67 W/m2. We compare the radiative forcings due to online (hourly varying) versus offline (monthly average) sulfate and find little difference on a global average, but we do find differences as great as 10% in some regions. Thus, for example, over some polluted continental regions the forcing due to offline sulfate exceeds that of online sulfate, while over some oceanic regions the online sulfate forcing is larger. We show that these patterns are probably related to the correlation between clouds and sulfate, with positive correlations occuring over some polluted continental regions and negative correlations over high-latitude oceanic regions.", "corpus_id": 54069444, "score": 0 }, { "doc_id": "128825462", "title": "A Prognostic Cloud Water Parameterization for Global Climate Models", "abstract": "Abstract An efficient new prognostic cloud water parameterization designed for use in global climate models is described. The scheme allows for life cycle effects in stratiform clouds and permits cloud optical properties to be determined interactively. The parameterization contains representations of all important microphysical processes, including autoconversion, accretion, Bergeron–Findeisen diffusional growth, and cloud/rain water evaporation. Small-scale dynamical processes, including detrainment of convective condensate, cloud-top entrainment instability, and stability-dependent cloud physical thickness variations, are also taken into account. Cloud optical thickness is calculated from the predicted liquid/ice water path and a variable droplet effective radius estimated by assuming constant droplet number concentration. Microphysical and radiative properties are assumed to be different for liquid and ice clouds, and for liquid clouds over land and ocean. The parameterization is validated in several s...", "corpus_id": 128825462, "score": 0 }, { "doc_id": "1780311", "title": "A semiempirical correlation between enthalpy of vaporization and saturation concentration for organic aerosol.", "abstract": "To model the temperature-induced partitioning of semivolatile organics in laboratory experiments or atmospheric models, one must know the appropriate heats of vaporization. Current treatments typically assume a constant value of the heat of vaporization or else use specific values from a small set of surrogate compounds. With published experimental vapor-pressure data from over 800 organic compounds, we have developed a semiempirical correlation between the saturation concentration (C*, microg m(-3)) and the heat of vaporization (deltaH(VAP), kJ mol(-1)) for organics in the volatility basis set. Near room temperature, deltaH(VAP) = -11 log(10)C(300)(*) + 129. Knowledge of the relationship between C* and deltaH(VAP) constrains a free parameter in thermodenuder data analysis. A thermodenuder model using our deltaH(VAP) values agrees well with thermal behavior observed in laboratory experiments.", "corpus_id": 1780311, "score": 1 }, { "doc_id": "16900410", "title": "Secondary organic aerosol formation from photooxidation of naphthalene and alkylnaphthalenes: implications for oxidation of intermediate volatility organic compounds (IVOCs)", "abstract": "Abstract. Current atmospheric models do not include secondary organic aerosol (SOA) production from gas-phase reactions of polycyclic aromatic hydrocarbons (PAHs). Recent studies have shown that primary emissions undergo oxidation in the gas phase, leading to SOA formation. This opens the possibility that low-volatility gas-phase precursors are a potentially large source of SOA. In this work, SOA formation from gas-phase photooxidation of naphthalene, 1-methylnaphthalene (1-MN), 2-methylnaphthalene (2-MN), and 1,2-dimethylnaphthalene (1,2-DMN) is studied in the Caltech dual 28-m3 chambers. Under high-NOx conditions and aerosol mass loadings between 10 and 40 μg m−3, the SOA yields (mass of SOA per mass of hydrocarbon reacted) ranged from 0.19 to 0.30 for naphthalene, 0.19 to 0.39 for 1-MN, 0.26 to 0.45 for 2-MN, and constant at 0.31 for 1,2-DMN. Under low-NOx conditions, the SOA yields were measured to be 0.73, 0.68, and 0.58, for naphthalene, 1-MN, and 2-MN, respectively. The SOA was observed to be semivolatile under high-NOx conditions and essentially nonvolatile under low-NOx conditions, owing to the higher fraction of ring-retaining products formed under low-NOx conditions. When applying these measured yields to estimate SOA formation from primary emissions of diesel engines and wood burning, PAHs are estimated to yield 3–5 times more SOA than light aromatic compounds over photooxidation timescales of less than 12 h. PAHs can also account for up to 54% of the total SOA from oxidation of diesel emissions, representing a potentially large source of urban SOA.", "corpus_id": 16900410, "score": 0 }, { "doc_id": "93798408", "title": "Secondary organic aerosol in the global aerosol – chemical transport model Oslo CTM2", "abstract": "The global chemical transport model Oslo CTM2 has been extended to include the formation, transport and deposition of secondary organic aerosol (SOA). Precursor hydrocarbons which are oxidised to form condensible species include both biogenic species such as terpenes and isoprene, as well as species emitted predominantly by anthropogenic activities (toluene, m-xylene, methylbenzene and other aromatics). A model simulation for 2004 gives an annual global SOA production of approximately 55 Tg. Of this total, 2.5 Tg is found to consist of the oxidation products of anthropogenically emitted hydrocarbons, and about 15 Tg is formed by the oxidation products of isoprene. The global production of SOA is increased to about 69 Tg yr −1 by allowing semi-volatile species to partition to ammonium sulphate aerosol. This brings modelled organic aerosol values closer to those observed, however observations in Europe remain significantly underestimated. Allowing SOA to partition into ammonium sulphate aerosol increases the contribution of anthropogenic SOA from about 4.5% to 9.4% of the total production. Total modelled organic aerosol (OA) values are found to represent a lower fraction of the measured values in winter (when primary organic aerosol (POA) is the dominant OA component) than in summer, which may be an indication that estimates of POA emissions are too low. Additionally, for measurement stations where the summer OA values are higher than in winter, the model generally underestimates the increase in summertime OA. In order to correctly model the observed increase in OA in summer, additional SOA sources or formation mechanisms may be necessary. The importance of NO 3 as an oxidant of SOA precursors is found to vary regionally, causing up to 50%–60% of the total amount of SOA near the surface in polluted regions and less than 25% in more remote areas, if the yield of condensible oxidation products for β-pinene is used for NO 3 oxidation of all terpenes. Reducing the yield for α-pinene and limonene oxidation in line with recent measurements reduces the global fraction of SOA formed from NO 3 oxidation products from 27% to about 21%. This study underscores the need for SOA to be represented in a more realistic way in global aerosol models in order to better reproduce observations of organic aerosol burdens in industrialised and biomass burning regions.", "corpus_id": 93798408, "score": 0 }, { "doc_id": "17825897", "title": "Predicted change in global secondary organic aerosol concentrations in response to future climate, emissions, and land use change", "abstract": "[1] The sensitivity of secondary organic aerosol (SOA) concentration to changes in climate and emissions is investigated using a coupled global atmosphere-land model driven by the year 2100 IPCC A1B scenario predictions. The Community Atmosphere Model (CAM3) is updated with recent laboratory determined yields for SOA formation from monoterpene oxidation, isoprene photooxidation and aromatic photooxidation. Biogenic emissions of isoprene and monoterpenes are simulated interactively using the Model of Emissions of Gases and Aerosols (MEGAN2) within the Community Land Model (CLM3). The global mean SOA burden is predicted to increase by 36% in 2100, primarily the result of rising biogenic and anthropogenic emissions which independently increase the burden by 26% and 7%. The later includes enhanced biogenic SOA formation due to increased emissions of primary organic aerosol (5–25% increases in surface SOA concentrations in 2100). Climate change alone (via temperature, removal rates, and oxidative capacity) does not change the global mean SOA production, but the global burden increases by 6%. The global burden of anthropogenic SOA experiences proportionally more growth than biogenic SOA in 2100 from the net effect of climate and emissions (67% increase predicted). Projected anthropogenic land use change for 2100 (A2) is predicted to reduce the global SOA burden by 14%, largely the result of cropland expansion. South America is the largest global source region for SOA in the present day and 2100, but Asia experiences the largest relative growth in SOA production by 2100 because of the large predicted increases in Asian anthropogenic aromatic emissions. The projected decrease in global sulfur emissions implies that SOA will contribute a progressively larger fraction of the global aerosol burden.", "corpus_id": 17825897, "score": 0 }, { "doc_id": "24235838", "title": "O/C and OM/OC ratios of primary, secondary, and ambient organic aerosols with high-resolution time-of-flight aerosol mass spectrometry.", "abstract": "A recently developed method to rapidly quantify the elemental composition of bulk organic aerosols (OA) using a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) is improved and applied to ambient measurements. Atomic oxygen-to-carbon (O/C) ratios characterize the oxidation state of OA, and O/C from ambient urban OA ranges from 0.2 to 0.8 with a diurnal cycle that decreases with primary emissions and increases because of photochemical processing and secondary OA (SOA) production. Regional O/C approaches approximately 0.9. The hydrogen-to-carbon (H/C, 1.4--1.9) urban diurnal profile increases with primary OA (POA) as does the nitrogen-to-carbon (N/C, approximately 0.02). Ambient organic-mass-to-organic-carbon ratios (OM/OC) are directly quantified and correlate well with O/C (R2 = 0.997) for ambient OA because of low N/C. Ambient O/C and OM/OC have values consistent with those recently reported from other techniques. Positive matrix factorization applied to ambient OA identifies factors with distinct O/C and OM/OC trends. The highest O/C and OM/OC (1.0 and 2.5, respectively) are observed for aged ambient oxygenated OA, significantly exceeding values for traditional chamber SOA,while laboratory-produced primary biomass burning OA (BBOA) is similar to ambient BBOA, O/C of 0.3--0.4. Hydrocarbon-like OA (HOA), a surrogate for urban combustion POA, has the lowest O/C (0.06--0.10), similar to vehicle exhaust. An approximation for predicting O/C from unit mass resolution data is also presented.", "corpus_id": 24235838, "score": 0 }, { "doc_id": "131008642", "title": "A global three‐dimensional model study of carbonaceous aerosols", "abstract": "We have developed detailed emission inventories for the amount of both black and organic carbon particles from biomass burning sources (wood fuel, charcoal burning, dung, charcoal production, agricultural, savanna and forest fires). We have also estimated an inventory for organic carbon particles from fossil fuel burning and urban activities from an existing inventory for fossil fuel sources of black carbon. We also provide an estimate for the natural source of organic matter. These emissions have been used together with our global aerosol model to study the global distribution of carbonaceous aerosols. The accuracy of the inventories and the model formulation has been tested by comparing the model simulations of carbonaceous aerosols in the atmosphere and in precipitation with observations reported in the literature. For most locations and seasons, the predicted concentrations are in reasonable agreement with the observations, although the model underpredicts black carbon concentrations in polar regions. The predicted concentrations in remote areas are extremely sensitive to both the rate of removal by wet deposition and the height of injection of the aerosols. Finally, a global map of the aerosol single scattering albedo was developed from the simulated carbonaceous particle distribution and a previously developed model for aerosol sulfates. The computed aerosol single scattering albedos compare well with observations, suggesting that most of the important aerosol species have been included in the model. For most locations and seasons, the single scattering albedo is larger than 0.85, indicating that these aerosols, in general, lead to a net cooling.", "corpus_id": 131008642, "score": 0 }, { "doc_id": "97871399", "title": "Atmospheric organic particulate matter: From smoke to secondary organic aerosol", "abstract": "We present an overview of the development of our understanding of the sources, formation mechanisms, physical and chemical transformations of atmospheric organic aerosol (OA) during the last thirty years. Until recently, organic particulate material was simply classified as either primary or secondary with the primary component being treated in models as nonvolatile and inert. However, this oversimplified view fails to explain the highly oxygenated nature of ambient OA, the relatively small OA concentration gradients between urban areas and their surroundings, and the concentrations of OA during periods of high photochemical activity. A unifying framework for the description of all components based on their volatility distribution (the volatility basis set) can be used for the treatment of a wide range of processes affecting organic aerosol loadings and composition in the atmosphere. These processes include direct organic particle and vapor emissions, chemical production of organic PM from volatile precursors, chemical reactions (aging) in all phases, as well as deposition of both particles and vapors and chemical losses to volatile products. The combination of this new framework with the recent results of laboratory studies can resolve some of the discrepancies between OA observations and laboratory results. The mass balance of the organic material as a function of its volatility is investigated and used to frame the corresponding constraints on the system. Finally we revisit the traditional definitions of primary and secondary organic aerosol and propose a new set of terms and definitions based on the improvements of our understanding.", "corpus_id": 97871399, "score": 0 }, { "doc_id": "53138894", "title": "Radiocarbon analysis of carbonaceous aerosols: recent developments", "abstract": "Carbonaceous aerosols are a major fraction of airborne particulate matter. They contribute to climate and health effects of the total aerosol burden of the atmosphere by counteracting the current trend of global warming and inducing respiratory and cardiovascular diseases, respectively. In spite of this general importance, only little is known about composition and sources of carbonaceous aerosols. Analysis of the long-lived radioactive isotope 14 C (radiocarbon) is a unique source apportionment tool: it unambiguously separates fossil from non-fossil sources, as 14 C has completely decayed in fossil fuels, whereas modern materials have the contemporary radiocarbon level. A novel separation method was developed for the direct determination of 14 C in organic carbon (OC) and elemental carbon (EC), two sub-fractions of total carbon (TC). The implementation of a gas ion source for measurement with accelerator mass spectrometry (AMS) made 14 C analysis more simple and robust. Based on this technique, all major contributions to the carbonaceous aerosol can be identified, which originate from fossil-fuel, biomass-burning and biogenic emissions. A survey of results from different field campaigns is shown.", "corpus_id": 53138894, "score": 0 }, { "doc_id": "94722635", "title": "Simulating secondary organic aerosol formation using the volatility basis-set approach in a chemical transport model", "abstract": "Abstract The secondary organic aerosol (SOA) module in PMCAMx, a three-dimensional chemical transport model, has been updated based on laboratory results from recent smog chamber experiments. A new modeling framework is used based on the SOA volatility basis-set approach instead of the two-product approach used in existing models. The different scenarios are simulated for July 2001, and the predicted organic aerosol (OA) concentrations are compared to the available ambient measurements from the EPA Speciation Trends Network (STN) and the Interagency Monitoring of Protected Visual Environments (IMPROVE). The base-case OA simulation slightly overpredicts the ambient measured OA concentrations at the rural IMPROVE monitoring sites with a bias of 0.33 μg m−3. Compared to the urban STN sites, the base-case scenario still underpredicts the observed OA concentrations but is performing significantly better than the two-product module in PMCAMx compared to observations. The contribution of biogenic and anthropogenic SOA to the predicted organic aerosol concentrations and the potential role of chemical aging are investigated. The higher yields of SOA from anthropogenic precursors reported in the most recent studies improve the model performance in urban areas.", "corpus_id": 94722635, "score": 0 } ]